Pyrrolopyridine derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor M4

Abstract

6,7-dihydrothiazolo[5,4-c]pyridine, substituted at position 5 with 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one or flu[3,4-b]pyridine-5(7H)-one, is a positive allosteric modulator of the muscarinic acetylcholine receptor M4 (mAChR M4) and may be used to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 496,806, filed on 18 April 2023, and to U.S. Provisional Patent Application No. 63 / 610,184, filed on 14 December 2023, each of which is incorporated herein by reference in whole.

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

[0003] Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs) by the binding of the endogenous orthosteric agonist acetylcholine (ACh). Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a decrease in acetylcholine content in the brain. This is thought to be due to the degeneration of cholinergic neurons in the basal forebrain, which broadly innervate multiple brain regions, including the association cortex and hippocampus, which are crucial for higher-order processes. Clinical data support the idea that impaired cholinergic function contributes to cognitive impairment in schizophrenic patients. Attempts to increase acetylcholine levels have focused on increasing choline levels, a precursor of acetylcholine synthesis, and inhibiting acetylcholinesterase (AChE), the enzyme that metabolizes acetylcholine. As a result, acetylcholinesterase (AChE) inhibitors, which inhibit the hydrolysis of ACh, have been approved in the United States for the treatment of palliative but non-disease-modifying cognitive impairment in AD patients.

[0004] Attempts to enhance central cholinergic function by administering choline or phosphatidylcholine have been unsuccessful. While AChE inhibitors have shown therapeutic efficacy, frequent cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, and diarrhea, have been observed. These gastrointestinal side effects are observed in approximately one-third of treated patients. In addition, some AChE inhibitors, such as tacrine, have been found to cause significant hepatotoxicity, accompanied by elevated hepatic transaminases, observed in approximately 30% of patients. The adverse effects of AChE inhibitors have significantly limited their clinical applicability. An alternative approach to pharmacologically targeting cholinergic dysfunction is the activation of mAChRs, which are widely expressed throughout the body.

[0005] mAChRs are members of the family of AG protein-coupled receptors (GPCRs) and include five subtypes designated M1-M5. The M1, M3, and M5 subtypes are primarily G q It is coupled to activate phospholipase C, where the M2 and M4 subtypes are mainly G i / o They are coupled to related effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system and are widely present and differentially expressed. M1-M5 have various roles in cognitive, sensory, motor, and autonomic functions. Therefore, although we do not wish to be bound by any particular theory, it is thought that selective agonists of mAChR subtypes that modulate processes involved in cognitive function may prove to be excellent therapies for the treatment of psychosis, schizophrenia, and related disorders. The muscarinic M4 receptor has been shown to play a major role in cognitive processing and is thought to play a major role in the pathophysiology of psychotic disorders, including schizophrenia.

[0006] Evidence suggests that the most prominent adverse effects of AChE inhibitors and other cholinergic agents are mediated by the activation of peripheral M2 and M3 mAChRs, including bradycardia, gastrointestinal weakness, excessive salivation, and sweating. In contrast, M4 has been considered the most likely subtype to mediate the effects of muscarinic acetylcholine receptor dysfunction in psychotic disorders, including schizophrenia, cognitive impairment, and neuropathic pain. For this reason, considerable effort has been made to develop selective M4 agonists for the treatment of these disorders. Unfortunately, many of these efforts have failed to develop compounds that are highly selective for mAChR M4. Consequently, mAChR agonists tested in clinical trials induce a variety of adverse effects by activating peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes and to further explore the therapeutic utility of mAChR ligands in psychoses, including schizophrenia, cognitive impairment, and other disorders, it may be important to develop compounds that are highly selective activators of mAChR M4 and other individual mAChR subtypes.

[0007] Previous attempts to develop agonists highly selective for individual mAChR subtypes have failed due to the high conservation of orthosteric ACh binding sites. To circumvent the problems associated with targeting highly conserved orthosteric ACh binding sites, it is being considered to develop compounds that act at allosteric sites on mAChRs that are distant from the orthosteric site and are not highly conserved. This approach is proving to be very promising in the development of selective ligands for multiple GPCR subtypes. In the case of mAChRs, the main goal is to develop allosteric ligands that selectively increase the activity of mAChR M4 or other mAChR subtypes. Allosteric activators can include allosteric agonists that act at sites distant from the orthosteric site to directly activate the receptor in the absence of ACh, as well as positive allosteric modulators (PAMs) that do not directly activate the receptor but enhance receptor activation by the endogenous orthosteric agonist ACh. Furthermore, a single molecule can possess both allosteric potentiatric and allosteric agonist activity.

[0008] More recently, it has been shown that muscarinic agonists containing xanomeline exhibit activity in animal models without causing catalepsy while having a profile similar to that of known antipsychotics (Bymaster et al., Eur. J. Pharmacol. 1998, 356, 109; Bymaster et al., Life Sci. 1999, 64, 527; Shannon et al., J. Pharmacol. Exp. Ther. 1999, 290, 901; Shannon et al., Schizophrenia Res. 2000, 42, 249). Furthermore, xanomeline has been shown to reduce psychotic behavioral symptoms such as delusions, suspicion, sudden vocalizations, and hallucinations in Alzheimer's disease patients (Bodick et al., Arch. Neurol. 1997, 54, 465). However, the clinical utility of this compound has been significantly limited by side effects induced by treatments such as effects on the gastrointestinal tract.

[0009] Despite the progress in the study of muscarinic acetylcholine receptors, there is still a lack of compounds that are potent, effective, and selective activators of the M4 mAChR and are also effective in the treatment of neurological and psychiatric disorders related to cholinergic activity and in the treatment of diseases involving the muscarinic M4 receptor. SUMMARY OF THE INVENTION

[0010] In one aspect, a compound of formula (I)

Chemical formula

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

[0012] Another embodiment provides a method for treating neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals, comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or composition thereof.

[0013] Other embodiments provide compounds of formula (I) or pharmaceutically acceptable salts or compositions thereof for use in the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0014] Another embodiment provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or composition thereof for the preparation of pharmaceuticals for the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0015] In other embodiments, the present invention provides a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition thereof, and instructions for use. [Modes for carrying out the invention]

[0016] Detailed explanation This specification discloses positive allosteric modulators (i.e., potents) of muscarinic acetylcholine receptor M4 (mAChR M4), methods for producing the same, pharmaceutical compositions containing the same, and methods for treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the same. These compounds include naphthyridine-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 described above, mAChR M4 is a member of the GPCR class A family, or rhodopsin-like GPCRs, characterized by rhodopsin-like structural features such as seven transmembrane segments. The muscarinic acetylcholine receptor has an N-terminus facing the extracellular surface of the membrane and a C-terminus located on the cytoplasmic surface.

[0018] Previous attempts to develop agonists with high selectivity for individual mAChR subtypes have failed due to the high conservation of orthosteric ACh binding sites. To avoid the problems associated with targeting highly conserved orthosteric ACh binding sites, it is conceivable to develop compounds that act on allosteric sites on mAChRs that are distant from orthosteric sites and have low conservation. While we do not wish to be bound by any particular theory, the compounds disclosed and the products produced by the methods disclosed are thought to bind to allosteric sites different from the orthosteric binding sites.

[0019] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. In case of any conflict, this specification shall prevail, including the definitions. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in the implementation or testing described herein. All publications, patent applications, patents and other references referred herein are incorporated herein by reference in their entirety. The materials, methods and examples disclosed herein are illustrative and not intended to be limiting.

[0020] The terms “include,” “contain,” “have,” “possess,” “can contain,” and their variations are intended, when used herein, to be unrestricted transitional phrases, terms, or words that do not preclude the possibility of additional actions or structures. The singular forms “a,” “an,” and “the” refer to multiple things unless otherwise explicitly indicated by the context. This disclosure also intends other embodiments that “include,” “consist of,” and “be essentially derived from” the embodiments or elements provided herein, whether expressly or not.

[0021] The modifier "approximately" used in relation to quantity includes the stated value and has a meaning determined by the context (for example, it includes the smallest degree of error associated with measuring a particular quantity). The modifier "approximately" should also be considered to reveal a range defined by the absolute values ​​of two endpoints. For example, the expression "approximately 2 to approximately 4" also reveals the range "2 to 4". The term "approximately" can refer to plus or minus 10% of a given number. For example, "approximately 10%" can indicate a range of 9% to 11%, and "approximately 1" can mean 0.9 to 1.1. Other meanings of "approximately," such as rounding, may be evident from the context, and therefore, for example, "approximately 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 defined as follows: Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Identification follows the Ed. (inside 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 as follows: Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rd This is described in Edition, Cambridge University Press, Cambridge, 1987 (the entire contents of each of these are incorporated herein by reference).

[0023] The term "alkoxy," as used herein, refers to an alkyl group as defined herein, bonded to the parent molecule via an oxygen atom. Representative examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0024] The term "alkyl," as used herein, means a straight or branched saturated hydrocarbon chain. The term "lower alkyl" or "C" 1~6 "Alkyl" refers to a straight-chain or branched-chain hydrocarbon containing 1 to 6 carbon atoms. 1~4 "Alkyl" refers to a linear or branched saturated hydrocarbon containing 1 to 4 carbon atoms. Representative examples of alkyls, though not limited to them, include 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" means a linear or branched hydrocarbon chain containing at least one carbon-carbon double bond.

[0026] The term "alkoxyalkyl," as used herein, refers to an alkoxy group as defined herein, which is attached to the parent molecule via an alkyl group as defined herein.

[0027] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group as defined herein that is attached to the 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-chain saturated hydrocarbon containing, for example, 1 to 6 carbon atoms. Representative examples of alkylenes include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0029] The term "alkylamino," as used herein, means at least one alkyl group as defined herein, which is attached to the parent molecule via an amino group as defined herein.

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

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

[0032] The term "amino" as used herein is -NR x R y (In the formula, R x and R y (which can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl or heteroalkyl). If aminoalkyl or amino is any other part to which two other parts are added together, amino is -NR x -(In the formula, R x (This can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.)

[0033] The term "aryl," as used herein, refers to phenyl, or phenyl that is attached to the parent molecule and condensed with a cycloalkane group (e.g., aryl may be indan-4-yl), condensed with a 6-membered allene group (i.e., aryl is naphthyl), or condensed with a non-aromatic heterocycle (e.g., aryl may be benzo[d][1,3]dioxol-5-yl). The term "phenyl" is used to refer to a substituent, and the term "6-membered allene" is used to refer to a fused ring. A 6-membered allene is monocyclic (e.g., benzene or benzo). Aryl can be monocyclic (phenyl) or bicyclic (e.g., a 9-12 member fused bicyclic system).

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

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

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

[0037] As used herein, the terms “cycloalkyl” or “cycloalkane” refer to a saturated ring system containing all carbon atoms and zero double bonds as ring members. The term “cycloalkyl” is used herein to refer to cycloalkanes when present as substituents. Cycloalkyls can be monocyclic cycloalkyls (e.g., cyclopropyl), condensed bicyclic cycloalkyls (e.g., decahydronaphthalenyl), or bridged cycloalkyls (where two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0038] The terms "cycloalkenyl" or "cycloalkene," as used herein, mean a non-aromatic monocyclic or polycyclic ring system having all carbon atoms as ring members, at least one carbon-carbon double bond, and preferably 5 to 10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to cycloalkenes when present as substituents. Cycloalkenyls can be monocyclic cycloalkenyls (e.g., cyclopentenyl), fused bicyclics (e.g., octahydronaphthalenyl), or bridged cycloalkenyls (where two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0039] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl." The term "carbocyclic ring" means "cycloalkane" or "cycloalkene." The term "carbocyclyl" refers to a "carbocyclic ring" when it exists as a substituent.

[0040] As used herein, the term "fluoroalkyl" means an alkyl group as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyls include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl (such as 3,3,3-trifluoropropyl).

[0041] The term "fluoroalkylene," as used herein, 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 fluoroalkylenes, but not limited to these, include -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, that is attached to the parent molecule via an oxygen atom. Representative examples of fluoroalkoxys include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0043] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

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

[0045] As used herein, the term "haloalkoxy" means at least one haloalkyl group, as defined herein, that is attached to the parent molecule via an oxygen atom.

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

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

[0048] As used herein, the term "heteroaryl" refers to an aromatic monocyclic heteroatom-containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term "heteroaryl" is also used herein to refer to heteroarenes when present as substituents. 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 (for example, one, two, three, or four heteroatoms independently selected from the group consisting of 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 8-12 membered ring systems, including fused bicyclic heteroaromatic ring systems (i.e., 10π electron systems), such as monocyclic heteroaryl rings fused with 6-membered allenes (e.g., quinoline-4-yl, indole-1-yl), monocyclic heteroaryl rings fused with monocyclic heteroarenes (e.g., naphthilidinyl), and phenyl groups fused with monocyclic heteroarenes (e.g., quinoline-5-yl, indole-4-yl). Bicyclic heteroaryl / heteralene groups include 9-membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom that donates 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) and benzoxadiazolyl. Bicyclic heteroaryls also include fused bicyclic systems consisting of one heteroaromatic ring and one nonaromatic ring, such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydroflu[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecule at the aromatic ring atom.Other typical examples of heteroaryls include, but are not limited to, indolyl (e.g., indole-1-yl, indole-2-yl, indole-4-yl), pyridinyl (including pyridine-2-yl, pyridine-3-yl, pyridine-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazole-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazole-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, thienyl, benzimidazolyl (e.g., Examples include benzimidazole-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranil, isobenzofuranil, furanil, oxazolyl, isoxazolyl, prinyl, isoindolyl, quinoxalinil, indazolyl (e.g., indazole-4-yl, indazole-5-yl), quinazolinil, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinil, quinolinil, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridinyl), naphthilidinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridinyl, and thiazolo[5,4-d]pyrimidine-2-yl.

[0049] The terms “heterocyclic” or “heterocyclic” as used herein mean monocyclic, bicyclic, or tricyclic heterocyclic rings. The term “heterocyclyl” is used herein to refer to a heterocyclic ring when it exists as a substituent. A monocyclic heterocyclic ring is a 3, 4, 5, 6, 7, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3 or 4-membered ring contains 0 or 1 double bond and 1 heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains 0 or 1 double bond and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains 0, 1, or 2 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain 0, 1, 2, or 3 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles, though not limited to them, include azetidinyl, azepanyl, azilidinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, ox Examples include cetanyl, oxepanil, oxocanil, piperazinil, piperidinil, pyranil, pyrazolinil, pyrazolidinil, pyrrolinil, pyrrolidinil, tetrahydrofuranil, tetrahydropyranil, tetrahydropyridinil, tetrahydrothienyl, thiadiazolinil, thiadiazolidinil, 1,2-thiadinil, 1,3-thiadinil, thiazolinil, thiazolidinil, thiomorpholinil, 1,1-dioxidethiomorpholinil (thiomorpholine sulfone), thiopyranil, and trithianil.A bicyclic heterocycle is a monocyclic heterocycle fused with a 6-membered allene, or a monocyclic heterocycle fused with a monocyclic cycloalkane, or a monocyclic heterocycle fused with a monocyclic cycloalkene, or a monocyclic heterocycle fused with a monocyclic heterocycle, or a monocyclic heteroelene, or a spiroheterocyclic group, or a bridging monocyclic heterocycle system (where two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms). In bicyclic heterocyclyls, the parent molecule is bonded at a non-aromatic ring atom (e.g., indoline-1-yl). Representative examples of bicyclic heterocyclils, though not limited to them, include croman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzotin-2-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), and azabicyclo[3.1.0]hexanyl (3-azabicyclo[3.1.0]hexane). Examples include (including -3-yl), 2,3-dihydro-1H-indole-1-yl, isoindorin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-1-yl, and 3-oxabicyclo[3.1.0]hexane-6-yl. Tricyclic heterocycles are exemplified by bicyclic heterocycles fused with a 6-membered allene, or bicyclic heterocycles fused with a monocyclic cycloalkane, or bicyclic heterocycles fused with a monocyclic cycloalkene, or bicyclic heterocycles fused with a monocyclic heterocycle, or bicyclic heterocycles in which two non-adjacent atoms of a bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms.Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). These monocyclic, bicyclic, and tricyclic heterocyclines are linked to the parent molecule at the non-aromatic ring atom.

[0050] The term "hydroxyl" or "hydroxy" as used herein means the -OH group.

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

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

[0053] Terms such as "alkyl," "cycloalkyl," and "alkylene" are symbols that indicate the number of atoms present in the group in a specific example (for example, "C"). 1~4 "Alkyl", "C 3~6 Cycloalkyl, C 1~4 The term "alkylene" may be preceded by "C". These symbols are used in the same way as is generally understood by those skilled in the art. For example, the expression "C" followed by a subscript number indicates the number of atoms present in the following group. Thus, "C3 alkyl" is an alkyl group containing three carbon atoms (i.e., n-propyl, isopropyl). 1~4 When a range is given, as in "C", the members of the subsequent group may have any number of carbon atoms within the indicated range. 1~4"Alkyl" refers to an alkyl group having 1 to 4 carbon atoms, regardless of its configuration (i.e., linear or branched).

[0054] The term "parent molecule" or "parent molecule portion" refers to the entire molecule to which the substituent is attached, i.e., the remainder of the molecule.

[0055] The term "sulfonamide" as used herein refers to -S(O)2NR z - or -NR z S(O)- means, and here, R z This can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.

[0056] A "substituent" refers to a group in which any atom of that group is "substituted," such as an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, or heterocyclic group. Any atom can be substituted.

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

[0058] With respect to the compounds described herein, the groups and substituents can be selected and substituted according to the recognized valencies of the atoms and substituents, such that a stable compound (for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination) is obtained.

[0059] The term "allosteric site," as used herein, refers to a ligand-binding site that is topographically distinct from the orthosteric binding site.

[0060] The term "modulator" as used herein refers to molecular compounds that modulate the activity of a target receptor protein (e.g., ligands and compounds disclosed, but not limited to these).

[0061] The term "ligand," as used herein, refers to a natural or synthetic molecular compound that can associate with or bind to a receptor to form a complex, thereby mediating, preventing, or modifying a biological effect. Therefore, the term "ligand" includes allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates, and analogues of natural substrates.

[0062] The terms “natural ligand” and “endogenous ligand” are used herein to mean the same thing and refer to naturally occurring ligands that are found in nature and bind to receptors.

[0063] The term "orthosteric site," as used herein, refers to the primary binding site on a receptor that is recognized by the receptor's endogenous ligand or agonist. For example, the orthosteric site on the mAChR M4 receptor is the site where acetylcholine binds.

[0064] The term "mAChR M4 receptor positive allosteric modulator" as used herein refers to any exogenously administered compound or agent that directly or indirectly enhances the activity of the mAChR M4 receptor in animals, particularly mammals, such as humans, in the presence or absence of acetylcholine or other agonists. For example, an mAChR M4 receptor positive allosteric modulator can enhance the activity of the mAChR M4 receptor in cells in the presence of extracellular acetylcholine. These cells may be Chinese hamster ovary cells (CHO-K1) transfused with human mAChR M4. These cells may be Chinese hamster ovary cells (CHO-K1) transfused with rat mAChR M4 receptor. These cells may be Chinese hamster ovary cells (CHO-K1) transfused with mammalian mAChR M4. The term "mAChR M4 receptor positive allosteric modulator" includes compounds that are either "mAChR M4 receptor allosteric potentiaters" or "mAChR M4 receptor allosteric agonists," as well as compounds having mixed activity encompassing the pharmacology of both "mAChR M4 receptor allosteric potentiaters" 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] The term "mAChR M4 receptor allosteric potentia," as used herein, refers to any exogenously administered compound or agent that directly or indirectly enhances the response mediated by an endogenous ligand (such as acetylcholine) when that ligand binds to the orthosteric site of the mAChR M4 receptor in animals, particularly mammals, such as humans. mAChR M4 receptor allosteric potentia bind to a site other than the orthosteric site, i.e., the allosteric site, and positively enhance the receptor's response to an agonist or endogenous ligand. In some embodiments, the allosteric potentia do not induce receptor desensitization, and the activity of a compound as an mAChR M4 receptor allosteric potentia offers advantages over the use of mAChR M4 receptor orthosteric agonists. Such advantages may include, for example, increased safety margins, high tolerability, reduced potential for abuse, and reduced toxicity.

[0066] The term "mAChR M4 receptor allosteric enhancer" as used herein refers to any exogenously administered compound or agent that directly or indirectly enhances the response induced by an endogenous ligand (such as acetylcholine) in animals, particularly mammals, such as humans. In some embodiments, the allosteric enhancer increases the affinity of a native ligand or agonist to the orthosteric site. In some embodiments, the allosteric enhancer enhances the agonist potency. The mAChR M4 receptor allosteric enhancer binds to a site other than the orthosteric site, i.e., the allosteric site, and positively enhances the receptor's response to an agonist or endogenous ligand. The allosteric enhancer does not affect the receptor alone and requires the presence of an agonist or native ligand to achieve its receptor effect.

[0067] The term "mAChR M4 receptor allosteric agonist," as used herein, 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 an endogenous ligand (such as acetylcholine). mAChR M4 receptor allosteric agonists bind to a site on the mAChR M4 receptor distinct from the orthosteric acetylcholine site. Because they do not require the presence of an endogenous ligand, the activity of a compound as an mAChR M4 receptor allosteric agonist offers advantages when cholinergic tone is low at a given synapse.

[0068] The term "mAChR M4 receptor neutral allosteric ligand" is used herein to refer to any exogenously administered compound or agent that binds to the allosteric site in animals, particularly mammals, such as humans, without affecting the binding or function of agonists or native ligands at the orthosteric site. However, neutral allosteric ligands can block the action of other allosteric modulators acting through the same site.

[0069] In the enumeration of numerical ranges described herein, the numbers within each range are explicitly intended to be of equal precision. For example, in the range 6–9, the numbers 7 and 8 are intended in addition to 6 and 9, and in 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 intended.

[0070] Abbreviation: AIBN is 2,2'-azobis(2-methylpropionitrile). AQ is water-based. BINAP is 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl. Boc is a tert-butoxycarbonyl compound. BrettPhos is 2-(dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl. BrettPhos Pd G3 is [(2-di-cyclohexylphosphino-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® is diatomaceous earth. DCE is 1,2-dichloroethane. DCM is dichloromethane. DEA is diethylamine. DMAP is 4-dimethylaminopyridine. DMF is N,N-dimethylformamide. DMP or Dess-Martin periodinane is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one. DIAD is diisopropyl azodicarboxylate. DIPEA or DIEA is diisopropylethylamine. DMSO is dimethyl sulfoxide. Dowtherm™ A is a eutectic mixture of 26.5% diphenyl + 73.5% diphenyloxide. DtBAD is di-tert-butyl-azodicarboxylate. eq or eq. is equivalent. EtOAC is ethyl acetate. (4,4’-dtbbpy)NiCl2 is 4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine]nickel(II) dichloride. EtOH is ethanol. h or hr is hour. Hex is hexane. IPA is isopropyl alcohol. KOAc is potassium acetate. LAH is lithium aluminum hydride. Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane. mCPBA is meta-chloroperbenzoic acid. MeCN or ACN is acetonitrile. MeOH is methanol. min is minute. 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-methyl-2-pyrrolidone. [Pd(allyl)(tBuBrettPhos)]OTf is allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)] palladium(II) trifluoromethanesulfonate. Pd(dppf)Cl2 is [1,1’-bis(diphenylphosphino)ferrocene] dichloropalladium(II). Pd(OAc)2 is palladium(II) acetate. Pd(PPh3)4 is tetrakis(triphenylphosphine) palladium(0). PPA is polyphosphoric acid. PPh3 is triphenylphosphine. PPTS is pyridinium p-toluenesulfonate. rt is room temperature. sat. is saturated. sec is per second. SCX cartridge or HF SCX cartridge is a strong cation exchanger cartridge (i.e., Agilent part# 14256027). SFC is supercritical fluid chromatography. TBAC or TBACl is tetrabutylammonium chloride. t-BuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl. TEA or Et3N is triethylamine. TFA is trifluoroacetic acid. THF stands for tetrahydrofuran. TMB stands for trimethylboroxine. TosCl is p-toluenesulfonyl chloride. tosyl is p-toluenesulfonyl.

[0071] 2.Compound In one embodiment, the present invention provides a compound of formula (I), where R 2 , R 4A , R 4B , R 6 , R 7 , R 8 , X 1 And n are as defined herein.

[0072] Unsubstituted or substituted rings (i.e., may be substituted), such as aryl and heteroaryl rings, consist of a ring system and any substituents on the ring system. Therefore, since a ring system can be defined independently of its substituents, redefining only the ring system allows any previous substituents to remain. For example, a 5- to 12-membered heteroaryl with any substituent can be further defined by explicitly stating that the ring system of the 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., a 5- to 6-membered heteroaryl ring system), in which case, unless otherwise indicated, any substituents on the 5- to 12-membered heteroaryl still exist on the 5- to 6-membered heteroaryl.

[0073] If a heterocyclic or aromatic heterocyclic system is defined as "containing" or "having" certain heteroatoms (for example, 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S), then any ring atom in the heterocyclic or aromatic heterocyclic system that is not one of the certain heteroatoms is a carbon atom.

[0074] The following numbered embodiments of the present invention are disclosed. The first embodiment is denoted as E1, and subsequent embodiments are denoted as E1.1, E1.2, E2, E3, E4, E4.1, and so on.

[0075] E1. Compounds of formula (I) [ka] (In the formula: X 1 , NR 5 , O or CR 5A R 5B and; R 2 G 2 , -NR 2a R 2b , halogen, cyano, C 1~6 Alkyl, C 1~6 Haloalkyl, -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 These are, independently, hydrogen and C 1~6 Alkyl, C 1~6 Haloalkyl, G 2 or -C 1~3 Alkilen-G 2 and; G 2Each instance is independently a 5-6 member heteroaryl, phenyl, 4-7 member heterocyclyl, or 3-7 member carbocyclyl containing 1-4 heteroatoms, where the heteroatoms are independently selected from the group consisting of O, N, and S, and G 2 These are halogen, cyano, and 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 Alkilen-OR x , -C 1~6 Alkylene-N(R) x )2, G 2a and -C 1~3 Alkilen-G 2a They may be arbitrarily substituted with 1 to 5 substituents independently selected from the group consisting of; R x Each time they appear, hydrogen and C appear independently. 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~6 Cycloalkyl or -C 1~3 Alkylene-C 3~6 It is a cycloalkyl; G 2a is C 3~6 It is a cycloalkyl; R 4A and R 4B These are, independently, hydrogen and C 1~4 Alkyl, C 3~4 Cycloalkyl or -C 1~3 It is alkylene-OH; or R 4A and R 4B These, along with the carbon to which they are bonded, are C 3~6 Forms a cycloalkyl group; R 5 is hydrogen, C 1~6 Alkyl, C 1~6 Fluoroalkyl, -C 1~6 Alkilen-R y , -C 1~6Fluoroalkylene-R y , G 5 or -C 1~3 Alkilen-G 5 and; R 5A and R 5B They are independently hydrogen, halogen, and C 1~4 Alkyl, C 1~4 Fluoroalkyl or -C 1~4 It is 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 they appear, hydrogen and C appear independently. 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 It is a cycloalkyl; G 5 This includes phenyl, 4- to 8-membered heterocyclines containing 1-2 heteroatoms, 5- to 6-membered heteroaryls containing 1-4 heteroatoms, or C 3~6 It is a cycloalkyl group, where the heteroatom is independently selected from the group consisting of O, N, and S, and G 5 These are halogen, cyano, and C 1~4 Alkyl, C 1~2 Fluoroalkyl, -OC 1~4 It may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, OH, and oxo; R 6 These are hydrogen, halogen, cyano, and C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 2~4 Alkenil, -OR 6a , -N(R 6a )2, -C 1~3 Alkilen-OR 6a or C 3~4 It is a cycloalkyl; R6a is, each time it appears independently, hydrogen, C 1~4 alkyl, C 1~4 fluoroalkyl, C 3~4 cycloalkyl or -C 1~3 alkylene-C 3~4 cycloalkyl; alternatively, two R 6a together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic ring containing the nitrogen to which R 6a is attached and, optionally, one additional heteroatom which is O, N or S, the heterocyclic ring being optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1~2 alkyl and C 1~2 fluoroalkyl; R 7 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 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 is, each time it appears 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 8Each cycloalkyl group in is independently either unsubstituted or C 1~4 A compound (substituted with 1 to 4 substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., fluoro) compounds), or a pharmaceutically acceptable salt thereof.

[0076] A compound of E1.1.E1, or a pharmaceutically acceptable salt thereof, where G 5 This includes phenyl, 4- to 8-membered heterocyclines containing 1-2 heteroatoms, 5- to 6-membered heteroaryls containing 1-4 heteroatoms, or C 3~6 It is a cycloalkyl group, where the heteroatom is independently selected from the group consisting of O, N, and S, and G 5 is halogen, C 1~4 Alkyl, C 1~2 Fluoroalkyl, -OC 1~4 It may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, OH, and oxo.

[0077] Compounds of E1.2.E1 or E1.1, or pharmaceutically acceptable salts thereof, where X 1 is NR 5 Or it is O.

[0078] A compound from E2.E1 to E1.2, or a pharmaceutically acceptable salt thereof, where R 2 G 2 , -NR 2a R 2b , halogen, cyano, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 2a , -C(O)OR 2a -C(O)NR 2a R 2b Or it is hydrogen.

[0079] A compound of E3.E2, or a pharmaceutically acceptable salt thereof, wherein R 2 is G 2 That is the case.

[0080] E4.A compound from E1 to E3, or a pharmaceutically acceptable salt thereof, where G 2 These are 3- to 7-membered carbocyclyl compounds, which may be substituted as needed.

[0081] E4.1.A compound from E1 to E4, or a pharmaceutically acceptable salt thereof, where G 2 The ring system of 3- to 7-membered carbocyclyls, which may be arbitrarily substituted, is C 3~7 It is a cycloalkyl group.

[0082] A compound of E4.2.E4.1, or a pharmaceutically acceptable salt thereof, wherein G 2 The 3- to 7-membered carbocyclyl ring systems, which may be optionally substituted, are cyclopropyl or cyclobutyl.

[0083] A compound from E4.3.E4~E4.2, or a pharmaceutically acceptable salt thereof, where G 2 C 1~4 It may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyls and halogens.

[0084] A compound of E4.4.E4.3, or a pharmaceutically acceptable salt thereof, where G 2 It may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of methyl and fluoro.

[0085] Compounds of E4.5.E4.4, or pharmaceutically acceptable salts thereof, where G 2 teeth [ka] That is the case.

[0086] E5.A compound from E1 to E3, or a pharmaceutically acceptable salt thereof, where G 2 This is a 5- to 6-membered heteroaryl compound, which may be optionally substituted.

[0087] E5.1.A compound of any of E1-E3 or E5, or a pharmaceutically acceptable salt thereof, where G 2 A ring system of 5-membered to 6-membered heteroaryls that may be arbitrarily substituted is a 5-membered heteroaryl.

[0088] Compounds of E5.2.E5 or E5.1, or pharmaceutically acceptable salts thereof, where G 2 The heteroaryl ring system, which may be optionally substituted, contains one or two heteroatoms independently selected from the group consisting of N and S.

[0089] A compound of E5.3.E5.2, or a pharmaceutically acceptable salt thereof, where G 2 The heteroaryl ring system, which may be optionally substituted, is thiophenyl or pyrazolyl.

[0090] Compounds of E5.4.E5.3, or pharmaceutically acceptable salts thereof, where G 2 The heteroaryl ring systems that may be optionally substituted are thiophen-2-yl or pyrazole-5-yl.

[0091] A compound from E5.5 to E5.4, or a pharmaceutically acceptable salt thereof, where G 2 C 1~4 It may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyls and halogens.

[0092] Compounds of E5.6.E5.5, or pharmaceutically acceptable salts thereof, where G 2 It may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of methyl and fluoro.

[0093] Compounds of E5.7.E5.6, or pharmaceutically acceptable salts thereof, where G 2 teeth, [ka] That is the case.

[0094] A compound from E6.E1 to E5.7, or a pharmaceutically acceptable salt thereof, where G 2 teeth, [ka] That is the case.

[0095] A compound of E7.E2, or a pharmaceutically acceptable salt thereof, wherein R 2 -NR 2a R 2b That is the case.

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

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

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

[0099] A compound of E9.1.E9, or a pharmaceutically acceptable salt thereof, wherein R 2 It is chloroform.

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

[0101] A compound of E11.E2, or a pharmaceutically acceptable salt thereof, wherein R 2 is -C(O)OR 2a That is the case.

[0102] A compound of E12.E2, or a pharmaceutically acceptable salt thereof, wherein R 2 -C(O)NR 2a R 2b That is the case.

[0103] E13.A compound of any of E1, E1.1, E1.2, E2, E4.1-E4.4, E5.1-E5.6, E7, or E11-E12, or a pharmaceutically acceptable salt thereof, where R 2a is hydrogen or C 1~6 It is alkyl.

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

[0105] A compound of E13.2.E13, or a pharmaceutically acceptable salt thereof, wherein R 2a is C 1~4 It is alkyl.

[0106] Compounds of E13.3.E13.2, or pharmaceutically acceptable salts thereof, where R 2a It is ethyl.

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

[0108] E15.A compound from E1 to E14, or a pharmaceutically acceptable salt thereof, where R 4A and R 4B It is hydrogen.

[0109] A compound of E15.1.E15, or a pharmaceutically acceptable salt thereof, wherein R 4A and R 4B Hydrogen in this case is deuterium ( 2 H) is the answer.

[0110] A compound from E16.E1 to E15.1, or a pharmaceutically acceptable salt thereof, where X 1 is NR 5 That is the case.

[0111] E17.A compound from E1 to E16, or a pharmaceutically acceptable salt thereof, where R 5 is hydrogen, C 1~6 Alkyl, G 5 or -C 1~3 Alkilen-G 5 That is the case.

[0112] A compound of E17.1.E17, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, C 1~6 Alkyl or G 5 That is the case.

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

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

[0115] Compounds of E17.4.E17.3, or pharmaceutically acceptable salts thereof, where R 5 is C 1~3 It is alkyl.

[0116] Compounds of E17.5.E17.4, or pharmaceutically acceptable salts thereof, where R 5 It is methyl.

[0117] A compound of E17.6.E17.1, or a pharmaceutically acceptable salt thereof, wherein R 5 is G 5 That is the case.

[0118] A compound of E17.7.E17, or a pharmaceutically acceptable salt thereof, wherein R 5 is -C 1~3 Alkilen-G 5 That is the case.

[0119] E17.8.A compound of any of E1~E17.1 or E17.6~E17.7, or a pharmaceutically acceptable salt thereof, where G 5 C may be replaced as desired. 3~6 It is a cycloalkyl group.

[0120] A compound from E17.9.E1~E17.1 or E17.6~E17.8, or a pharmaceutically acceptable salt thereof, where G 5 C may be arbitrarily replaced. 3~6 The cycloalkyl ring systems are cyclopropyl, cyclobutyl, or cyclopentyl.

[0121] A compound from E17.10.E1~E17.1 or E17.6~E17.9, or a pharmaceutically acceptable salt thereof, where G 5 C in 3~6 Cycloalkyls include halogens, cyanos, and C 1~4 It may be optionally substituted with one or two substituents independently selected from the group consisting of alkyl groups.

[0122] Compounds of E17.11.E17.10, or pharmaceutically acceptable salts thereof, where G 5 C in 3~6 The cycloalkyl group may be optionally substituted with one or two substituents independently selected from the group consisting of fluoro, cyano, and methyl groups.

[0123] Compounds of E17.12.E17.11, or pharmaceutically acceptable salts thereof, where G 5 It is cyclopropyl or cyclopentyl.

[0124] A compound from E17.13.E1~E17.1 or E17.6~E17.7, or a pharmaceutically acceptable salt thereof, where G 5 This is a phenyl compound that may be optionally substituted.

[0125] A compound from E17.14.E1~E17.1, E17.6~E17.7, or E17.13, or a pharmaceutically acceptable salt thereof, where G 5 The phenyl in the compound may be optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, cyano, methyl, and -OCH3.

[0126] Compounds of E17.15.E17.14, or pharmaceutically acceptable salts thereof, where G 5 It is 2,4-dimethoxyphenyl.

[0127] A compound from E18.E1 to E15.1, or a pharmaceutically acceptable salt thereof, where X 1 It is O.

[0128] A compound from E19.E1 to E15.1, or a pharmaceutically acceptable salt thereof, where X 1 CR 5A R 5B That is the case.

[0129] A compound from E19.1.E1 to E15.1 or E19, or a pharmaceutically acceptable salt thereof, where R 5A and R 5B It is hydrogen.

[0130] A compound from any of E20 E1 to E19.1, or a pharmaceutically acceptable salt thereof, where R 6 It is hydrogen.

[0131] A compound from any of E20.1.E1 to E19.1, or a pharmaceutically acceptable salt thereof, where R 6 is C 1~4It is alkyl.

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

[0133] A compound from E21.E1 to E20.2, or a pharmaceutically acceptable salt thereof, where R 7 C 1~4 Alkyl, halogen, cyano, C 2~4 Alkenil, CO2R 7a , or unsubstituted or substituted C 3~6 It is a cycloalkyl group.

[0134] A compound of E21.1.E21, or a pharmaceutically acceptable salt thereof, wherein R 7 C 1~4 Alkyl, halogen, cyano, or unsubstituted or substituted C 3~6 It is a cycloalkyl group.

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

[0136] E21.3.A compound from E1 to E21.2, or a pharmaceutically acceptable salt thereof, where R 7 C in 1~4 Alkyl is methyl.

[0137] A compound from E21.4.E1 to E21.2, or a pharmaceutically acceptable salt thereof, where R 7 C in 1~4 Alkyl is ethyl.

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

[0139] A compound of E21.6.E21.1, or a pharmaceutically acceptable salt thereof, wherein R 7 is unsubstituted C 3~6 It is a cycloalkyl group.

[0140] A compound of any of E21.7.E1~E21.1 or E21.6, or a pharmaceutically acceptable salt thereof, where R 7 It is cyclopropyl.

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

[0142] E21.9.E1-E21.1, E21.3, E21.4, or E21.8, or a pharmaceutically acceptable salt thereof, where R 7 The halogen in this context is bromine.

[0143] A compound of E21.10.E21, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 2~4 It is Alkenil.

[0144] E21.11.A compound of any of E1-E21, E21.3, E21.4, E21.9, or E21.10, or a pharmaceutically acceptable salt thereof, where R 7 C in 2~4 Alkenyl is vinyl or prop-1-en-2-yl.

[0145] A compound of E21.12.E21, or a pharmaceutically acceptable salt thereof, wherein R 7 CO2R 7a That is the case.

[0146] E21.13.A compound of any of E1-E21, E21.3, E21.4, E21.9, E21.10, E21.11 or E21.12, or a pharmaceutically acceptable salt thereof, where R 7a is C1~4 It is alkyl.

[0147] E21.14.A compound of any of E1-E21, E21.3, E21.4, E21.9, E21.10, E21.11, or E21.12-E21.13, or a pharmaceutically acceptable salt thereof, where R 7a C in 1~4 Alkyl is methyl.

[0148] A compound from E21.15.E1 to E20.2, or a pharmaceutically acceptable salt thereof, where R 7 It is hydrogen.

[0149] E22 is a compound from E1 to E21.15, or a pharmaceutically acceptable salt thereof, where n is 0.

[0150] E23.: 2-(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-methyl-2-(2-(thiophen-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; Ethyl 5-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate; 3-methyl-2-(2-methyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-methyl-2-(2-(1-methyl-1H-pyrazole-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-chloro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(tert-butyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3,6-dimethyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopropyl-2-(2-Cyclopropyl-6,7-Dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopropyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopentyl-2-(2-Cyclopropyl-6,7-Dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopentyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopropyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopentyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methylfl[3,4-b]pyridine-5(7H)-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)flo[3,4-b]pyridine-5(7H)-one; 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-Cyclopropyl-2-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonitriel; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-3-(prop-1-en-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; Methyl 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate; 5-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; A compound of type E1 selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[0151] A pharmaceutical composition comprising one of the compounds E24.E1 to E23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0152] E25. A method for treating neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals, comprising administering to a mammal a therapeutically effective amount of any compound from E1 to E23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E24.

[0153] The method described in E26.E25, where the failure is related to mAChR M4 dysfunction.

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

[0155] E28. Any of the methods E25-E27, where the disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, sleep disorders, pain disorders, and cognitive disorders.

[0156] The method is the same as in E29.E28, where the disorder is Alzheimer's disease.

[0157] E30.E25~E27, wherein the disorder is selected from the group consisting of psychotic mood disorders such as psychosis, schizophrenia, conduct disorder, destructive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, and 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, motor disorders, Tourette syndrome, akinesia / rigidity syndrome, motor disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0158] E31.A compound from E1 to E23, or a pharmaceutically acceptable salt thereof, and: (a) at least one agent known to enhance 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 connection with cognitive or behavioral therapy. A kit containing one or more of the following.

[0159] E32. Any compound from E1 to E23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E24, for use in the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0160] E33. Use of any compound from E1 to E23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E24, for the preparation of pharmaceuticals for the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0161] Compounds may exist as stereoisomers containing a chiral or asymmetric center. The stereoisomers are designated "R" or "S" depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S" as used herein refer to the configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45:13-30. This disclosure intends for a variety of stereoisomers and mixtures thereof, which are clearly included within the scope of the invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Each stereoisomer of this compound can be prepared from commercially available starting materials containing a chiral or asymmetric center by synthesis or by preparation of racemic mixtures followed by division methods well known to those skilled in the art. These separation methods are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of optically pure products from the auxiliary (as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England), or (2) direct separation of the mixture of optically enantiomers using a chiral chromatography column, or (3) fractional recrystallization methods.

[0162] It should be understood that the compound may have tautomers and geometric isomers, and that these also constitute embodiments of the present disclosure.

[0163] In the compound of formula (I) and any of the subformulas, any "hydrogen" or "H" is a hydrogen isotope, whether explicitly stated in the structure or listed in the index. 1 H (protium) and 2It contains H (deuterium).

[0164] This disclosure also includes isotope-labeled compounds, which are equivalent to those described in formula (I), except that one or more atoms are substituted by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 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 is one example. Deuterium, that is 2 Substitution with heavier isotopes, such as H, may be preferable in some situations because it can lead to certain therapeutic benefits resulting from greater metabolic stability, such as an extended in vivo half-life or a reduced need for dosage. This compound can incorporate positron emission isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron emission isotopes that can be incorporated into the compound of formula (I) are: 11 C, 13 N, 15 O and 18 It is F.

[0165] Isotope-enriched forms of compounds of formula (I), or any subformula, can generally be prepared by the prior art known to those skilled in the art, or by processes similar to those described in the appended examples, using appropriate isotope-enriched reagents instead of non-isotope-enriched reagents. The degree of isotope enrichment can be characterized as the percentage of a particular isotope incorporated into the isotope-labeled atom (e.g., deuterium incorporation %) in deuterium labeling.

[0166] a. Pharmaceutically acceptable salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a water- or oil-soluble or dispersible salt or zwitterion of the compound that is suitable for the treatment of a disorder without excessive toxicity, irritation, and allergic reactions, and is effective for its intended use, with a reasonable benefit-risk ratio. These salts may be prepared during the final isolation 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 such as methanol and water, but is not limited to, and treated with at least one acid equivalent such as hydrochloric acid. The resulting salt may be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Typical salts include acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, and phosphate. The amino group of this compound can also be quaternized by chlorination, bromide, and alkyl iodide, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, and stearyl.

[0167] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reacting a carboxyl group with a hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or with a suitable base such as a primary, secondary, or tertiary organic amine. Quaternary amine salts can also be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0168] b. General synthesis The compound of formula (I) can be prepared by synthetic or metabolic processes. Metabolic preparations of this compound include processes that occur in the human or animal body (in vivo) or in vitro.

[0169] The compound of formula (I) can be synthesized as shown in schemes 1 to 10.

[0170] Scheme 1 [ka] As shown in Scheme 1, intermediate (ii) can be obtained by treating tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (i) with a thioamide while heating in a solvent (e.g., ethanol) to about 70-80°C. Intermediate (iii) can be formed by treating intermediate (ii) with an acid (e.g., TFA, HCl, etc.).

[0171] Scheme 2 [ka] As shown in Scheme 2, tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (iv) can be subjected to Suzuki reaction conditions in the presence of a base (e.g., sodium carbonate, cesium carbonate) and a solvent such as dioxane or a dioxane / water mixture, along with a appropriately substituted boronic acid or ester reagent and a palladium catalyst (e.g., Pd(PPh3)4, Pd(dppf)Cl2). Subsequent deprotection under acidic conditions (e.g., TFA, HCl) may form intermediate compound (iii).

[0172] Scheme 3 [ka] As shown in Scheme 3, the intermediate compound of formula (iii) can be subjected to standard nucleophilic substitution conditions with 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (vi), a base (e.g., DIPEA), and a solvent (e.g., DMSO), while heating to approximately 90-120°C, to obtain the compound having formula (vii).

[0173] Scheme 4 [ka] As shown in Scheme 4, the ester intermediate (viii) (where Y, Y 1 and Y 2 (ix) can be obtained by treating (where is Cl, Br, or I) with an amine, a base (e.g., DIEA), and a solvent (e.g., THF) without heating, or while heating to 40-50°C.

[0174] Scheme 5 [ka] As shown in Scheme 5, the intermediate compound (iii) can be subjected to standard nucleophilic substitution conditions with intermediate (x) (where Y is a halogen), a base (e.g., DIPEA), and a solvent (e.g., DMSO) while heating to approximately 90-120°C to obtain the compound having formula (xi).

[0175] Scheme 6 [ka] As shown in Scheme 6, the intermediate of formula (xi) (where Y is a halogen) can be coupled with a boronic acid or ester (e.g., trimethylboroxine) under Suzuki coupling conditions, which are generally known in the art, to obtain (xii). The coupling reaction can be carried out with a palladium catalyst such as Pd(dppf)Cl2 and a base (e.g., K2CO3, Cs2CO3) in a solvent mixture of DMF or an organic solvent such as 1,4-dioxane and water, while heating to about 70-90°C. The reaction can be accelerated by microwave irradiation.

[0176] Scheme 7 [ka] As shown in Scheme 7, the intermediate of 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) while heating to 120-140°C to obtain the compound of formula (xiii).

[0177] Scheme 8 [ka] As shown in Scheme 8, intermediate (xiv) can be coupled with an amine under Buchwald coupling conditions, which are generally known in the art, to obtain product (xv). A similar reaction can be carried out with intermediate (iv) to obtain -NR2a R 2b Substitutive intermediate compounds can be obtained.

[0178] Scheme 9 [ka] As shown in Scheme 9, intermediate (xiv) can be coupled with an alkoxide-type reagent in a suitable solvent to obtain product (xvi). A similar reaction can be carried out with intermediate (iv) to obtain -OR 2a Substitutive intermediate compounds can be obtained.

[0179] Scheme 10 [ka] As shown in Scheme 10, intermediate (xiv) can be reacted with zinc metal and Zn(CN)2 together with a palladium catalyst (e.g., Pd(dppf)Cl2) in a suitable solvent while heating to obtain (xvii). A similar reaction can be carried out with intermediate (iv) to obtain a cyano-substituted intermediate compound.

[0180] Boronic acids / esters, amines, and alcohols suitable for the coupling reactions described herein are readily available from commercial suppliers or can be prepared by standard methods well known to those skilled in the art.

[0181] Compounds and intermediates can be isolated and purified by methods well known to those skilled in the field of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography, thin-layer chromatography, distillation at various pressures, sublimation in vacuum, and trituration on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups by recrystallization at high or low temperatures, with optional pretreatment with activated carbon, as described in "Vogel's Textbook of Practical Organic Chemistry" 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0182] The disclosed compounds may have at least one basic nitrogen (so that the compound can be treated with an acid to form a desired salt). For example, the compound can be reacted with an acid at room temperature or above room temperature to provide a desired salt (which precipitates and is collected by filtration after cooling). Examples of acids suitable for this reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, atrolactic 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, phosphoric acid of hydrogen bromide, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0183] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants used and the substituents present in the reactants. Specific procedures are provided in the Examples section. The reaction can be post-treated in a conventional manner, for example, by removing the solvent from the residue, and further purified according to methodologies commonly known in the art, including but not limited to crystallization, distillation, extraction, polishing, and chromatography. Unless otherwise stated, starting materials and reagents are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature. If not commercially available, starting materials can be prepared by procedures selected from standard organic chemistry techniques, techniques similar to the synthesis of known structurally similar compounds, or techniques similar to the schemes or synthesis examples described above.

[0184] Conventional experimental methods, including reaction conditions, reagents and the order of the synthesis route, and appropriate handling of the protection and deprotection of any chemical functionalities that are not compatible with the reaction conditions and the appropriate timing of deprotection in the reaction sequence of the method, are within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art, and examples thereof are incorporated herein by reference in Protective Groups in Organic Synthesis (4) th This can be referenced in Greene's book titled (ed.) PGM Wuts and TW Greene, John Wiley & Sons, NY (2006). The synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthesis schemes described above and in the specific examples.

[0185] If an optically active form of the disclosed compound is required, it can be obtained by performing one of the procedures described herein using an optically active starting material (e.g., prepared by asymmetric induction of an appropriate reaction step), or by the resolution of a mixture of stereoisomers of the compound or intermediate using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0186] Similarly, if a pure geometric isomer of this compound is required, it can be obtained by performing one of the above procedures using the pure geometric isomer as a starting material, or by separating a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0187] It should be understood that the described synthesis schemes and specific examples are illustrative and should not be construed as limiting the scope of the invention as defined in the appended claims. All alternative forms, modifications, and equivalents of the synthesis methods and specific examples are included within the scope of the claims.

[0188] c. Muscarinic acetylcholine receptor M4 activity In some embodiments, the compounds disclosed enhance the agonist response of mAChR M4 (e.g., acetylcholine). In some embodiments, the compounds disclosed enhance the mAChR M4 response to non-maximal concentrations of the agonist in the presence of the compound compared to the response to the agonist in the absence of the compound. The increase in mAChR M4 activity can be demonstrated by methodologies known in the art. For example, activation of mAChR M4 activity is performed by Ca 2+ - This can be determined by measuring the calcium flux in response to an agonist, such as acetylcholine, and the co-expression of chimeric or promiscuous G proteins in cells loaded with a sensitive fluorescent dye (e.g., Fluo-4). In some embodiments, calcium flux was measured as an increase in the fluorescence static ratio. In some embodiments, positive allosteric modulator activity is measured as EC20 The response was analyzed as a concentration-dependent increase in the acetylcholine response (i.e., the response of mAChR M4 at acetylcholine concentrations that yielded 20% of the maximum response).

[0189] In some embodiments, the disclosed compounds activate the mAChR M4 response as an increase in calcium fluorescence in mAChR M4-transfected CHO-K1 cells in the presence of the compound, compared to the response of equivalent CHO-K1 cells in the absence of the compound. In some embodiments, the disclosed compounds are present in concentrations of 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 of EC. 50 This activates the mAChR M4 reaction. In some embodiments, mAChR M4-transfected CHO-K1 cells are transfected with human mAChR M4. In some embodiments, mAChR M4-transfected CHO-K1 cells are transfected with rat mAChR M4.

[0190] The disclosed compounds may exhibit positive allosteric modulation of the mAChR M4 response to acetylcholine, as an increase in the response to non-maximal concentrations of acetylcholine in transfected CHO-K1 cells in the presence of the compounds compared to the response to acetylcholine in the absence of the compounds. In some embodiments, the disclosed compounds are present in EC concentrations of 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. 50 This demonstrates positive allosteric regulation of the mAChR M4 response to acetylcholine. In some embodiments, EC is shown to regulate positive allosteric regulation. 50 This is determined in CHO-K1 cells into which mAChR M4 has been transfused. In some embodiments, mAChR M4 is transfused human mAChR M4. In some embodiments, mAChR M4 is transfused rat mAChR M4.

[0191] The disclosed compounds may exhibit selectivity for the mAChR M4 receptor to one or more of the mAChR M1, M2, M3, or M5 receptors. For example, the disclosed compounds may induce the mAChR M4 response in mAChR M4-transferred CHO-K1 cells to EC in one or more of the mAChR M1, M2, M3, or M5-transferred CHO-K1 cells. 50 e-commerce below 50 It can be activated by . In some embodiments, the disclosed compounds have an EC of about 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower, about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that of mAChR M1. 50 The mAChR M4 reaction can be activated. In some embodiments, the disclosed compounds have an EC of about 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower, about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that of mAChR M2. 50 The mAChR M4 reaction can be activated. In some embodiments, the disclosed compounds have an EC of about 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower, about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that of mAChR M3. 50 The mAChR M4 reaction can be activated. In some embodiments, the disclosed compounds have an EC of about 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower, about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that of mAChR M5. 50 The mAChR M4 reaction can be activated. In some embodiments, the disclosed compounds have an EC that is 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower than that for M2-M5 receptors, and about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that for mAChR M1, M2, M3 or M5 receptors. 50 This can activate the mAChR M4 reaction.

[0192] The disclosed compounds have an EC of less than approximately 10 μM. 50 This can activate the mAChR M4 reaction in M4-transfected CHO-K1 cells and exhibit selectivity for the M4 receptor over one or more mAChR M1, M2, M3, or M5 receptors. For example, in some embodiments, the compound may have an EC of 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. 50 The compound may have an EC of approximately 5 times, 10 times, 20 times, 30 times, 50 times, 100 times, 200 times, 300 times, 400 times, or more than 500 times lower than that of mAChR M1. 50 The mAChR M4 reaction can be activated. In some embodiments, the compound is EC2 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. 50 The compound may have an EC of approximately 5 times lower, 10 times lower, 20 times lower, 30 times lower, 50 times lower, 100 times lower, 200 times lower, 300 times lower, 400 times lower, or more than 500 times lower than that of mAChR M2. 50 The mAChR M4 reaction can be activated. In some embodiments, the compound is EC2 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. 50 The compound may have an EC of approximately 5 times lower, 10 times lower, 20 times lower, 30 times lower, 50 times lower, 100 times lower, 200 times lower, 300 times lower, 400 times lower, or more than 500 times lower than that of mAChR M3. 50 This can also activate the mAChR M4 reaction. In some embodiments, the compound is EC2 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. 50The compound may have an EC of approximately 5 times lower, 10 times lower, 20 times lower, 30 times lower, 50 times lower, 100 times lower, 200 times lower, 300 times lower, 400 times lower, or more than 500 times lower than that of mAChR M5. 50 This can also activate the mAChR M4 reaction. In some embodiments, the compound is EC2 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. 50 The compound may have an EC that is approximately 5 times lower, 10 times lower, 20 times lower, 30 times lower than that for M2-M5 receptors, approximately 50 times lower, 100 times lower, 200 times lower, 300 times lower, 400 times lower than that for M2, M3, or M5, or more than 500 times lower than that for mAChR M1, M2, M3, or M5 receptors. 50 Therefore, it can also activate the mAChR M4 reaction.

[0193] The in vivo efficacy of the disclosed compounds can be measured in numerous preclinical rat behavioral models in which known and clinically useful antipsychotics exhibit similar positive responses. For example, the disclosed compounds can reverse amphetamine-induced hypermotility in male sprague-dory rats at doses ranging from 1 to 100 mg / kg po.

[0194] 3. Pharmaceutical compositions and preparations The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to subjects (such as patients, which may be human or non-human). The disclosed compounds can also be provided as formulations such as spray-dried dispersions.

[0195] These pharmaceutical compositions and formulations may contain a “therapeutic dose” or a “preventive dose.” “Therapeutic dose” refers to the amount effective in the dosage and duration required to achieve the desired therapeutic outcome. The therapeutic dose of this composition can be determined by those skilled in the art and may vary depending on factors such as the individual’s disease state, age, sex, and weight, as well as the composition’s ability to elicit the desired response in the individual. The therapeutic dose is also the amount in which the therapeutically beneficial effects of any of the compounds of the present invention (e.g., compounds of formula (I)) outweigh any toxic or harmful effects. “Preventive dose” refers to the amount effective in the dosage and duration required to achieve the desired preventive outcome. Generally, since preventive doses are used for targets before or in the early stages of disease, the preventive dose will be lower than the therapeutic dose.

[0196] For example, the therapeutically effective doses of the compound of formula (I) are approximately 1 mg / kg to 1000 mg / kg, 5 mg / kg to 950 mg / kg, 10 mg / kg to 900 mg / kg, 15 mg / kg to 850 mg / kg, 20 mg / kg to 800 mg / kg, 25 mg / kg to 750 mg / kg, 30 mg / kg to 700 mg / kg, 35 mg / kg to 650 mg / kg, 40 mg / kg to 600 mg / kg, and 45 mg / kg. It may be approximately mg / kg to 550 mg / kg, approximately 50 mg / kg to 500 mg / kg, approximately 55 mg / kg to 450 mg / kg, approximately 60 mg / kg to 400 mg / kg, approximately 65 mg / kg to 350 mg / kg, approximately 70 mg / kg to 300 mg / kg, approximately 75 mg / kg to 250 mg / kg, approximately 80 mg / kg to 200 mg / kg, approximately 85 mg / kg to 150 mg / kg, and approximately 90 mg / kg to 100 mg / kg.

[0197] This pharmaceutical composition and formulation may contain pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier” as used herein means any non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid of any kind. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and dulcis; Iz oil; glycols; for example, propylene glycol; esters, for example, ethyl oleate and ethyl laurate (but not limited); agar; buffers, for example, magnesium hydroxide and aluminum hydroxide (but not limited); alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer; and other non-toxic, suitable lubricants, for example, sodium lauryl sulfate and magnesium stearate (but not limited), as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants may also be present in the composition at the discretion of the compounder.

[0198] Therefore, this compound and its pharmaceutically acceptable salts can be formulated, for example, in solid tablets, eye drops, oil-based topical preparations, injection, inhalation (through the mouth or nose), implantable tablets, or for oral, buccal, parenteral, or rectal administration. The techniques and formulations can generally be referenced in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions should generally be sterile and stable under manufacturing and storage conditions.

[0199] The route by which the disclosed compound is administered and the form of the composition determine the type of carrier used. The composition may be in various forms suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implantable, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0200] Carriers for systemic administration generally include at least one of the following: diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, fluidizers, solvents, suspending agents, wetting agents, surfactants, or combinations thereof. All carriers are optional within the composition.

[0201] Suitable diluents include sugars, such as glucose, lactose, dextrose, and sucrose; diols, such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent in a systemic or topical composition is generally about 50-90%.

[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 oil. The amount of lubricant in a composition for whole-body or topical use is generally about 5 to about 10%.

[0203] Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starch, such as sorghum starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder in the whole composition is generally about 5 to 50%.

[0204] Suitable disintegrants include agar, alginic acid and its sodium salts, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clay, and ion exchange resins. The amount of disintegrant in a whole-body or topical composition is generally about 0.1 to about 10%.

[0205] Suitable colorants include FD&C dyes. When used, the amount of colorant in a whole-body or topical composition is generally about 0.005 to 0.1%.

[0206] Suitable flavors include menthol, peppermint, and fruit flavors. When used, the amount of flavor in a systemic or topical composition is generally about 0.1 to 1.0%.

[0207] Suitable sweeteners include aspartame and saccharin. The amount of sweetener in a whole-body or topical composition is generally about 0.001% to about 1%.

[0208] Suitable antioxidants include butylhydroxyanisole ("BHA"), butylhydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant in a systemic or topical composition is generally about 0.1 to 5%.

[0209] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative in a systemic or topical composition is generally about 0.01 to 5%.

[0210] A suitable fluidizing agent is silicon dioxide. The amount of fluidizing agent in a whole-body or topical composition is generally about 1 to 5%.

[0211] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, castor oil hydroxide, alcohols such as ethanol, and phosphate buffer. The amount of solvent in a whole-body or topical composition is generally about 0 to 100%.

[0212] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent in a systemic or topical composition is generally about 1 to 8%.

[0213] Suitable surfactants include lecithin, polysorbate 80, sodium lauryl sulfate, and TWEENS (from Atlas Powder Company of Wilmington, Delaware). Other suitable surfactants are disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Wilmington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant in a systemic or topical composition is generally about 0.1% to about 5%.

[0214] The amounts of components in a systemic composition may vary depending on the type of systemic composition being prepared, but generally, a systemic composition contains 0.01% to 50% of an active compound (e.g., a compound of formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration generally contain 0.1% to 10% of an active substance and 90% to 99.9% of a carrier (including diluents and solvents).

[0215] Compositions for oral administration may have various dosage forms. For example, solid dosage forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of the active substance, usually at least about 5%, more specifically about 25% to about 50%. These oral medication compositions contain about 50% to about 95%, more specifically about 50% to about 75% of the carrier.

[0216] Tablets can be compressed, wet-coated (tablet triturate), enteric-coated, sugar-coated, film-coated, or multi-compressed. Tablets generally contain an active ingredient and a carrier containing an ingredient selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, fluidizers, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are FD&C dyes that can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or combinations thereof.

[0217] Capsules (including implantable tablets, sustained-release and sustained-release formulations) generally comprise an active compound (e.g., a compound of formula (I)) and a carrier containing one or more of the disclosed diluents in a gelatin-containing capsule. Granules generally comprise the disclosed compound and a fluidizing agent, preferably silicon dioxide, to improve flowability. Implantable tablets may be biodegradable or non-biodegradable.

[0218] The selection of components in the carrier for oral compositions depends on auxiliary considerations such as taste, cost, and storage stability, which are not important to the purpose of the present invention.

[0219] The solid composition can be conventionally coated with a pH or time-dependent coating so that the disclosed compound is released into the gastrointestinal tract or near the desired site of application, or at various locations and times, in order to maintain the desired effect. The coating generally comprises one or more components selected from the group consisting of cellulose phthalate acetate, vinyl polyphthalate acetate, hydroxypropyl methylcellulose phthalate, ethylcellulose, EUDRAGIT® coating (available from Evonik Industries of Essen, Germany), wax, and shellac.

[0220] Compositions for oral administration can take the form of a liquid. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-foaming granules, suspensions reconstituted from non-foaming granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, and syrups. Liquid compositions for oral administration generally comprise the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Oral liquid compositions preferably contain one or more components selected from colorants, flavors, and sweeteners.

[0221] Other compositions useful for achieving systemic delivery of the target compound include sublingual, buccal, and nasal dosage forms. These compositions generally contain diluents, including sucrose, sorbitol, and mannitol; and one or more soluble fillers, such as gum arabic, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. These compositions may further contain lubricants, colorants, flavors, sweeteners, antioxidants, and fluidizers.

[0222] The disclosed compounds can be administered topically. Topical compositions that can be applied topically to the skin may be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-in and rinse-off hair conditioners, emulsions, cleansers, moisturizers, sprays, skin patches, and the like. A topical composition comprises the disclosed compound (e.g., the compound of formula (I)) and a carrier. The carrier of the topical composition preferably facilitates the penetration of the compound into the skin. The carrier may further comprise one or more optional components.

[0223] The amount of carrier used with the disclosed compound is sufficient to provide a composition of a useful dose for administration per unit dose of the compound. Techniques and compositions for producing useful dosage forms in the method of the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0224] The carrier may consist of a single component or a combination of two or more components. In topical compositions, this 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 myristyl propionate, dimethyl isosorbide, castor oil, and combinations thereof. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, and even more specifically, phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0225] The carrier for the topical composition may further include one or more components selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, dyes, 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 laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, and sebaci. Examples include di-n-butyl phosphate, 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 for the skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in topical compositions for skin use is generally about 5% to about 95%.

[0227] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant in a topical composition is generally about 0% to about 95%.

[0228] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific examples of solvents include ethyl alcohol and homotopic alcohol. The amount of solvent in a topical composition is generally about 0% to about 95%.

[0229] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. A specific example of a humectant is glycerin. The amount of humectant in a topical composition is generally between 0% and 95%.

[0230] The amount of thickener in topical compositions is generally between approximately 0% and 95%.

[0231] Suitable powders include β-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's clay, kaolin, starch, rubber, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, aluminum silicate hydrate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder in a topical composition is generally 0% to 95%.

[0232] The amount of fragrance in topical compositions is generally about 0% to 0.5%, and especially about 0.001% to 0.1%.

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

[0234] The pharmaceutical composition or preparation has an EC of less than approximately 10 μM, less than approximately 5 μM, less than approximately 1 μM, less than approximately 500 nM, or less than approximately 100 nM. 50 Positive allosteric regulation of mAChR M4 may be observed. The pharmaceutical composition or formulation may have an EC of about 10 μM to about 1 nM, about 1 μM to about 1 nM, about 100 nM to about 1 nM, or about 10 nM to about 1 nM. 50 This may indicate positive allosteric regulation of mAChR M4.

[0235] a. Spray-dried dispersion formulation The disclosed compounds can be formulated as spray-dried dispersions (SDDs). An SDD is a single-phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution containing a compound molecularly "dissolved" in a solid matrix. SDDs are obtained by dissolving the drug and polymer in an organic solvent and then spray-drying this solution. The use of spray-drying for pharmaceutical applications can result in amorphous dispersions with increased solubility for Biopharmaceutical Classification System (BCS) Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) drugs. Formulation and operating conditions are selected so that the given time is insufficient for phase separation or crystallization due to the rapid evaporation of the solvent from the droplets. SDDs exhibit long-term stability and manufacturability. For example, SDDs have demonstrated a shelf life exceeding two years. The advantages of SDD include, but are not limited to, enhanced oral bioavailability of water-soluble compounds, delivery using conventional solid dosage forms (e.g., tablets and capsules), a reproducible, controllable, and scalable manufacturing process, and broad applicability to structurally different insoluble compounds with a wide range of properties.

[0236] Therefore, in one embodiment, the present disclosure can provide a spray-dried dispersion formulation comprising a compound of formula (I).

[0237] 4.How to use The disclosed compounds, pharmaceutical compositions, and formulations may be used in methods for treating disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions may also be used in methods for increasing muscarinic acetylcholine receptor activity in mammals and in methods for enhancing cognition in mammals. These methods further include synergistic therapies 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 simultaneously with or subsequently to the disclosed compounds and compositions.

[0238] a. Treatment of the disability The disclosed compounds, pharmaceutical compositions, and formulations may be used to treat disorders or in methods for treating disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. Methods of treatment may include administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula (I), or a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I).

[0239] In some embodiments, a method for enhancing cognition in mammals is provided, comprising the step of administering to a mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I).

[0240] The compounds and compositions disclosed herein may be useful for treating, preventing, improving, controlling, or reducing the risk of a variety of disorders associated with selective mAChR M4 receptor activation. For example, the treatment may include selective mAChR M4 receptor activation to an extent effective in affecting cholinergic activity. The disorder may be related to cholinergic activity, for example, impaired cholinergic function. Therefore, a method is provided for treating or preventing a disorder in a subject, comprising the step of administering to the subject at least one of the disclosed compounds or at least one forged pharmaceutical composition in an amount effective for treating the disorder in the subject.

[0241] Furthermore, a method is provided for treating one or more impairments related to mAChR M4 receptor activity in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods of treating disorders associated with the mAChR M4 receptor. In some embodiments, the Disclosure provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods of treating disorders associated with the mAChR M4 receptor.

[0243] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof used in the manufacture of pharmaceuticals for the treatment of disorders associated with the mAChR M4 receptor.

[0244] In some embodiments, the Disclosure provides a method for treating disorders associated with muscarinic acetylcholine receptor dysfunction in mammals, comprising the step of administering to a mammal an effective amount of at least one compound of the Disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the Disclosure, or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof used in methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0246] In some embodiments, the Disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0247] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof used in the manufacture of pharmaceuticals for the treatment of disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0248] In some embodiments, the compounds and compositions disclosed are useful for treating 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, short-term psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, delayed-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 psychosis associated with a disorder selected from major depressive disorder, affective disorder, bipolar disorder, electrolyte disorder, Alzheimer's disease, neurological disorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder.

[0249] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods of treating neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, particularly those described herein. In some embodiments, the Disclosure provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods of treating neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, particularly those described herein. In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for treating neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, particularly those described herein.

[0250] In some embodiments, the disorder is a neurological disorder selected from brain tumors, dementia with Lewy bodies, 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, brief psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, and shared 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, amphetamine and other psychostimulants, and cocaine).

[0252] In some embodiments, the Disclosure provides a method for treating cognitive impairment, comprising administering an effective amount of a compound or composition of the Disclosure to a subject in need. In some embodiments, cognitive impairments include dementia (associated with Alzheimer's disease, ischemia, polyinfarct dementia, trauma, vascular problems or stroke, HIV infection, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other common medical conditions or substance abuse), delirium, amnesia, substance-induced persistent delirium, dementia due to HIV infection, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinson's disease-ALS dementia complex, Alzheimer's-like dementia, age-related cognitive decline and mild cognitive impairment.

[0253] The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides diagnostic tools for cognitive disorders, 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 DC) provides diagnostic tools for neurocognitive disorders (NCDs), including delirium, the syndromes of severe NCD and mild NCD, and their etiological subtypes. Severe or mild NCD subtypes include NCD due to Alzheimer's disease, vascular NCD, NCD with Lewy bodies, NCD due to Parkinson's disease, frontotemporal NCD, NCD due to traumatic brain injury, NCD due to HIV infection, substance / medication-induced NCD, NCD due to Huntington's disease, NCD due to prion diseases, NCD due to other medical conditions, NCD due to multiple etiologies, and unspecified NCD. The NCD category in DSM-5 encompasses a group of disorders in which the primary clinical impairment lies in cognitive function and is acquired rather than developmental. As used herein, the term “cognitive impairment” includes the treatment of these cognitive and neurocognitive disorders as described in DSM-IV-TR or DSM-5. Those skilled in the art will recognize that alternative nomenclature, disease classifications, and classification systems exist for mental disorders, and that these systems evolve with medical and scientific advances. Therefore, the term “cognitive impairment” is intended to include similar disorders as described in other diagnostic materials.

[0254] In some embodiments, the Disclosure provides methods for treating schizophrenia or psychosis, comprising administering an effective amount of a compound or composition of the Disclosure to a subject requiring treatment. Specific schizophrenic or psychotic pathologies include paranoid, disorganized, catatonic, or undifferentiated schizophrenia and substance-induced psychotic disorders. DSM-IV-TR provides diagnostic tools including paranoid, disorganized, catatonic, undifferentiated, or residual schizophrenia and substance-induced psychotic disorders. DSM-5 excludes subtypes of schizophrenia and instead includes a dimensional approach for assessing the severity of core symptoms of schizophrenia to capture heterogeneity in the types and severity of symptoms expressed among individuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the treatment of these mental disorders as described in DSM-IV-TR or DSM-5. Those skilled in the art will recognize that alternative nomenclature, disease classifications, and classification systems exist for mental disorders, and that these systems evolve with medical and scientific advances. Therefore, the term “schizophrenia or psychosis” is intended to include similar disorders described in other diagnostic materials.

[0255] In some embodiments, the Disclosure provides a method for treating pain, comprising administering an effective amount of a compound or composition of the Disclosure to a subject requiring treatment. Specific forms of pain include bone and joint pain (osteoarthritis), repetitive pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, and neuropathic pain.

[0256] This compound and composition may be even more useful in preventing, treating, controlling, improving, or reducing the risk of the diseases, disorders, and conditions referred to herein. This compound and composition may be even more useful in combination with other agents in methods for preventing, treating, controlling, improving, or reducing the risk of the aforementioned diseases, disorders, and conditions.

[0257] In the treatment of conditions requiring mAChR M4 activity, appropriate dose levels may range from approximately 0.01 to 500 mg / kg patient body weight / day, which can be administered as a single or multiple dose. Preferred dose levels may range from approximately 0.1 to approximately 250 mg / kg / day or approximately 0.5 to approximately 100 mg / kg / day. Preferred dose levels may range from approximately 0.01 to 250 mg / kg / day, approximately 0.05 to 100 mg / kg / day, or approximately 0.1 to 50 mg / kg / day. Within this range, doses may range from 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg / day. For oral administration, the composition is provided in the form of tablets containing 1.0 to 1000 milligrams 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 milligrams of the active ingredient, allowing for symptomatic adjustment of the dosage to the patient being treated. The compound can be administered 1 to 4 times daily, preferably in a regimen of once or twice daily. This dosage regimen can be adjusted to provide an optimal therapeutic response. However, it will be understood that the specific dose level and frequency for any particular patient can vary and depend on various factors, including the activity of the particular compound used, its metabolic stability and duration of action, age, weight, general health, sex, diet, mode and timing of administration, excretion rate, drug combinations, severity of the particular condition, and the host being treated.

[0258] Accordingly, in some embodiments, the present disclosure relates to a method for activating mAChR M4 receptor activity in at least one cell, comprising the step of contacting at least one cell with at least one disclosed compound or at least one product of the disclosed method in an amount effective to activate mAChR M4 in at least one cell. In some embodiments, the cell is a mammal, for example, human. In some embodiments, the cell is isolated from the subject before the contact step. In some embodiments, the contact is via administration to the subject.

[0259] In some embodiments, the present invention relates to a method for activating mAChR M4 activity in a subject, comprising the step of administering to the subject at least one disclosed compound or at least one product of the disclosed method in doses and amounts effective for activating mAChR M4 activity in the subject. In some embodiments, the subject is a mammal, for example, a human. In some embodiments, the mammal has been diagnosed as requiring mAChR M4 agonism prior to the administration step. In some embodiments, the mammal has been diagnosed as requiring mAChR M4 activation prior to the administration step. In some embodiments, the method further comprises the step of identifying a subject requiring mAChR M4 agonism.

[0260] In some embodiments, the present invention relates to a method for treating a disorder in a mammal associated with selective mAChR M4 activation, such as a disorder associated with cholinergic activity, comprising the step of administering to the mammal at least one compound or at least one product of the method disclosed in doses and amounts effective for treating the disorder in the mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as requiring treatment for the disorder prior to the administration step. In some embodiments, the method further includes the step of identifying a subject who requires treatment for the disorder.

[0261] In some embodiments, the disorder can be selected from psychotic mood disorders such as psychosis, schizophrenia, conduct disorder, destructive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, and 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, motor disorders, Tourette syndrome, akinesia / rigidity syndrome, motor disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

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

[0263] b. Enhancement of muscarinic acetylcholine receptor activity In some embodiments, the present disclosure relates to a method for increasing muscarinic acetylcholine receptor activity in a mammal, comprising the step of administering to the mammal an effective amount of at least one compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof used in a method for increasing muscarinic acetylcholine receptor activity in mammals. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof used in a method for increasing muscarinic acetylcholine receptor activity in mammals.

[0265] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof used in the manufacture of pharmaceuticals that increase muscarinic acetylcholine receptor activity in mammals.

[0266] In some embodiments, increased muscarinic acetylcholine receptor activity is an enhancement of muscarinic acetylcholine receptor activity. In some embodiments, increased muscarinic acetylcholine receptor activity is a partial agonism of muscarinic acetylcholine receptor activity. In some embodiments, increased muscarinic acetylcholine receptor activity is a positive allosteric regulation of muscarinic acetylcholine receptor activity.

[0267] In some embodiments, the administered compound has an EC of 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. 50This shows an increase in mAChR M4. In some embodiments, the administered compound is EC2 at approximately 10 μM to approximately 1 nM, approximately 1 μM to approximately 1 nM, approximately 100 nM to approximately 1 nM, or approximately 10 nM to approximately 1 nM. 50 This shows an increase in mAChR M4.

[0268] In some embodiments, the mammal is human. In some embodiments, the mammal has been diagnosed as requiring increased muscarinic acetylcholine receptor activity prior to the administration step. In some embodiments, the method further includes the step of identifying the mammal requiring increased muscarinic acetylcholine receptor activity. In some embodiments, increased muscarinic acetylcholine receptor activity addresses a disorder in the mammal associated with muscarinic acetylcholine receptor activity. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.

[0269] In some embodiments, increased muscarinic acetylcholine receptor activity in mammals is related to the treatment of neurological and / or psychiatric disorders associated with muscarinic receptor dysfunction, such as neurological or psychiatric disorders disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4.

[0270] In some embodiments, the Disclosure provides a method for increasing muscarinic acetylcholine receptor activity in cells, comprising the step of contacting cells with an effective amount of at least one compound of the Disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are mammalian (e.g., human). In some embodiments, the cells are isolated from the mammal before the contact step. In some embodiments, the contact is via administration to the mammal.

[0271] c. Reinforcement of cognition In some embodiments, the present invention relates to a method for enhancing cognition in mammals, comprising the step of administering to a mammal an effective amount of at least one compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, or variant thereof.

[0272] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof used in methods for enhancing cognition in mammals. In some embodiments, the Disclosure provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof used in methods for enhancing cognition in mammals.

[0273] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof used in the manufacture of pharmaceuticals for enhancing cognition in mammals.

[0274] In some embodiments, the mammal is human. In some embodiments, the mammal is diagnosed as needing cognitive enhancement before the administration step. In some embodiments, the method further includes the step of identifying the mammal that needs cognitive enhancement. In some embodiments, the need for cognitive enhancement is related to 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. Collaborative therapy The present invention further relates to the administration of selective mAChR M4 activators for improving treatment outcomes in the context of cognitive or behavioral therapy. Specifically, in some embodiments, the present invention relates to a coordinated therapy comprising the step of administering to a mammal an effective amount and dosage of at least one compound from the disclosure, or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in synergistic therapy with cognitive or behavioral treatment in mammals. In some embodiments, the Disclosure provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof for use in synergistic therapy with cognitive or behavioral treatment in mammals.

[0278] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for use in conjunction with cognitive or behavioral therapies in mammals.

[0279] In some embodiments, the administration improves treatment outcomes in conjunction with cognitive or behavioral therapy. Administration in conjunction with cognitive or behavioral therapy may be continuous or intermittent. Administration does not need to be simultaneous with therapy and may be before, during, and / or after therapy. For example, cognitive or behavioral therapy may be provided within 1, 2, 3, 4, 5, 6, or 7 days before or after administration of the compound. As a further example, cognitive or behavioral therapy may be provided within 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 within the 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the compound being administered.

[0280] It is understood that the disclosed co-therapeutic methods may be used in connection with the disclosed compounds, compositions, kits, and their use.

[0281] e. Combination therapy In the methods of use described herein, further therapeutic agents may be administered simultaneously with or consecutively with the disclosed compound and composition. Consecutive administration includes administration before or after the disclosed compound and composition. In some embodiments, the additional therapeutic agent may be administered in the same composition as the disclosed compound. In other embodiments, there may be a time interval between the administration of the additional therapeutic agent and the administration of the disclosed compound. In some embodiments, administration of the additional therapeutic agent with the disclosed compound may allow for administration of other therapeutic agents at lower doses and / or at less frequent intervals. When used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used at lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compound of formula (I). The above combinations include not only combinations of the compound of the present invention with one other active compound, but also combinations 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 agents in the treatment, prevention, control, improvement or reduction of risk of the aforementioned diseases, disorders and conditions in which the compound or other agents are useful, where the combination of agents is safer or more effective than either agent alone. The other agents may be administered simultaneously with or immediately following the disclosed compound, in the routes and amounts commonly used for such administration. When the disclosed compound is used simultaneously with one or more other agents, a pharmaceutical composition in unit dosage form containing such agents and the disclosed compound may be used. However, combination therapy may also be administered on overlapping schedules. It is also conceivable that a combination of one or more active ingredients and the disclosed compound may be more effective than any of them as single agents. Therefore, when used in combination with one or more other active ingredients, the disclosed compound and the other active ingredients may be used at lower doses than when each is used alone.

[0283] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutic compounds described herein that are typically applied to the treatment of the above-mentioned pathological conditions.

[0284] The above combinations include not only combinations of the disclosed compound with one other active compound, but also combinations with two or more other active compounds. Similarly, the disclosed compound can be used in combination with other drugs used in the prevention, treatment, control, improvement, or reduction of risk of diseases or conditions in which the disclosed compound is useful. Such other drugs can be administered simultaneously with or sequentially to the compound of the present invention in the routes and amounts commonly used for that purpose. When the compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing these other drugs in addition to the disclosed compound is preferred. Therefore, such pharmaceutical compositions may include those containing one or more other active ingredients in addition to the compound of the present invention.

[0285] The weight ratio of the disclosed compound to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, the effective dose of each is used. For example, when the compound of the present invention is combined with another agent, the weight ratio of the disclosed compound to the other agent is generally in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. The combination of the compound of the present invention with other active ingredients is also generally within the range described above, but the effective dose of each active ingredient should be used in each case.

[0286] In such combinations, the disclosed compound and other active agents can be administered separately or together. Furthermore, the administration of one element may occur before, simultaneously with, or after the administration of the other agent.

[0287] Therefore, the disclosed compound may be used alone or in combination with other agents known to be beneficial for the target indication, or with other agents that affect receptors or enzymes, thereby increasing the efficacy, safety, or convenience of the disclosed compound, or reducing undesirable side effects or toxicity. The target compound and other agents may be administered simultaneously in combination therapy or in certain amounts.

[0288] In some embodiments, the compound can 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 other embodiments, the compound can be used with analgesics, hypnotics, anxiolytics, antipsychotics (typical and atypical), anxiolytics, cyclopyrrolone, imidazopyridine, pyrazolopyrimidine, weak tranquilizers, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, barbiturates, 5HT-2 antagonists, etc., including: azinazolam, arobarbital, aronimide, alprazolam, amisulpride, amitriptyline, amo Barbital, amoxapine, aripiprazole, bentazepam, benzoctamin, brotizolam, bupropion, buspirone, porcine barbital, butarbital, capride, carbochloral, chloralbetaine, chloralhydrate, clomipramine, clonazepam, cloperidone, chlorazepate, chlordiazepoxide, chlorate, chlorpromazine, clozapine, siprazepam, desipramine, dexcramol, diazepam, dichloralph Enazon, Divalproex, Diphenhydramine, Doxepin, Estazolam, Etochlorbinol, Etomidate, Phenobam, Flunitrazepam, Flupentixol, Fluphenazine, Flurazepam, Fluvoxamine, Fluoxetine, Fosazepam, Glutethimide, Harazepam, Haloperidol, Hydroxyzine, Imipramine, Lithium, Lorazepam, Lormetazepam, Maprotiline, Meclocalon, Melatonin, Mefobarbital, Meprobam Methacalon, Midaflul, Midazolam, Nefazodone, Nisobamate, Nitrazepam, Nortriptyline, Olanzapine, Oxazepam, Paraaldehyde, Paroxetine, Pentobarbital, Perlapine, Perphenazine, Phenelzine, Phenobarbital, Prazepam, Promethazine, Propofol, Protriptyline, Quazepam, Quetiapine, Licralazepam, Risperidone, Lorethamide, Secobarbital, Sertraline, Suprocron,This compound can be used in combination with temazepam, thioridazine, thiothixene, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifloperazine, trimethodine, trimipramine, urdazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and their salts, as well as combinations thereof, or the compound can be administered in combination with the use of physical methods such as phototherapy or electrical stimulation.

[0289] In some embodiments, this compound can be used in combination with anticholinergic agents such as levodopa (with or without a selective extraneurocarboxylase inhibitor such as carbidopa or benserazide), biperiden (optionally as its hydrochloride or lactate), and trihexyphenidyl (benzhexol) hydrochloride, as well as 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, including allentemol, bromocriptine, phenoldopam, rislide, naxagolide, pergolide, and pramipexole. Dopamine agonists are recognized as being available in pharmaceutically acceptable salt forms, such as alentemol hydrobromide, bromocriptine mesylate, phenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Rislide and pramipexole are commonly used in non-salt forms.

[0290] In some embodiments, this compound can be used in combination with neuroleptic compounds of the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine, and indolone class. Preferred examples of phenothiazines include chlorpromazine, mesolidazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifloperazine. Preferred examples of thioxanthene include chlorprothixene and thiothixene. An example of dibenzazepine is clozapine. An example of butyrophenone is haloperidol. An example of diphenylbutylpiperidine is pimozide. An example of indolone is morindron. Other neuroleptics include roxapine, sulpiride, and risperidone. When used in combination with this compound, nerve blockers should be in pharmaceutically acceptable salt forms, such as chlorpromazine hydrochloride, mesolidazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enate, fluphenazine decanoate, trifloperazine hydrochloride, thiothixen hydrochloride, haloperidol decanoate, roxapine succinate, and morindone hydrochloride. Perphenazine, chlorprothixen, clozapine, haloperidol, pimozide, and risperidone are typically used in non-salt forms. Therefore, this compound can be used in combination with acetophenazine, allentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixen, clozapine, diazepam, phenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, rislid, roxapine, mesolidazine, morindron, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixen, trifloperazine, or ziprasidone.

[0291] In some embodiments, this compound can be used in combination with norepinephrine reuptake inhibitors (including tertiary and secondary amine tricyclics), 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, α-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, particularly 5-HT1A partial agonists, and antidepressants or anxiolytics including corticotropin-releasing factor (CRF) antagonists. Specific drugs include: amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazide, phenelzine, tranylcypromine, and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone, and piroxazine; alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, harazepam, lorazepam, oxazepam, and prazepam; buspirone, fresinoxane, gepirone, and ipsapirone, as well as pharmaceutically acceptable salts thereof.

[0292] In some embodiments, the compound can be co-administered with orthosteric muscarinic agonists, muscarinic potensiators, or cholinesterase inhibitors. In some embodiments, the compound can be co-administered with GlyT1 inhibitors, including but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof, as well as combinations thereof.

[0293] f. Mode of administration The therapeutic method may include any number of forms of administration of the disclosed composition. Forms of administration may include tablets, pills, sugar-coated tablets, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the drug may be mixed with commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (e.g., mannitose, methylcellulose, lactose, etc.), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g., etheric oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol), or bioavailability enhancers (e.g., Gelucire®). In pharmaceutical compositions, the drug may also be dispersed in fine particles, such as nanoparticle compositions.

[0294] For parenteral administration, the drug may be dissolved or suspended in a physiologically acceptable diluent, such as water, a buffer, an oil with or without a solubilizer, a surfactant, a dispersant, or an emulsifier. Examples of oils that can be used include, but are not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil. More generally, for parenteral administration, the drug may be in the form of an aqueous, lipid, oily, or other type of solution or suspension, or it may be administered in the form of liposomes or nanosuspensions.

[0295] As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions.

[0296] 5. Kit In one embodiment, the present disclosure relates to at least one compound of the disclosure, or a pharmaceutically acceptable salt thereof, and: (a) At least one drug known to enhance mAChR M4 activity; (b) At least one drug known to reduce mAChR M4 activity; (c) At least one drug known to treat disorders related to cholinergic activity; (d) Instructions for treating disorders related to cholinergic activity; (e) Instructions for treating disorders related to M4 receptor activity; or (f) Instructions for administering the compound in connection with cognitive or behavioral therapy We offer a kit that includes one or more of the following.

[0297] In some embodiments, at least one disclosed compound and at least one drug are co-formulated. In some embodiments, at least one disclosed compound and at least one drug are co-packaged. These kits may also include compounds and / or products that are co-packaged, co-formulated and / or co-delivered together with other components. For example, a drug manufacturer, drug distributor, physician, pharmacy or pharmacist may provide a kit containing the disclosed compound and / or product and another component for delivery to a patient.

[0298] The disclosed kit can be used in conjunction with the disclosed method of use.

[0299] These kits may include information, descriptions, or both indicating that the use of the kit provides treatment for a medical condition in mammals (especially humans). This information and descriptions may be in the form of words, images, or both. The kits may further or selectively include information, descriptions, or both indicating compounds, compositions, or both that have, for example, the benefit of treating or preventing a medical condition in mammals (e.g., humans); and information, descriptions, or both indicating how to apply the compounds or compositions.

[0300] The compounds and processes of the present invention will be better understood by referring to the following examples, which are intended to illustrate but not limit the scope of the invention. [Examples]

[0301] 6. Examples All NMR spectra were recorded using a 400 MHz AMX Bruker NMR spectrometer. The 1H chemical shift is reported as a δ value at ppm (low field) using a deuterated solvent as an internal standard. Data are reported as follows: chemical shift, multiplicity (s=single line, bs=broad single line, d=double line, t=triple line, q=quadruline, dd=double line of double lines, m=multiline, ABq=AB quadruple line), coupling constant, and integral value. Reverse-phase LCMS analysis was performed using an Agilent 1200 system consisting of a binary pump with degasser, high-performance autosampler, thermostat-equipped column compartment, C18 column, diode array detector (DAD), and Agilent 6150 MSD, with the following parameters. The gradient conditions were as follows: 5% to 95% acetonitrile in an aqueous phase of 0.1% TFA in water for 1.4 minutes, retained in 95% acetonitrile for 0.1 minutes, 0.5 mL / min, 55°C ("90-second method"). Samples were separated at 0.5 mL / min on a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 × 50 mm) while maintaining the column and solvent temperature at 55°C. The DAD was set to scan at 190–300 nm, and the signals used were at 220 nm and 254 nm (both using bands with a width of 4 nm). The MS detector was set up with an electrospray ionization source, and low-resolution mass spectra were obtained by scanning at 140–700 AMU with a step size of 0.2 AMU and a peak width of 0.008 min at 0.13 cycles / second. The drying gas flow was set to 13 liters / minute at 300°C, and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set to 3000V, and the fragmenter voltage was set to 100V. Data was acquired using Agilent Chemstation and Analytical Studio Reviewer software.

[0302] a. Preparation of intermediates [ka] 1-Methylcyclopropanecarbothioamide. Lawson's reagent (4.5 g, 11.1 mmol) was added to a suspension of 1-methylcyclopropanecarboxamide (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 hours, the reaction mixture was concentrated, and the resulting residue was diluted with SiO2 and washed with water (twice) and brine. The organic layer was concentrated and dried under high pressure to obtain the title compound (1.2 g). ES-MS[M+1] + :116.9.

[0303] [ka] 1-Fluorocyclopropane-1-carbothioamide. 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 hours, the reaction mixture was concentrated, and the resulting residue was diluted with ELISA and washed with water (twice) and brine. The organic layer was concentrated to obtain the desired compound, which was then subjected to the next step without further purification. 1 H NMR(400MHz,DMSO)δ 9.74(d,J=194.7Hz,2H),1.63(td,J=8.7,5.2Hz,2H),1.49-1.38(m,2H).

[0304] [ka] 2-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. To a suspension of 1-methylcyclopropanecarbothioamide (1.0 g, 9.0 mmol) in ethanol (46 mL), N-Boc-3-bromo-4-oxopiperidine (2.5 g, 9.0 mmol) was added, and the reaction was heated at 80°C for 48 hours. The crude reaction mixture was concentrated under reduced pressure. DCM (25 mL) and TFA (6.9 mL) were added to this residue. After 1 hour at room temperature, the reaction mixture was concentrated. The residue was dissolved in toluene and saturated Na2CO3 solution. The mixture was separated, and the aqueous layer was extracted with toluene (twice). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by normal-phase column chromatography (0-70% siRNA / hexane, followed by a 0-10% DCM:MeOH:1% NH4OH gradient) to obtain the title compound (1.59 g). 1 H NMR(400MHz,CDCl3)δ4.00(t,J=1.8Hz,2H),3.71(t,J=5.8Hz,2H),2.80~2.76(m,2H ),1.54(s,3H),1.23(dd,J=6.8,4.4Hz,2H),0.91(dd,J=6.5,4.1Hz,2H);ES-MS[M+1] + :295.1 and 195.1.

[0305] [ka] 2-Cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride. Cyclopropanecarbothioamide (1.8 g, 18.0 mmol) and N-Boc-3-bromo-4-oxopiperidine (5.0 g, 18.0 mmol) were stirred in ethanol (30 mL) at 80°C for 2 hours. The solution was concentrated, and then 1,4-dioxane (8 mL) and a 4M hydrochloric acid solution in 1,4-dioxane (40 mL) were added. After 1 hour at room temperature, the solution was concentrated under reduced pressure to obtain the title compound (4.0 g). 1H NMR(400MHz,DMSO-d6)δ 4.30(s,2H),2.91(t,J=6.0Hz,2H),2.59(t,J=6.5Hz,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] [ka] 2-(2,2-dimethylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. In a vial, 2,2-dimethylcyclopropanecarbothioamide (232 mg, 1.8 mmol) and N-Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) were combined in ethanol (2 mL). After 2 hours 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 hour at room temperature, the solution was concentrated, diluted with saturated aqueous Na2CO3 solution, and extracted with DCM (3 times). The combined organic layer was passed through a hydrophobic phase separator and concentrated to obtain the title compound (195 mg). 1 H NMR(400MHz,DMSO)δ 3.83(d,J=1.8Hz,2H),2.96(t,J=5.8Hz,2H),2.61(t,J=4.1.2H),2.14(dd, J=8.4,5.6Hz,1H),1.17(s,3H),1.11-1.01(m,2H),0.97(s,3H);ES-MS[M+1] + :209.3.

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

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

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

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

[0311] [ka] 2-(thiophen-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. In a vial, thiophen-2-boronic acid (105 mg, 0.82 mmol), tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (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). After purging the reaction with nitrogen (3 times), the reaction was heated at 80°C for 2 hours. The reaction was filtered with Celite® and washed with Celite® in DCM (2 × 25 mL). The filtrate was concentrated and purified by normal-phase chromatography (0-40% toluene / hexane) to obtain the desired Boc-protected amine. The Boc-protected amine was dissolved in DCM (2 mL) and trifluoroacetic acid (0.59 mL). After 1 hour, the reaction was concentrated, basicized with saturated Na2CO3, extracted with DCM (3 times), passed through a hydrophobic phase separator, and concentrated to obtain the title compound (112 mg). 1 H NMR(400MHz,CDCl3)δ 7.44(dd,J=3.7,1.2Hz,1H),7.36(dd,J=5.1,1.2Hz,1H),7.06(dd,J=5.1,3.7Hz,1H ),4.10(s,2H),3.24(t,J=5.9Hz,2H),2.90(ddd,J=6.0,4.1,1.8Hz,2H);ES-MS[M+1] + :223.1.

[0312] [ka] 2-(1-methyl-1H-pyrazole-5-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. Tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (300 mg, 0.94 mmol), cesium carbonate (924 mg, 2.82 mmol), Pd(dppf)Cl2 (69 mg, 0.09 mmol), and 1-methylpyrazole-5-boronic acid pinacol ester (391 mg, 1.88 mmol) were heated at 100°C for 18 hours in 1,4-dioxane (2.3 mL) and water (0.4 mL). The mixture was filtered through a Celite® pad, and the filtrate was concentrated. The residue was purified by normal-phase chromatography (0-40% toluene / hexane) to obtain Boc-amine, which was dissolved in DCM (2 mL) and trifluoroacetic acid (1.1 mL). After 1 hour, the reaction was concentrated, basicized with saturated Na2CO3 solution, extracted with DCM (3 times), 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=2.0Hz,1H),6.60(d,J=2.1Hz,1H),4.26(d,J=1.6Hz,2H),4.22(s,3H),3.39(t,J=5.9Hz,2H),3.10-3.01(m,2H);ES-MS[M+1] + :221.2.

[0313] [ka] To a solution of tert-butyl 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid, 5-(tert-butyl)2-ethyl 6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate (300 mg, 0.96 mmol) in ethanol (4.8 mL), a 5 M aqueous solution of NaOH (384 μL, 1.92 mmol) was added. After 3 hours, the reaction mixture was concentrated and used for the next step without further purification. ES-MS[M+H]+ = 285.

[0314] [ka] tert-butyl2-carbamoyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate. To a solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (273 mg, 0.96 mmol) in 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) were added. The mixture was heated at 75°C for 18 hours. At room temperature, the reaction was diluted with water and extracted with chloroform / IPA (3:1) (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was purified using normal-phase column chromatography (0-2% MeOH / DCM). 1 H NMR(400MHz,CDCl3)δ 7.01(s,1H),5.46(s,1H),4.71(s,2H),3.77(t,J=5.3Hz,2H),2.90(t,J=5.1Hz,2H),1.49(s,9H);ES-MS[M+H] + =284.

[0315] [ka] 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide. To a solution of tert-butyl2-carbamoyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (272 mg, 0.96 mmol) in DCM (6.4 mL), TFA (735 μL, 9.6 mmol) was added. After 18 hours at room temperature, the reaction was concentrated and then dissolved in MeOH and charged into an SCX cartridge (HF bond). After flushing the cartridge with MeOH, the cartridge was eluted with a 7N NH3 / MeOH solution. The solvent was removed under reduced pressure to obtain the title compound. 1 H NMR(400MHz,DMSO)δ 7.15(s,1H),6.80(s,1H),3.05(t,J=1.7Hz,2H),2.10(t,J=5.8Hz,2H),1.83(ddd,J=7.4,3.8,1.5Hz,2H);ES-MS[M+H] + =184.

[0316] [ka] Ethyl 5-bromo-6-hydroxy-2-methylnicotinate. To a solution of ethyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (10 g, 55.2 mmol) in DMF (185 mL), N-bromosuccinimide (10.8 g, 60.7 mmol) was slowly added in several portions at 0°C. The ice bath was removed. After 18 hours, saturated sodium bisulfite (aq) was added to the reaction and stirred for 30 minutes. The reaction was filtered, and the recovered solid was dried in a vacuum oven to obtain the title compound (14.2 g). 1 H NMR(400MHz,DMSO)δ 8.15(s,1H),4.20(q,J=7.1Hz,2H),3.32(s,3H),2.55(s,1H),1.27(t,J=7.1Hz,3H);ES-MS[M+1] + :260.0 / 262.0.

[0317] [ka] Ethyl 5-bromo-6-chloro-2-methylnicotinate. In a 500 mL round-bottom flask, ethyl 5-bromo-6-hydroxy-2-methylnicotinate (14.2 g, 54.6 mmol) in MeCN (300 mL) was added, followed by phosphorus(V) oxychloride (29.4 mL, 316 mmol). A condenser was placed over the reaction and the mixture was heated at 85 °C. After 18 hours, 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. An additional DCM (25 mL) was added, and the mixture was stirred for 30 minutes. The organic layer was separated, and the aqueous layer was re-extracted with 3:1 chloroform / IPA (3 × 20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-25% toluene / hexane) to obtain the compound indicated in the title (12 g). 1 H NMR(400MHz,CDCl3)δ 8.40(s,1H),4.38(q,J=7.1Hz,2H),2.76(s,3H),1.40(t,J=7.1Hz,3H).ES-MS[M+1] + :277.9 / 279.9.

[0318] [ka] Ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate. To a solution of ethyl 5-bromo-6-chloro-2-methylnicotinate (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) was added in several portions at 50 °C. After 30 minutes, the reaction was heated to 80 °C. After 18 hours, the reaction was cooled to room temperature, diluted with water, and the organic layer was separated. The aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were dried with (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-4% toluene / hexane) to obtain the title compound (13.6 g). 1H NMR(400MHz,CDCl3)δ 8.48(s,1H),4.91(s,2H),4.44(q,J=7.1Hz,2H),1.43(t,J=7.1Hz,3H).ES-MS[M+1] + :357.9 / 359.9.

[0319] [ka] 3-Bromo-2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. To a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (2.5 g, 6.99 mmol) in THF (140 mL), a 2.0 M solution of methylamine (17.5 mL, 35.0 mmol) was added at 0°C, and the reaction was stirred for 30 minutes. The reaction was concentrated at room temperature and purified by normal-phase chromatography (0-30% Â / DCM) to obtain the title compound (948 mg). 1 H NMR(400MHz,DMSO)δ 8.49(s,1H),4.50(s,2H),3.09(s,3H).ES-MS[M+1] + :261.1 / 263.1.

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

[0321] [ka] 3-bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 3-bromo-2-chloro-6-methyl-7H-pyrrolo[3,4-b]pyridine-5-one (30 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) were dissolved in DMSO (0.57 mL), to which 2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (27.0 mg, 0.14 mmol) was added. The reaction was heated at 70°C for 18 hours. The reaction was purified by reverse-phase HPLC (18-58% MeCN / water / 0.05% NH4OH) to obtain the compound described in the title. ES-MS[M+1] + :425 / 426; 1 H NMR(400MHz,CDCl3)δ 8.17(d,J=1.5Hz,1H),4.68(q,J=1.8Hz,2H),4.26(d,J=1.5Hz,2H),3.82(td,J=5.7,1.6Hz,2H) ,3.19(d,J=1.5Hz,3H),3.09(ddd,J=7.6,3.8,1.8Hz,2H),1.65-1.54(m,2H),1.51-1.41(m,2H).

[0322] [ka] 3-Bromo-2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 2,4-dimethoxybenzylamine (2.1 mL, 14.0 mmol) was slowly added to a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (1300 mg, 2.8 mmol) in THF (55 mL), and the reaction was stirred at room temperature for 30 minutes. Triethylamine (0.58 mL, 4.2 mmol) was added. After 18 hours at room temperature, the reaction was concentrated in Celite® and purified by normal-phase chromatography (0-25% Â / DCM) to obtain the title compound. 1H NMR(400MHz,CDCl3)δ 8.30(s,1H),7.22(dd,J=7.8,0.7Hz,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] [ka] 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 2-cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (604 mg, 3.4 mmol) was added to a solution of 3-bromo-2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (888 mg, 2.2 mmol) and N,N-diisopropylethylamine (1.94 mL, 11.2 mmol) in NMP (5.6 mL). The reaction was heated to 120 °C. After 18 hours, water was added, the precipitate was filtered, rinsed with water, and dried under an N2 atmosphere to obtain the compound described in the title. 1 H NMR(400MHz,CDCl3)δ 8.16(s,1H),7.20(d,J=8.1Hz,1H),6.45-6.43(m,J=2.4Hz,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=5.6,1.9Hz,2H),2.25(tt,J=8.2,4.9Hz,1H),1.13-1.07(m,2H),1.03-0.97(m,2H).ES-MS[M+1] + :541 / 543.

[0324] [ka] 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. A mixture of 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (200 mg, 0.37 mmol), pinacol vinylboronic acid (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 irradiated with microwaves at 130°C for 30 minutes. The reaction mixture was filtered with Celite®, washed with 3:1 CHCl3 / IPA, and the solvent was removed under reduced pressure. The crude sample was purified by reverse-phase chromatography (15-65% MeCN / water / 0.05% NH4OH) to obtain the compound indicated in the title. ES-MS[M+1] + :489.

[0325] [ka] Ethyl 5-bromo-6-chloro-2-formylnicotinate. Ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (1.36 g, 3.8 mmol) was dissolved in MeCN (21.5 mL) and 4-methylmorpholine N-oxide (893 μL, 8.6 mmol) was added. The mixture was stirred at ambient temperature for 2 hours. The solution was diluted with Âlyte 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% Âlyte / hexane) to obtain the title compound (668 mg). ES-MS[M+1] + :292 / 294; 1 H NMR(400MHz,CDCl3)δ 10.22(s,1H),8.34(d,J=0.5Hz,1H),4.45(q,J=7.2Hz,2H),1.41(t,J=7.1Hz,3H).

[0326] [ka] 3-Bromo-2-chloroflou[3,4-b]pyridine-5(7H)-one. Sodium borohydride (27 mg, 0.70 mmol) was added to a solution of ethyl 5-bromo-6-chloro-2-formylnicotinate (668 mg, 1.76 mmol) in THF (8.8 mL) at -40°C. The reaction was stirred at -40°C for 45 minutes. Water was added to the reaction mixture and the reaction was warmed to room temperature. After extraction of the reaction with RINKAN (3 times), the combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was placed in 1,4-dioxane (4 mL), then hydrochloric acid (879 μL, 3.52 mmol; 4 M in 1,4-dioxane) was added, and the mixture was heated at 50°C for 18 hours. 4M HCl (400 μL, 1.6 mmol) was added to 1,4-dioxane, and the mixture was heated to 50°C. After 4 hours, the mixture was concentrated under reduced pressure, 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 obtain the title compound. ES-MS[M+1] + :248 / 250; 1 H NMR(400MHz,CDCl3)δ 8.42(t,J=0.5Hz,1H),5.28(d,J=0.5Hz,2H).

[0327] [ka] 3-Bromo-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)flou[3,4-b]pyridine-5(7H)-one. 3-Bromo-2-chloroflou[3,4-b]pyridine-5(7H)-one (40 mg, 0.13 mmol) was dissolved in NMP (1 mL), to which 3-bromo-2-chloro-7H-flou[3,4-b]pyridine-5-one hydrochloride (40 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.39 mmol) were added. The mixture was heated at 50°C for 18 hours. The mixture was cooled to ambient temperature, diluted with water, and extracted with ELISA (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated. The product was subjected to the next step without further purification. ES-MS[M+1] + :406 / 408.

[0328] [ka] 3-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-2-ol. Bromine (150 μL, 2.9 mmol) was added to a vial containing 6,7-dihydro-5H-cyclopenta[b]pyridine-2-ol (500 mg, 3.7 mmol) and acetic acid (5.3 mL) at 0°C. The reaction was allowed to proceed to room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and saturated sodium thiosulfate solution was added to the residue, which was then neutralized with saturated sodium carbonate aqueous solution. The mixture was extracted with RINKAN (3 times). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by normal-phase column chromatography (0-10% DCM / MeOH + 1% NH4OH additive) to obtain the desired compound (493 mg). 1 H NMR(400MHz,CDCl3)δ 7.74(s,1H),2.91(tt,J=8.1,1.2Hz,2H),2.79-2.70(m,2H),2.21-2.09(m,2H);ES-MS[M+1] + :214 / 216.

[0329] [ka] 3-Bromo-2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine. 3-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-2-ol (493 mg, 2.3 mmol) in POCl3 (1.2 mL, 13.2 mmol). The solution was heated at 90°C for 18 hours. The reaction mixture was concentrated. Saturated aqueous sodium carbonate was slowly added to the residue. The mixture was extracted by DCM (3 times). The combined organic layers were washed with water (3 times). The organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by normal-phase column chromatography (0-60% siRNA / Hex) to obtain the title compound (316 mg). 1 H NMR(400MHz,CDCl3)δ 7.72(t,J=1.2Hz,1H),3.00-2.88(m,4H),2.17(p,J=7.7Hz,2H);ES-MS[M+1] + :232 / 234.

[0330] [ka] 3-Bromo-2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-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), 3-bromo-2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (316 mg, 1.36 mmol) was added. The mixture was stirred at 40°C for 3 hours. The reaction mixture was filtered with Celite® and washed with ethyl acetate and MeOH. The filtrate was concentrated. The residue was dissolved in water / ethyl acetate (1:1; 50 mL). The organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate (twice). 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% siRNA / hexane) to obtain the compound indicated in the title. ES-MS[M+1] + :246 / 248; 1H NMR(400MHz,CDCl3)δ 8.22(s,1H),3.26-3.18(m,2H),2.87-2.80(m,2H).

[0331] [ka] 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one. 3-Bromo-2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one (13 mg, 0.05 mmol) was dissolved in DMSO (0.5 mL), to which 2-cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (10 mg, 0.06 mmol) and N,N-diisopropylethylamine (55 μL, 0.32 mmol) were added. The mixture was heated to 120 °C. After 18 hours, the mixture was poured into water and extracted with ethyl acetate (3 times). The combined organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified using normal-phase column chromatography (0-80% toluene / hexane) to obtain the compound described in the title. [M+1] + :390 / 392.

[0332] [ka] Ethyl 6-hydroxy-2,4-dimethylnicotinate. To a solution of ethyl(Z)-3-aminobuta-2-enoate (1.96 mL, 15.5 mmol) in toluene (11.6 mL), a solution of hydrochloric acid (4 M in dioxane) (7.74 mL, 30.9 mmol) was added, and the reaction was heated at 115 °C for 18 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude residue was purified by normal-phase chromatography (0-90% siRNA / DCM) to obtain the title compound. 1H NMR(400MHz,CDCl3)δ 6.25(s,1H),4.34(q,J=7.1Hz,2H),2.46(s,3H),2.29(s,3H),1.37(t,J=7.1Hz,3H).ES-MS[M+1] + :196.

[0333] [ka] Ethyl 5-bromo-6-hydroxy-2,4-dimethylnicotinate. Prepared in the same manner as ethyl 5-bromo-6-hydroxy-2-methylnicotinate. 1 H NMR(400MHz,CDCl3)δ 4.36(q,J=7.1Hz,2H),2.43(s,3H),2.42(s,3H),1.38(t,J=7.1Hz,3H).ES-MS[M+1] + :274 / 276.

[0334] [ka] Ethyl 5-bromo-6-chloro-2,4-dimethylnicotinate was prepared in the same manner as ethyl 5-bromo-6-chloro-2-methylnicotinate. 1 H NMR(400MHz,CDCl3)δ 4.43(q,J=7.1Hz,2H),2.47(s,3H),2.43(s,3H),1.40(t,J=7.1Hz,3H).ES-MS[M+1] + :292 / 294.

[0335] [ka] Ethyl 5-bromo-2-(bromomethyl)-6-chloro-4-methylnicotinate: Prepared in the same manner as ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate. 1H NMR(400MHz,CDCl3)δ 4.53(s,2H),4.48(q,J=7.2Hz,2H),2.48(s,3H),1.43(t,J=7.2Hz,3H).ES-MS[M+1] + :370 / 372 / 374.

[0336] [ka] 3-Bromo-2-chloro-4,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one was prepared in the same manner as 3-bromo-2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 1 H NMR(400MHz,DMSO)δ 4.43(s,2H),3.07(s,3H),2.75(s,3H).ES-MS[M+1] + :275 / 277.

[0337] [ka] 3-Bromo-2-chloro-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one:ethyl 5-bromo-2-(bromomethyl)-6-chloro-4-methylnicotinate (320 mg, 0.86 mmol) was dissolved in methanol (15.4 mL), to which ammonia (7N in MeOH) (615 μL, 4.31 mmol) was added, and the reaction was stirred at room temperature for 18 hours. Additional ammonia (7N in MeOH) (615 μL, 4.31 mmol) was added, and the reaction was stirred for a further 18 hours. The reaction was concentrated under reduced pressure 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=1.2Hz,2H),2.75(s,3H).ES-MS[M+1] + :261 / 263.

[0338] [ka] 3-Bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. Prepared similarly to 3-Bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 1 H NMR(400MHz,CDCl3)δ 4.63(d,J=1.9Hz,2H),4.20(s,2H),3.75(t,J=5.6Hz,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] [ka] 3-bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. Prepared similarly to 3-bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 1 H NMR(400MHz,CDCl3)δ 5.90(s,1H),4.65(t,J=1.8Hz,2H),4.28(d,J=1.1Hz,2H),3.78(t,J=5.6Hz,2H),3. 11(t,J=5.7Hz,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]

[0341] b. Typical synthesis of the compounds of the present invention [ka] 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 2). 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4-b]pyridine-5-one (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) were dissolved in DMSO (0.8 mL), to which 2-cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine hydrochloride (21 mg, 0.10 mmol) was added. The reaction was heated at 120 °C for 18 hours. The reaction was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH). The desired fraction was concentrated to obtain the title compound (2.1 mg). 1 H NMR(400MHz,CDCl3)δ 7.82(s,1H),6.50(s,1H),4.52(s,2H),4.35(s,2H),3.57(t,J=5.6Hz,2H),3.02(t,J=5.6 Hz,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] [ka] 3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 3). 2-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (19 g, 0.10 mmol) was added to a solution of 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4-b]pyridine-5-one (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL). The reaction was heated at 120 °C for 18 hours. The reaction was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH). The desired fraction was concentrated to obtain the compound indicated in the title (9.4 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.37(s,1H),7.77(s,1H),4.49(s,2H),4.25(s,2H),3.54(t,J=5.5Hz,2H),2.91(t,J=5.4Hz,2H) ,2.37(s,3H),1.50(s,3H),1.13(dd,J=6.7,2.6Hz,2H),0.96(dd,J=6.3,3.7Hz,2H);ES-MS[M+1] + :341.0.

[0343] [ka] 2-(2-cyclopropyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-yl)-3,6-dimethyl-7H-pyrrolo[3,4-b]pyridine-5-one (compound 12). 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (225 mg, 0.56 mmol), cesium carbonate (543 mg, 1.67 mmol), trimethylboroxine (50% wt in THF) (0.47 mL, 1.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (81 mg, 0.11 mmol), and 1,4-dioxane (2.9 mL) were charged into vials. The mixture was reduced in pressure, purged with nitrogen, and stirred at 80°C for 18 hours. The reaction was filtered through a Celite® pad and thoroughly rinsed with 3:1 CHCl3 / IPA. The solvent was removed, and the crude sample was purified by reverse-phase chromatography (5-40% MeCN / water / 0.1% TFA). The desired fraction was basicized with saturated NaHCO3, extracted with 3:1 CHCl3 / IPA, and concentrated to obtain the title compound (36 mg). 1 H NMR(400MHz,CDCl3)δ 7.79(s,1H),4.50(s,2H),4.26(s,2H),3.55(t,J=5.6Hz,2H),3.18(s,3H),3.06-2.99(m,2H),2 .39(s,3H),2.31(d,J=4.7Hz,1H),1.14(dd,J=7.9,3.1Hz,2H),1.09-1.00(m,2H).;ES-MS[M+1] + :341.2.

[0344] [ka] 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 23). 3-Bromo-2-[2-(1-fluorocyclopropyl)-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-yl]-6-methyl-7H-pyrrolo[3,4-b]pyridine-5-one (21.0 mg, 0.05 mmol), cesium carbonate (48.0 mg, 0.15 mmol), trimethylboroxine (50% wt in THF) (40.0 μL, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were charged into a microwave vial. The mixture was reduced in pressure, purged with nitrogen, and stirred at 80°C for 18 hours. The reaction was filtered through a Celite® pad and rinsed thoroughly with ELISA. After removing the solvent, the crude sample was purified by reverse-phase chromatography (15-55% MeCN / water / 0.1% TFA). The desired fraction was basicized with saturated NaHCO3, extracted with 3:1 CHCl3 / IPA, and concentrated to obtain the title compound. ES-MS[M+1] + :359.2; 1 H NMR(400MHz,CDCl3)δ 7.80(d,J=0.9Hz,1H),4.57(t,J=1.9Hz,2H),4.27(s,2H),3.56(t,J=5.7Hz,2H),3.18(s,3H) ),3.02(tt,J=5.7,1.8Hz,2H),2.40(d,J=0.9Hz,3H),1.65-1.52(m,2H),1.52-1.41(m,2H).

[0345] [ka] 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)flo[3,4-b]pyridine-5(7H)-one (compound 24). A solution of 3-bromo-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)flo[3,4-b]pyridine-5(7H)-one (57 mg, 0.13 mmol), cesium carbonate (126 mg, 0.39 mmol), trimethylboroxine (50% wt. in THF) (108 μL, 0.39 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.025 mmol) in 1,4-dioxane (1 mL) was placed in a vial. The mixture was reduced in pressure, purged with nitrogen (3 times), and stirred at 80°C. After 4 hours, the mixture was cooled to ambient temperature, and additional cesium carbonate (126 mg, 0.39 mmol), trimethylboroxine (50% wt. in THF) (108 μL, 0.39 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.025 mmol) were added to the mixture, and the mixture was stirred at 85°C for a further 4 hours. The reaction was filtered through a Celite® pad, thoroughly washed with DCM / MeOH, and then concentrated. The crude product was purified by reverse-phase chromatography (10-60% MeCN / water / 0.1% TFA), the desired fraction was basicized with saturated NaHCO3, and then extracted with chloroform / IPA (3:1) (3 times). The organic layers were combined, passed through a phase separator, and concentrated. Next, the product was purified using normal-phase column chromatography (0-70% siRNA / Hex) to obtain the compound indicated in the title. ES-MS[M+1] + :342.

[0346] [ka] Methyl 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate (compound 31). To a solution of 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (50 mg, 0.12 mmol) in triethylamine (0.4 mL, 2.8 mmol) and methanol (0.05 mL, 1.2 mmol), xanthophos (14 mg, 0.02 mmol) and palladium(II) acetate (2.8 mg, 0.01 mmol) were added, and the resulting reaction vial was sealed. The vial was purged with a CO gas atmosphere. The reaction was then heated at 70°C for 16 hours under a CO gas balloon. After cooling to room temperature, the crude reaction was diluted 3:1 CHCl3 / IPA, filtered, and concentrated. The crude oil was purified by reverse-phase chromatography (10-60% MeCN / water / 0.1% TFA). The desired fraction was subjected to basic post-treatment to obtain 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 .1Hz,2H),2.26(tt,J=8.2,4.9Hz,1H),1.15-1.07(m,2H),1.06-0.97(m,2H).ES-MS[M+1] + :385.

[0347] [ka] 5-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (compound 32). A solution of 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (23 mg, 0.12 mmol) and 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (15 mg, 0.08 mmol) in NMP (0.5 mL) was mixed with N,N-diisopropylethylamine (72 μL, 0.41 mmol), and the reaction was heated at 160 °C for 18 hours. The crude residue was purified using RP-HPLC (5-50% ACN / 0.1% aqueous TFA). The fraction containing the title compound was basicized with saturated NaHCO3, and then extracted with chloroform / IPA (3:1) three times. The combined organic matter was passed through a hydrophobic phase separator to remove the solvent and obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 7.86(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=5.7Hz,2H),3.10(t,J=5.7Hz,2H),2.43(s,3H);ES-MS[M+H] + =330.

[0348] [ka] 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 33). In a reaction vial, 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (36 mg, 0.07 mmol) was suspended in ethanol (2 mL). The mixture was reduced in pressure and purged with nitrogen (3 times). Activated carbon-supported palladium (CAS#7440-05-3; 8 mg, 0.01 mmol) and activated carbon-supported palladium hydroxide (CAS#12135-22-7; 10 mg, 0.01 mmol) were added. The resulting mixture was purged with H2 gas for 1 minute. The balloon was removed and the reaction was stirred at 50°C for 5 hours. The suspension was filtered through a Celite® pad and rinsed thoroughly with 10% MeOH / DCM. The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography (15-65% MeCN / water / 0.05% NH4OH) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 7.92(s,1H),7.21(d,J=8.2Hz,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),3.5 2-3.45(m,2H),3.05(s,2H),2.71(q,J=7.5Hz,2H),2.38(s,1H),1.29(t,J=7.4Hz,3H),1.21(s,2H),1.10(s,2H).ES-MS[M+1] + :491.

[0349] [ka] 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 34). A mixture of 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (12 mg, 0.02 mmol) in trifluoroacetic acid (75 μL, 0.98 mmol) was stirred at 60°C for 4 hours. The reaction mixture was concentrated to obtain a crude residue, which was purified by reverse-phase chromatography (5-45% MeCN / water / 0.1% TFA) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 7.95(s,1H),6.06(s,1H),4.49(s,2H),4.36(s,2H),3.55(t,J=5.7Hz,2H),3.09(t,J=5.9Hz,2H),2.74(q, ES-MS[M+1] + :341.

[0350] [ka] 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one (compound 35). 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one (8.0 mg, 0.02 mmol), cesium carbonate (20 mg, 0.06 mmol), trimethylboroxine (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 charged into microwave vials. The mixture was reduced in pressure, purged with nitrogen, and stirred at 80°C for 18 hours. The reaction mixture was diluted with toluene, filtered through Celite®, and concentrated. The crude residue was dissolved in DMSO (1.5 mL) and purified by reverse-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 (three times). The combined organic compounds were passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 7.69(s,1H),4.61(t,J=1.9Hz,2H),3.66(t,J=5.6Hz,2H),3.04(dt,J=9.4,6.0Hz,4H),2.73-2.66 (m,2H),2.36(d,J=0.9Hz,3H),2.27(ddd,J=13.1,8.3,4.9Hz,1H),1.17-0.98(m,4H).ES-MS[M+1] + :326.2.

[0351] [ka] 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 36). Prepared in the same manner as compound 23. 1H NMR(400MHz,CDCl3)δ 5.82(s,1H),4.56-4.51(m,2H),4.28(s,2H),3.51(t,J=5.7Hz,2H),3.04(t,J=5.8H) z,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] [ka] 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 38). Prepared in the same manner as compound 23. 1 H NMR(400MHz,CDCl3)δ 4.51(t,J=1.8Hz,2H),4.21(s,2H),3.48(t,J=5.7Hz,2H),3.16(s,3H),3.03(tt,J=5.7, 1.8Hz,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 appropriate starting materials and the methods described in the scheme and examples above.

[0354] [Table 2]

[0355] [Table 3]

[0356] [Table 4]

[0357] [Table 5]

[0358] [Table 6]

[0359] [Table 7]

[0360] [Table 8]

[0361] biological activity A. Cell lines expressing muscarinic acetylcholine receptors Human and rat M4 cDNA were used to create chimeric G protein G qi5 In addition, Chinese hamster ovary cells (CHO-K1) purchased from the American Type Culture Collection were transfused using Lipofectamine 2000. Stable cell lines were created by treating the transfused cells with antibiotics (G418 sulfate (1 mg / ml) was used to select M4-expressing cells, and G qi5 Hygromycin B (500 μg / mL) was used to select expression cells. The resulting multiple clones were further screened for a compound screening assay using hM4-G. qi5 and rM4-G qi5 A monoclonal cell was obtained. Stable monoclonal cells were maintained in a humidified incubator at 37°C in the presence of 5% CO2 in Ham's F-12 medium containing 10% thermoinactivated bovine fetal serum (FBS), 1X Antibiotic / Antimycotic, 20 mM HEPES, 500 μg / mL G418 sulfate, and 200 μg / mL hygromycin B.

[0362] B. Cell-based functional assay of muscarinic acetylcholine receptor activity A high-throughput assay was employed to measure the receptor-induced recruitment of intracellular calcium and determine the compound activity. The test compound was added to cells expressing muscarinic receptors loaded with a calcium-sensitive fluorescent dye. After an incubation period of approximately 2.5 minutes, the activity was measured below maximum (EC2). 20 Acetylcholine at a concentration of ) was added, and the response was measured. This reaction rate assay allows for simultaneous screening and efficacy determination of multiple pharmacological action modes, including agonist and potentiator activity. CHO-K1 cells that stably express muscarinic receptors were seeded at 15,000 cells / 20 μL / well in growth medium lacking G418 and hygromycin in Greiner Bio-One transparent-bottom plates treated with Greiner 384-well blackwall tissue culture (TC). The cells were incubated overnight at 37°C and 5% CO2. The following day, a calcium assay buffer (Hanks equilibrium salt solution (HBSS), 20 mM HEPES, 2.5 mM probenecid, 4.16 mM sodium bicarbonate (Sigma-Aldrich, St. Louis, MO)) was prepared, and the compound, agonist, and fluo-4-acetomethoxyester (fluo-4-AM) and fluorescent calcium indicator dye were diluted. The compound was continuously diluted (1:3) in a 10-point concentration response curve in DMSO using a Bravo liquid handler (Agilent, Santa Clara, CA), transferred to a 384-well daughter plate using an Echo acoustic liquid handler (Beckman Coulter, Indianapolis, Indiana), and diluted to the 2X final concentration in the assay buffer. The agonist plate was diluted to the 5X final concentration in the assay buffer, and the EC2 was determined. 20 and EC MAXThe acetylcholine (ACh, Sigma-Aldrich, St. Louis, MO) concentration related to the response was used for preparation. A 2X dye solution (2.3 μM) was prepared by mixing 2.3 mM Fluo-4-AM stock in DMSO with 10% (w / v) pluronic acid F-127 in a 1:1 ratio in assay buffer. The cells were washed three times with assay buffer using a microplate washer (BioTek, Winooski, VT) to remove the culture medium. After the final wash, 20 μL of assay buffer remained in the cell plate. Immediately, 20 μL of 2X dye solution (final 1.15 μM) was added to each well of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA). The cells were incubated with the dye solution at 37°C in the presence of 5% CO2 for 45 minutes. After that, the dye solution was removed and replaced with assay buffer using a microplate washer, leaving 20 μL of assay buffer in the cell plate.

[0363] The prepared compounds, agonists, and cell plates were placed in a Functional Drug Screening System uCell (FDSS uCell, Hamamatsu, Japan) and the calcium flux was measured. Ca kinetics were measured using a triple dosing protocol; compounds, EC 20 ACh and EC 80 The following ACh compounds were added in sequence. Briefly, after a 2-second fluorescence baseline was established (excitation at 480 nm; emission at 530 nm), the first addition was performed by adding 20 μL of the test compound to the cells, and the response was measured for 140 seconds. Subsequently, the second addition was performed; 10 μL (5X) of EC 20 A concentration of ACh agonist was added to the cells, and the cellular response was measured for 125 seconds. Immediately afterward, 12 μl (5X) of EC was added. 80 A third addition was performed by adding ACh at a specific concentration, and the cellular response was measured for 90 seconds. Acetylcholine-mediated maximal response (EC) max The EC50 was measured by adding 1 mM ACh as a third additive in the control well. 20 , EC80 and ECmax To evaluate the response, a DMSO vehicle was added to the control well during the first addition. Calcium fluorescence was recorded as a multiple of the base fluorescence, and the raw data was normalized to the maximum response to the ACh agonist. Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon addition of the compound. Positive allosteric modulator activity was measured using EC. 20 Antagonist activity was analyzed as a concentration-dependent increase in the acetylcholine response. 80 The acetylcholine response was analyzed as a concentration-dependent decrease. Concentration-response curves were generated using a four-coefficient logistic equation with GraphPad Prism (La Jolla, CA) or Dotmatics software platform (Woburn, MA).

[0364] The above assay was also performed in a second mode, where, after establishing a fluorescence baseline for approximately 3 seconds, the compound of the present invention at an appropriate fixed concentration was added to the cells, and the response in the cells was measured. After 140 seconds, an appropriate concentration of agonist was added, and the calcium response (maximum-local minimum response) was measured. EC of the agonist in the presence of the test compound. 50 The values ​​were determined by nonlinear curve fitting. The EC of the agonist increased with increasing concentration of the compound of the present invention. 50 A decrease in the value (a leftward shift in the agonist concentration-response curve) is an indicator of the degree of muscarinic positive allosteric regulation at a given concentration of the compound of the present invention. The EC of the agonist increases with increasing concentration of the compound of the present invention. 50 An increase in the value (a rightward shift in the agonist concentration response curve) is an indicator of the degree of muscarinic antagonism at a given concentration of the compound of the present invention. The second mode also indicates whether the compound of the present invention affects the maximal response of the muscarinic receptor to the agonist.

[0365] Compound activity in C.mAChR M4 cell-based assay The compound was synthesized as described above. Activity (EC 50 and E maxThe compound numbers were measured using the M4 cell-based functional assay as described above. The data are shown in Table 3. The compound numbers correspond to the compound numbers used in Table 2.

[0366] [Table 9]

[0367] [Table 10]

[0368] Functional assessment of M4 activator compounds in D cell cAMP assays. cellular cAMP G i HTRF assay Activation of the M4 receptor is G i / o This results in inhibition of cAMP production through coupling with proteins. To measure the level of cAMP inhibition by M4 allosteric modulators, a homogeneous time-resolved fluorescence (HTRF®) cAMP assay was used with CHO cells stably expressing human or rat M4 receptors. The HTRF cAMP assay is a time-resolved resonance energy transfer (TR-FRET) competitive immunoassay. Endogenous intracellular cAMP produced by cells competes with europium cryptotate-labeled cAMP (europium donor, emission 665 nm) for binding to cAMP antibodies labeled with d2 (d2 receptor, emission 620 nm). Therefore, the fluorescence emission ratio (665 nm / 620 nm) is inversely proportional to the amount of cAMP in the cell. Compound-mediated M4 activation results in an increase in the HTRF ratio (665 nm / 620 nm), indicating a decrease in intracellular cAMP levels. To monitor agonist activity, submaximal intracellular cAMP levels were induced in EC 80 The compound was added to M4 cells in the presence of forskolin (adenylyl cyclase activator) at a specific concentration. To evaluate the potentia activity, the compound was subjected to EC (European Cycle). 20 In the presence of acetylcholine at a certain concentration, EC 80 It was added to M4 cells along with forskolin at a concentration. This functional assay showed that Gi / o This makes it possible to determine the efficacy and effectiveness of compounds that directly activate or increase the binding M4 receptor.

[0369] The functional agonist and potenciator activity of the compound is HTRF cAMP G i / o cAMP levels were determined by measuring the levels of Chinese hamster ovary cells (CHO) that stably express human or rat M4 muscarinic receptors using a kit. Cells were maintained in F12 medium containing 10% FBS, 20 mM HEPES, 1X Antibiotic / Antimycotic, and G418 (500 μg / ml) in the presence of 5% CO2 in a humidified incubator at 37°C. The day before the assay, the cells were trypsinized and resuspended in seeding medium (growth medium without G418). Cells were seeded in white solid flat-bottom 384-well plates at densities of 4,000 and 6,000 human and rat M4 cells / 10 μL / well, respectively. The cell plates were spun at 100 × g for 1 minute, and immediately thereafter in an incubator at 37°C in the presence of 5% CO2 overnight.

[0370] The following day, the reagents were freshly diluted to a 2-fold concentration in the assay buffer using F12 basal medium or stimulant buffer. All assay buffers contained 500 μM IBMX to inhibit cAMP degradation. Activation of M4 by the compound induces submaximal intracellular cAMP levels due to forskolin EC14. 80 The test was performed on cells stimulated by concentration. Forskolin EC 80 The concentration was determined from the forskolin concentration response curve (CRC) and was in the range of 1.5 to 2.5 μM. The compound (10 mM) was prepared in 100% DMSO and further serially diluted in DMSO at 13 points of CRC in a 384-well microplate using a Bravo Liquid Handler to either a 1:3 or 1:5 ratio.

[0371] The ability of M4 compounds to directly activate the M4 receptor in the absence of the agonist, acetylcholine, was evaluated using the agonist assay mode. Ten serial dilutions of the compound, starting at a final concentration of 30 μM, were transferred to compound plates using the Echo plate reformatting protocol. 80 A 2X assay buffer containing a specific concentration of forskolin was added to the compound plate. The vehicle (1% DMSO) was added to the following control wells: baseline cAMP (without forskolin), forskolin max, and forskolin EC. 80 10 μl / well of the prepared 2X assay buffer was immediately added to the cell plate using a Bravo 384-well tip liquid handler. The cell plate was immediately spun at 100 × g for 30 seconds and incubated at 37°C for 10 minutes with gentle shaking at 50 rpm. Acetylcholine CRC was also measured to its maximum (EC) to prepare for the subsequent potentia-mode assay. max ) and maximum lower (EC 20 )In order to determine the concentration of acetylcholine that induces cAMP inhibition, EC 80 The procedure was performed in the presence of a concentration of forskolin.

[0372] In potenciator assay mode, 10 serially diluted compounds, starting at a final concentration of 1.1 μM, were transferred to compound plates using the Echo plate reformatting protocol. 80 Forskolin and EC concentrations 20 A 2X assay buffer containing a concentration of acetylcholine was added to the compound plate. The following vehicles (1% DMSO) were added: (1) For forskolin control wells - baseline cAMP (without forskolin), forskolin max, and forskolin EC 80 (2) Forskolin EC 80 A base (without agonist) containing acetylcholine EC 20 and EC max10 μl / well of the prepared 2X assay buffer was immediately added to the cell plate using a Bravo 384-well tip liquid handler. The cell plate was immediately spun at 100 × g for 30 seconds and incubated at 37°C for 10 minutes with gentle shaking at 50 rpm. During the 10-minute incubation period, cAMP Eu-cryptate donor (20X) and anti-cAMP d2 antibody receptor (20X) were diluted in lysis / detection buffer in separate tubes. Immediately after incubation, cells were lysed by sequentially adding 10 μl / well of cAMP Eu-cryptate solution and 10 μl / well of anti-cAMP d2 antibody solution. Immediately afterward, the cell plate was spun at 100 × g for 30 seconds and incubated at 25°C for 60 minutes with gentle shaking at 50 rpm. Immediately after detection incubation, TR-FRET signals were measured in two channels, 665 and 620 nm, using an EnVision plate reader (Perkin Elmer). All emission ratios (665 / 620) were normalized to %acetylcholine max. Individual CRCs were generated using a 4-coefficient logistic equation with GraphPad Prism (La Jolla, CA), and the EC was adjusted from the fitted values. 50 The values ​​were extracted, and the maximum response (%ACh Max) was determined.

number

[0373] [Table 11]

[0374] E. In vitro secondary pharmacology Compound 2 was tested using Eurofins LeadProfilingScreen®, which detects potential off-target activity and determines relative selectivity. The screening included 68 primary molecular targets, including several CNS targets recommended by EMEA (European Medicines Evaluation Agency) for assessing the potential for drug dependence. Compound 70 showed <50% inhibition for each target at 10 μM (bound) on LeadProfilingScreen®, with the exception of human muscarinic compound 2 (58% inhibition at 10 μM).

[0375] F. In vitro and in vivo drug metabolism and pharmacokinetics Compound 2 was tested in several in vitro assays to investigate both its metabolism and pharmacokinetics. These assays can be performed according to known methods generally described in the following literature: Conde-Ceide et al. ACS Med.Chem.Lett. 2015, 6, 716-720; Morris et al. J.Med.Chem. 2014, 57, 10192-10197; and Bubser et al. ACS Chem.Neurosci. 2014, 5, 920-942. The in vitro assays include those listed in the table below.

[0376] [Table 12]

[0377] Compound 2 was tested in several in vivo assays, and the pharmacokinetic parameters listed in the table below can be determined from rat or dog pharmacokinetic studies according to known methods generally described in the following literature: Garrison et al. J.Med.Chem. 2022, 65, 6273-6286; Felts et al. J.Med.Chem 2017, 60, 5072-5085; and Yu et al. J.Med.Chem. 2021, 64, 4709-4729.

[0378] [Table 13]

[0379] The above detailed description and attached examples are for illustrative purposes only and should not be considered as limitations to the scope of the invention as defined solely by the attached claims and their equivalents.

[0380] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those relating to chemical structure, substituents, derivatives, intermediates, synthesis, composition, formulation, or method of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula: X １ NR ５ , O or CR ５Ａ R ５Ｂ And; R ２ is G ２ , -NR ２ａ R ２ｂ , halogen, cyano, C １～６ alkyl, C １～６ haloalkyl, -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 These are, independently, hydrogen and C １～６ Alkyl, C １～６ Haloalkyl, G ２ or -C １～３ Alkilen-G ２ And; G ２ Each instance is independently a 3- to 7-membered carbocyclyl, a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms, a phenyl, or a 4- to 7-membered heterocyclyl containing 1 to 2 heteroatoms, where the heteroatoms are independently selected from the group consisting of O, N, and S, and G ２ These are halogen, cyano, and 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 Alkilen-G ２ａ They may be arbitrarily substituted with 1 to 5 substituents independently selected from the group consisting of; R ｘ Each time they appear, hydrogen and C appear independently. １～４ Alkyl, C １～４ Fluoroalkyl, C ３～６ Cycloalkyl or -C １～３ Alkylene-C ３～６ It is cycloalkyl; G ２ａ is C ３～６ It is cycloalkyl; R ４Ａ and R ４Ｂ These are, independently, hydrogen and C １～４ Alkyl, C ３～４ Cycloalkyl or -C １～３ It is alkylene-OH; or R ４Ａ and R ４Ｂ These, along with the carbon to which they are bonded, are C ３～６ Forms a cycloalkyl group; R ５ is hydrogen, C １～６ Alkyl, C １～６ Fluoroalkyl, -C １～６ Alkilen-R ｙ , -C １～６ Fluoroalkylene-R ｙ G ５ or -C １～３ Alkilen-G ５ And; R ５Ａ and R ５Ｂ These are independently hydrogen, halogen, and C １～４ Alkyl, C １～４ Fluoroalkyl or -C １～４ It is 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 And; R ５ａ Each time they appear, hydrogen and C appear independently. １～４ Alkyl, C １～４ Fluoroalkyl, C ３～４ Cycloalkyl or -C １～３ Alkylene-C ３～４ It is cycloalkyl; G ５ is phenyl, a 4- to 8-membered heterocyclyl containing 1 to 2 heteroatoms, a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms or C ３～６ cycloalkyl, wherein the heteroatom is independently selected from the group consisting of O, N and S, and G ５ is optionally substituted with 1 to 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 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 they appear, hydrogen and C appear independently. １～４ Alkyl, C １～４ Fluoroalkyl, C ３～４ Cycloalkyl or -C １～３ Alkylene-C ３～４ It is cycloalkyl; Alternatively, two R's ６ａ These, along with the nitrogen to which they are bonded, R ６ａ The nitrogen bonded to the carbon atom optionally contains one additional heteroatom which is O, N, or S, forming a 4- to 8-membered heterocycle, wherein the heterocycle contains a halogen, C １～２ Alkyl and C １～２ It may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl groups; R ７ C １～４ Alkyl, hydrogen, halogen, cyano, C １～４ Fluoroalkyl, C ２～４ Alkenil, -OR ７ａ , -C １～３ Alkylene-OR ７ａ CO ２ R ７ａ COR ７ａ or C ３～６ It is cycloalkyl; R ７ａ is hydrogen, C １～４ Alkyl, C １～４ Fluoroalkyl, C ３～４ Cycloalkyl or -C １～３ Alkylene-C ３～４ It is cycloalkyl; R ８ Each time it appears, halogen, C １～４ Alkyl, C １～４ Fluoroalkyl or C ３～４ It is cycloalkyl; and n is 0, 1, 2, 3, or 4; Here, R ｘ G ２ａ , R ６ , R ６ａ , R ７ , R ７ａ and R ８ Each cycloalkyl group in is independently either unsubstituted or C １～４ (The substituents are substituted with 1 to 4 substituents independently selected from alkyl and halogen compounds.)

2. R ２ G ２ , -NR ２ａ R ２ｂ , halogen, cyano, C １～６ Alkyl, C １～６ Haloalkyl, -OR ２ａ , -C(O)OR ２ａ , -C(O)NR ２ａ R ２ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

3. R ２ is G ２ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

4. G ２ The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein is a 3- to 7-membered carbocyclyl which may be optionally substituted.

5. G ２ The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein is an optionally substituted five- to six-membered heteroaryl.

6. G ２ teeth 【Chemistry 2】 The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. R ２ Ha-NR ２ａ R ２ｂ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

8. R ２ is C １～６ The compound according to claim 2, or a pharmaceutically acceptable salt thereof, which is alkyl.

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

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

11. R ２ ha-C(O)OR ２ａ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

12. R ２ Ha-C(O)NR ２ａ R ２ｂ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

13. R ２ａ is hydrogen or C １～６ A compound according to any one of claims 1, 2, 7, or 11 to 12, which is alkyl, or a pharmaceutically acceptable salt thereof.

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

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

16. X １ NR ５ The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. R ５ is hydrogen, C １～６ Alkyl, G ５ or -C １～３ Alkilen-G ５ The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

18. X １ A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is O.

19. X １ CR ５Ａ R ５Ｂ The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

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

21. R ７ C １～４ Alkyl, halogen, cyano, or C ３～６ A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

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

23. 2-(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-methyl-2-(2-(thiophen-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; Ethyl 5-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate; 3-methyl-2-(2-methyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-methyl-2-(2-(1-methyl-1H-pyrazole-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-chloro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(tert-butyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3,6-dimethyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopropyl-2-(2-Cyclopropyl-6,7-Dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopropyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopentyl-2-(2-Cyclopropyl-6,7-Dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopentyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopropyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopentyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methylflox[3,4-b]pyridine-5(7H)-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)flo[3,4-b]pyridine-5(7H)-one; 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 3-Cyclopropyl-2-(2-Cyclopropyl-6,7-Dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonitrile; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-3-(prop-1-en-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; Methyl 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate; 5-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

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

25. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for use in the treatment of neurological and / or psychiatric disorders selected from Alzheimer's disease, schizophrenia, sleep disorders, pain disorders and cognitive impairments.

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