1,6-naphthiridine derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor M4, useful in the treatment of neurological and psychiatric disorders.

Abstract

5,6,7,8-tetrahydro-1,6-naphthiridine, in which the 6-position is substituted with 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5(7H)-one, 6,7-dihydro-5H-cyclopenta[b]pyridine-5-one, or [1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one, and their derivatives are positive allosteric modulators 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] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 496,811, filed on 18 April 2023, and to U.S. Provisional Patent Application No. 63 / 610,209, filed on 14 December 2023, each of which is incorporated herein by reference in its entirety.

[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). Symptoms associated with cognitive impairment, such as those in Alzheimer's disease, are accompanied by a decrease in acetylcholine levels in the brain. This is thought to be a result of degeneration of cholinergic neurons in the basal forebrain, which broadly innervate multiple brain regions, including the association cortex and hippocampus, which are critically involved in higher-order processes. Clinical data support the idea that cholinergic dysfunction contributes to cognitive deficits in patients with schizophrenia. Efforts 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, are approved in the United States for the palliative treatment (not disease-modifying treatment) of cognitive deficits in patients with AD.

[0004] Attempts to enhance central cholinergic function through the administration of choline or phosphatidylcholine have been unsuccessful. While AChE inhibitors have shown therapeutic efficacy, they have been found to have frequent cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, and diarrhea. These gastrointestinal side effects are observed in approximately one-third of treated patients. Furthermore, some AChE inhibitors, such as tacrine, have been found to cause significant hepatotoxicity, with elevated hepatic transaminases observed in approximately 30% of patients. The adverse effects of AChE inhibitors severely limit their clinical utility. An alternative pharmacological approach 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 called M1-M5. The M1, M3, and M5 subtypes are primarily G q It binds to and activates phospholipase C, but the M2 and M4 subtypes mainly use G i / o They also bind to associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system, where they are widely found and expressed differently. M1-M5 have various roles in cognitive, sensory, motor, and autonomic functions. Therefore, while we do not wish to be bound by any particular theory, selective agonists of mAChR subtypes that control processes involved in cognitive function are thought to be potentially excellent therapeutic agents for psychosis, schizophrenia, and related disorders. The muscarinic M4 receptor has been shown to play an important role in cognitive processes and is thought to play a crucial role in the pathophysiology of mental 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, impaired GI, excessive salivation, and sweating. In contrast, M4 has been considered the most likely subtype to mediate the effects of muscarinic acetylcholine receptor dysfunction in psychiatric disorders, including schizophrenia, cognitive impairment, and neuropathic pain. Therefore, considerable effort has been dedicated to developing selective M4 agonists for the treatment of these disorders. Unfortunately, most of these efforts have been unsuccessful, as it has been impossible to develop compounds highly selective for mAChR M4. Consequently, mAChR agonists tested in clinical studies induce a wide range of adverse effects through the activation of 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 for mAChR M4 and other individual mAChR subtypes.

[0007] Previous attempts to develop highly selective agonists for individual mAChR subtypes have failed due to the high conservation of the orthosteric ACh binding site. To circumvent the problems associated with targeting highly conserved orthosteric ACh binding sites, it is considered important to develop compounds that act at the allosteric site of mAChRs, which is removed from the orthosteric site and is not highly conserved. This approach has proven highly effective in developing selective ligands for multiple GPCR subtypes. In the case of mAChRs, the primary goal was to develop allosteric ligands that selectively enhance the activity of mAChR M4 or other mAChR subtypes. Allosteric activators include allosteric agonists that act at sites distant from the orthosteric site to directly activate the receptor in the absence of ACh, and 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 enhancer and allosteric agonist activity.

[0008] More recently, muscarinic agonists, including xanomeline, have been shown to exhibit activity in animal models with a similar profile to known antipsychotics, but without causing catalepsy (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, while xanomerin has been shown to alleviate psychotic behavioral symptoms such as delusions, paranoia, vocal outbursts, and hallucinations in patients with Alzheimer's disease (Bodick et al., Arch. Neurol. 1997, 54, 465), the clinical utility of this compound is severely limited by treatment-induced side effects, such as gastrointestinal effects.

[0009] Although research on muscarinic acetylcholine receptors has advanced, there is still a shortage of compounds that are potent and effective selective activators of M4 mAChR and are effective in the treatment of neurological and psychiatric disorders related to cholinergic activity and diseases involving the muscarinic M4 receptor.

Summary of the Invention

[0010] In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is disclosed

Chemical formula

Chemical formula

[0011] In another embodiment, 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 the compound described in formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0013] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

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

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

[0016] Detailed explanation This specification discloses positive allosteric modulators (i.e., enhancers) of muscarinic acetylcholine receptor M4 (mAChR M4), methods for producing the same, pharmaceutical compositions containing the same, and methods for using the same to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. 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 mentioned earlier, 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. Muscarinic acetylcholine receptors have their N-terminus facing the extracellular side of the membrane and their C-terminus located in the cytoplasm.

[0018] Previous attempts to develop highly selective agonists 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 considered important to develop compounds that act at the allosteric site of mAChR, which is removed from the orthosteric site and is not highly conserved. While we do not wish to be bound by any particular theory, the compounds disclosed and the products of the disclosed methods are expected to bind to an allosteric site different from the orthosteric binding site.

[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 thEdition, 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] As used herein, the term "alkoxy" refers to an alkyl group as defined herein, which is attached 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, for example, from a straight-chain or branched saturated hydrocarbon consisting of 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 part of the molecule to which the substituent is attached, that is, the remaining part of the molecule.

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

[0056] The term "substituent" refers to a group that is "substituted" at any atom of the group, such as an alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, cycloalkyl group, heteroalkyl group, 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 non-hydrogen substituents. 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, the group is optionally substituted. In some embodiments, the group is optionally substituted with one, two, three, four, or five substituents. In some embodiments, the aryl, heteroaryl, cycloalkyl, or heterocycle is 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] As used herein, the term "allosteric site" refers to a ligand-binding site that is tissue-distributed differently from an orthosteric binding site.

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

[0061] As used herein, the term "ligand" refers to a natural or synthetic molecular entity 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" encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates, and analogues of natural substrates.

[0062] The terms “natural ligand” and “endogenous ligand” are used interchangeably as herein and refer to naturally occurring ligands that bind to receptors.

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

[0064] The term “mAChR M4 receptor positive allosteric modulator” as used herein refers to an 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 another agonist. For example, an mAChR M4 receptor positive allosteric modulator can enhance the activity of the intracellular mAChR M4 receptor in the presence of extracellular acetylcholine. The cells may be Chinese hamster ovary (CHO-K1) cells transfected with human mAChR M4. The cells may be Chinese hamster ovary (CHO-K1) cells transfected with rat mAChR M4 receptor. The cells may be Chinese hamster ovary (CHO-K1) cells transfected with mammalian mAChR M4. The term "mAChR M4 receptor positive allosteric modulator" includes compounds that are either "mAChR M4 receptor allosteric enhancers" or "mAChR M4 receptor allosteric agonists," as well as compounds with mixed activity that includes the pharmacological effects of both "mAChR M4 receptor allosteric enhancers" and "mAChR M4 receptor allosteric agonists." The term "mAChR M4 receptor positive allosteric modulator" also includes compounds that are "mAChR M4 receptor allosteric enhancers."

[0065] The term “mAChR M4 receptor allosteric enhancer” as used herein refers to an exogenously administered compound or agent that directly or indirectly enhances the response mediated by an endogenous ligand (such as acetylcholine) when the endogenous ligand binds to the orthosteric site of the mAChR M4 receptor in animals, particularly mammals, such as humans. mAChR M4 receptor allosteric enhancers 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, allosteric enhancers do not induce receptor desensitization, and the activity of a compound as an mAChR M4 receptor allosteric enhancer offers advantages over the use of a pure mAChR M4 receptor orthosteric agonist. Such advantages may include, for example, increased safety margins, improved tolerability, reduced potential for abuse, and reduced toxicity.

[0066] The term "mAChR M4 receptor allosteric enhancer," as used herein, refers to an 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 potency of the agonist. 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 the agonist or endogenous ligand. The allosteric enhancer does not affect the receptor by itself 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 an 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," as used herein, refers to an 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 may block the action of other allosteric modulators acting via 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: AcOH is acetic acid; AQ is water-based; ATM stands for atmospheric pressure; BINAP is 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl; Boc is a tert-butoxycarbonyl; Boc2O is a di-tert-butyl dicarbonate; B2pin2 is bis(pinacorato)diborone; 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; Bu is butyl; t-BuOH is tert-butanol; CDI is 1,1'-carbonyldiimidazole; CD2O is deuterated formaldehyde; Celite® is diatomaceous earth; CSA is (1S,4R)-10-camphor sulfonic acid; DCE is 1,2-dichloroethane; DCM is dichloromethane; DEA is diethylamine; DMAP is 4-dimethylaminopyridine; DMF is N,N-dimethylformamide; DMP, or Des Martin periodinane, is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-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% diphenyl oxide; DtBAD is di-tert-butyl azodicarboxylate; eq or eq. is equivalent;  is ethyl acetate; (4,4'-dtbbpy)NiCl2 is 4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride; Et2O is diethyl ether; EtOH is ethanol; h or hr is time; Hex is hexane; HMPA is hexamethylphosphoramide; IPA is isopropyl alcohol; KOAc is potassium acetate; LAH is lithium aluminum hydride; LDA is lithium diisopropylamide; LiHMDS / LHMDS is lithium bis(trimethylsilyl)amide; mCPBA is metachloroperbenzoic acid; MeCN or ACN is acetonitrile; MeI is iodomethane / methyl iodide; MeOD is CD3OD (methanol-d4); MeOH is methanol; min is minutes; NaOAc is sodium acetate; NaOtBu is sodium tert-butoxide; NaOMe is sodium methoxide; NBS is N-bromosuccinimide; NCS is N-chlorosuccinimide; NH4OAc is ammonium acetate; NMO is 4-methylmorpholine N-oxide; NMP is N-methyl-2-pyrrolidone; [Pd(allyl)(tBuBrettPhos)]OTf is trifluoromethanesulfonate allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II); Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II); Pd(OAc)2 is palladium(II) acetate; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0); PPA is polyphosphate; PPh3 is triphenylphosphine; PPTS is pyridinium p-toluenesulfonate; rt is room temperature; sat. is saturated; sec is a second; SCX cartridges or HF SCX cartridges are strong cation exchange cartridges (e.g., Agilent part number 14256027); SFC is supercritical fluid chromatography; TBAC or TBACl is tetrabutylammonium chloride; t-BuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; t-BuXPhos-Pd-G1 is [2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride; TCICA is trichloroisocyanuric acid; TEA or Et3N is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TMB is trimethylboroxine; TosCl is p-toluenesulfonyl chloride; Tosyl is p-toluenesulfonyl; Xantphos is 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0071] 2.Compound In one embodiment, the present invention provides a compound of formula (I), where R 1 , R 2 , R 3 , R 8 , G 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 and heteroaromatic ring 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 all ring atoms in the heterocyclic and heteroaromatic ring system that are not one of the certain heteroatoms are carbon atoms.

[0074] The following numbered embodiments of the present invention are disclosed. The first embodiment is shown as E1, and subsequent embodiments are shown as E1.1, E1.2, E2, E2.1, E3, E4, E4.1, E4.2, E4.3, E4.4, E4.5, E4.6, E4.7, E5, E5.1, and so on.

[0075] E1. Compounds of formula (I), or pharmaceutically acceptable salts thereof. [ka] (In the formula: G 1 teeth, [ka] And, X 1 , NR 5 , O, or CR 5A R 5B and; X 2 CR 6 or N; R 1 and R 3 These are, independently, hydrogen, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Fluoroalkyl, -OC 1-4 Alkyl, or -OC 1-4 It is a fluoroalkyl group; R 2 G 2 , -NR b R c , C 1-6 Haloalkyl, halogen, cyano, NO2, C 1-6 Alkyl, C 2-6 Alkenil, -OR b , -NR c C(O)R b , -NR c SO2R a -N=S(O)(R a )2, -P(O)(R a )2, -C 1-3 Alkilen-G 2 , -C2-4 Alkenirene-G 2 , or hydrogen; R a Each time it appears, C 1-6 Alkyl, C 1-6 Haloalkyl, G 2 , or -C 1-3 Alkilen-G 2 and; Here, by choice, -N=S(O)(R a )2 or -P(O)(R a )2 of 2 a They bond as straight alkylene chains, forming 5-7 membered heterocycles; R b and R c 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 5-12 member heteroaryl, a 6-12 member aryl, a 4-12 member heterocyclyl, or a 3-12 member carbocyclyl, where each heteroaryl and heterocyclyl contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and G 2 These are halogen, cyano, and C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, -OR x , -N(R x )2, -SR x , -SO2R x , -C(O)R x , -C(O)OR x ,-C(O)N(R x )2, -C 1-6 Alkilen-OR x , -C 1-6 Alkylene-N(R) x )2, G 2a , and -C 1-3 Alkilen-G 2a It is optionally substituted with a first substituent selected from the group consisting of halogens, cyanos, and C 1-6 Alkyl, C1-6 Haloalkyl and -OR x They are further optionally substituted with 1 to 4 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 Haloalkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, phenyl, or -C 1-3 Alkylene-phenyl, where each cycloalkyl or phenyl is a halogen, C 1-4 Alkyl and C 1-4 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl groups; G 2a This is a phenyl, a 5-6 member heteroaryl containing 1-3 heteroatoms, a 4-8 member heterocyclyl containing 1-2 heteroatoms, or a 3-8 member carbocyclyl, where the heteroatoms are independently selected from the group consisting of O, N, and S, and G 2a Each time it appears, it is independently a halogen, cyano, and C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-6 Alkylene-OH, oxo-OH, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, C 3-4 Cycloalkyl, and -C 1-3 Alkylene-C 3-4 It is optionally substituted with 1 to 5 substituents independently selected from the group consisting of cycloalkyl groups; 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; 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 These are, independently, hydrogen, halogen, and C 1-4 Alkyl, C 1-4 Alkyl, 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, G 5 , or -C 1-3 Alkilen-G 5 and; G 5 This includes phenyl, a 5-6 membered heteroaryl containing 1-3 heteroatoms, a 4-8 membered heterocyclyl containing 1-2 heteroatoms, or C 3-8 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 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, OH, and oxo; Alternatively, R 4A and R 4B C 3-6 Forms a cycloalkyl group; or R 4B and R 5 Together with the atoms to which they are attached, they form a 5- to 7-membered heterocycle that optionally contains one additional heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; R 6Hydrogen, halogen, cyano, 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 3-6 It is a 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 a cycloalkyl; Alternatively, two R's 6a Along with the nitrogen to which they are attached, R 6a It forms a 4-8 membered heterocycle containing nitrogen attached to it and 1-2 additional heteroatoms which are optionally and independently O, N, or S, and the heterocycle is a halogen, C 1-2 Alkyl and C 1-2 It is 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, -OR 7a , -C 1-3 Alkilen-OR 7a , or G 7 and; Alternatively, R 6 and R 7 Together with the atoms to which they are attached, they form a 5-7 membered heterocycle or 5-7 membered carbon ring containing one heteroatom, where the heteroatom is independently selected from the group consisting of N, O, and S, and the heterocycle and carbon ring are C 1-4 Alkyl, halogen, -OC 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, and C 1-2 Alkylene-C 3-4It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl groups; 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 a cycloalkyl; G 7 This includes phenyl, a 5-6 membered heteroaryl containing 1-3 heteroatoms, a 4-8 membered heterocyclyl containing 1-2 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 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, OH, and oxo; R 8 Each time it appears, halogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, or C 3-4 It is a cycloalkyl; and n is 0, 1, 2, 3, or 4. Here, R 6 , R 6a , R 7 , R 7a , and R 8 Each cycloalkyl group in is either unsubstituted or C 1-4 (Substituted with 1 to 4 substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., fluoro) elements).

[0076] E1.1.R 2 G 2 , -NR b R c , C 1-6 Haloalkyl, halogen, cyano, NO2, C 1-6 Alkyl, -OR b , -NRc C(O)R b , -NR c SO2R a -N=S(O)(R a )2, -P(O)(R a )2, -C 1-3 Alkilen-G 2 , or hydrogen; G 2 Each instance is independently a 5-12 member heteroaryl, a 6-12 member aryl, a 4-12 member heterocyclyl, or a 3-12 member carbocyclyl, where each heteroaryl and heterocyclyl contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and G 2 These are halogen, cyano, and C 1-6 Alkyl, C 1-6 Haloalkyl, 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 It is optionally substituted with a first substituent selected from the group consisting of halogens, cyanos, and C 1-6 Alkyl, C 1-6 Haloalkyl and -OR x They are further optionally substituted with 1 to 4 substituents independently selected from the group consisting of; R 5 is hydrogen, C 1-6 Alkyl, C 1-6 Fluoroalkyl, -C 1-6 Alkilen-R y , G 5 , or -C 1-3 Alkilen-G 5 and; R 5a Each time they appear, hydrogen and C appear independently. 1-4 Alkyl, C 1-4Fluoroalkyl, C 3-4 Cycloalkyl, or -C 1-3 Alkylene-C 3-4 It is a cycloalkyl; G 5 This includes phenyl, a 5-6 membered heteroaryl containing 1-3 heteroatoms, a 4-8 membered heterocyclyl containing 1-2 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 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, OH, and oxo; R 6 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -OR 6a , -N(R 6a )2, -C 1-3 Alkilen-OR 6a , or C 3-6 It is a cycloalkyl; R 7 C 1-4 Alkyl, hydrogen, halogen, cyano, C 1-4 Fluoroalkyl, -OR 7a , -C 1-3 Alkilen-OR 7a , or C 3-6 It is a cycloalkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

[0077] E1.2. Compounds of formula (I-A) [ka] And, n is 0, 1, or 2. Compounds listed in E1 or E1.1, or pharmaceutically acceptable salts thereof.

[0078] E2.R1 However, hydrogen or C 1-4 A compound that is alkyl, as described in E1, E1.1, or E1.2, or a pharmaceutically acceptable salt thereof.

[0079] E2.1.R 1 However, the compounds listed in E2, or pharmaceutically acceptable salts thereof, are hydrogen.

[0080] E3.R 3 However, hydrogen is a compound listed in any of E1 to E2.1, or a pharmaceutically acceptable salt thereof.

[0081] E4.R 2 However, G 2 , -NR b Rc, C 1-6 Haloalkyl, C 2-6 Alkenyl, cyano, hydrogen, or -C 2-4 Alkenirene-G 2 The compound described in any of E1 to E3, or a pharmaceutically acceptable salt thereof.

[0082] E4.1.R 2 However, G 2 , -NR b R c , or C 1-6 A compound described in E4 that is a haloalkyl, or a pharmaceutically acceptable salt thereof.

[0083] E4.2.R 2 However, the compounds listed in E4, or pharmaceutically acceptable salts thereof, are hydrogen.

[0084] E4.3.R 2 However, the compounds listed in E4, or pharmaceutically acceptable salts thereof, are cyano compounds.

[0085] E4.4.R 2 However, C 2-6 The compounds listed in E4, which are alkenyls, or pharmaceutically acceptable salts thereof.

[0086] E4.5.R 2 but, [ka] The compounds described in E4.4, or pharmaceutically acceptable salts thereof.

[0087] E4.6.R 2 However, -C 2-4 Alkenirene-G 2 The compound described in E4, or a pharmaceutically acceptable salt thereof.

[0088] E4.7.R 2 but, [ka] The compounds described in E4.6, or pharmaceutically acceptable salts thereof.

[0089] E5.R 2 However, C 1-6 A compound described in E4 or E4.1 that is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0090] E5.1.R 2 However, CF3 is the compound described in E5, or a pharmaceutically acceptable salt thereof.

[0091] E6.R 2 However, G 2 The compounds described in E4 or E4.1, or pharmaceutically acceptable salts thereof.

[0092] E7.G 2 However, the compounds described in any of E1 to E4.1, E4.6, E4.7, or E6, or pharmaceutically acceptable salts thereof, are substituted with an optional 5- to 12-membered heteroaryl.

[0093] E7.1.G 2A compound according to any of E1-E4.1, E4.6, E4.7, or E6-E7, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5-12 membered heteroaryl ring system in is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

[0094] E7.2.G 2 The compounds described in E7.1, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 5-6 member heteroaryl ring system in is pyridinyl, pyrazolyl, or isoxazolyl.

[0095] E7.3.G 2 The compounds described in E7.2, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 5-6 membered heteroaryl ring system in is pyridine-2-yl, pyridine-3-yl, pyrazole-4-yl, pyrazole-5-yl, or isoxazole-4-yl.

[0096] E7.4.G 2 but, [ka] The compound described in any of E7 to E7.3, or a pharmaceutically acceptable salt thereof.

[0097] E7.5.G 2 but, [ka] The compound described in any of E7 to E7.4, or a pharmaceutically acceptable salt thereof.

[0098] E7.6.G 2 but, [ka] The compound described in any of E7 to E7.5, or a pharmaceutically acceptable salt thereof.

[0099] E7.7.G 2 but, [ka] The compounds described in E7.4, or pharmaceutically acceptable salts thereof.

[0100] E7.8.G 2 but, [ka] The compound described in any of E7.5 to E7.7, or a pharmaceutically acceptable salt thereof.

[0101] E7.9.G 2 but, [ka] The compounds described in any of E7.6 to E7.8, or pharmaceutically acceptable salts thereof.

[0102] E7.10.G 2 A compound according to any of E1-E4.1, E4.6, E4.7, or E6-E7, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5-12 membered heteroaryl ring system in is a 9-10 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

[0103] E7.11.G 2 The compounds described in E7.10, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 9-10 membered heteroaryl ring system in is quinolinyl, isoquinolinyl, or imidazopyridinyl.

[0104] E7.12.G 2Compounds described in E7.10 or E7.11, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 9-10 member heteroaryl ring system in isoquinolinyl or imidazopyridinyl.

[0105] E7.13.G 2 The compounds described in E7.11, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 9-10 membered heteroaryl ring system in is quinoline-5-yl, isoquinoline-4-yl, isoquinoline-5-yl, or imidazo[1,2-a]pyridine-6-yl.

[0106] E7.14.G 2 The compounds described in E7.13, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 9-10 membered heteroaryl ring system in is quinoline-5-yl, isoquinoline-5-yl, or imidazo[1,2-a]pyridine-6-yl.

[0107] E7.15.G 2 Compounds described in E7.12 or E7.14, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 9-10 membered heteroaryl ring system in isoquinoline-5-yl or imidazo[1,2-a]pyridine-6-yl.

[0108] E7.16.G 2 but, [ka] The compounds described in E7.13, or pharmaceutically acceptable salts thereof.

[0109] E7.17.G 2 but, [ka] The compounds described in any of E7.14 to E7.16, or pharmaceutically acceptable salts thereof.

[0110] E7.18.G 2 but, [ka] The compounds described in any of E7.15 to E7.17, or pharmaceutically acceptable salts thereof.

[0111] E7.19.G 2 However, halogen, cyano, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -OR x , and G 2a It is optionally substituted with a first substituent selected from the group consisting of, halogen and C 1-4 Compounds described in any of E1-E4.1, E4.6, E4.7, E6-E7.3, or E7.10-E7.15, or pharmaceutically acceptable salts thereof, which are further optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl groups.

[0112] E7.20.G 2 However, halogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -OR x , and G 2a It is optionally substituted with a first substituent selected from the group consisting of, halogen and C 1-4 The compounds described in E7.19, or pharmaceutically acceptable salts thereof, further optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups.

[0113] E7.21.G 2 However, fluoro, cyano, methyl, isopropyl, CF3, CHF2, -OR x , and G 2a The compound described in E7.19, or a pharmaceutically acceptable salt thereof, optionally substituted with a first substituent selected from the group consisting of , and optionally further substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl.

[0114] E7.22.G 2 However, fluoromethyl isopropyl CF3, CHF2, -OR x , and G 2a A compound as described in E7.20 or E7.21, or a pharmaceutically acceptable salt thereof, which is optionally substituted with a first substituent selected from the group consisting of , and optionally further substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl.

[0115] E7.23.R x However, each time it appears, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -CH2-C 3-4 Compounds selected from the group consisting of cycloalkyl and -CH2-phenyl, as described in any of E1-E4.1, E4.6, E4.7, E6-E7.5, E7.10-E7.15, or E7.19-E7.22, or pharmaceutically acceptable salts thereof.

[0116] E7.24.R x However, C 1-4 A compound described in E7.23 that is alkyl, or a pharmaceutically acceptable salt thereof.

[0117] E7.25.R x However, the compounds listed in E7.24, or pharmaceutically acceptable salts thereof, are methyl.

[0118] E7.26.G 2a However, C 3-6 A cycloalkyl compound as described in any of E1-E4.1, E4.6, E4.7, E6-E7.5, E7.10-E7.15, or E7.19-E7.25, or a pharmaceutically acceptable salt thereof.

[0119] E7.27.G 2a However, the compounds described in E7.26, which are cyclopropyl or cyclobutyl, or pharmaceutically acceptable salts thereof.

[0120] E8.G 2However, the compounds described in any of E1 to E4.1, E4.6, E4.7, or E6, or pharmaceutically acceptable salts thereof, are substituted with an optional 6- to 12-membered aryl compound.

[0121] E8.1.G 2 A compound described in any of E1 to E4.1, E4.6, E4.7, E6, or E8, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 6-12 membered aryl ring system in is phenyl.

[0122] E8.2.G 2 but, [ka] The compounds described in E8.1, or pharmaceutically acceptable salts thereof.

[0123] E8.3.G 2 but, [ka] The compounds described in E8.2, or pharmaceutically acceptable salts thereof.

[0124] E8.4.G 2 but, [ka] The compounds described in E8.2, or pharmaceutically acceptable salts thereof.

[0125] E8.5.G 2 but, [ka] The compounds described in E8.3 or E8.4, or pharmaceutically acceptable salts thereof.

[0126] E8.6.G 2 However, halogen, cyano, C1-4 Alkyl, C 1-4 Fluoroalkyl, -OR x , -SR x ,-C(O)N(R x )2, and G 2a It is optionally substituted with a first substituent selected from the group consisting of, halogen and C 1-4 Compounds described in any of E1-E4.1, E4.6, E4.7, E6, or E8-E8.1, or pharmaceutically acceptable salts thereof, which are further optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl groups.

[0127] E8.7.G 2 However, halogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -OR x , and G 2a It is optionally substituted with a first substituent selected from the group consisting of, halogen and C 1-4 The compounds described in E8.6, or pharmaceutically acceptable salts thereof, are further optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl groups.

[0128] E8.8.G 2 However, fluoro, cyano, methyl, isopropyl, tert-butyl, CF3, CHF2, CF3, -OR x , -SR x ,-C(O)N(R x )2, and G 2a The compound described in E8.6, or a pharmaceutically acceptable salt thereof, is optionally substituted with a first substituent selected from the group consisting of , and further optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoro and methyl.

[0129] E8.9.G 2 However, fluoromethyl isopropyl CF3, CHF2, -OR x , and G 2aA compound described in E8.7 or E8.8, or a pharmaceutically acceptable salt thereof, which is optionally substituted with a first substituent selected from the group consisting of , and further optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoro and methyl.

[0130] E8.10.R x However, each time they appear, hydrogen and C appear independently. 1-4 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -CH2-C 3-4 Compounds selected from the group consisting of cycloalkyl and -CH2-phenyl, as described in any of E1-E4.1, E4.6, E4.7, E6-E7.6, E7.10-E7.15, E7.19-E7.22, E8-E8.3, or E8.6-E8.9, or pharmaceutically acceptable salts thereof.

[0131] E8.11.R x However, each time it appears, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -CH2-C 3-4 Compounds described in E8.10, selected from the group consisting of cycloalkyl and -CH2-phenyl, or pharmaceutically acceptable salts thereof.

[0132] E8.12.R x However, each time it appears, independently of hydrogen or C 1-4 A compound that is alkyl, as described in E8.10, or a pharmaceutically acceptable salt thereof.

[0133] E8.13.R x However, hydrogen is a compound listed in E8.12, or a pharmaceutically acceptable salt thereof.

[0134] E8.14.R x However, C 1-4 A compound described in E8.11 or E8.12 that is alkyl, or a pharmaceutically acceptable salt thereof.

[0135] E8.15.R x However, the compounds listed in E8.14, or pharmaceutically acceptable salts thereof, are methyl.

[0136] E8.16.R x However, the compounds listed in E8.11, which are -CH2-phenyl, or pharmaceutically acceptable salts thereof.

[0137] E8.17.G 2a However, C 3-4 A cycloalkyl compound as described in any of E1-E4.1, E4.6, E4.7, E6-E7.6, E7.10-E7.15, E7.19-E8.3, or E8.6-E8.16, or a pharmaceutically acceptable salt thereof.

[0138] E9.G 2 However, the compounds described in any of E1 to E4.1, E4.6, E4.7, or E6, which are 4 to 12-membered heterocyclines that are optionally substituted, or pharmaceutically acceptable salts thereof.

[0139] E9.1.G 2 A compound according to any of E1 to E4.1, E4.6, E4.7, E6, or E9, or a pharmaceutically acceptable salt thereof, wherein the ring system of a 4 to 12-membered heterocyclil that is optionally substituted in is a 4 to 6-membered heterocyclil containing 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S.

[0140] E9.2.G 2 A compound described in E9.1, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 6-membered heterocyclyl ring system contains one oxygen atom.

[0141] E9.3.G 2 The compounds described in E9.2, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 4- to 6-membered heterocyclyl ring system in is 2,5-dihydrofuranyl or oxetanyl.

[0142] E9.4.G 2The compounds described in E9.3, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 4- to 6-membered heterocyclyl ring system in is 2,5-dihydrofuran-3-yl or oxetan-3-yl.

[0143] E9.5.G 2 but, [ka] The compounds described in E9.3 or E9.4, or pharmaceutically acceptable salts thereof.

[0144] E10.G 2 However, the compounds described in any of E1-E4.1, E4.6, E4.7, or E6, which are 3- to 12-membered carbocyclyls that are optionally substituted, or pharmaceutically acceptable salts thereof.

[0145] E10.1.G 2 In C 3-6 A cycloalkyl compound as described in any of E1-E4.1, E4.6, E4.7, E6, or E10, or a pharmaceutically acceptable salt thereof.

[0146] E10.2.G 2 However, the compounds listed in E10.1, which are cyclopropyl, or pharmaceutically acceptable salts thereof.

[0147] E10.3.G 2 However, the compounds described in E10.1, which are cyclobutyl or cyclopentyl, or pharmaceutically acceptable salts thereof.

[0148] E11.G 2 but, (a) [ka] 5- to 12-member heteroaryls that are optionally substituted, selected from the group consisting of the following; or (b) [ka] A 6- to 12-membered aryl selected from the group consisting of the following, which is substituted by arbitrary choice; or (c) [ka] A 4- to 12-membered heterocycline that is optionally substituted, selected from the group consisting of the following: or (d) [ka] These are 3-12 member carbocyclils that have been optionally substituted. The compound described in any of E6 to E10.3, or a pharmaceutically acceptable salt thereof.

[0149] E11.1.G 2 but, (a) [ka] 5- to 12-member heteroaryls that are optionally substituted, selected from the group consisting of the following; or (b) [ka] A 6- to 12-membered aryl selected from the group consisting of the following, which is substituted by arbitrary choice; or (c) [ka] A 4- to 12-membered heterocycline that is optionally substituted, selected from the group consisting of the following: or (d) [ka] These are 3-12 member carbocyclils that have been optionally substituted. The compound described in E11, or a pharmaceutically acceptable salt thereof.

[0150] E11.2.G 2 but, (a)G 2 A 5-12 member heteroaryl, which is optionally substituted, is selected from the group consisting of the following: [ka] Is it; or (b) [ka] A 6-12 member aryl that is arbitrarily substituted, selected from the group consisting of the following: The compounds listed in E11.1, or pharmaceutically acceptable salts thereof.

[0151] E12. R 2 However, -NR b R c and; R b However, C 1-6 Alkyl, G 2 , or -C 1-3 Alkilen-G 2 and; R c However, hydrogen or C 1-6 It is alkyl. Compounds described in E4 or E4.1, or pharmaceutically acceptable salts thereof.

[0152] E13.R b However, G 2 The compounds described in E1 to E4.1 or E12, or pharmaceutically acceptable salts thereof.

[0153] E14.G 2 However, the compound described in either E12 or E13, or a pharmaceutically acceptable salt thereof, is a 5- to 12-membered heteroaryl substituted by optional choice.

[0154] E14.1.G 2 A compound according to any of E1 to E4.1 or E12 to E14, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5- to 12-membered heteroaryl ring system is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S.

[0155] E14.2.G 2 The compounds described in E14.1, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 5-6 member heteroaryl ring system is pyridinyl.

[0156] E14.3.G 2 The compounds described in E14.2, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 5- to 6-membered heteroaryl ring system in is pyridine-3-yl.

[0157] E14.4.G 2 The compounds described in E14.2, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 5-6 membered heteroaryl ring system in is pyridine-4-yl.

[0158] E14.5.G 2 However, halogen, C 1-4 Alkyl, C 1-2 Fluoroalkyl, -OR x , and G 2a It is optionally substituted with a first substituent selected from the group consisting of, halogen and C 1-4 Compounds described in any of E1 to E4.1 or E12 to E14.4, or pharmaceutically acceptable salts thereof, which are further optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups.

[0159] E14.6.G 2 However, fluoromethyl isopropyl CF3, CHF2, -OR x , and G 2a The compound described in E14.5, or a pharmaceutically acceptable salt thereof, is optionally substituted with a first substituent selected from the group consisting of , and further optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl.

[0160] E14.7.R x However, each time it appears, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -CH2-C 3-4 Compounds selected from the group consisting of cycloalkyl and -CH2-phenyl, as described in any of E1 to E4.1 or E12 to E14.6, or pharmaceutically acceptable salts thereof.

[0161] E14.8.R x However, C 1-4 A compound that is alkyl, as described in E14.7, or a pharmaceutically acceptable salt thereof.

[0162] E14.9.R x However, the compounds listed in E14.8, or pharmaceutically acceptable salts thereof, are methyl.

[0163] E14.10.G 2a However, C 3-4 A cycloalkyl compound as described in E1-E4.1 or E12-E14.9, or a pharmaceutically acceptable salt thereof.

[0164] E14.11.G 2 However, halogen and C 1-4 A compound described in any of E12 to E14.10, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups.

[0165] E14.12.G 2The compounds described in E14.11, or pharmaceutically acceptable salts thereof, are optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl.

[0166] E14.13.R 2 but, [ka] The compound described in any of E12 to E14.11, or a pharmaceutically acceptable salt thereof.

[0167] E14.14.R 2 but, [ka] The compounds described in E14.12 or E14.13, or pharmaceutically acceptable salts thereof.

[0168] E15.G 2 However, the compounds described in E12 or E13, or pharmaceutically acceptable salts thereof, are substituted with a 6- to 12-membered aryl compound by any choice.

[0169] E15.1. Optionally substituted 6-12 member aryl G 2 A compound described in any of E1-E4.1, E12, E13, or E15, or a pharmaceutically acceptable salt thereof, wherein the ring system is phenyl.

[0170] E15.2.G 2 However, halogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -OR x , and G 2a It is optionally substituted with a first substituent selected from the group consisting of, halogen and C 1-4Compounds described in any of E1-E4.1, E12-E13, or E15-E15.1, or pharmaceutically acceptable salts thereof, which are optionally further substituted with one or two substituents independently selected from the group consisting of alkyl groups.

[0171] E15.3.G 2 However, fluoromethyl isopropyl CF3, CHF2, -OR x , and G 2a The compound described in E15.2, or a pharmaceutically acceptable salt thereof, is optionally substituted with a first substituent selected from the group consisting of , and further optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoro and methyl.

[0172] E15.4.R x However, each time it appears, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -CH2-C 3-4 Compounds selected from the group consisting of cycloalkyl and -CH2-phenyl, as described in any of E1-E4.1, E12-E13, or E15-E15.3, or pharmaceutically acceptable salts thereof.

[0173] E15.5.R x However, C 1-4 A compound that is alkyl, as described in E15.4, or a pharmaceutically acceptable salt thereof.

[0174] E15.6.R x However, the compounds listed in E15.5, or pharmaceutically acceptable salts thereof, are methyl.

[0175] E15.7.G 2a However, C 3-4 A cycloalkyl compound as described in E1-E4.1, E12-E13, or E15-E15.6, or a pharmaceutically acceptable salt thereof.

[0176] E15.8.G 2 However, halogen and C 1-4Compounds described in any of E12-E13 or E15-E15.7, or pharmaceutically acceptable salts thereof, which are optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups.

[0177] E15.9.G 2 The compound described in E15.8, or a pharmaceutically acceptable salt thereof, is optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl.

[0178] E15.10.R 2 but, [ka] The compounds described in E15.8, or pharmaceutically acceptable salts thereof.

[0179] E15.11.R 2 but, [ka] The compounds described in any of E15.8 to E15.10, or pharmaceutically acceptable salts thereof.

[0180] E16.R c However, the compound is hydrogen, as described in E1-E4.1 or E12-E15.11, or a pharmaceutically acceptable salt thereof.

[0181] E17.R 2 but, [ka] The compound described in any of E12 to E16, or a pharmaceutically acceptable salt thereof.

[0182] E18.R 4A and R 4B However, hydrogen is a compound listed in any of E1 to E17, or a pharmaceutically acceptable salt thereof.

[0183] E18.1.R 4A and R 4B Hydrogen in deuterium ( 2 H) The compound described in E18, or a pharmaceutically acceptable salt thereof.

[0184] E19.R 5 However, hydrogen, C 1-6 Alkyl, C 1-6 Fluoroalkyl, -C 1-6 Alkilen-R y , G 5 or -C 1-3 Alkilen-G 5 The compound described in any of E1 to E18.1, or a pharmaceutically acceptable salt thereof.

[0185] E19.1.R 5 However, hydrogen, C 1-6 Alkyl, -C 1-6 Alkilen-R y , or -C 1-3 Alkilen-G 5 The compound described in E19, or a pharmaceutically acceptable salt thereof.

[0186] E19.2.R 5 However, hydrogen, methyl, CD3, -C 1-6 Alkilen-R y , G 5 , or -C 1-3 Alkilen-G 5 The compounds described in E19 or E19.1, or pharmaceutically acceptable salts thereof.

[0187] E19.3.R 5 However, hydrogen is a compound listed in any of E1 to E19.2, or a pharmaceutically acceptable salt thereof.

[0188] E19.4.R 5 However, C 1-6 A compound that is alkyl, as described in any of E1 to E19.2, or a pharmaceutically acceptable salt thereof.

[0189] E19.5.R 5 The compounds described in E19.4, or pharmaceutically acceptable salts thereof, which are methyl, ethyl, isobutyl, neopentyl, or CD3.

[0190] E19.6.R 5 However, C 1-6 A fluoroalkyl compound as described in any of E1 to E18.1, or a pharmaceutically acceptable salt thereof.

[0191] E19.7.R 5 However, the compound described in E19.6, which is 2-fluoro-2-methylpropyl, or a pharmaceutically acceptable salt thereof.

[0192] E19.8.R 5 However, -C 1-6 Alkilen-R y The compound described in any of E1 to E19.2, or a pharmaceutically acceptable salt thereof.

[0193] E19.9.R 5 However, -CH2CH2-R y or -CH(CH3)CH2-R y The compounds described in E19.8, or pharmaceutically acceptable salts thereof.

[0194] E19.10.R 5 However, G 5 The compounds listed in any of E1 to E19 or E19.2, or pharmaceutically acceptable salts thereof.

[0195] E19.11.R 5 However, -C 1-3 Alkilen-G 5 The compound described in any of E1 to E19.2, or a pharmaceutically acceptable salt thereof.

[0196] E19.12.R 5 However, -CH2-G 5 The compounds described in E19.21, or pharmaceutically acceptable salts thereof.

[0197] E19.13.R y However, -OR 5a or -C(O)OR 5a The compounds listed in E1-E19.2 or E19.8-E19.9, or pharmaceutically acceptable salts thereof.

[0198] E19.14.R 5a However, each time it appears, C 1-4 A compound that is alkyl, as described in any of E1-E19.2, E19.8-E19.9, or E19.13, or a pharmaceutically acceptable salt thereof.

[0199] E19.15.R 5a However, the compounds described in E19.14, or pharmaceutically acceptable salts thereof, are methyl or isopropyl.

[0200] E19.16.R 5a However, the compounds listed in E19.15, or pharmaceutically acceptable salts thereof, are methyl.

[0201] E19.17.R 5a However, G 5 The compounds described in E1-E19.2, E19.8-E19.9, or E19.13, or pharmaceutically acceptable salts thereof.

[0202] E19.18.G 5 However, 4- to 8-membered heterocyclines, C, are replaced by optional substitution. 3-8 A compound described in any of E1 to E19.17, which is cycloalkyl or phenyl, or a pharmaceutically acceptable salt thereof.

[0203] E19.19.G 5 4- to 8-membered heterocyclines or C are optionally substituted in the above. 3-8A compound from any of E1 to E19.18, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl ring system is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolan-4-yl, 2-oxaspiro[3.3]heptan-6-yl, cyclopropyl, cyclobutyl, cyclopentyl, or bicyclo[2.2.1]heptan-2-yl.

[0204] E19.20.G 5 The compounds described in any of E1 to E19.19, or pharmaceutically acceptable salts thereof, are optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoro, cyano, methyl, and -OCH3.

[0205] E19.21.G 5 However, 4- to 8-membered heterocyclines or C are optionally substituted. 3-6 A cycloalkyl compound as described in any of E1 to E19.18 or E19.20, or a pharmaceutically acceptable salt thereof.

[0206] E19.22.G 5 However, the compound described in any of E19.19 to E19.21, which is oxetanyl, tetrahydrofuranil, cyclopropyl, or cyclopentyl, or a pharmaceutically acceptable salt thereof.

[0207] E19.23.R 5 However, hydrogen, methyl, ethyl, isobutyl, neopentyl, CD3, 2-fluoro-2-methylpropyl, -CH(CH3)-C(O)OCH3, -CH2CH2OCH3, -CH(CH3)CH2OCH3, [ka] -CH2CH2OCH(CH3)2, cyclopropyl, cyclopentyl, bicyclo[2.2.1]heptan-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, [ka] The compounds listed in any of E19 to E19.22, or pharmaceutically acceptable salts thereof.

[0208] E19.24.R 5 The compounds described in E19.23, or pharmaceutically acceptable salts thereof, wherein the compound is hydrogen, methyl, CD3, -CH(CH3)-C(O)OCH3, -CH(CH3)CH2OCH3, cyclopropyl, cyclopentyl, tetrahydrofuran-3-yl, or oxetane-3-ylmethyl.

[0209] E20.R 4B and R 5 A compound described in any of E1 to E17, or a pharmaceutically acceptable salt thereof, which forms a 5- to 7-membered heterocycle together with the atoms to which they are attached.

[0210] E20.1.R 4B and R 5 A compound according to any of E1 to E17 or E20, or a pharmaceutically acceptable salt thereof, wherein the 5- to 7-membered heterocycle formed by is piperazine.

[0211] E21.R 6 However, hydrogen, halogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -OR 6a , or C 3-6 A cycloalkyl compound as described in any of E1 to E20.1, or a pharmaceutically acceptable salt thereof.

[0212] E21.1.R 6 However, the compounds listed in E21, or pharmaceutically acceptable salts thereof, are hydrogen.

[0213] E21.2.R 6 However, the compounds listed in E21 that are halogens, or pharmaceutically acceptable salts thereof.

[0214] E21.3.R 6A compound described in any of E1 to E21 or E21.2, or a pharmaceutically acceptable salt thereof, wherein the halogen in the compound is chloro.

[0215] E21.4.R 6 However, C 1-4 A compound that is alkyl, as described in E21, or a pharmaceutically acceptable salt thereof.

[0216] E21.5.R 6 C in 1-4 A compound described in any of E1-E21 or E21.3-E21.4, wherein the alkyl group is methyl, or a pharmaceutically acceptable salt thereof.

[0217] E21.6.R 6 However, C 1-4 A fluoroalkyl compound as described in E21, or a pharmaceutically acceptable salt thereof.

[0218] E21.7.R 6 C in 1-4 A compound described in any of E1-E21, E21.3, or E21.5-E21.6, wherein the fluoroalkyl group is -CHF2, or a pharmaceutically acceptable salt thereof.

[0219] E21.8.R 6 However, -OR 6a The compound described in E21, or a pharmaceutically acceptable salt thereof.

[0220] E21.9.R 6a However, C 1-4 A compound that is alkyl, as described in any of E1-E21, E21.3, E21.5, or E21.7-E21.8, or a pharmaceutically acceptable salt thereof.

[0221] E21.10.R 6a C in 1-4 A compound described in any of E1-E21, E21.3, E21.5, or E21.7-E21.9, wherein the alkyl group is methyl, or a pharmaceutically acceptable salt thereof.

[0222] E21.11.R 6 However, C 3-6 A cycloalkyl compound as described in E21, or a pharmaceutically acceptable salt thereof.

[0223] E21.12.R 6 C in 3-6 A compound described in any of E1-E21, E21.3, E21.5, E21.7, or E21.9-E21.11, wherein the cycloalkyl is cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0224] E22.R 7 However, C 1-4 Alkyl, halogen, cyano, or G 7 The compound described in any of E1 to E21.12, or a pharmaceutically acceptable salt thereof.

[0225] E22.1.R 7 However, C 1-4 A compound described in any of E1 to E22, which is alkyl, halogen, or cyano, or a pharmaceutically acceptable salt thereof.

[0226] E22.2.R 7 However, C 1-4 A compound that is alkyl, as described in E22.1, or a pharmaceutically acceptable salt thereof.

[0227] E22.3.R 7 C in 1-4 A compound listed in any of E1 to E22.2, wherein the alkyl group is methyl, or a pharmaceutically acceptable salt thereof.

[0228] E22.4.R 7 However, the compounds listed in E22.1, or pharmaceutically acceptable salts thereof, are cyano compounds.

[0229] E22.5.R 7 However, the compounds listed in E22.1 that are halogens, or pharmaceutically acceptable salts thereof.

[0230] E22.6.R 7 The halogen in is a compound described in any of E1 to E22.1, E22.3, or E22.5, or a pharmaceutically acceptable salt thereof, wherein the halogen is bromo.

[0231] E22.7.R 7 A compound described in any of E1 to E22.1, E22.3, or E22.5, or a pharmaceutically acceptable salt thereof, wherein the halogen in the compound is chloro.

[0232] E22.8.R 7 However, G 7 The compound described in any of E1 to E22, or a pharmaceutically acceptable salt thereof.

[0233] E22.9.G 7 However, the compounds described in any of E1 to E22.1, E22.3, or E22.6 to E22.8, which are optionally substituted 5-6 member heteroaryl compounds containing 1 to 3 heteroatoms, or pharmaceutically acceptable salts thereof.

[0234] E22.10.G 7 A compound described in any of E1-E22.1, E22.3, or E22.6-E22.9, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5-6 membered heteroaryl ring system in is pyridinyl.

[0235] E22.11.G 7 but, [ka] The compounds described in E22.10, or pharmaceutically acceptable salts thereof.

[0236] A compound listed in any of E1 to E22.11, or a pharmaceutically acceptable salt thereof, wherein E23n is 0.

[0237] E24.G 1 but, [ka] The compound described in any of E1 to E23, or a pharmaceutically acceptable salt thereof.

[0238] E25.X 1 However, NR 5 The compound described in any of E1 to E24, or a pharmaceutically acceptable salt thereof.

[0239] E26.X 1 However, the compound is O, as described in any of E1-E18.1 or E21-E24, or a pharmaceutically acceptable salt thereof.

[0240] E27.X 1 However, CR 5A R 5B The compounds described in E1-E18.1 or E21-E24, or pharmaceutically acceptable salts thereof.

[0241] E27.1.R 5A and R 5B However, the compounds listed in any of E1-E18.1, E21-E24, or E27, or pharmaceutically acceptable salts thereof, which are independently hydrogen, fluoro, or methyl.

[0242] E27.2.R 5A and R 5B However, the compounds listed in E27.1, or pharmaceutically acceptable salts thereof, are fluoro.

[0243] E27.3.R 5A and R 5B However, the compounds listed in E27.1, or pharmaceutically acceptable salts thereof, are methyl.

[0244] E27.4.R 5A and R 5B However, hydrogen is a compound listed in E27.1, or a pharmaceutically acceptable salt thereof.

[0245] E28.X2 However, CR 6 The compound described in any of E1 to E27.4, or a pharmaceutically acceptable salt thereof.

[0246] E29.X 2 However, the compound is N, as described in any of E1 to E27.4, or a pharmaceutically acceptable salt thereof.

[0247] E30.G 1 but, [ka] The compound described in any of E1 to E23, or a pharmaceutically acceptable salt thereof.

[0248] E31.R 6 and R 7 A compound described in any of E1 to E20.1 or E23 to E30, or a pharmaceutically acceptable salt thereof, which, together with the atoms to which they are attached, forms a 5-7 membered heterocycle or 5-7 membered carbon ring that is optionally substituted.

[0249] E31.1.R 6 and R 7 The compounds described in E31, or pharmaceutically acceptable salts thereof, which, together with the atoms to which they are attached, form a 5- to 7-membered heterocycle that is optionally substituted.

[0250] E31.2.R 6 and R 7 The compounds described in E31.1, or pharmaceutically acceptable salts thereof, which, together with the atoms to which they are attached, form dihydrothiophene or dihydrofuran.

[0251] E31.3.G 1 but, [ka] The compounds described in E31.2, or pharmaceutically acceptable salts thereof.

[0252] E31.4.R 6 and R 7 A compound described in any of E1 to E20.1 or E23 to E30, or a pharmaceutically acceptable salt thereof, which, together with the atoms to which they are attached, forms a 5- to 7-membered carbon ring that is optionally substituted.

[0253] E31.5.R 6 and R 7 The compounds described in E31.4, or pharmaceutically acceptable salts thereof, which, together with the atoms to which they are attached, form cyclopentene or cyclohexene.

[0254] E31.6.G 1 but, [ka] The compounds described in E31.5, or pharmaceutically acceptable salts thereof.

[0255] E32.

[0256] [Table 1]

[0257] [Table 2]

[0258] [Table 3]

[0259] [Table 4]

[0260] [Table 5]

[0261] Table 6

[0262] Table 7

[0263] Table 8

[0264] Table 9

[0265] Table 10

[0266] Table 11

[0267] Table 12

[0268] Table 13

[0269] Table 14

[0270] Table 15

[0271] Table 16

[0272] [Table 17]

[0273] [Table 18]

[0274] [Table 19]

[0275] [Table 20]

[0276] [Table 21]

[0277] [Table 22]

[0278] [Table 23]

[0279] [Table 24]

[0280] [Table 25]

[0281] A compound described in E1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

[0282] A pharmaceutical composition comprising a compound described in any of E33.E1 to E32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0283] E34. 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 of the compounds described in E1 to E32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in E33.

[0284] E35. The method described in E34, wherein the disorder is related to mAChR M4 dysfunction.

[0285] E36. The method according to E34 or E35, wherein the disorder is a neurological and / or psychiatric disorder associated with mAChR M4 dysfunction.

[0286] E37. The method according to any one of E34-E36, wherein the disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, sleep disorders, pain disorders, and cognitive impairment.

[0287] E38. The method described in E37, where the disorder is Alzheimer's disease.

[0288] E39. The method according to any one of E34-E36, 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 anxiety episode, 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 symptoms of intellectual disability, autism spectrum disorder, 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.

[0289] A kit comprising one of the compounds described in any of E40.E1 to E32, or a pharmaceutically acceptable salt thereof, and one or more instructions for administering compounds related to cognitive therapy or behavioral therapy: (a) at least one agent known to increase mAChR M4 activity; (b) at least one agent known to decrease mAChR M4 activity; (c) at least one agent known to treat disorders related to cholinergic activity; (d) instructions for treating disorders related to cholinergic activity; (e) instructions for treating disorders related to mAChR M4 receptor activity; and (f) instructions for administering compounds related to cognitive therapy or behavioral therapy.

[0290] E38. A compound according to any of E1 to E32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to E33, for use in the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0291] E39. Use of any compound described in E1 to E32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in E33, for the preparation of a medicament for the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0292] 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 the mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product 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 in a chiral chromatography column, or (3) fractional recrystallization methods.

[0293] It should be understood that this compound may have tautomers and geometric isomers, and that these also constitute embodiments of the present disclosure.

[0294] In compounds of formula (I) and any subformula, any "hydrogen" or "H", whether explicitly or implicitly indicated in the structure, is a hydrogen isotope. 1 H (protium) and 2 It contains H (deuterium).

[0295] The present invention also includes isotope-labeled compounds identical to those described in formula (I), but in which one or more atoms are replaced with atoms having atomic weights 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] The compound of formula (I) can be synthesized as shown in schemes 1 to 14. Scheme 1 [ka]

[0301] As shown in Scheme 1, the intermediate compound of formula P2 can be subjected to standard nucleophilic substitution conditions with the intermediate of formula P1, a base (e.g., DIPEA), and a solvent (e.g., DMSO), and heated to about 90-160°C to obtain the compound of formula P3. Scheme 2 [ka]

[0302] As shown in Scheme 2, a P4 type intermediate can be protected with di-t-butyl carbonate under Boc protection conditions commonly known in the art to obtain a P5 type Boc-protected intermediate. The P5 type intermediate can be coupled with an amine under Buchwald coupling conditions commonly known in the art, and subsequently deprotected to obtain a P6 type product. Scheme 3 [ka]

[0303] Scheme 3 shows a general route for preparing the intermediate of formula P7. The P5 type intermediate can be coupled with a boronic acid or ester under Suzuki coupling conditions commonly known in the art, followed by deprotection, to obtain the compound of formula P7, where R 2 is alkyl or G 2 G 2 The aryl or heteroaryl ring system is optionally substituted, as defined herein. The coupling reaction is carried out by heating to about 70–90°C in a solvent mixture of an organic solvent such as DMF or 1,4-dioxane and water, using a palladium catalyst such as Pd(dppf)Cl2 and a base (e.g., K2CO3, Cs2CO3). The reaction can be accelerated by microwave irradiation. Scheme 4 [ka]

[0304] As shown in Scheme 4, the intermediate compound of formula P3a is divided into a base (e.g., NaH, LiHMDS, etc.), a solvent (e.g., DMSO), and R 5 By subjecting it to -X (where X is a halogen, mesylate, or other leaving group), a compound of formula P8 may be obtained. Scheme 5 [ka]

[0305] As shown in Scheme 5, the ester intermediate P9 (where Y, Y) 1 and Y 2 Compound P1a can be obtained by subjecting Cl, Br, or I) to an amine, a base (e.g., DIEA), and a solvent (e.g., THF) without heating, or while heating to 40-50°C. Scheme 6 [ka]

[0306] As shown in Scheme 6, the intermediate compound of formula P2 can be subjected to standard nucleophilic substitution conditions with the intermediate of formula P1b (wherein Y is a halogen), a base (e.g., DIPEA), and a solvent (e.g., DMSO), and heated to about 90-120°C to obtain the compound of formula P10. Scheme 7 [ka]

[0307] As shown in Scheme 7, the intermediate of formula P10 (wherein Y is a halogen) can be coupled with a boronic acid or ester under Suzuki coupling conditions commonly known in the art. The coupling reaction is carried out by heating to about 70-90°C in a solvent mixture of an organic solvent such as DMF or 1,4-dioxane and water, using a palladium catalyst such as Pd(dppf)Cl2 and a base (e.g., K2CO3, Cs2CO3). The reaction can be accelerated by microwave irradiation. Scheme 8 [ka]

[0308] As shown in Scheme 8, the intermediate of formula P10 (wherein Y is a halogen) can be subjected to a catalyst (e.g., Pd(PPh3)4), a cyanide source (e.g., Zn(CN)2), and a solvent (e.g., DMF), and heated to 120-140°C to obtain the compound of formula P11a. The reaction can be accelerated by microwave irradiation. Scheme 9 [ka]

[0309] As shown in Scheme 9, equation P12 (wherein Y and Y 1 The compound of formula P13 can be obtained by subjecting an intermediate compound of fluorine, chlorine, or bromine to standard nucleophilic substitution conditions using an amine, a base (e.g., DIEA, Et3N, etc.), and a solvent (e.g., NMP, DMF). Scheme 10 [ka]

[0310] As shown in Scheme 10, the intermediate of formula P13 (wherein Y is a halogen) can be subjected to hydrazine in a solvent (e.g., ethanol), heated to 70-80°C, followed by ring formation (e.g., CDI (CAS number 530-62-1)), and then heated to 70-85°C to form the compound of formula P14. Scheme 11 [ka]

[0311] As shown in Scheme 11, the compound of formula P5 can be reacted with an alcohol under Ullmann conditions commonly known in the art, followed by deprotection with an acid (e.g., TFA) to obtain a P15 type intermediate. Suitable Ullmann conditions for coupling with phenol involve the use of a base (e.g., Cs2CO3), 2,2,6,6-tetramethylheptane-3,5-dione, and a copper salt (e.g., copper(I) iodide), and heating to about 100-120°C in a solvent such as NMP. Scheme 12 [ka]

[0312] As shown in Scheme 12, compound P17 can be prepared from P16 by alkylation with a base (e.g., NaH) and a suitable alkylating agent (e.g., MeI). Scheme 13 [ka]

[0313] As shown in Scheme 13, compound P18 can react with compound P2 in the presence of a base to produce P19, similar to Schemes 1 and 6. Reducing the nitrile of P19 (e.g., Raney nickel, ammonia, hydrogen (g)) may yield compound P20. Scheme 14 [ka]

[0314] As shown in Scheme 14, compound P21 is a base (e.g., K2CO3) and a suitable alkylating agent (e.g., R 5 -X, where X can be prepared from P14 by alkylation with a halogen, tosylate, etc.

[0315] To prepare the compound of formula (I), the following intermediates may be used in the above scheme: 3-bromo-2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one and 3-bromo-2-chloro-6,6-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one, as described in International Publication No. 2018 / 118736.

[0316] Boronic acids / esters, amines, and alcohols suitable for the coupling reactions described herein can be readily obtained from commercial sources or prepared by standard methods well known to those skilled in the art.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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 the appropriate reaction step), or by dividing a mixture of stereoisomers of the compound or intermediate using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0322] 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 dividing a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0323] 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.

[0324] c. Muscarinic acetylcholine receptor M4 activity In some embodiments, the disclosed compounds enhance the agonist response of mAChR M4 (e.g., acetylcholine). In some embodiments, the disclosed compounds increase the mAChR M4 response to non-maximal concentrations of agonists in the presence of the compound compared to the response to agonists in the absence of the compound. The enhancement of mAChR M4 activity can be demonstrated by methodologies known in the art. For example, activation of mAChR M4 activity is Ca 2+ The activity can be determined by measuring the calcium flux in response to an agonist, such as acetylcholine, in cells loaded with a sensitive fluorescent dye (e.g., Fluo-4), and by co-expression of a chimeric or promiscuous G protein. In some embodiments, the calcium flux was measured as an increase in the fluorescence resting ratio. In some embodiments, positive allosteric modulator activity is measured by EC 20This is analyzed as a concentration-dependent increase in the acetylcholine response (i.e., the mAChR M4 response at the acetylcholine concentration that produces 20% of the maximum response).

[0325] 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.

[0326] 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 CHO-K1 cells transfected with mAChR M4 in the presence of the compounds, compared to the response to acetylcholine in the absence of the compounds. In some embodiments, the disclosed compounds exhibit positive allosteric modulation of the mAChR M4 response to acetylcholine, and EC 50 These are 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. In some embodiments, positive allosteric regulation of EC is observed in CHO-K1 cells transfected with mAChR M4. 50 This is determined. In some embodiments, mAChR M4 was transfected with human mAChR M4. In some embodiments, mAChR M4 was transfected with rat mAChR M4.

[0327] The disclosed compounds may exhibit selectivity for the mAChR M4 receptor to one or more mAChR M1, M2, M3, or M5 receptors. For example, the disclosed compounds may exhibit selectivity for EC in one or more mAChR M1, M2, M3, or M5 transfected CHO-K1 cells. 50 e-commerce below 50 This can activate the mAChR M4 reaction in mAChR M4-transfected CHO-K1 cells. 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 for 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.

[0328] The disclosed compounds have an EC of less than approximately 10 μM. 50This 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 also 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 also 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 The mAChR M4 reaction can also 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 M5. 50The mAChR M4 reaction can also 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 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, the mAChR M4 reaction can also be activated.

[0329] The in vivo potency of the disclosed compounds can be measured in numerous preclinical rat behavioral models in which known clinically useful antipsychotics exhibit similar positive responses. For example, the disclosed compounds can reverse amphetamine-induced hyperkineticism in male Sprague-Dawley rats at doses ranging from 1 to 100 mg / kg at post-occlusion (PO).

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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 Soybean 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.

[0334] 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.

[0335] 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).

[0336] 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.

[0337] 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%.

[0338] 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%.

[0339] 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%.

[0340] 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%.

[0341] 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%.

[0342] 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%.

[0343] 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%.

[0344] 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%.

[0345] 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%.

[0346] 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%.

[0347] 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%.

[0348] 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%.

[0349] 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%.

[0350] 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).

[0351] 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.

[0352] 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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).

[0360] 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.

[0361] 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).

[0362] 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%.

[0363] 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%.

[0364] 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%.

[0365] 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%.

[0366] The amount of thickener in topical compositions is generally between approximately 0% and 95%.

[0367] 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%.

[0368] The amount of fragrance in topical compositions is generally about 0% to 0.5%, and especially about 0.001% to 0.1%.

[0369] Suitable pH-adjusting additives include HCl or NaOH in sufficient quantities to adjust the pH of the topical pharmaceutical composition.

[0370] 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 modulation of mAChR M4 can be observed. The pharmaceutical composition or formulation has 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 demonstrates the positive allosteric modulation of mAChR M4.

[0371] 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.

[0372] Therefore, in one embodiment, the present disclosure can provide a spray-dried dispersion formulation comprising a compound of formula (I).

[0373] 4.How to use The disclosed compounds, pharmaceutical compositions, and formulations can be used in methods for the treatment of disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions can also be used in methods for enhancing muscarinic acetylcholine receptor activity in mammals and for enhancing cognitive abilities in mammals. These methods further include co-therapeutic methods for improving treatment outcomes in the context of cognitive therapy or behavioral therapy. In the methods of use described herein, further therapeutic agents may be administered simultaneously with or sequentially with the disclosed compounds and compositions.

[0374] a. Treatment of the disability The disclosed compounds, pharmaceutical compositions, and formulations may be used for the treatment of or in methods for the treatment of disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. Methods of treatment may include administering a therapeutically effective amount of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of formula (I), to a subject requiring such treatment.

[0375] In some embodiments, the present disclosure provides a method for enhancing the cognitive abilities of a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I).

[0376] The compounds and compositions disclosed herein may be useful for treating, preventing, improving, controlling, or mitigating the risk of various disorders associated with selective mAChR M4 receptor activation. For example, treatment may include selective mAChR M4 receptor activation to an extent effective in affecting cholinergic activity. The disorder may be associated with cholinergic activity, e.g., impaired cholinergic function. Accordingly, a method is provided for treating or preventing a disorder in a subject, the method comprising the step of administering to the subject at least one disclosed compound or at least one disclosed pharmaceutical composition in an amount effective in treating the disorder in the subject.

[0377] 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.

[0378] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method for treating disorders associated with the mAChR M4 receptor. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method for treating disorders associated with the mAChR M4 receptor.

[0379] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for the treatment of disorders associated with the mAChR M4 receptor.

[0380] In some embodiments, the present 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 disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0381] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for treating disorders associated with dysfunction of muscarinic acetylcholine receptors in mammals.

[0382] In some embodiments, the present 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 dysfunction of muscarinic acetylcholine receptors in mammals.

[0383] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for the treatment of disorders associated with dysfunction of muscarinic acetylcholine receptors in mammals.

[0384] In some embodiments, the disclosed compounds and compositions 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 not otherwise specified, short-term psychotic disorder, schizophrenic disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic seizures, delayed-onset psychosis, myxedema psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar type I disorder with psychotic features, and substance-induced psychotic disorder. In some embodiments, the psychotic disorder is a psychosis associated with a disease selected from major depressive disorder, affective disorder, bipolar disorder, electrolyte disorder, Alzheimer's disease, neuropathy, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder.

[0385] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for the treatment of neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, in particular, as described herein. In some embodiments, the Disclosure provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for the treatment of neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, in particular, as 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 the treatment of neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, in particular, as described herein.

[0386] In some embodiments, the disorder is a neurological disorder selected from brain tumors, Lewy body dementia, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, and anti-NMDA receptor encephalitis.

[0387] 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 schizoid personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some embodiments, the mental 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).

[0388] 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 patient in need thereof. In some embodiments, cognitive impairment includes dementia (associated with Alzheimer's disease, ischemia, polyinfarct dementia, trauma, vascular problems or stroke, HIV disease, 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 disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinson's disease-ALS dementia complex, Alzheimer's type dementia, age-related cognitive decline, and mild cognitive impairment.

[0389] The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides diagnostic tools for cognitive impairments, including dementia, delirium, amnesic disorders, and age-related cognitive decline. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (2013, American Psychiatric Association, Washington DC) provides diagnostic tools for neurocognitive disorders (NCDs), including delirium, followed by severe NCDs, mild NCDs, and syndromes of their etiological subtypes. Severe or mild NCD subtypes include NCD due to Alzheimer's disease, vascular NCD, Lewy body NCD, NCD due to Parkinson's disease, frontotemporal NCD, NCD due to traumatic brain injury, NCD due to HIV infection, substance / drug-induced NCD, NCD due to Huntington's disease, NCD due to prion disease, NCD due to other medical conditions, NCD due to multiple etiologies, and NCD of unknown origin. The NCD category in DSM-5 encompasses a group of disorders in which the primary clinical deficit lies in cognitive function and is acquired rather than developmental. As used herein, the term “cognitive impairment” includes the treatment of cognitive and neurocognitive disorders as described in DSM-IV-TR or DSM-5. Skilled technicians recognize that there are alternative nomenclature, disease taxonomy, and classification systems for mental disorders, and these systems evolve with advances in medicine and science. Therefore, the term “cognitive impairment” is intended to include similar disorders as described in other diagnostic sources.

[0390] In some embodiments, the Disclosure provides a method for treating schizophrenia or psychosis, comprising administering an effective amount of a compound or composition of the Disclosure to a patient in need thereof. Specific schizophrenic or psychotic conditions include paranoid, disorganized, catatonic, or anaplastic schizophrenia and substance-induced psychotic disorders. The DSM-IV-TR provides diagnostic tools including paranoid, disorganized, catatonic, anaplastic, or residual schizophrenia and substance-induced psychotic disorders. The DSM-5 eliminates the subtypes of schizophrenia and instead includes a dimensional approach to assess the severity of the core symptoms of schizophrenia, capturing the diversity of symptom types and severity present among individuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the treatment of mental disorders as described in the DSM-IV-TR or DSM-5. Experienced technicians recognize that mental disorders have alternative nomenclature, disease classifications, and classification systems, and that these systems evolve with advances in medicine and science. Therefore, the term “schizophrenia or psychosis” is intended to include similar disorders described in other diagnostic sources.

[0391] In some embodiments, the Disclosure provides a method for treating pain, comprising administering an effective amount of the compound or composition of the Disclosure to a patient in need thereof. Specific forms of pain include bone and joint pain (osteoarthritis), pain from repetitive movements, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, and neuropathic pain.

[0392] 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.

[0393] In the treatment of conditions requiring mAChR M4 activation, 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.

[0394] 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.

[0395] 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 activity prior to the administration step. In some embodiments, the method further comprises the step of identifying a subject requiring mAChR M4 agonism.

[0396] In some embodiments, the present invention relates to a method for treating a disorder in a mammal associated with selective mAChR M4 activation, for example, a disorder associated with cholinergic activity, comprising the step of administering to a mammal at least one compound disclosed or at least one product of the disclosed method in a dosage and amount 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 needing treatment for the disorder prior to the administration step. In some embodiments, the method further includes the step of identifying a subject that needs treatment for the disorder.

[0397] In some embodiments, the disorder may be selected from psychotic mood disorders such as psychosis, schizophrenia, conduct disorder, destructive behavior disorder, bipolar disorder, psychotic anxiety episodes, 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 symptoms of intellectual disability, autism spectrum disorder, 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.

[0398] In some embodiments, the disorder is Alzheimer's disease.

[0399] b. Enhancement of muscarinic acetylcholine receptor activity In some embodiments, the present disclosure relates to a method for enhancing muscarinic acetylcholine receptor activity in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0400] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for enhancing the activity of muscarinic acetylcholine receptors in mammals. In some embodiments, the disclosure provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for enhancing the activity of muscarinic acetylcholine receptors in mammals.

[0401] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals that enhance the activity of muscarinic acetylcholine receptors in mammals.

[0402] In some embodiments, enhancement of muscarinic acetylcholine receptor activity increases muscarinic acetylcholine receptor activity. In some embodiments, enhancement of muscarinic acetylcholine receptor activity is partial activation of muscarinic acetylcholine receptors. In some embodiments, enhancement of muscarinic acetylcholine receptor activity is positive allosteric regulation of muscarinic acetylcholine receptors.

[0403] 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 enhancement of mAChR M4. In some embodiments, the administered compound is EC 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 demonstrates the enhancement of mAChR M4.

[0404] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as needing enhancement of muscarinic acetylcholine receptor activity before the administration step. In some embodiments, the method further includes the step of identifying the mammal that needs enhancement of muscarinic acetylcholine receptor activity. In some embodiments, enhancement of muscarinic acetylcholine receptor activity treats a disorder related to muscarinic acetylcholine receptor activity in the mammal. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.

[0405] In some embodiments, enhancement of muscarinic acetylcholine receptor activity in mammals is related to the treatment of neurological and / or psychological disorders associated with muscarinic receptor dysfunction, such as the neurological or psychological disorders disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4.

[0406] In some embodiments, the present disclosure provides a method for enhancing muscarinic acetylcholine receptor activity in cells, comprising the step of contacting cells with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are mammalian (e.g., human). In some embodiments, the cells are isolated from the mammal before the contact step. In some embodiments, the contact is via administration to the mammal.

[0407] c. Improvement of cognitive abilities In some embodiments, the present invention relates to a method for enhancing the cognitive abilities of a mammal, the method comprising the step of administering to a mammal an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0408] In some embodiments, the Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for improving the cognitive abilities of mammals. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for improving the cognitive abilities of mammals.

[0409] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for improving cognitive abilities in mammals.

[0410] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as needing cognitive enhancement prior to 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 associated with muscarinic receptor dysfunction. In some embodiments, the muscarinic receptor is mAChR M4.

[0411] In some embodiments, the improvement in cognitive ability is a statistically significant increase in novel object recognition. In some embodiments, the improvement in cognitive ability is a statistically significant improvement in performance on the Wisconsin Card Sorting Test.

[0412] d.Co-treatment method The present invention further relates to the administration of selective mAChR M4 activators for improving therapeutic outcomes in the context of cognitive therapy or behavioral therapy. Specifically, in some embodiments, the present invention relates to a co-therapeutic method comprising the step of administering at least one disclosed compound or a pharmaceutically acceptable salt thereof in effective amounts and doses to a mammal.

[0413] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a co-therapeutic method with cognitive or behavioral therapy in mammals. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a co-therapeutic method with cognitive or behavioral therapy in mammals.

[0414] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for co-therapeutic methods with cognitive or behavioral therapy in mammals.

[0415] 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.

[0416] It is understood that the disclosed co-therapeutic methods may be used in connection with the disclosed compounds, compositions, kits, and their use.

[0417] 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.

[0418] 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.

[0419] 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.

[0420] 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.

[0421] 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.

[0422] 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.

[0423] 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.

[0424] In some embodiments, the compound can be used in combination with anti-Alzheimer's drugs, β-secretase inhibitors, cholinergics, 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 in question can be used with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), anxiolytics, cyclopyrrolone, imidazopyridine, pyrazolopyrimidine, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, barbiturates, 5HT-2 antagonists, such as azinazolam, arobarbital, aronimide, alprazolam, amisulpride, amitriptyline, amobarbital. Tar, amoxapine, aripiprazole, bentazepam, benzothamine, brotizolam, bupropion, buspirone, butabarbital, butarbital, capride, carbochloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, chlorate, chlorpromazine, clozapine, siprazepam, desipramine, dexcramol, diazepam, dichlor Luphenazone, divalproex, diphenhydramine, doxepin, estazolam, etochlorbinol, etomidate, phenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimid, harazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, meclocalon, melatonin, mefobarbital, meprobamate Metacaron, Midaflul, Midazolam, Nefazodone, Nisobamate, Nitrazepam, Nortriptyline, Olanzapine, Oxazepam, Paraaldehyde, Paroxetine, Pentobarbital, Perlapine, Perphenazine, Phenelzine, Phenobarbital, Prazepam, Promethazine, Propofol, Protriptyline, Quazepam, Quetiapine, Leclazepam, Risperidone, Lorethamide, Secobarbital, Sertraline, Suprocron, Temazepam,Thioridazine, thiothixen, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimethodine, trimipramine, urdazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and their salts, and combinations thereof, etc., can be used in combination with these, or the target compound can be administered in combination with the use of physical methods such as phototherapy or electrical stimulation.

[0425] In some embodiments, the compound can be used in combination with levodopa (with or without a selective extraneurodecarboxylase inhibitor such as carbidopa or benserazide), anticholinergics (e.g., biperiden (optionally as its hydrochloride or lactate) and trihexyphenidyl (benzhexol) hydrochloride), COMT inhibitors (e.g., entacapone), MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, choline agonists, NMDA receptor antagonists, serotonin receptor antagonists, and dopamine receptor agonists (e.g., allentemol, bromocriptine, phenoldopam, rislide, naxagolide, pergolide, and pramipexole). It is understood that dopamine agonists may be in the form of pharmaceutically acceptable salts, such as alentemol hydrobromide, bromocriptine mesylate, phenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Lithulide and pramipexole are typically used in their non-salt forms.

[0426] In some embodiments, the compound can be used in combination with compounds from the classes of nerve relaxants: phenothiazines, thioxanthenes, heterocyclic dibenzoazepines, butyrophenones, diphenylbutylpiperidines, and indolones. Suitable examples of phenothiazines include chlorpromazine, mesolidazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is morindron. Other nerve blockers include roxapine, sulpiride, and risperidone. It should be understood that when nerve relaxants are used in combination with the target compound, they may be in pharmaceutically acceptable salt forms, such as chlorpromazine hydrochloride, mesolidazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, flurphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, roxapine succinate, and morindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide, and risperidone are commonly used in non-salt forms. Therefore, the compounds of the present invention can be used in combination with acetophenazine, allentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixen, clozapine, diazepam, phenoldopam, fluphenazine, haloperidol, levodopa, levodopa and benserazide, levodopa and carbidopa, rislid, roxapine, mesolidazine, morindron, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixen, trifluoperazine, or ziprasidone.

[0427] In some embodiments, the compound can be used in combination with antidepressants or anxiolytics, including 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 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, clorazepic acid, diazepam, harazepam, lorazepam, oxazepam, and prazepam; buspirone, fresinoxane, gepirone, and ipsapirone, as well as their pharmaceutically acceptable salts.

[0428] In some embodiments, the compound can be administered co-administered with an orthosteric muscarinic agonist, a muscarinic enhancer, or a cholinesterase inhibitor. In some embodiments, the compound can be administered co-administered with GlyT1 inhibitors, including but not limited to risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and their salts, as well as combinations thereof.

[0429] 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.

[0430] 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.

[0431] As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions.

[0432] 5. Kit In one embodiment, the present disclosure provides a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof and one or more of the following: (a) At least one agent known to increase mAChR M4 activity; (b) At least one drug known to reduce mAChR M4 activity; (c) At least one drug known to treat disorders related to cholinergic activity; (d) Instructions for the treatment of disorders related to cholinergic activity; (e) Instructions for the treatment of disorders related to M4 receptor activity; or (f) Instructions for administering compounds related to cognitive therapy or behavioral therapy.

[0433] 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.

[0434] The disclosed kit can be used in conjunction with the disclosed method of use.

[0435] These kits may include information, descriptions, or both indicating that the use of the kit may provide 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 a compound, composition, or both that has the benefit of treating or preventing a medical condition in mammals (e.g., humans); and a method of applying the compound or composition.

[0436] 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]

[0437] 6. Examples All NMR spectra were recorded using a 400 MHz AMX Bruker NMR spectrometer. 1 The H chemical shift is reported as a δ value at ppm (low field) using a deuterated solvent as an internal standard. The data are reported as follows: chemical shift, multiplicity (s=single line, bs=broad single line, d=double line, t=triple line, q=quadruple line, dd=double line of double lines, m=multiple line, ABq=AB quadruple line), coupling constant, and integral value. Reverse-phase LC-MS 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 5% to 95% acetonitrile over 1.4 minutes (aqueous phase: 0.1% TFA (in water)), held in 95% acetonitrile for 0.1 min, 0.5 mL / min, 55°C ("90-second method"). The sample was separated at 0.5 mL / min using 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 a 4 nm wide band). 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 / min at 300°C, and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set to 3000 V, and the fragmenter voltage was set to 100 V. Data was acquired using Agilent Chemstation and Analytical Studio Reviewer software.

[0438] a. Preparation of intermediates [ka] Ethyl 5-bromo-6-hydroxy-2-methylnicotinate. At 0°C, N-bromosuccinimide (10.8 g, 60.7 mmol) was gradually added to a solution of ethyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (10 g, 55.2 mmol) in DMF (185 mL). The ice bath was removed. After 18 hours, saturated sodium bisulfite (aq) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered, and the collected 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.

[0439] [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). The reaction was carried out in a condenser and heated to 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. Another 25 mL of DCM 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% siRNA / hexane) to obtain the title compound (12 g). 1H 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.

[0440] [ka] Ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate. At 50°C, N-bromosuccinimide (8.43 g, 47.4 mmol) was gradually added to a solution of ethyl 5-bromo-6-chloro-2-methylnicotinic acid (12 g, 43.1 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.71 g, 4.3 mmol) in carbon tetrachloride (287 mL). After 30 min, the reaction mixture was heated to 80°C. After 18 hours, the reaction mixture 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 over (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-4% HCl / hexane) to obtain the title compound (13.6 g). 1 H 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.

[0441] [ka] 3-Bromo-2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. At 0°C, a 2.0 M solution of methylamine (17.5 mL, 35.0 mmol) was added to a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (2.5 g, 6.99 mmol) in THF (140 mL), and the reaction mixture was stirred for 30 minutes. After concentrating the reaction mixture by rt, it was purified by normal-phase chromatography (0-30% Â / DCM) to obtain the title compound. 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.

[0442] [ka] (S)-3-bromo-2-chloro-6-(1-methoxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. To a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (201 mg, 0.3 mmol) in THF (2.5 mL), (S)-(+)-1-methoxy-2-propylamine (0.11 mL, 1.0 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. Additional (S)-(+)-1-methoxy-2-propylamine (0.11 mL, 1.0 mmol) was added. After 12 hours, the mixture was concentrated under vacuum and purified by normal-phase column chromatography (0-80% Â / hexane) to obtain the title compound (138 mg). 1 H NMR(400MHz,CDCl3)δ 8.32(s,1H),4.68(pd,J=6.9,4.5Hz,1H),4.42(q,J=18.4Hz,3H),3.60-3.48(m,3H),3.33(s,4H),1.32(d,J=7.0Hz,4H).ES-MS[M+1] + :319.0 / 321.0.

[0443] [ka] (R)-3-bromo-2-chloro-6-(1-methoxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. Prepared by the same method as (S)-3-bromo-2-chloro-6-(1-methoxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 1 H NMR(400MHz,CDCl3)δ 8.32(s,1H),4.68(pd,J=6.9,4.5Hz,1H),4.42(q,J=18.4Hz,3H),3.60-3.48(m,3H),3.33(s,4H),1.32(d,J=7.0Hz,4H).ES-MS[M+1] + :319.0 / 320.9.

[0444] [ka] Ethyl 5-bromo-6-chloro-2-formylnicotinate. To a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (1.36 g, 3.8 mmol) in MeCN (21.5 mL), 4-methylmorpholine N-oxide (893 μL, 8.6 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with Âlyde 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% Âlyde / 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).

[0445] [ka] 3-Bromo-2-chloroflou[3,4-b]pyridine-5(7H)-one. At -40°C, 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). The reaction mixture was stirred at -40°C for 45 minutes. Water was added to the reaction mixture, and the mixture was warmed to room temperature. After extracting the reaction mixture with RINKAN (3x), the combined organic layers were dried in (MgSO4), filtered, and concentrated. The residue was dissolved 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. Further, 4 M HCl in 1,4-dioxane (400 μL, 1.6 mmol) was added, and the mixture was heated to 50°C. After 4 hours, the mixture was concentrated under vacuum, and the residue was dissolved in DCM. The solution was washed with saturated NaHCO3 aqueous solution. The organic layer was separated, dried, and concentrated (MgSO4). 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).

[0446] [ka] 3-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-2-ol. In a vial, 6,7-dihydro-5H-cyclopenta[b]pyridine-2-ol (500 mg, 3.7 mmol) and acetic acid (5.3 mL) were added at 15°C. Bromine (150 μL, 2.9 mmol) was added. The reaction mixture was allowed to cool to room temperature over 3 hours. The reaction mixture was concentrated under vacuum. Ether was added to the residue, the mixture was quenched with a sat. sodium thioate solution, and neutralized with a saturated sodium carbonate aqueous solution. The mixture was extracted with Ether (3x), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by normal-phase column chromatography (containing 0-10% DCM / MeOH and 1% NH4OH) to obtain the title 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.

[0447] [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 sodium carbonate aqueous solution was slowly added to the residue. The mixture was extracted with DCM (3x). The organic layers were combined and washed with water (3x). The organic matter was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by normal-phase column chromatography (0-60% toluene / hexane) 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.

[0448] [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), potassium permanganate (430 mg, 2.7 mmol), 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 through Celite® and washed with ethyl acetate and MeOH. The filtrate was concentrated and treated with water / ethyl acetate (2x). The combined organic layers were washed with brine (2x), filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (0-60% ethyl acetate / hexane) to obtain the title compound (40 mg). 1 H NMR(400MHz,CDCl3)δ 8.22(s,1H),3.26-3.18(m,2H),2.87-2.80(m,2H).ES-MS[M+1] + :246 / 248.

[0449] [ka] Ethyl 5-chloro-6-hydroxy-2-methylnicotinate. At 0°C, N-chlorosuccinimide (814 mg, 6.1 mmol) was gradually added to a solution of ethyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1 g, 5.5 mmol) in DMF (37 mL). After removing the ice bath and warming to room temperature, the mixture was heated at 50°C for 22 hours. After cooling to ambient temperature, saturated sodium bisulfite (aq) was added to the reactants, and the mixture was stirred for 30 minutes. The mixture was then further diluted with water (50 mL) and extracted with dimethyl ammonium (3x). The combined organic layers were washed with brine, dried, filtered, and concentrated to obtain the title compound. ES-MS[M+1]+:216; 11H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.74 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).

[0450]

Chem.

[0451]

Chem.

[0452]

Chem.

[0453] [ka] 3,5-Dichloro-6-methyl-2H-1,4-oxazin-2-one. Under an inert atmosphere, a solution of oxalyl chloride (49.1 mL, 563 mmol) in chlorobenzene (75 mL) cooled to 0°C was dropped into a solution of DL-lactonitrile (10 g, 140.7 mmol) in chlorobenzene (11 mL). The solution was then heated to 90°C, and triethylamine hydrochloride (1.43 g, 10.4 mmol) was gradually added at 90°C. The resulting mixture was then stirred for 3 hours, cooled to ambient temperature, and concentrated under vacuum. The resulting solution was diluted with Et2O (approximately 300 mL), and the solid was filtered off. The filtrate was concentrated, and 16.8 g of the title compound was obtained by normal-phase column chromatography (0-15% siRNA / Hex) on silica gel. 1 H NMR(400MHz,CDCl3)δ 2.38(s,1H).

[0454] [ka] 5-Chloro-3-iodo-6-methyl-2H-1,4-oxazin-2-one. To a solution of 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one (16.8 g, 93.4 mmol) in acetone (359 mL), sodium iodide (56.4 g, 374 mmol) and (1S,4R)-10-camphorsulfonic acid (1.52 g, 6.5 mmol) were added under an inert atmosphere. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, then diluted with water, and extracted with DCM (3x). After sequential washing with saturated aqueous solution of Na2S2O3 and brine, the combined organic matter was dried to (MgSO4), filtered, and concentrated to obtain 22 g of the title compound. The process was carried out without further purification of the substance. 11H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H); ES-MS [M+1] + : 272.

[0455]

Chem.

[0456]

Chem.

[0457] [ka] Methyl 2-(aminomethyl)-6-chloro-5-methylnicotinate. Platinum(IV) oxide (1.48 g, 6.5 mmol) was added to a round-bottom flask under nitrogen. Next, a solution of methyl 6-chloro-2-cyano-5-methylnicotinate (8.1 g, 38.5 mmol) in ethanol / chloroform (240 mL, 3:1) was added. The flask was evacuated under vacuum and purged with H2(g)(3x). The mixture was stirred under a hydrogen atmosphere (balloon) for 36 hours. Solid matter was removed by filtration with Celite®, washed with DCM, and the filtrate was concentrated. The substance was then dissolved in MeOH and equally divided into eight Agilent Bond Elut SCX cartridges (10 g cartridges). The cartridges were flushed with MeOH (approximately 80 mL per column), and the eluate was concentrated to obtain 5.46 g of methyl 2-(aminomethyl)-6-chloro-5-methylnicotinate. 1 H NMR(400MHz,MeOD)δ 8.38(d,J=0.8Hz,1H),4.62(s,2H),3.96(s,3H),2.47(q,J=0.7Hz,3H).ES-MS[M+1] + :215.

[0458] [ka] 2-Chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. A methanol (127 mL) solution of methylmethyl 2-(aminomethyl)-6-chloro-5-methylnicotinate (5.46 g, 25.4 mmol) and triethylamine (17.7 mL, 127 mmol) was added to a vial. The solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated by half under vacuum, then the solids were removed by vacuum filtration, and the mixture was washed with MeOH to obtain 1.99 g of the desired product. The filtrate was concentrated under reduced pressure on Celite® and purified by normal-phase column chromatography on silica gel (0-3.5% MeOH / DCM, 1% NH4OH additive) to obtain 138 mg of the desired product. The combined substances yielded 2.13 g of the title compound. 1 H NMR(400MHz,DMSO)δ 8.82(s,1H),8.11(d,J=0.9Hz,1H),4.39(s,2H),2.42(d,J=0.8Hz,3H);ES-MS[M+1] + :183.

[0459] [ka] tert-butyl 3-bromo-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate. At ambient temperature, 10 g of 3-bromo-5,6,7,8-tetrahydro-1,6-naphthiridine dichloride was added to a 150 mL suspension in DCM, to which 12 mL of di-tert-butyl dicarbonate was added, followed by the slow addition of 24.4 mL of DIEA. After stirring at room temperature for 18 hours, the mixture was concentrated under reduced pressure. Purification by normal-phase chromatography (0-50% siRNA / hexane) yielded 10.7 g of the title compound. 1 H NMR(400MHz,CDCl3)δ 8.49(d,J=2.2Hz,1H),7.60(s,1H),4.59(s,2H),3.74(t,J=6.0Hz,2H),2.98(t,J=6.0Hz,2H),1.49(s,9H);ES-MS[M+1] + :313.3 / 315.3.

[0460] [ka] tert-butyl 3-(6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate. The mixture was evenly divided into three microwave vials, and tert-butyl 3-bromo-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate (2.82 g), 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.66 g), NaOtBu (1.73 g), tBuXPhos (382 mg), and tBuXPhos-Pd-G1 (619 mg) were added in 1,4-dioxane (15 mL) and t-BuOH (45 mL) solutions. The solutions were purged with nitrogen and stirred at 100°C for 4 hours. After cooling to ambient temperature, the mixture was filtered through a Celite® pad and thoroughly washed with Â1 / DCM. The filtrate was vacuum concentrated, and the resulting residue was dissolved in DMSO / DMF (1:1) (36 mL). After passing through a syringe filter, the residue was purified by RP-HPLC (10-50% MeCN / 0.1% TFA aqueous solution) to obtain the title compound (3.71 g). 1 H NMR(400MHz,DMSO-d6)δ 8.49(d,J=2.6Hz,1H),7.86(d,J=2.6Hz,1H),7.30(d,J=2.1Hz,1H),5.80(d,J=2.1Hz,1H),4.61(s,2H),4.13(t,J=6.2Hz, 2H),3.91-3.70(m,2H),3.67(t,J=5.9Hz,2H),2.91(t,J=5.9Hz,2H),2.21(p,J=6.1Hz,2H),1.43(s,9H);ES-MS[M+1-TFA] + :356.5.

[0461] [ka] 3-(6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine dihydrochloride. To a solution of tert-butyl 3-(6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-yl)-7,8-dihydro-1,6-naphthirizine-6(5H)-carboxylate (3.72 g) in DCM (50 mL), TFA (10 mL) was added, and the solution was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under vacuum, and the crude substance was suspended in THF (10 mL). A 4M HCl solution (20 mL) in 1,4-dioxane was added, and the mixture was stirred for 30 minutes, then concentrated under vacuum. The residue was then azeotropically removed with MeOH (3x) to remove excess solvent. The solid was dried in a vacuum oven to obtain 1.85 g of the title compound, which was then removed without further purification before proceeding to the next step: ES-MS[M+1-2·HCl] + :256.2.

[0462] [ka] 1-(5,6,7,8-tetrahydro-1,6-naphthirizine-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine. tert-butyl 3-bromo-7,8-dihydro-5H-1,6-naphthirizine-6-carboxylate (2.82 g, 9.0 mmol), 8-azabenzomorpholine (1.47 g, 10.8 mmol), tert-butoxide sodium (1.73 g, 18 mmol), t-BuXPhos paradacycle Gen1 (928 mg, 1.35 mmol), t-BuXPhos (573 mg, 1.35 mmol), 1,4-dioxane (9.0 mL), and t-BuOH (27 mL) were combined in a vial and degassed (3x). The reaction mixture was heated at 100°C for 2.5 hours. The reaction mixture was filtered through Celite®, rinsed with DCM, and concentrated. The crude oily substance was purified by reverse-phase chromatography (5-45% MeCN / water / 0.1% TFA aqueous solution). The desired fraction was concentrated, and the residue was dissolved in DCM (40 mL) and TFA (2.07 mL). After 2 hours, the solvent was removed, diluted with MeOH, and packed onto an SCX cartridge (HF bonded). The cartridge was washed with MeOH, and the title compound (1.2 g) was eluted with 7N NH3 in MeOH. ES-MS[M+H] + = 269.5.

[0463] [ka] Prepared in the same manner as 3-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine. Also prepared by 1-(5,6,7,8-tetrahydro-1,6-naphthiridine-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine. ES-MS[M+H] + = 270.4.

[0464] [ka] 3-(2-fluorophenoxy)-5,6,7,8-tetrahydro-1,6-naphthiridine. In a microwave vial, tert-butyl 3-bromo-7,8-dihydro-5H-1,6-naphthiridine-6-carboxylate (3.0 g, 9.58 mmol), 2-fluorophenol (2.15 g, 19.2 mmol), cesium carbonate (6.28 g, 19.2 mmol), dipivaloylmethane (200 μL, 0.96 mmol), and copper(I) iodide (91.2 mg, 0.48 mmol) were added. After degassing the solids, NMP (48 mL) was added. The resulting solution was stirred at 140 °C for 18 hours. The reaction mixture was filtered through Celite®, washed with DCM, and concentrated. The obtained solution was passed through a syringe filter and purified by reverse-phase HPLC (5-45% MeCN / 0.1% TFA aqueous solution). The desired fraction was concentrated, and the residue was dissolved in DCM (48 mL) and TFA (7.34 mL, 95.8 mmol). After 1 hour, the reaction product was concentrated, purified using an SCX cartridge (10 G), washed with MeOH, and eluted with 7N NH3 / MeOH to obtain the title compound (950 mg). ES-MS[M+H] + = 245.4.

[0465] [ka] tert-butyl8-methyl-3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate. To a solution of N-Boc-3-methyl-4-piperidone (400 mg) in THF (8 mL) (-15°C), a solution of 1 M lithium bis(trimethylsilyl)amide (1.88 mL) was added dropwise. The reaction mixture was warmed to room temperature for 1.5 hours, and then added to a suspension of [(Z)-3-(dimethylamino)-2-(trifluoromethyl)prop-2-enilidene]dimethylammonium hexafluorophosphate (638 mg) in THF (5 mL) at -15°C. The resulting mixture was stirred at -15°C for 2 hours, then acetic acid (0.161 mL) was added, and the mixture was warmed to room temperature. After 1 hour, ammonium acetate (413 mg) was added, and the mixture was heated at 65°C for 2 hours. The mixture was cooled, diluted with water, and extracted with diethyl ether. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-50% siRNA / hexane) on silica gel to obtain the title compound (60 mg). ES-MS[M+1] + :317.2.

[0466] [ka] 8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine; 2,2,2-trifluoroacetic acid. To a vial, tert-butyl8-methyl-3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthiridine-6-carboxylate (60 mg), DCM (0.9 mL), and trifluoroacetic acid (0.15 mL) were added. The reaction mixture was stirred for 1 hour and concentrated to obtain the title compound (75 mg). ES-MS[M+1] + :217.2.

[0467] [ka] 1-(2,4-dimethoxybenzyl)piperidine-2,2,6,6-d4-4-ol. Deuterated formaldehyde (7.58 mL, 55.0 mmol) was added to 2,4-dimethoxybenzylamine (3.64 mL, 23.9 mmol). Then trifluoroacetic acid (1.83 mL, 23.9 mmol) was added. The resulting mixture was sonicated for 10 minutes and then stirred at room temperature for 1 hour. Allyltrimethylsilane (4.18 mL, 26.3 mmol) was added to the resulting solution and the reaction was heated at 40°C for 18 hours. The reaction was diluted with water (8 mL) and DCM (8 mL) and solid potassium carbonate (1.67 g, 12.0 mmol) was added. The mixture was stirred for 10 minutes and then extracted with 3:1 CHCl3 / IPA (5x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude oily substance was purified by silica gel chromatography (0-20% MeOH / DCM) to obtain the title compound. 1 H NMR(400MHz,MeOD)δ 7.22(d,J=8.6Hz,1H),6.58(d,J=2.3,1H),6.53(dd,J=8.3,2.4Hz,1H),3.84(s,3H),3.83-3.8 0(m,5H),3.35(s,1H),1.89(dd,J=13.7,3.7Hz,2H),1.65(dd,J=13.6,8.1Hz,2H);ES-MS[M+1] + :256.2.

[0468] [ka] tert-butyl4-hydroxypiperidine-1-carboxylate-2,2,6,6-d4. To a degassed solution of 1-(2,4-dimethoxybenzyl)piperidine-2,2,6,6-d4-4-ol (3.5 g, 13.7 mmol) in methanol (300 mL), palladium hydroxide (0.29 g, 2.1 mmol) and 10% palladium activated carbon (0.22 g, 2.1 mmol) were added. H2 was added to the reaction mixture and the mixture was stirred at 50°C for 48 hours under a pressure of 50 psi. The reaction mixture was filtered through Celite®, washed with methanol, and concentrated under reduced pressure. The solid was combined with 1,4-dioxane (45 mL), acetonitrile (45 mL), and N,N-diisopropylethylamine (2.9 mL, 16.4 mmol). Di-tert-butyl dicarbonate (4.7 mL, 20.5 mmol) was added to the solution, and the reaction mixture was stirred at room temperature. After 3 hours, the reaction mixture was concentrated, and the crude oily substance was purified by normal-phase chromatography (0-20% MeOH / DCM) to obtain the title compound (2.18 g). 1 H NMR(400MHz,MeOD)δ 3.79-3.71(m,1H),1.79(dd,J=13.1,3.8Hz,2H),1.45(s,9H),1.39-1.34(m,2H).

[0469] [ka] tert-butyl 4-oxopiperidine-1-carboxylate-2,2,6,6-d4. Dess-Martin periodinane (6.75 g, 15.9 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate-2,2,6,6-d4 (2.18 g, 10.6 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated with Celite® and then purified by normal-phase chromatography (0-50% siRNA / hexane) to obtain the title compound (1.69 g). 1 H NMR(400MHz,CDCl3)δ 2.42(s,4H),1.49(s,9H).

[0470] [ka] tert-butyl 3-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate-5,5,7,7-d4. Equal amounts of 1-methyl-3,5-dinitro-2-pyridone (1.0 g, 5.1 mmol), tert-butyl 4-oxopiperidine-1-carboxylate-2,2,6,6-d4 (1.0 g, 5.1 mmol), and 2M ammonia-methanol solution (20.2 mL) were combined in four separate microwave vials. The mixture was heated in a microwave reactor at 120°C for 20 min. The reaction product was concentrated with Celite® and then purified by normal-phase chromatography (0-30% siRNA / hexane) to obtain the title compound (1.23 g). 1 H NMR(400MHz,CDCl3)δ 9.25(d,J=2.5Hz,1H),8.23(d,J=2.5,1H),3.11(s,2H),1.50(s,9H);ES-MS[M+1] + :284.1.

[0471] [ka] tert-butyl3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate-5,5,7,7-d4. To a solution of tert-butyl3-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate-5,5,7,7-d4 (1.23 g, 4.3 mmol) in ethanol (10 mL) and THF (10 mL), 10% palladium-activated carbon (527 mg, 4.9 mmol) was added. The mixture was degassed and placed under an H2 balloon at 1 atm for 3 hours. The reaction product was filtered through Celite®, washed with ethanol, and the filtrate was concentrated to obtain the title compound (1.03 g). 1 H NMR(400MHz,CDCl3)δ 7.94(d,J=2.6Hz,1H),6.73(d,J=2.6,1H),3.60(s,2H),2.87(s,2H),1.48(s,9H);ES-MS[M+1] + :254.1.

[0472] [ka] tert-butyl 3-bromo-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4. Copper bromide (767 mg, 3.4 mmol) was added to a solution of tert-butyl 3-amino-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4 (580 mg, 2.3 mmol) in MeCN (8 mL). The reaction mixture was cooled to 0°C, and tert-butyl nitrite (0.33 mL, 2.8 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, and then stirred at room temperature for 5 hours. The mixture was diluted with water and 3:1 CHCl3 / IPA. The layers were separated, and the aqueous layer was re-extracted with 3:1 CHCl3 / IPA (2x). The combined organic phases were washed with brine (2x), dried (MgSO4), filtered, and concentrated. The crude oily substance was purified by normal-phase chromatography (0-40% HCl / hexane) to obtain the title compound (520 mg). 1 H NMR(400MHz,CDCl3)δ 8.47(d,J=2.2Hz,1H),7.56(d,J=2.2,1H),2.93(s,2H),1.48(s,9H);ES-MS[M+1] + :317.1 / 319.1.

[0473] [ka] tert-butyl 3-((3-fluoropyridine-4-yl)amino)-7,8-dihydro-1,6-naphthirizine-6(5H)-carboxylate-5,5,7,7-d4. In a vial, 4-bromo-3-fluoropyridine hydrochloride (415 mg, 1.9 mmol), tert-butyl 3-amino-7,8-dihydro-1,6-naphthirizine-6(5H)-carboxylate-5,5,7,7-d4 (330 mg, 1.3 mmol), tris(dibenzylideneacetone)dipalladium (0) (119 mg, 0.1 mmol), xanthophos (113 mg, 0.2 mmol), and cesium carbonate (1.7 g, 5.2 mmol) were combined in 1,4-dioxane (6.5 mL). The reaction mixture was degassed and heated at 100°C for 2 hours. The mixture was cooled, filtered through a Celite® pad, and washed with 3:1 CHCl3 / IPA. After removing the solvent, the crude product was purified by normal-phase chromatography (0-5% MeOH / DCM) to obtain the title compound (314 mg). 1 H NMR(400MHz,CDCl3)δ 8.38(d,J=2.5Hz,1H),8.32(d,J=2.9Hz,1H),8.13(d,J=5.5Hz,1H),7.33(d,J=2.5H z,1H),6.94(dd,J=7.0,5.8,1H),6.24(s,1H),3.00(s,2H),1.50(s,9H);ES-MS[M+1] + :349.3.

[0474] [ka] N-(3-fluoropyridine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-5,5,7,7-d4-3-amine. In a vial, tert-butyl3-((3-fluoropyridine-4-yl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4 (314 mg, 0.9 mmol), trifluoroacetic acid (1.07 mL, 14.0 mmol), and DCM (4 mL) were combined. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, purified using an SCX cartridge, and eluted with 2N NH3 / MeOH solution. The solvent was removed to obtain the title compound (178 mg). 1 H NMR(400MHz,CDCl3)δ 8.30(d,J=2.5Hz,1H),8.23(s,1H),8.17(d,J=5.7Hz,1H),7.22(d,J=2.6Hz,1H),6.79(d,J=5.6,1H),5.68(s,1H),2.94(s,2H);ES-MS[M+1] + :249.3.

[0475] [ka] tert-butyl 3-((3-methylpyridine-4-yl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4. In a vial, 4-bromo-3-methylpyridine hydrochloride (407 mg, 1.95 mmol), tert-butyl 3-amino-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4 (330 mg, 1.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (119 mg, 0.13 mmol), xanthophos (113 mg, 0.2 mmol), and cesium carbonate (1700 mg, 5.21 mmol) were combined in 1,4-dioxane (6.5 mL). The mixture was heated at 100°C for 2 hours. The mixture was cooled, filtered through a Celite® pad, and washed with 3:1 CHCl3 / IPA. After removing the solvent, the crude product was purified by normal-phase chromatography (0-10% MeOH / DCM) to obtain the title compound (366 mg). ES-MS[M+1] + :345.3.

[0476] [ka] N-(3-methylpyridine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-5,5,7,7-d4-3-amine. In a vial, tert-butyl3-((3-methylpyridine-4-yl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4 (366 mg, 1.06 mmol), trifluoroacetic acid (1.30 mL, 17.0 mmol), and DCM (4 mL) were combined. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with a 3:1 CHCl3:IPA and saturated Na2CO3 solution. The layers were separated, and the aqueous layer was extracted (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated to obtain the title compound (258 mg). 1H NMR(400MHz,CDCl3)δ 8.31(d,J=2.6Hz,1H),8.26-8.21(m,1H),8.18(d,J=5.6Hz,1H),7.22(d,J=2.6H z,1H),6.80(d,J=5.7Hz,1H),5.69(s,1H),2.95(s,2H),2.25(s,3H);ES-MS[M+1] + :245.3.

[0477] [ka] tert-butyl 3-(3,5-dimethylisoxazole-4-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4. 200 mg, 0.63 mmol, 169 mg, 0.76 mmol, cesium carbonate (413 mg, 1.26 mmol), and Pd(dppf)Cl2 (69 mg, 0.09 mmol) were added to 2.5 mL of 1,4-dioxane and 0.5 mL of water, and the mixture was degassed (3x). The reaction mixture was heated at 100 °C for 2.5 hours. The mixture was filtered through a Celite® pad, washed with  / DCM, and the filtrate was concentrated under reduced pressure. The oily substance was purified by normal-phase chromatography (0-4% MeOH / DCM) to obtain the title compound (202 mg). 1 H NMR(400MHz,CDCl3)δ 8.34(d,J=2.0Hz,1H),7.31(d,J=2.1Hz,1H),3.04(s,2H),2.41(s,3H),2.27(s,3H),1.51(s,9H);ES-MS[M+1] + :334.1.

[0478] [ka] 3,5-dimethyl-4-(5,6,7,8-tetrahydro-1,6-naphthirizine-3-yl-5,5,7,7-d4) isoxazole. tert-butyl3-(3,5-dimethylisoxazole-4-yl)-7,8-dihydro-1,6-naphthirizine-6(5H)-carboxylate-5,5,7,7-d4 (200 mg, 0.6 mmol) was combined with DCM (3 mL) and trifluoroacetic acid (0.69 mL, 9.0 mmol). After 2 hours, the reaction was complete and the mixture was concentrated under vacuum. The crude oil was purified using an SCX cartridge, washed with MeOH, and the compound was eluted with a 7N NH3 / MeOH solution. The solvent was removed to obtain the title compound (114 mg). 1 H NMR(400MHz,CDCl3)δ 8.31(d,J=2.2Hz,1H),7.20(d,J=2.2Hz,1H),2.98(s,2H),2.39(s,3H),2.25(s,3H);ES-MS[M+1] + :234.3.

[0479] [ka] tert-butyl 3-((2-fluorophenyl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4. In a vial, xanthophos (86 mg, 0.15 mmol), 2-fluorobromobenzene (0.16 mL, 1.48 mmol), tert-butyl 3-amino-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4 (250 mg, 0.99 mmol), tris(dibenzylideneacetone)dipalladium (0) (90 mg, 0.1 mmol), and cesium carbonate (1294 mg, 3.95 mmol) were combined in 1,4-dioxane (6.5 mL). The container was degassed (3x) and heated at 100°C for 2 hours. The mixture was cooled, filtered through a Celite® pad, and washed with 3:1 CHCl3 / IPA. After removing the solvent, the crude product was purified by normal-phase chromatography (0-7% MeOH / DCM) to obtain the title compound (407 mg). ES-MS[M+1] + :348.4.

[0480] [ka] N-(2-fluorophenyl)-5,6,7,8-tetrahydro-1,6-naphthiridine-5,5,7,7-d4-3-amine. In a vial, tert-butyl 3-((2-fluorophenyl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4 (407 mg, 1.17 mmol), trifluoroacetic acid (1.39 mL, 18.2 mmol), and DCM (4.7 mL) were combined. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with a 3:1 CHCl3:IPA and saturated Na2CO3 solution. The layers were separated, and the aqueous layer was extracted (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated to obtain the title compound (241 mg). 1 H NMR(400MHz,CDCl3)δ 8.26(d,J=2.7Hz,1H),7.23-6.96(m,5H),6.92-6.82(m,1H),5.71(s,1H),2.90(s,2H);ES-MS[M+1] + :248.2.

[0481] [ka] tert-butyl 3-(1-methyl-1H-pyrazole-5-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4. tert-butyl 3-bromo-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate-5,5,7,7-d4 (170 mg, 0.54 mmol), 1-methylpyrazole-5-boronic acid pinacol ester (133 mg, 0.64 mmol), cesium carbonate (351 mg, 1.07 mmol), and Pd(dppf)Cl2 (59 mg, 0.08 mmol) were combined in 1,4-dioxane (2.5 mL) / water (0.5 mL). The container was degassed, and the reaction mixture was heated at 100 °C for 2.5 hours. After cooling, the mixture was filtered through a Celite® pad and thoroughly washed with  / DCM. The filtrate was concentrated under reduced pressure. The residue was purified by normal-phase chromatography (0-5% MeOH / DCM) to obtain the title compound (109 mg). ES-MS[M+1] + :319.3.

[0482] [ka] 3-(1-methyl-1H-pyrazole-5-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine-5,5,7,7-d4. tert-butyl3-(1-methyl-1H-pyrazole-5-yl)-7,8-dihydro-1,6-naphthirizine-6(5H)-carboxylate-5,5,7,7-d4 (109 mg, 0.34 mmol) was combined with DCM (2.3 mL) and trifluoroacetic acid (0.39 mL, 5.1 mmol). After 2 hours, the reaction product was concentrated. The crude residue was purified using an SCX cartridge, washed with MeOH, and eluted with 7NNH3 / MeOH solution. The solvent was removed to obtain the title compound (71 mg). ES-MS[M+1] + :219.1.

[0483] [ka] In a vial, cesium carbonate (942 mg, 2.9 mmol) in 1,4-dioxane / water (11 mL; 5:1), tert-butyl 3-bromo-7,8-dihydro-1,6-naphthirizine-6(5H)-carboxylate (300 mg, 0.96 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (532 mg, 2.4 mmol), and Pd(dppf)Cl2 (70 mg, 0.10 mmol) were mixed. The mixture was stirred at 80°C for 20 hours. After cooling to room temperature, the reaction mixture was filtered with Celite®, washed with DCM / MeOH, and concentrated. Purification by normal-phase column chromatography (0-60% MeOH / DCM) on silica gel yielded 292 mg of the title compound. ES-MS[M+1] + :329.

[0484] [ka] 3-(1,3-dimethyl-1H-pyrazole-5-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine hydrochloride. To a solution of tert-butyl 3-(1,3-dimethyl-1H-pyrazole-5-yl)-7,8-dihydro-1,6-naphthirizine-6(5H)-carboxylate (314 mg, 0.96 mmol) in DCM (4.8 mL), hydrochloric acid (4 M in 1,4-dioxane) (1.2 mL, 4.78 mmol) was added, the mixture was stirred for 18 hours, and then concentrated under vacuum. The process was carried out without further purification of the substance. ES-MS[M+1] + :229.

[0485] [ka] In a vial, cesium carbonate (942 mg, 2.9 mmol), tert-butyl 3-bromo-7,8-dihydro-1,6-naphthirizine-6(5H)-carboxylate (300 mg, 0.96 mmol), 2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (489 mg, 1.9 mmol), and Pd(dppf)Cl2 (70 mg, 0.10 mmol) were mixed in 1,4-dioxane / water (11 mL; 5:1). The mixture was stirred at 90°C for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered with Celite®, washed with chloroform / IPA (3:1), and concentrated. Purification by normal-phase column chromatography (0-80% Â / DCM) on silica gel yielded 318 mg of the title compound. ES-MS[M+1] + :362; 1 H NMR(400MHz,MeOD)δ 8.72(dd,J=4.8,1.6Hz,1H),8.39(d,J=2.2Hz,1H),7.93-7.89(m,1H),7.74-7.60(m,2H),6. 72(t,J=53.9Hz,1H),4.70(s,2H),3.82(t,J=6.0Hz,2H),3.04(t,J=6.0Hz,2H),1.51(s,9H).

[0486] [ka] 3-(2-(difluoromethyl)pyridine-3-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine. To a solution of tert-butyl 3-(2-(difluoromethyl)pyridine-3-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate (346 mg, 0.96 mmol) in DCM (3.2 mL), trifluoroacetic acid (730 μL) was added, and the mixture was stirred for 18 hours, then concentrated under vacuum. The substance was dissolved in MeOH and purified by strong cation exchange chromatography to obtain the title compound. ES-MS[M+1]+ :262; 1 H NMR(400MHz,MeOD)δ 8.71(dd,J=4.8,1.6Hz,1H),8.36(d,J=2.2Hz,1H),7.90(ddt,J=7.9,1.6,0.8Hz,1H),7.67(ddt,J=7.9,4.7,0.9Hz,1H),7.59(d,J=2.2Hz,1H),

[0487] [ka] 4-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. In a vial, 5-bromo-4-fluoro-1-methyl-1H-pyrazole (375 mg, 2.1 mmol), potassium acetate (617 mg, 6.29 mmol), bis(pinacorato)diborone (798 mg, 3.14 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (154 mg, 0.21 mmol) were added in 1,4-dioxane (11 mL). The vial was heated at 85°C for 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, followed by filtration through Celite® and concentration. The substance was proceeded to the next stage without further purification. ES-MS[M+1] + :145.1.

[0488] [ka] 3-(4-fluoro-1-methyl-1H-pyrazole-5-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine. A mixture of tert-butyl 3-bromo-7,8-dihydro-5H-1,6-naphthirizine-6-carboxylate (532 mg, 1.7 mmol), 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (461 mg, 2.0 mmol), cesium carbonate (1.67 g, 5.1 mmol), and Pd(dppf)Cl2 (125 mg, 0.17 mmol) in 1,4-dioxane (7 mL) and water (0.7 mL) was added to a vial. The mixture was stirred at 90°C for 18 hours, filtered through Celite®, and washed with ethylacetate (50 mL). Next, the organic matter was washed with sat.NaHCO3 and concentrated. The crude residue was purified using silica gel chromatography (0-100% MeOH / DCM). The intermediate was dissolved in DCM (7 mL) and trifluoroacetic acid (1.3 mL) was added. After 18 hours at rt, the reaction product was concentrated. The crude residue was purified using an SCX cartridge (HF bonded), packed and washed with MeOH, and eluted with 2N NH3 in MeOH. The solvent was removed to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 8.49(d,J=2.1Hz,1H),7.44-7.39(m,2H),4.14(s,2H),3.83(d,J=0.7Hz,3H),3.33(t,J=6.1Hz,2H),3.07(t,J=6.0Hz,2H).ES-MS[M+1] + :233.3.

[0489] [ka] tert-butyl 3-((3-methylpyridine-4-yl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-carboxylate. In a microwave vial, 250 mg, 0.8 mmol of tert-butyl 3-bromo-7,8-dihydro-5H-1,6-naphthiridine-6-carboxylate, 129 mg, 1.2 mmol of 4-amino-3-methylpyridine, 785 mg, 2.39 mmol of cesium carbonate, 73 mg, 0.08 mmol of tris(dibenzylideneacetone)dipalladium (0), and 69 mg, 0.12 mmol of xanthophos were added in 4 mL of 1,4-dioxane. The reaction mixture was degassed (3x) and heated at 100°C for 18 hours. The reaction mixture was cooled, filtered through a Celite® plug, rinsed with 3:1 CHCl3 / IPA, and concentrated. The crude residue was purified by normal-phase chromatography to obtain the title compound (265 mg). 1 H NMR(400MHz,CDCl3)δ 8.35(d,J=2.5Hz,1H),8.23(d,J=25.8Hz,2H),7.32(d,J=2.5Hz,1H),6.83(s,1H),6.05(s,1H), 4.61(s,2H),3.78(t,J=6.0Hz,2H),3.01(t,J=6.0Hz,2H),2.28(s,3H),1.50(s,9H);ES-MS[M+1] + :341.2.

[0490] [ka] N-(3-methylpyridine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-3-amine. tert-butyl 3-[(3-methylpyridine-4-yl)amino]-7,8-dihydro-5H-1,6-naphthiridine-6-carboxylate (204 mg, 0.6 mmol) was combined with DCM (3 mL) and trifluoroacetic acid (0.69 mL). After 2 hours, the reaction product was concentrated. The crude residue was purified using an SCX cartridge, washed with MeOH, and eluted with 7NNH3 / MeOH solution. The solvent was removed to obtain the title compound (158 mg). ES-MS[M+1] + :241.2.

[0491] [ka] 2-(3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. Prepared in the same manner as compound 2, to obtain the desired compound. ES-MS[M+1] + :359 / 361; 1 H NMR(400MHz,MeOD)δ 8.46(d,J=2.2Hz,1H),7.88(d,J=2.3Hz,1H),7.85(d,J=0.9Hz,1H),4.34(s,2H), 3.67(t,J=5.9Hz,2H),3.35(s,2H),3.10(t,J=5.9Hz,2H),2.45(d,J=0.8Hz,3H).

[0492] [ka] 3-Methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-1,6-naphthirizine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. The vial contained 2-(3-bromo-7,8-dihydro-1,6-naphthirizine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (80 mg, 0.22 mmol), bis(pinacorato)diborone (85 mg, 0.33 mmol), Pd(dppf)Cl2 (16 mg, 0.02 mmol), and potassium acetate (66 mg, 0.67 mmol). After flushing the vial with nitrogen, degassed 1,4-dioxane (1.1 mL) was added, and the reaction mixture was heated at 90°C for 18 hours. The reaction mixture was filtered through Celite®, rinsed with 3:1 CHCl3 / IPA, and concentrated. The process was carried out without further purification of the substance. ES-MS[M+1] + :325 (mass of boronic acid).

[0493] [ka] 2-(3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. The title compound was obtained by preparation in the same manner as for compound 8. ES-MS[M+1] + :373 / 375; 1 H NMR(400MHz,CDCl3)δ 8.55(s,1H),7.84(s,1H),7.80(s,1H),4.56(s,2H),4.29(s,2H),3.59(t,J=5.9Hz,2H),3.32-3.24(m,2H),3.19(s,3H),2.40(s,3H).

[0494] [ka] 3-Bromo-2-(3-(2-(difluoromethyl)pyridine-3-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-yl)flou[3,4-b]pyridine-5(7H)-one (intermediate A). A solution of 3-(2-(difluoromethyl)pyridine-3-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine (49 mg, 0.19 mmol), 3-bromo-2-chloroflou[3,4-b]pyridine-5(7H)-one (36 mg, 0.14 mmol), and N,N-diisopropylethylamine (252 μL, 1.45 mmol) in NMP (0.5 mL) was heated at 160 °C for 16 hours. After completion, the reaction mixture was cooled to ambient temperature and then added to water. A precipitate formed, and the solid was collected by vacuum filtration to obtain 61 mg of the title compound. The process was carried out without further purification of the substance. ES-MS[M+1] + :473 / 475. - -

[0495] [ka] 3-Bromo-2-(3-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)furo[3,4-b]pyridin-5(7H)-one. To a solution of 3-(4-fluoro-2-methylpyrazol-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine (19 mg, 0.08 mmol) in NMP (0.5 mL) were added 3-bromo-2-chloro-7H-furo[3,4-b]pyridin-5-one (20 mg, 0.07 mmol) and N,N-diisopropylethylamine (0.04 mL, 0.22 mmol). The mixture was heated at 50 °C for 18 h. The reaction mixture was added to water and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The material was carried on to the next step without further purification. ES-MS [M+1] + : 444.1.

[0496]

Chemical Structure

[0497]

Chemical Structure

[0498] [ka] (S)-3-bromo-6-(1-methoxypropan-2-yl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. (S)-3-bromo-2-chloro-6-(1-methoxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (30 mg, 0.09 mmol) was dissolved in DMSO (0.5 mL), to which 7-(trifluoromethyl)-2,5-diazatetraline dihydrochloride (28.4 mg, 0.1 mmol) and N,N-diisopropylethylamine (98 μL, 0.56 mmol) were added. The mixture was heated at 70 °C for 48 hours. After cooling to rt, the mixture was poured into water and extracted with ethyl(3x). The organic matter was pooled, dried over Na2SO4, filtered, and concentrated. The residue was purified using reverse-phase HPLC (20-60% MeCN / 0.05% NH4OH aqueous solution). The fraction containing the desired product was concentrated to obtain the title compound (26 mg). 1 H NMR(400MHz,CDCl3)δ 8.72(d,J=2.0Hz,1H),8.21(s,1H),7.70(d,J=2.2Hz,1H),4.73-4.63(m,1H),4.68(s,2H),4.34(q,2H),3. 85(t,J=5.8Hz,2H),3.60-3.46(m,2H),3.34(s,3H),3.34-3.30(m,2H),1.31(d,J=7.0Hz,3H).ES-MS[M+1] + :485.2 / 487.2.

[0499] [ka] (R)-3-bromo-6-(1-methoxypropan-2-yl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. (S)-3-bromo-6-(1-methoxypropan-2-yl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. Prepared by the same method. ES-MS[M+1] + :485.2 / 487.2.

[0500] [ka] 3-bromo-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-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 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (10 mg, 0.06 mmol) and N,N-diisopropylethylamine (55 μL, 0.32 mmol) were added. The mixture was heated at 50 °C for 18 hours. The mixture was poured into water and extracted with ELISA (3x). The organic matter was pooled, dried over MgSO4, filtered, and concentrated. The crude residue was purified using normal-phase column chromatography (containing 0-5% MeOH / DCM and 1% NH4OH) to obtain the title compound (19 mg). 1 H NMR(400MHz,CDCl3)δ 8.73(d,J=2.2Hz,1H),8.11(s,1H),7.73(d,J=2.3Hz,1H),4.80(s,2H),3.97(t, J=5.9Hz,2H),3.35(t,J=5.9Hz,2H),3.11-3.04(m,2H),2.79-2.72(m,2H).[M+1]+ :412 / 414.

[0501] [ka] Methyl 2-iodo-5-methyl-6-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthirizine-6(5H)-yl)nicotinate. 500 mg, 1.6 mmol of methyl 6-chloro-2-iodo-5-methylnicotinic acid (500 mg, 1.6 mmol) was dissolved in DMF (7 mL) and 662 mg, 2.4 mmol, and N,N-diisopropylethylamine (1.7 mL, 9.6 mmol) were added. The mixture was heated at 50°C for 48 hours. The reaction product was diluted with water (approximately 100 mL) and extracted with toluene (3x). The combined organic matter was dried (MgSO4), filtered, and concentrated. Purification by normal-phase column chromatography (0-30% toluene / Hex) on silica gel yielded 239 mg of the title compound. ES-MS[M+1] + :478.

[0502] [ka] Methyl 5-methyl-2-(pyrazine-2-yl)-6-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)nicotinate. Methylmethyl 2-iodo-5-methyl-6-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)nicotinate (239 mg, 0.5 mmol) and 2-(tributylstannyl)pyrazine (277 mg, 0.75 mmol) were dissolved in toluene (7.7 mL), to which tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.05 mmol) was added. The reaction mixture was stirred at 100 °C for 18 hours under an inert atmosphere. The mixture was cooled to room temperature, and 2-(tributylstannyl)pyrazine (277 mg, 0.75 mmol) was added, and the reaction mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with toluene (3x). The combined organic matter was washed with water (20 mL x 3), dried, filtered, and concentrated. Purification by normal-phase column chromatography (0-60% toluene / Hex) on silica gel yielded 140 mg of the title compound. ES-MS[M+1] + :430; 1 H NMR(400MHz,CDCl3)δ 9.13(d,J=1.5Hz,1H),8.81(s,1H),8.60(d,J=2.6Hz,1H),8.60-8.54(m,1H),8.17(s,1H),7 .90(s,1H),4.78(s,2H),3.76(s,3H),3.69(t,J=5.8Hz,2H),3.66-3.51(m,2H),2.44(s,3H).

[0503] [ka] 3-Bromo-6-(2-chloro-5-methylpyrimidine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine (intermediate B). 800 mg, 3.2 mmol of 3-bromo-5,6,7,8-tetrahydro-1,6-naphthirizine hydrochloride was dissolved in 9.7 mL of DMF. Triethylamine (2.2 mL, 16.0 mmol) and 2,4-dichloro-5-methylpyrimidine (575 mg, 3.5 mmol) were added. The mixture was stirred at room temperature for 18 hours. The mixture was then diluted with water, and the precipitate was collected by vacuum filtration to obtain 857 mg of the title compound. ES-MS[M+1] + :339 / 341; 1 H NMR(400MHz,MeOD)δ 8.47(d,J=2.2Hz,1H),8.01(d,J=0.9Hz,1H),7.92(d,J=2.2Hz,1H),4.81( s,2H),3.94(t,J=5.9Hz,2H),3.09(t,J=5.9Hz,2H),2.35(d,J=0.9Hz,3H).

[0504] [ka] 6-(2-chloro-5-methylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine. The title compound was obtained by preparation in the same manner as for intermediate B. ES-MS[M+1] + :329; 1 H NMR(400MHz,CDCl3)δ 8.73(d,J=1.2Hz,1H),8.05(q,J=0.8Hz,1H),7.74(d,J=1.5Hz,1H),4.78( s,2H),3.87(t,J=5.9Hz,2H),3.26(t,J=5.9Hz,2H),2.32(d,J=0.9Hz,3H).

[0505] [ka] 6-(2,6-dichloro-5-methylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine. 2,4,6-trichloro-5-methylpyrimidine (110 mg, 0.55 mmol) was dissolved in DMSO (1.5 mL), to which 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine (139 mg, 0.54 mmol) and N,N-diisopropylethylamine (352 μL, 2.52 mmol) were added. The mixture was heated at 70°C for 18 hours. The mixture was poured into water and extracted with RINKAN (3x). The organic matter was pooled, dried over MgSO4, filtered, and concentrated. The crude residue was purified by normal-phase column chromatography (0-80% RINKAN / hexane) to obtain the title compound (140 mg).

[0506] [ka] 3-Bromo-6-(2-hydrazinyl-5-methylpyrimidine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine (intermediate C). Hydrazine (370 μL, 11.8 mmol) was added to a solution of 3-bromo-6-(2-chloro-5-methylpyrimidine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine (200 mg, 0.59 mmol) in ethanol (4.0 mL), and the mixture was stirred at 80°C for 4 hours. After cooling to room temperature, the mixture was concentrated under vacuum and the process proceeded without further purification. ES-MS[M+1] + :335 / 337.

[0507] [ka] 6-(2-hydrazinyl-5-methylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine: Prepared in the same manner as intermediate C to obtain the title compound. ES-MS[M+1] + :325.

[0508] [ka] 6-(6-chloro-2-hydrazinyl-5-methylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthirizine. Hydrazine (0.17 mL, 5.51 mmol) was added to a vial containing 6-(2,6-dichloro-5-methylpyrimidine-4-yl)-3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthirizine (100 mg, 0.28 mmol) in ethanol (10 mL), and the mixture was stirred at 40°C for 6 hours. After cooling to room temperature, the mixture was concentrated under vacuum and the process proceeded without further purification. ES-MS[M+1] + :335 / 337.

[0509] [ka] 7-(3-bromo-7,8-dihydro-1,6-naphthiridine-6(5H)-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (intermediate D). 3-bromo-6-(2-hydrazinyl-5-methylpyrimidine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine (557 mg, 1.7 mmol) was dissolved in 1,4-dioxane (2.9 mL) and 1,1'-carbonyldiimidazole (431 mg, 2.7 mmol) was added. The reaction mixture was heated at 80°C for 18 hours, after which the mixture was cooled to ambient temperature. The mixture was then diluted with water, and the precipitate was collected by vacuum filtration to obtain 425 mg of the title compound. ES-MS[M+1] + :361 / 363; 1 H NMR(400MHz,CDCl3)δ 8.53(d,J=2.2Hz,1H),8.50(s,1H),7.69(d,J=1.4Hz,1H),7.63(d,J=2.2Hz,1H), 4.71(s,2H),3.81(t,J=5.9Hz,2H),3.16(t,J=5.9Hz,2H),2.31(d,J=1.3Hz,3H).

[0510] [ka] 7-(3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (intermediate E). Potassium carbonate (155 mg, 1.11 mmol) was added to a solution of 7-(3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (200 mg, 0.55 mmol) in DMF (5.5 mL), followed by iodomethane (52 μL, 0.83 mmol). The mixture was heated at 50 °C for 18 hours. After cooling to ambient temperature, the reaction product was diluted with water and extracted with ELISA (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated to obtain 170 mg of the title compound. The process was carried out without further purification of the substance. ES-MS[M+1] + :375 / 377; 1 H NMR(400MHz,CDCl3)δ 8.52(d,J=2.3Hz,1H),7.68(q,J=1.3Hz,1H),7.61(d,J=2.2Hz,1H),4.69(s,2H), 3.79(t,J=5.9Hz,2H),3.58(s,3H),3.15(t,J=5.8Hz,2H),2.30(d,J=1.2Hz,3H).

[0511] [ka] 2,4-Dichloro-6-cyclopropyl-5-methylpyrimidine. A solution of 2,4-dichloro-5-methylpyrimidine (1.0 g, 6.1 mmol), silver nitrate (521 mg, 3.1 mmol), and cyclopropanecarboxylic acid (1.47 mL, 18.4 mmol) in water (31 mL) was heated to 72°C. Ammonium persulfate (2.1 g, 9.2 mmol) was gradually added over 15 minutes. After heating at 72°C for a further 20 minutes, sulfuric acid (491 μL, 9.2 mmol) was added, and the mixture was heated at 90°C for 1 hour. After cooling to ambient temperature, the reaction mixture was slowly poured into a solution of saturated bicarbonate aqueous solution and DCM, and stirred for a further 20 minutes. The organic layer was separated, and the aqueous layer was further extracted with DCM (3x). The combined organic layers were dried over (MgSO4), filtered, and concentrated. The title compound (872 mg) was obtained by purification by normal-phase column chromatography (0-25% siRNA / hexane). ES-MS[M+1]+:203 / 205; 1 H NMR(400MHz,CDCl3)δ 2.45(s,3H),2.11(tt,J=7.9,4.6Hz,1H),1.29-1.23(m,2H),1.18-1.12(m,2H).

[0512] [ka] 6-(2-chloro-5,6-dimethylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine. The title compound was obtained by preparation in the same manner as for intermediate B. ES-MS[M+1]+:343; 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),7.72(s,1H),4.65(s,2H),3.69(t,J=5.9Hz,2H),3.27(t,J=5.9Hz,2H),2.44(s,3H),2.22(s,3H).

[0513] [ka] 6-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine. The title compound was obtained by preparation in the same manner as for intermediate B. ES-MS[M+1]+:355; 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),7.74(s,1H),4.98(s,2H),4.07(t,J=6.0Hz,2H),3.20(t,J=6.0 Hz,2H),3.11(t,J=7.3Hz,2H),2.89(t,J=7.9Hz,2H),2.13(p,J=7.7Hz,2H).

[0514] [ka] 6-(2-chloro-6-cyclopropyl-5-methylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine. The title compound was obtained by preparation in the same manner as for intermediate B. ES-MS[M+1]+:369; 1 H NMR(400MHz,CDCl3)δ 8.72(dd,J=2.2,0.8Hz,1H),7.71(dd,J=2.0,0.9Hz,1H),4.62(s,2H),3.66(t,J=5.9Hz,2H), 3.27(t,J=5.9Hz,2H),2.33(s,3H),2.07-1.96(m,1H),1.24-1.14(m,2H),1.08-0.99(m,2H).

[0515] [ka] 6-(2-hydrazinyl-5,6-dimethylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine. The title compound was obtained by preparation in the same manner as for intermediate C. ES-MS[M+1] + :339.

[0516] [ka] 6-(2-hydrazinyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine. The title compound was obtained by preparation in the same manner as for intermediate C. ES-MS[M+1] + :351.

[0517] [ka] 6-(6-cyclopropyl-2-hydrazinyl-5-methylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine. The title compound was obtained by preparation in the same manner as for intermediate C. ES-MS[M+1] + :365.

[0518] [ka] 2,4,5-Trimethylpyridine-3-yltrifluoromethanesulfonate. A 21 mL solution of 2,4,5-trimethylpyridine-3-ol (1.0 g, 7.29 mmol), triethylamine (2.03 mL, 14.6 mmol), and 4-dimethylaminopyridine (178 mg, 1.46 mmol) in DCM was cooled to 0°C, and N-phenylbis(trifluoromethanesulfonimide) (2.76 g, 7.73 mmol) was added. The solution was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated using Celite® and purified by normal-phase chromatography (0-15% siRNA / Hex) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 8.25(s,1H),2.57(s,3H),2.30(s,3H),2.28(s,3H).ES-MS[M+1] + :270.

[0519] [ka] Ethyl 2,4,5-trimethylnicotinate. Triethylamine (9.8 mL, 70.6 mmol), 1,3-bis(diphenylphosphin)propane (437 mg, 1.06 mmol), and palladium(II) acetate (240 mg, 1.06 mmol) were added to a solution of 2,4,5-trimethylpyridine-3-yltrifluoromethanesulfonate (1.9 g, 7.06 mmol) in ethanol (12 mL) and DMSO (6 mL). The mixture was then CO2-100. (g) The mixture was placed under a (50 psi) atmosphere and heated at 80°C for 18 hours. The reaction mixture was filtered through a Celite® pad, washed with DCM / MeOH, and concentrated. The residue was then diluted with water (approximately 150 mL) and extracted with ÃO(4x). The combined organic layers were dried over (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-60% ÃO / Hex) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 8.25(s,1H),4.42(q,J=7.1Hz,2H),2.49(s,3H),2.23(s,3H),2.21(s,3H),1.40(t,J=7.1Hz,3H).ES-MS[M+1] + :194.

[0520] [ka] Ethyl 2-(chloromethyl)-4,5-dimethylnicotinate. Trichloroisocyanuric acid (1085 mg, 4.67 mmol) was added to a solution of ethyl 2,4,5-trimethylnicotinate (752 mg, 3.89 mmol) in DCM (19.5 mL), and the mixture was stirred at ambient temperature for 12 hours. Additional TCICA (226 mg, 0.97 mmol) was added, and the mixture was stirred for a further 18 hours. Additional TCICA (300 mg, 1.29 mmol) was added, and the mixture was stirred for 3 hours. The pH was adjusted to 8 with saturated Na2CO3 aqueous solution. The organic layer was separated, and the aqueous layer was further extracted with DCM (3x). The combined organic matter was dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-5% MeOH / DCM) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 8.35(s,1H),4.71(s,2H),4.46(q,J=7.2Hz,2H),2.29(s,3H),2.28(s,3H),1.43(t,J=7.1Hz,3H).ES-MS[M+1] + :228.

[0521] [ka] 2-(chloromethyl)-3-(ethoxycarbonyl)-4,5-dimethylpyridine 1-oxide. At 0°C, 3-chloroperoxybenzoic acid (285 mg, 1.65 mmol) was gradually added to a solution of ethyl 2-(chloromethyl)-4,5-dimethylnicotinic acid (216 μL, 1.38 mmol) in DCM (6.9 mL). After removing the ice bath and refracting for 18 hours, the mixture was concentrated directly onto Celite® and purified by normal-phase chromatography (0-80% Â / DCM, then 0-10% MeOH / DCM) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 8.15(s,1H),4.84(s,2H),4.48(q,J=7.2Hz,2H),2.25(s,3H),2.22(s,3H),1.44(t,J=7.2Hz,3H).ES-MS[M+1] + :244.

[0522] [ka] Ethyl 6-chloro-2-(chloromethyl)-4,5-dimethylnicotinate. 2-(chloromethyl)-3-(ethoxycarbonyl)-4,5-dimethylpyridine 1-oxide (182 mg, 0.75 mmol) was dissolved in MeCN (1.6 mL) and phosphorus(V) oxychloride (348 μL, 3.73 mmol) was added. The vial was sealed and the mixture was heated at 90°C for 20 hours. After cooling to ambient temperature, the reaction mixture was slowly added to a stirred solution of saturated NaHCO3 aqueous solution while maintaining an alkaline pH. DCM was added and the mixture was stirred for 30 minutes. The organic layer was separated, and the aqueous layer was back-extracted with chloroform / IPA (3:1) (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-15% Âxate / hexane) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 4.66(s,2H),4.46(q,J=7.2Hz,2H),2.39(s,3H),2.33(s,3H),1.42(t,J=7.2Hz,3H).ES-MS[M+1] + :262 / 264.

[0523] [ka] 2-Chloro-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. To a solution of ethyl 6-chloro-2-(chloromethyl)-4,5-dimethylnicotinate (68 mg, 0.26 mmol) in THF (1.3 mL), methylamine (2.0 M solution in THF) (650 μL, 1.3 mmol) was added, and the reaction mixture was heated at 30 °C for 18 hours. The reaction mixture was concentrated under vacuum to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 4.29(s,3H),3.18(s,2H),2.73(s,3H),2.39(s,3H).ES-MS[M+1] + :211.

[0524] [ka] 6-Hydroxy-4,5-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile. 2-cyanoacetamide (2.0 g, 23.8 mmol) was dissolved in methanol (30 mL), to which ethyl 2-methyl-3-oxobutanoic acid (3.37 mL, 23.89 mmol) and potassium hydroxide (2.04 g, 35.7 mmol) were added. The mixture was then stirred at 65°C for 4 hours and then cooled to 4°C. The solid was collected by vacuum filtration and rinsed with MeOH. The solid was dissolved in approximately 175 mL of hot water (70°C). The solution was adjusted to pH approximately 1 with aqueous HCl (5 M), and a precipitate was observed. The solid was collected by vacuum filtration and rinsed with water to obtain the title compound. 1 H NMR(400MHz,DMSO)δ 2.23(s,1H),1.90(s,1H).ES-MS[M+1] + :165.

[0525] [ka] 2,6-Dichloro-4,5-dimethylnicotinonitrile. A solution of 6-hydroxy-4,5-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (2.28 g, 13.88 mmol) in phosphorus(V) oxychloride (10 mL) was heated to 180 °C. After 6 hours, the heat source was removed, and the reaction mixture was poured into ice water (100 mL) using rt. The precipitate was collected by vacuum filtration to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 2.58(s,3H),2.39(s,3H).ES-MS[M+1] + :201 / 203.

[0526] [ka] 2,6-Dichloro-4,5-dimethylnicotinate. A solution of 2,6-dichloro-4,5-dimethylnicotinonitrile (1.48 g, 7.36 mmol) in sulfuric acid (2.0 mL) was stirred and heated at 110°C for 1 hour. After cooling to ambient temperature, the reaction mixture was cooled to 0°C, and sodium nitrite aqueous solution (671 mg, 9.58 mmol) (2.6 M in water) was added dropwise over 15 minutes, generating heat and brown gas. The mixture was then warmed to ambient temperature for 15 minutes, and then heated at 60°C for 18 hours. After cooling to ambient temperature, the reaction mixture was cooled again to 0°C, and sodium nitrite aqueous solution (186 mg, 2.66 mmol) (2.6 M in water) was added dropwise over 15 minutes. The mixture was then warmed to ambient temperature for 15 minutes, and then heated at 60°C for a further 18 hours. After cooling to room temperature, the reaction mixture was added to ice water, and the precipitate was collected by vacuum filtration to obtain the title compound. 1 H NMR(400MHz,DMSO)δ 2.32(s,3H),2.31(s,3H).ES-MS[M+1] + :220 / 222.

[0527] [ka] Methyl 2,6-dichloro-4,5-dimethylnicotinate. To a solution of 2,6-dichloro-4,5-dimethylnicotinic acid (960 mg, 4.36 mmol) in DMF (14.5 mL), potassium carbonate (918 mg, 6.54 mmol) and iodomethane (543 μL, 8.73 mmol) were added. The mixture was stirred at ambient temperature for 1 hour, then diluted with water and extracted with RINKAN (3x). The combined organic layers were dried over (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-10% RINKAN / Hex) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 3.97(s,3H),2.35(s,3H),2.29(s,3H).ES-MS[M+1] + :234 / 236.

[0528] [ka] Methyl 6-chloro-2-cyano-4,5-dimethylnicotinate. A solution of methyl 2,6-dichloro-4,5-dimethylnicotinate (868 mg, 3.71 mmol) in NMP (4.4 mL) and copper(I) cyanide (498 mg, 5.56 mmol) was stirred at 180°C for 3 hours under an inert atmosphere. After cooling to ambient temperature, the reaction mixture was poured into ice water, the solids were removed by filtration, and the mixture was washed with ethyl acetate. The filtrate was then extracted with ethyl acetate (3x), the combined organic matter was dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-40% ethyl acetate / Hex) to obtain the title compound. ES-MS[M+1] + :225.

[0529] [ka] Methyl 2-(aminomethyl)-6-chloro-4,5-dimethylnicotinate. To a solution of methyl 6-chloro-2-cyano-4,5-dimethylnicotinate (219 mg, 0.98 mmol) in ethanol (4.6 mL) / chloroform (1.5 mL) (3:1), platinum(IV) oxide (38 mg, 0.17 mmol) was added. The flask was evacuated under vacuum and purged with hydrogen gas (the process was repeated 3 times). The mixture was stirred under a hydrogen atmosphere (balloon) for 25 hours. The reaction mixture was filtered through Celite®, washed with DCM / MeOH, the filtrate was concentrated, and the process proceeded without further purification. ES-MS[M+1] + :229.

[0530] [ka] 2-Chloro-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. A methanol (4.9 mL) solution of methyl 2-(aminomethyl)-6-chloro-4,5-dimethylnicotinate (236 mg, 0.97 mmol) and triethylamine (680 μL, 4.88 mmol) was added to a vial. The solution was stirred at ambient temperature for 18 hours, then concentrated on Celite®, and purified by normal-phase chromatography (0-3% MeOH / DCM) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 6.06(s,1H),4.38(s,2H),2.74(s,3H),2.41(s,3H).ES-MS[M+1] + :197.

[0531] [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 mixture was heated at 115 °C for 18 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under vacuum, and the crude residue was purified by normal-phase chromatography (0-90% siRNA / DCM) to obtain the title compound. 1 H 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.

[0532] [ka] Ethyl 5-bromo-6-hydroxy-2,4-dimethylnicotinate. Prepared in the same manner as ethyl 5-bromo-6-hydroxy-2-methylnicotinate. 1H 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.

[0533] [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.

[0534] [ka] Ethyl 5-bromo-2-(bromomethyl)-6-chloro-4-methylnicotinate: Prepared in the same manner as ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate. 1 H 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.

[0535] [ka] 3-Bromo-2-chloro-4,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one was prepared by the same method as 3-bromo-2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 1H NMR(400MHz,DMSO)δ 4.43(s,2H),3.07(s,3H),2.75(s,3H).ES-MS[M+1] + :275 / 277.

[0536] [ka] 3-bromo-2-(3-cyclopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-4,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. 3-cyclopropyl-5,6,7,8-tetrahydro-1,6-naphthyridine (51 mg, 0.29 mmol) and 3-bromo-2-chloro-4,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (40 mg, 0.15 mmol) were dissolved in DMSO (0.5 mL), to which N,N-diisopropylethylamine (126 μL, 0.73 mmol) was added. The reaction mixture was heated at 100 °C for 18 hours. After cooling, the reaction mixture was added to water (approximately 10 mL), and the solid was collected by vacuum filtration to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 8.27(d,J=2.2Hz,1H),7.07(d,J=2.2Hz,1H),4.53(s,2H),4.22(s,2H),3.74(t,J=5.8Hz,2H),3.23(t,J=5.8Hz,2H) ,3.17(s,3H),2.79(s,3H),1.88(tt,J=8.5,5.1Hz,1H),1.06-0.91(m,2H),0.69(dt,J=6.6,4.8Hz,2H).ES-MS[M+1] + :414.

[0537] b. Synthesis of representative compounds of the present invention [ka] 3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 2). 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (100 mg, 0.55 mmol) was dissolved in DMSO (1.8 mL), to which 7-(trifluoromethyl)-2,5-diazatetraline dihydrochloride (226 mg, 0.82 mmol) and N,N-diisopropylethylamine (572 μL, 3.3 mmol) were added. The mixture was heated at 120°C for 18 hours. Further addition of N,N-diisopropylethylamine (572 μL, 3.3 mmol) was added, and the mixture was heated at 120°C for 18 hours. After cooling to ambient temperature, the mixture was poured into water (approximately 30 mL), and a precipitate formed. The solid was collected by vacuum filtration and dried under a nitrogen stream to obtain the title compound. ES-MS[M+1] + :349; 1 H NMR(400MHz,CDCl3)δ 8.76(s,1H),7.89(d,J=0.9Hz,1H),7.86(s,1H),5.99(s,1H),4.66(s,2H),4. 39(s,2H),3.66(t,J=5.8Hz,2H),3.39(t,J=5.8Hz,2H),2.43(d,J=0.8Hz,3H).

[0538] [ka] 3,6-dimethyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 1). Lithium bis(trimethylsilyl)amide (43 μL, 0.04 mmol) (1 M in THF) was added to a solution of 3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (15 mg, 0.04 mmol) in DMSO (0.62 mL) at ambient temperature. After stirring the reaction mixture for 20 minutes, iodomethane (2.7 μL, 0.04 mmol) was added. The reaction mixture was stirred for 4 hours, and the mixture was directly purified by RP-HPLC (5-60% ACN / 0.05% NH4OH aqueous solution) to obtain the title compound. ES-MS[M+1] + :363; 1 H NMR(400MHz,CDCl3)δ 8.87(s,1H),8.29(s,1H),8.00(s,1H),4.91(s,2H),4.46(s,2H),3.87-3.72(m,2H),3.76-3.66(m,2H),3.23(s,3H),2.48(s,3H).

[0539] [ka] Methyl 2-(3-methyl-5-oxo-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)propanoate (compound 3). The title compound was obtained by preparation in the same manner as compound 1. ES-MS[M+1] + :435; 1H NMR(400MHz,CDCl3)δ 8.76(s,1H),7.88(s,2H),5.20(q,J=7.5Hz,1H),4.67(s,2H),4.51(d,J=17.0Hz,1H),4.35(d,J=17.1Hz, 1H),3.73(s,3H),3.66(t,J=5.8Hz,2H),3.45-3.30(m,0H),2.43(d,J=0.9Hz,3H),1.58(d,J=7.5Hz,3H).

[0540] [ka] 3-methyl-2-(3-(1-methyl-1H-pyrazole-4-yl)-7,8-dihydro-1,6-naphthirizine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 4). 3-(1-methyl-1H-pyrazole-4-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine hydrochloride (39 mg, 0.12 mmol) and N,N-diisopropylethylamine (86 μL, 0.49 mmol) were added to a DMSO (0.5 mL) solution of 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (15 mg, 0.08 mmol). The mixture was heated at 120 °C for 18 hours. After cooling to ambient temperature, the crude mixture was purified using RP-HPLC (5-45% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain 11.4 mg of the title compound. ES-MS[M+1] + :361; 1 H NMR(400MHz,CDCl3)δ 8.58(d,J=2.2Hz,1H),7.85(d,J=0.9Hz,1H),7.76(d,J=0.8Hz,1H),7.65(s,1H),7.53(d,J=2.2Hz,1H),5.9 6(s,1H),4.58(s,2H),4.38(s,2H),3.97(s,3H),3.63(t,J=5.9Hz,2H),3.22(t,J=5.8Hz,2H),2.44(s,3H).

[0541] [ka] 2-(3-(6-fluoro-4-methylpyridine-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 5). The title compound was obtained by preparing it in the same manner as compound 4. ES-MS[M+1] + :390; 1 H NMR(400MHz,CDCl3)δ 8.42(d,J=2.2Hz,1H),8.05(s,1H),7.87(d,J=0.9Hz,1H),7.42(d,J=2.2Hz,1H),6.89(d,J=2.0Hz,1H),5.9 8(s,1H),4.62(s,2H),4.39(s,2H),3.66(t,J=5.9Hz,2H),3.29(t,J=5.9Hz,2H),2.50(s,3H),2.34(s,3H).

[0542] [ka] 3-methyl-6-(methyl-d3)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 8). At 0°C, lithium diisopropylamide (35 μL, 0.03 mmol) (1 M in THF) was added to a solution of 3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (10 mg, 0.03 mmol) in THF (400 μL) and HMPA (100 μL). The reaction mixture was warmed to ambient temperature and stirred for 30 minutes, after which iodomethane-d3 (4.3 μL, 0.04 mmol) was added. The reaction mixture was stirred for 50 minutes, then water was added, and the mixture was extracted with siRNA (3x). The organic matter was dried (MgSO4), filtered, and concentrated. The crude product was dissolved in DMSO (2 mL) and purified using RP-HPLC (5-60% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :366; 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),7.83(s,1H),7.71(d,J=1.9Hz,1H),4.58(s,2H),4.29(s,2H),3.61(t,J=5.9Hz,2H),3.27(t,J=5.9Hz,2H),2.41(s,3H).

[0543] [ka] 3-methyl-6-(oxetane-3-ylmethyl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 9). The title compound was obtained by preparation in the same manner as compound 8. ES-MS[M+1] + :419.

[0544] [ka] 2-(3-(1,3-dimethyl-1H-pyrazole-5-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 24). The title compound was obtained by preparation in the same manner as compound 4. ES-MS[M+1] + :375; 1 H NMR(400MHz,CDCl3)δ 8.52(d,J=2.1Hz,1H),7.87(d,J=0.9Hz,1H),7.50(d,J=2.1Hz,1H),6.14(s,1H),5.99(s,1H),4.6 1(s,2H),4.39(s,2H),3.84(s,3H),3.64(t,J=5.9Hz,2H),3.26(s,2H),2.44(s,3H),2.31(s,3H).

[0545] [ka] 3-methyl-2-(3-(1-methyl-1H-pyrazole-5-yl)-7,8-dihydro-1,6-naphthirizine-6(5H)-yl-5,5,7,7-d4)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 10). 3-(1-methyl-1H-pyrazole-5-yl)-5,6,7,8-tetrahydro-1,6-naphthirizine-5,5,7,7-d4 (18 mg, 0.08 mmol) was added to a DMSO (0.8 mL) 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). The reaction mixture was heated at 120°C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (3.2 mg). 1H NMR(400MHz,CDCl3)δ 8.54(d,J=2.2Hz,1H),7.87(d,J=0.9Hz,1H),7.54(dd,J=9.6,2.1Hz,2H),6.36(d,J=1.9Hz, 1H),6.06(s,1H),4.38(s,2H),3.92(s,3H),3.27(s,2H),2.44(d,J=0.8Hz,3H);ES-MS[M+1] + :365.5.

[0546] [ka] 2-(3-(3,5-dimethylisoxazole-4-yl)-7,8-dihydro-1,6-naphthyrizine-6-(5H)-yl-5,5,7,7-d4)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 11). 3,5-dimethyl-4-(5,6,7,8-tetrahydro-1,6-naphthyrizine-3-yl-5,5,7,7-d4)isoxazole (19 mg, 0.08 mmol) was added to a DMSO (0.8 mL) 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). The reaction mixture was heated at 120°C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (5.7 mg). ES-MS[M+1] + :380.5; 1 H NMR(400MHz,CDCl3)δ 8.41(d,J=2.1Hz,1H),7.87(s,1H),7.52(s,1H),6.33(s,1H),4.38(s,2H),3.37(s,2H),2.61(s,3H),2.44(s,3H),2.29(s,3H).

[0547] [ka] 2-(3-(6-methoxypyridine-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 20). In a vial, cesium carbonate (41 mg, 0.13 mmol), 2-(3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (15 mg, 0.04 mmol), (6-methoxypyridine-3-yl)boronic acid (13 mg, 0.08 mmol), and Pd(dppf)Cl2 (3.1 mg, 0.004 mmol) were mixed in 1,4-dioxane (350 μL) / water (70 μL) (5:1). The mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite®, washed with DCM / MeOH, and concentrated. The crude product was dissolved in DMSO (2 mL) and purified by RP-HPLC (5-50% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :388; 1 H NMR(400MHz,CDCl3)δ 8.69(d,J=2.1Hz,1H),8.42(dd,J=2.8,0.6Hz,1H),7.91(s,1H),7.78(dd,J=8.7,2.7Hz,1H),6.93(d,J=8 .6Hz,1H),5.96(s,1H),4.74(s,2H),4.37(s,2H),4.08-3.91(m,4H),3.68(s,3H),2.43(d,J=0.8Hz,3H).

[0548] [ka] 2-(3-(5-fluoro-2-methylpyridine-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 33). In a vial, cesium carbonate (55 mg, 0.17 mmol), 3-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (23 mg, 0.06 mmol), 3-bromo-5-fluoro-2-methylpyridine (21 mg, 0.11 mmol), and Pd(dppf)Cl2 (4.1 mg, 0.01 mmol) were combined in 1,4-dioxane (350 μL) / water (70 μL) (5:1). The mixture was stirred at 90°C for 18 hours and then cooled to ambient temperature. The reaction mixture was filtered with Celite® and rinsed with 3:1 CHCl3 / IPA. The organic matter was then washed with saturated NaHCO3 aqueous solution, passed through a phase separator, and concentrated. The crude residue was dissolved in DMSO (1.5 mL) and purified by RP-HPLC (5-45% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :390; 1 H NMR(400MHz,CDCl3)δ 8.45(d,J=2.2Hz,1H),8.42(d,J=2.9Hz,1H),7.87(d,J=0.9Hz,1H),7.45(d,J=2.2Hz,1H),7.28(dd,J=8.6,2.9Hz,1H), 6.00(s,1H),4.62(s,2H),4.39(s,2H),3.66(t,J=5.9Hz,2H),3.30(t,J=5.9Hz,2H),2.50(d,J=1.2Hz,3H),2.45(s,3H).

[0549] [ka] 2-(3-(4-fluoro-1-methyl-1H-pyrazole-5-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 37). The title compound was obtained by preparation in the same manner as compound 33. ES-MS[M+1] + :379; 1 H NMR(400MHz,CDCl3)δ 8.54(d,J=2.1Hz,1H),7.87(s,1H),7.58-7.53(m,1H),7.44(d,J=4.5Hz,1H),6.01(s,1H),4.6 3(s,2H),4.39(s,2H),3.87(s,3H),3.65(t,J=5.9Hz,2H),3.29(t,J=5.9Hz,2H),2.45(s,3H).

[0550] [ka] 2-(3-(2-(difluoromethyl)pyridine-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methylflou[3,4-b]pyridine-5(7H)-one (compound 38). 3-bromo-2-(3-(2-(difluoromethyl)pyridine-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)flou[3,4-b]pyridine-5(7H)-one (30 mg, 0.05 mmol), cesium carbonate (46 mg, 0.14 mmol), trimethylboroxine (50% wt in THF) (40 μL, 0.14 mmol), Pd(dppf)Cl2 (7.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were placed in a vial. The mixture was vacuumed, purged with nitrogen, and then stirred at 80°C for 18 hours. After cooling to ambient temperature, the reaction was filtered through a Celite® pad and thoroughly rinsed with DCM / MeOH. The solvent was removed, and the crude sample was dissolved in DMSO (1.5 mL) and purified by RP-HPLC (30-50% ACN / 0.05% NH4OH aqueous solution). The fraction containing the desired product was concentrated to obtain 6.5 mg of the title compound. ES-MS[M+1] + :409.

[0551] [ka] 2-(3-(4-fluoro-1-methyl-1H-pyrazole-5-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-methylfluoro[3,4-b]pyridine-5(7H)-one (compound 44). 3-Bromo-2-[3-(4-fluoro-2-methylpyrazole-3-yl)-7,8-dihydro-5H-1,6-naphthyrizin-6-yl]-7H-fl[3,4-b]pyridine-5-one (15 mg, 0.03 mmol), cesium carbonate (33 mg, 0.1 mmol), trimethylboroxine (50% wt in THF) (0.03 mL, 0.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were placed in a vial. The vial was vacuumed, purged with nitrogen (3x), and heated at 80°C for 18 hours. The reaction mixture was filtered through a Celite® pad and thoroughly rinsed with ELISA. The solvent was removed under vacuum, and the crude residue was purified by RP-HPLC (15-55% MeCN / water / 0.1% TFA). The desired fraction was base-treated with saturated NaHCO3, extracted with CHCl3 / iPA (3:1), and the organic layer was concentrated to obtain the title compound. ES-MS[M+1] + :423.

[0552] [ka] 2-(3-(2-(difluoromethyl)pyridine-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-5-oxo-5,7-dihydrofl[3,4-b]pyridine-3-carbonitrile (compound 42). 3-bromo-2-[3-[2-(difluoromethyl)pyridine-3-yl]-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-7H-fl[3,4-b]pyridine-5-one (25 mg, 0.05 mmol) and zinc cyanide (9.3 mg, 0.08 mmol) were suspended in DMF (0.5 mL). The mixture was degassed with nitrogen, and then tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.01 mmol) was added. The reaction mixture was heated at 80°C for 5 hours. The reaction mixture was diluted with ELISA. The organic phase was washed with sat.NaHCO3(aq)(2x) and brine, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-10%NH4OH / MeOH / DCM) to obtain the title compound. ES-MS[M+1] + :420.3.

[0553] [ka] 2-(3-(2-(difluoromethyl)pyridine-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 39). The title compound was obtained by preparation in the same manner as compound 38. ES-MS[M+1] + :422; 1 H NMR(400MHz,CDCl3)δ 8.76(dd,J=4.7,1.6Hz,1H),8.48(d,J=2.2Hz,1H),7.83(d,J=0.9Hz,1H),7.76-7.69(m,1H),7.53(m,2H),6.64(t ,J=54.2Hz,1H),4.60(s,2H),4.30(s,2H),3.64(t,J=5.9Hz,2H),3.29(t,J=5.9Hz,2H),3.20(s,3H),2.44(s,1H).

[0554] [ka] 3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one-7,7-d2 (compound 12). 3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (41 mg, 0.12 mmol) was dissolved in THF (780 μL) and heavy water (410 μL). Next, sodium deuterium hydroxide (40 wt%) in D2O was added, and the resulting mixture was stirred at 35°C for 16 hours. The mixture was extracted with DCM (3x), and the combined extract was concentrated by passing it through a phase separator. The crude substance was subjected to the same reaction conditions as above. After 16 hours, the reaction mixture was extracted with DCM (3x), and the combined extract was concentrated by passing it through a phase separator. The title compound was obtained by purification using normal-phase chromatography on silica gel (0-80% alkyl / DCM, followed by 0-1% MeOH / DCM). The substance underwent a second purification using RP-HPLC (5-55% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution, and then extracted with 3:1 chloroform / IPA (3:1) (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :351 (Deuterium uptake by HRMS approximately 98%) 1 H NMR(400MHz,CDCl3)δ 8.78(s,1H),7.98(s,1H),7.91(s,1H),5.96(s,1H),4.71(s,2H),3.68(t,J=5.8Hz,2H),3.49(t,J=5.6Hz,2H),2.44(d,J=0.8Hz,3H).

[0555] [ka] 3-Methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-a]pyrazine-5(7H)-one (compound 6). Methyl 5-methyl-2-(pyrazine-2-yl)-6-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)nicotinate (40 mg, 0.09 mmol), palladium activated carbon (19.8 mg, 0.02 mmol), and platinum(IV) oxide (2.1 mg, 0.01 mmol) were added to an autoclave reactor in ethanol (5 mL). The reaction mixture was heated at 60 °C for 20 hours with stirring under a hydrogen gas atmosphere of 52 psi. The mixture was cooled to ambient temperature, filtered with Celite®, and washed with ethyl acetate. The organic matter was concentrated, the crude residue was dissolved in DMSO (2 mL), and purified using RP-HPLC (5-50% ACN / 0.05% NH4OH aqueous solution). The fraction containing the desired product was concentrated to obtain the title compound. ES-MS[M+1] + :404.

[0556] [ka] 3-Methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one (compound 50). 3-Bromo-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one (19 mg, 0.05 mmol), cesium carbonate (45 mg, 0.14 mmol), trimethylboroxine (50% wt in THF) (35 μL, 0.04 mmol), Pd(dppf)Cl2 (7.0 mg, 0.009 mmol), and 1,4-dioxane (0.5 mL) were placed in a vial. The mixture was vacuumed, purged with nitrogen, and stirred at 80°C for 18 hours. The reaction mixture was diluted with RINKAN, filtered through Celite®, and concentrated. The crude residue was dissolved in DMSO (1.5 mL) and purified using reverse-phase chromatography (10-50% MeCN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with sat.NaHCO3 (aq) and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound (4.3 mg). 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),7.73(s,2H),4.70(s,2H),3.72(t,J=5.9Hz,2H),3.29(t,J=6. 0Hz,2H),3.12-3.05(m,2H),2.75-2.68(m,2H),2.39(d,J=0.9Hz,3H).[M+1] + :348.2.

[0557] [ka] (S)-6-(1-methoxypropan-2-yl)-3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 51). (S)-3-bromo-6-(1-methoxypropan-2-yl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (26 mg, 0.05 mmol), cesium carbonate (52 mg, 0.16 mmol), trimethylboroxine (50% wt in THF) (0.04 mL, 0.16 mmol), Pd(dppf)Cl2 (8.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were placed in a vial. The mixture was vacuumed, purged with nitrogen, and stirred at 80°C for 18 hours. The reaction mixture was diluted with Â, filtered through Celite®, and concentrated. The crude residue was purified using reverse-phase HPLC (20-60% MeCN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with sat.NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound (8.5 mg). ES-MS[M+1] + :421.4.

[0558] [ka] (R)-6-(1-methoxypropan-2-yl)-3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 52). Prepared by the same method as compound 51. ES-MS[M+1] + :421.4.

[0559] [ka] 3-Chloro-6-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 55). The title compound was obtained by preparation in the same manner as for intermediate A. ES-MS[M+1] + :383; 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),8.00(s,1H),7.71(s,1H),4.72(s,2H),4.30(s,2H),3.89(t,J=5.8Hz,2H),3.31(t,J=5.9Hz,2H),3.19(s,3H).

[0560] [ka] 2-(3-((3-fluoropyridine-4-yl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-yl-5,5,7,7-d4)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound A2). N-(3-fluoropyridine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-5,5,7,7-d4-3-amine (25 mg, 0.1 mmol) was added to a DMSO (0.8 mL) 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). The reaction mixture was heated at 120°C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (3.5 mg). 1 H NMR(400MHz,CDCl3)δ 8.41(d,J=2.6Hz,1H),8.32(d,J=3.0Hz,1H),8.13(d,J=5.6Hz,1H),7.86(s,1H),7.40(d,J=2.6Hz,1H) ,6.96(dd,J=7.4,5.5Hz,1H),6.21(d,J=5.1Hz,2H),4.38(s,2H),3.21(s,2H),2.44(s,3H);ES-MS[M+1] + :395.5.

[0561] [ka] 3-methyl-2-(3-((3-methylpyridine-4-yl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-yl-5,5,7,7-d4)-6,7-dihydro-5H-pyrrole[3,4-b]pyridine-5-one (compound A3). N-(3-methylpyridine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-5,5,7,7-d4-3-amine (24 mg, 0.1 mmol) was added to a DMSO (0.8 mL) solution of 2-chloro-3-methyl-6,7-dihydropyrrole[3,4-b]pyridine-5-one (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol). The reaction mixture was heated at 120 °C for 18 hours. The reaction product was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (3.7 mg). 1 H NMR(400MHz,CDCl3)δ 8.36(d,J=2.6Hz,1H),8.25(s,1H),8.18(d,J=5.7Hz,1H),7.85(s,1H),7.38(d,J=2.6Hz,1H),6.85(d,J ES-MS[M+1] + :391.5.

[0562] [ka] 2-(3-((2-fluorophenyl)amino)-7,8-dihydro-1,6-naphthyridine-6-(5H)-yl-5,5,7,7-d4)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound A6). N-(2-fluorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5,5,7,7-d4-3-amine (20 mg, 0.08 mmol) was added to a DMSO (0.8 mL) 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). The reaction mixture was heated at 120 °C for 18 hours. The reaction product was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (8.3 mg). ES-MS[M+1] + :394.1; 1 H NMR(400MHz,CDCl3)δ 8.32(d,J=2.6Hz,1H),7.83(d,J=1.0Hz,1H),7.26-7.20(m,2H),7.16-7.00(m,2H), 6.97-6.88(m,1H),6.56(s,1H),6.06(s,1H),4.36(s,2H),3.18(s,2H),2.41(s,3H).

[0563] [ka] 3-methyl-2-(3-((3-methylpyridine-4-yl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound A7). N-(3-methylpyridine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-3-amine (20 mg, 0.08 mmol) was added to a DMSO (0.8 mL) 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). The reaction mixture was heated at 120 °C for 18 hours. The reaction product was purified by reverse-phase HPLC (5-35% MeCN / water / 0.05% NH4OH) to obtain the title compound (3.3 mg). 1 H NMR(400MHz,CDCl3)δ 8.36(d,J=2.5Hz,1H),8.25(s,1H),8.19(d,J=5.7Hz,1H),7.86(d,J=0.9Hz,1H),7.38(d,J=2.5Hz,1H),6.85(d,J=5.7Hz,1H),6.09(s ,1H),5.75(s,1H),4.56(s,2H),4.38(s,2H),3.62(t,J=5.9Hz,2H),3.22(t,J=5.9Hz,2H),2.46-2.42(m,3H),2.27(s,3H);ES-MS[M+1] + :387.4.

[0564] [ka] 2-(3-((3-fluoropyridine-4-yl)amino)-7,8-dihydro-1,6-naphthiridine-6(5H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound A4). To a solution of 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (15 mg, 0.08 mmol) in DMSO (0.5 mL), N-(3-fluoropyridine-4-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-3-amine dihydrochloride (39 mg, 0.12 mmol) and N,N-diisopropylethylamine (86 μL, 0.49 mmol) were added. The mixture was heated at 120 °C for 40 hours and then cooled to ambient temperature. The title compound was obtained by purification using RP-HPLC (5-45% ACN / 0.05% NH4OH aqueous solution), which, as determined by LC-MS, still contained impurities. The substance underwent a second RP-HPLC purification (5-35% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA (3:1) (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :391; 1 H NMR(400MHz,CDCl3)δ 8.41(d,J=2.5Hz,1H),8.32(d,J=3.1Hz,1H),8.13(d,J=5.5Hz,1H),7.87(d,J=0.9Hz,1H),7.40(d,J=2.5Hz,1H),6.96(dd,J=7.4,5.5Hz ,1H),6.16(d,J=3.2Hz,1H),5.98(s,1H),4.58(s,2H),4.38(s,2H),3.63(t,J=5.9Hz,2H),3.23(t,J=5.9Hz,2H),2.44(d,J=0.9Hz,3H).

[0565] [ka] 2-(3-((3-fluoro-2-methylpyridine-4-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound A8). 2-(3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (15 mg, 0.04 mmol), 3-fluoro-2-methylpyridine-4-amine (7.6 mg, 0.06 mmol), cesium carbonate (40 mg, 0.12 mmol), xanthophos (3.5 mg, 0.01 mmol), and tris(dibenzylideneacetone)dipalladium(0) (3.7 mg, 0.004 mmol) were added to a vial in 1,4-dioxane (0.5 mL) (degassed). The mixture was heated at 80°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to ambient temperature, filtered through a Celite® pad, thoroughly washed with MeOH / DCM, and concentrated. The residue was dissolved in DMSO (2 mL) and purified by RP-HPLC (5-40% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :419.

[0566] [ka] 6-methyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B1). The title compound was obtained by preparation in the same manner as for intermediate D. ES-MS[M+1] + :351.

[0567] [ka] 7-(3-(3,5-dimethylisoxazole-4-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B2). A mixture of cesium carbonate (82 mg, 0.25 mmol), 7-(3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (30 mg, 0.08 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (37 mg, 0.17 mmol), and Pd(dppf)Cl2 (6 mg, 0.01 mmol) in 1,4-dioxane (460 μL) / water (93 μL) (5:1) was added to a vial. The mixture was stirred at 80°C for 18 hours. Further addition of 3,5-dimethylisoxazole-4-boronic acid pinacol ester (37 mg, 0.17 mmol) was added, and the mixture was heated at 80°C for a further 2.5 hours. After cooling to room temperature, the mixture was filtered through Celite® and washed with chloroform / IPA (3:1). The organic matter was then washed with saturated NaHCO3, passed through a phase separator, and concentrated. The residue was purified using RP-HPLC (5-40% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :378; 1 H NMR(400MHz,CDCl3)δ 8.69(s,1H),8.39(d,J=2.2Hz,1H),7.71(q,J=1.2Hz,1H),7.38(d,J=2.1Hz,1H),4.79(s,2H), 3.86(t,J=5.9Hz,2H),3.26(t,J=5.9Hz,2H),2.43(s,3H),2.34(d,J=1.3Hz,3H),2.28(s,3H).

[0568] [ka] 7-(3-(3,5-dimethylisoxazole-4-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B10). A mixture of cesium carbonate (40 mg, 0.12 mmol), 7-(3-bromo-7,8-dihydro-5H-1,6-naphthyrizin-6-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (15 mg, 0.04 mmol), 3,5-dimethylisoxazole-4-boronic acid (14 mg, 0.1 mmol), and Pd(dppf)Cl2 (3.0 mg, 0.004 mmol) in 1,4-dioxane (0.5 mL) / water (0.1 mL) (5:1) was added to a vial. The mixture was stirred at 80°C for 16 hours, filtered with Celite®, washed with ethyl acetate, and concentrated. The crude residue was purified using RP-HPLC (5-50% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with sat.NaHCO3, and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :392.3. 1 H NMR(400MHz,DMSO)δ 8.43(d,J=2.2Hz,1H),7.99(d,J=1.4Hz,1H),7.78(d,J=2.2Hz,1H),4.72(s,2H),3.83(t,J=5. 8Hz,2H),3.41(s,3H),3.12(t,J=5.8Hz,2H),2.43(s,3H),2.29(d,J=1.2Hz,3H),2.25(s,3H).

[0569] [ka] 7-(3-(4-methoxy-2,5-dimethylphenyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B11). The title compound was obtained by preparation in the same manner as compound B10. ES-MS[M+1]+ :430.5; 1 H NMR(400MHz,DMSO)δ 8.34(d,J=2.2Hz,1H),7.98(d,J=1.3Hz,1H),7.65(d,J=2.2Hz,1H),7.01(s,1H),6.89(s,1H),4.71(s,2H),3.88 -3.82(m,2H),3.82(s,3H),3.40(s,3H),3.11(t,J=5.8Hz,2H),2.29(d,J=1.3Hz,3H),2.24(s,3H),2.14(s,3H).

[0570] [ka] 7-(3-(2,4-dimethylphenyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B12). The title compound was obtained by preparation in the same manner as compound B2. ES-MS[M+1] + :387.2; 1 H NMR(400MHz,DMSO)δ 8.35(d,J=2.2Hz,1H),7.94(d,J=1.3Hz,1H),7.69(d,J=2.2Hz,1H),7.13(dd,J=12.3,4.7Hz,3H),4.70 (s,2H),3.82(t,J=5.8Hz,3H),3.12(t,J=6.2Hz,3H),2.32(s,3H),2.28(d,J=1.2Hz,3H),2.23(s,3H).

[0571] [ka] 7-(3-(4-methoxy-2-methylphenyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B13). The title compound was obtained by preparation in the same manner as compound B2. ES-MS[M+1] + :417.3; 1H NMR(400MHz,DMSO)δ 8.33(d,J=2.2Hz,1H),7.94(d,J=1.5Hz,1H),7.65(d,J=2.2Hz,1H),7.01(s,1H),6.89(s,1H),4.69 (s,2H),3.86-3.79(m,5H),3.11(t,J=5.9Hz,2H),2.28(d,J=1.3Hz,3H),2.24(s,3H),2.14(s,3H).

[0572] [ka] 2,6-dimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (compound B24). Potassium carbonate (12 mg, 0.086 mmol) was added to a solution of 6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-2H-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (15 mg, 0.043 mmol) in DMF (0.7 mL), followed by iodomethane (3.9 μL, 0.064 mmol). The mixture was heated at 60°C for 2.5 hours. After cooling to rt, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified using RP-HPLC (10-60% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution, and then extracted with chloroform / IPA (3:1) (3x). The combined organic compounds were passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :365; 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),7.70(d,J=1.3Hz,2H),4.76(s,2H),3.83(t,J=5.9Hz,2H),3.58(s,3H),3.27(t,J=5.9Hz,2H),2.31(d,J=1.2Hz,3H).

[0573] [ka] 2-ethyl-6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (compound B25). Potassium carbonate (12 mg, 0.086 mmol) was added to a solution of 6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-2H-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (15 mg, 0.043 mmol) in DMF (0.7 mL), followed by ethane bromide (4.8 μL, 0.064 mmol). The mixture was heated at 60°C for 2.5 hours. After cooling to rt, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified using RP-HPLC (10-65% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution, and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :379; 1 H NMR(400MHz,CDCl3)δ 8.76(s,1H),8.00(d,J=1.3Hz,1H),7.78(d,J=1.9Hz,1H),4.87(s,2H),4.12(q,J=7.2H) z,2H),3.99(t,J=5.9Hz,2H),3.32(t,J=6.0Hz,2H),2.40(s,3H),1.46(t,J=7.2Hz,3H).

[0574] [ka] 5,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B26). The title compound was obtained by preparation in the same manner as for intermediate D. ES-MS[M+1]+:365; 1H NMR(400MHz,CDCl3)δ 8.72(s,1H),8.51(s,1H),7.70(s,1H),4.66(s,2H),3.67(t,J=5.9Hz,2H),3.28(t,J=6.0Hz,2H),2.81(d,J=1.0Hz,3H),2.17(d,J=1.0Hz,3H).

[0575] [ka] 5-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyrimidine-1-one (compound B27). The title compound was obtained by preparation in the same manner as for intermediate D. ES-MS[M+1]+:377; 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),8.37(s,1H),7.71(s,1H),4.99(s,2H),4.06(t,J=5.9Hz,2H),3.38(t ,J=7.8Hz,2H),3.22(t,J=6.0Hz,2H),3.04(t,J=7.3Hz,2H),2.25(p,J=7.7Hz,2H).

[0576] [ka] 1-[[6-methyl-3-oxo-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-[1,2,4]triazolo[4,3-a]pyrimidine-2-yl]methyl]cyclopropane-1-carbonitrile (compound B47). Potassium carbonate (10.4 mg, 0.074 mmol) was added to a solution of 6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-2H-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (13 mg, 0.037 mmol) in DMF (0.5 mL), followed by the addition of 1-(bromomethyl)cyclopropane-1-carbonitrile (5.6 μL, 0.056 mmol). The mixture was heated at 60°C for 2.5 hours. After cooling to rt, the reaction product was further dissolved in DMF (1 mL), filtered, and purified using RP-HPLC (20-70% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :430; 1 H NMR(400MHz,MeOD)δ 8.70(d,J=1.2Hz,1H),8.06(d,J=1.0Hz,1H),7.85(q,J=1.2Hz,1H),4.86(s,2H),4.00(s,2H),3.97( t,J=5.9Hz,2H),3.27(t,J=6.0Hz,2H),2.38(d,J=1.3Hz,3H),1.34-1.32(m,2H),1.31-1.28(m,2H).

[0577] [ka] 2,5,6-trimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (compound B53). 5,6-dimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-2H-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (13 mg, 0.036 mmol) was dissolved in DMF (0.7 mL) and potassium carbonate (10 mg, 0.071 mmol) was added, followed by iodomethane (3.5 μL, 0.054 mmol). The mixture was heated at 60°C for 18 hours. After cooling to rt, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified using RP-HPLC (15-65% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution, and then extracted with chloroform / IPA (3:1) (3x). The combined organic compounds were passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :379; 1 H NMR(400MHz,CDCl3)δ 8.71(s,1H),7.68(s,1H),4.64(s,2H),3.66(t,J=5.9Hz,2H),3.55(s,3H),3.26(t,J=5.9Hz,2H),2.82(d,J=0.9Hz,3H),2.16(d,J=1.0Hz,3H).

[0578] [ka] 5-Chloro-6-methyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthiridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B55). To a solution of 6-(6-chloro-2-hydrazinyl-5-methylpyrimidine-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine (10 mg, 0.03 mmol) in 1,4-dioxane (0.2 mL), triphosgene (8.3 mg, 0.03 mmol) was added at 25 °C. After 2 hours, the reaction mixture was concentrated, and the crude residue was purified using reverse-phase chromatography (20-50% MeCN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with sat.NaHCO3, and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound (4 mg). ES-MS[M+1] + :385.1 / 387.1.

[0579] [ka] 5-Chloro-2,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B56). At room temperature, 15 mg, 0.04 mmol of 5-chloro-6-methyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (15 mg, 0.04 mmol) and potassium carbonate (11 mg, 0.08 mmol) were dissolved in DMF (0.5 mL), to which 4 μL, 0.06 mmol of iodomethane was added, and the mixture was stirred at 60 °C for 18 hours. The mixture was further dissolved in DMF (1 mL), filtered, and purified using reverse-phase chromatography (30-60% MeCN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with sat.NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a hydrophobic phase separator and concentrated to obtain the title compound (9 mg). 1 H NMR(400MHz,DMSO)δ 8.78(s,1H),8.17(dd,J=2.4,1.0Hz,1H),4.68(s,2H),3.75(t,J=5.9Hz,2H),3.38(s,3H),3.17(t,J=5.8Hz,2H),2.23(s,3H).ES-MS[M+1] + :399.3 / 401.2.

[0580] [ka] 2-(cyclopropylmethyl)-6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (compound B74). 6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-2H-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (13 mg, 0.037 mmol) was dissolved in DMF (0.5 mL) and potassium carbonate (10.4 mg, 0.074 mmol) was added, followed by (bromomethyl)cyclopropane (5.4 μL, 0.056 mmol). The mixture was heated at 60°C for 18 hours. After cooling to rt, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified using RP-HPLC (20-75% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution, and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a hydrophobic phase separator and concentrated to obtain the title compound. ES-MS[M+1] + :405; 1 H NMR(400MHz,CDCl3)δ 8.73(d,J=2.2Hz,1H),7.71(q,J=1.2Hz,1H),7.69(s,1H),4.77(s,2H),3.82(t,J=5.9Hz,2H),3.78(d,J=7.1Hz,2H ),3.27(t,J=5.9Hz,2H),2.31(d,J=1.3Hz,3H),1.37-1.26(m,1H),0.61-0.50(m,2H),0.42(dt,J=6.2,4.6Hz,2H).

[0581] [ka] 2-(cyclopropylmethyl)-5,6-dimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (compound B80). Potassium carbonate (10 mg, 0.071 mmol) was added to a solution of 5,6-dimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-2H-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (13 mg, 0.036 mmol) in DMF (0.5 mL), followed by (bromomethyl)cyclopropane (5.2 μL, 0.054 mmol). The mixture was heated at 60°C for 5 hours. After cooling to rt, the reaction mixture was further dissolved in DMF (1.0 mL), filtered, and purified using RP-HPLC (20-80% ACN / 0.1% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution, and then extracted with chloroform / IPA (3:1) (3x). The combined organic compounds were passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound. ES-MS[M+1] + :419; 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),7.67(s,1H),4.65(s,2H),3.74(d,J=7.1Hz,2H),3.65(t,J=5.9Hz,2H),3.27(t,J=5.9Hz,2H ),2.82(d,J=0.9Hz,3H),2.16(d,J=1.0Hz,3H),1.37-1.23(m,1H),0.61-0.50(m,2H),0.46-0.38(m,2H).

[0582] [ka] 5-Methoxy-2,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B85). At 0°C, 5-chloro-2,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (6 mg, 0.02 mmol) was added to a methanol (0.20 mL) solution of sodium methoxide (60 μL, 0.03 mmol). After removing the ice bath and allowing to stand at room temperature for 30 minutes, the reaction mixture was concentrated. The residue was purified using reverse-phase chromatography (5-40% MeCN / 0.05% NH4OH aqueous solution). The fraction containing the desired product was concentrated to obtain impurities. The impurities were re-purified using reverse-phase chromatography (10-40% MeCN / 0.1% aqueous TFA). The fraction containing the desired product was made basic with sat.NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compound (5 mg). 1 H NMR(400MHz,CDCl3)δ 8.72(s,1H),7.69(s,1H),4.70(s,2H),4.14(s,3H),3.75(t,J=5.9Hz,2H),3.54(s,3H),3.26(t,J=5.9Hz,2H),2.17(s,3H).ES-MS[M+1] + :395.3.

[0583] [ka] 5-Cyclopropyl-6-methyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B93). The title compound was obtained by preparation in the same manner as for intermediate D. ES-MS[M+1]+:391; 1H NMR(400MHz,CDCl3)δ 8.72(s,1H),8.38(s,1H),7.69(s,1H),4.67(s,2H),3.68(t,J=5.9Hz,2H),3.26(t,J=5.9H z,2H),2.29(d,J=1.3Hz,3H),2.27-2.15(m,1H),1.39-1.28(m,2H),0.89(q,J=5.8Hz,2H).

[0584] [ka] 5-Cyclopropyl-2,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound B94). The title compound was obtained by preparation in the same manner as for intermediate E. ES-MS[M+1]+:405; 1 H NMR(400MHz,CDCl3)δ 8.71(dd,J=2.1,0.8Hz,1H),7.68(dd,J=2.4,1.0Hz,1H),4.65(s,2H),3.67(t,J=5.9Hz,2H),3.55(s,3H) ),3.25(t,J=5.9Hz,2H),2.28(d,J=1.3Hz,3H),2.24-2.15(m,1H),1.40-1.28(m,2H),0.95-0.83(m,2H).

[0585] [ka] 2,5,6-trimethyl-7-[3-(oxetan-3-yl)-7,8-dihydro-5H-1,6-naphthyridine-6-yl]-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (compound B140) and 7-(7,8-dihydro-5H-1,6-naphthyridine-6-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (compound B141). To a solution of 7-(3-bromo-7,8-dihydro-5H-1,6-naphthyrizin-6-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3-one (30 mg, 0.077 mmol) in DME (1.0 mL), 3-bromooxetane (19.2 μL, 0.231 mmol), tris(trimethylsilyl)silane (35.7 μL, 0.116 mmol), lithium hydroxide (5.5 mg, 0.231 mmol), and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (4.3 mg, 0.0039 mmol) were added. Nitrogen was bubbling into the reaction mixture 10 minutes before the addition of [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride (1.5 mg, 0.0039 mmol). Nitrogen was further bubbling into the reaction mixture for 5 minutes, followed by sonication under an inert atmosphere, sealing with Parafilm, and stirring under blue LED light at rt. After 18 hours, compounds B140 and B141 were observed in a 1:1 ratio by LC-MS. The reaction mixture was concentrated and purified using RP-HPLC (0-50% ACN / 0.1% aqueous TFA). The fractions containing each desired product were basicized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organic layers were passed through a hydrophobic phase separator, and the solvent was concentrated to obtain the title compounds, respectively. [Reference: Zhang et al.J.Am.Chem.Soc.2016,138,8084-8087].

[0586] Compound B140: ES-MS[M+1] + :367; 1H NMR(400MHz, CDCl3)δ 8.44(d,J=2.2Hz,1H),7.56(d,J=2.2Hz,1H),5.11(dd,J=8.3,6.1Hz,2H),4.73(t,J=6.3Hz,2H),4.61(s,2H),4.22(tt,J =8.3,6.5Hz,1H),3.65(t,J=5.9Hz,2H),3.54(s,3H),3.19(t,J=5.9Hz,2H),2.81(d,J=1.0Hz,3H),2.16(d,J=1.0Hz,3H);

[0587] Compound B141: ES-MS[M+1] + :311; 1 H NMR(400MHz, CDCl3)δ 8.46(dd,J=4.8,1.6Hz,1H),7.46(dd,J=7.7,1.6Hz,1H),7.15(dd,J=7.8,4.8Hz,1H),4.59(s,2H),3. 63(t,J=5.9Hz,2H),3.54(s,3H),3.21(t,J=5.9Hz,2H),2.80(d,J=0.9Hz,3H),2.16(d,J=1.0Hz,3H).

[0588]

change

[0589]

change

[0590] [ka] 2-(3-cyclopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. Prepared in the same manner as intermediate A. 1 H NMR(400MHz,CDCl3)δ 8.27(d,J=2.2Hz,1H),7.08(d,J=2.2Hz,1H),5.86(s,1H),4.43(s,2H),4.31(s,2H),3.50(t,J=5.9Hz,2H),3.18(t,J ES-MS[M+1] + :335.

[0591] [ka] 2-(3-cyclopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. A solution of 3-bromo-2-(3-cyclopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-4,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (33 mg, 0.06 mmol), cesium carbonate (59 mg, 0.18 mmol), trimethylboroxine (50 wt% in THF) (50 μL, 0.18 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.8 mg, 0.01 mmol) in 1,4-dioxane (0.5457 mL) was stirred at 80°C for 18 hours. After cooling, the reaction product was filtered through a Celite® pad and rinsed thoroughly with chloroform / IPA / MeOH. The solvent was removed, and the crude sample was purified by RP-HPLC to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 8.27(d,J=2.2Hz,1H),7.08(d,J=2.2Hz,1H),4.41(s,2H),4.23(s,2H),3.47(t,J=5.9Hz,2H),3.19-3.14(m, 5H),2.66(s,3H),2.27(s,3H),1.89(tt,J=8.5,5.1Hz,1H),1.05-0.96(m,2H),0.76-0.63(m,2H).ES-MS[M+1] + :349.

[0592] The compounds shown in Table 1 can be prepared using appropriate starting materials and the methods described in the scheme and examples above.

[0593] [Table 26]

[0594] [Table 27]

[0595] Table 28

[0596] Table 29

[0597] Table 30

[0598] Table 31

[0599] Table 32

[0600] Table 33

[0601] Table 34

[0602] Table 35

[0603] Table 36

[0604] Table 37

[0605] Table 38

[0606] Table 39

[0607] Table 40

[0608] Table 41

[0609] Table 42

[0610] Table 43

[0611] Table 44

[0612] Table 45

[0613] Table 46

[0614] Table 47

[0615] Table 48

[0616] Table 49

[0617] Table 50

[0618] Table 51

[0619] Table 52

[0620] Table 53

[0621] Table 54

[0622] Table 55

[0623] Table 56

[0624] Table 57

[0625] Table 58

[0626] Table 59

[0627] [Table 60]

[0628] [Table 61]

[0629] [Table 62]

[0630] [Table 63]

[0631] [Table 64]

[0632] biological activity A. Cell lines expressing muscarinic acetylcholine receptors Human and rat M4 cDNA were used to create chimeric G protein G qi5 Along with this, Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection were transfected with lipofectamine 2000. The transfected cells were subjected to antibiotic selection treatment to generate stable cell lines; G418 sulfate (1 mg / ml) was used to select M4-expressing cells. qi5 Hygromycin B (500 μg / mL) was used to select expression cells. The resulting polyclones were further screened for hM4-G compound screening assays. qi5 and rM4-G qi5Monoclonal cells were obtained. Stable monoclonal cells were maintained in a 37°C humidified incubator in the presence of 5% CO2 in Ham's F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1X antibiotic / antifungal agent, 20 mM HEPES, 500 μg / mL G418 sulfate, and 200 μg / mL hygromycin B.

[0633] B. Cell-based functional assay of muscarinic acetylcholine receptor activity To determine the activity of the compound, a high-throughput assay was employed to measure the receptor-induced recruitment of intracellular calcium. 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 maximum (EC) was measured. 20Acetylcholine at a concentration of ) was added, and the response was measured. This kinetic assay allows for simultaneous screening and efficacy measurement of multiple pharmacological mechanisms of action, including the activity of agonists and enhancers. CHO-K1 cells stably expressing muscarinic receptors were seeded at 15,000 cells / 20 μL / well in a Greiner 384-well blackwall tissue culture (TC) treated clear-bottom plates (Greiner Bio-One) at a growth medium lacking G418 and hygromycin. 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 the fluorescent calcium indicator dye Fluo-4-acetomethoxyester (Fluo-4-AM) were diluted. The compounds were serially diluted 1:3 in DMSO using a Bravo Liquid Handler (Agilent, Santa Clara, CA) to create a 10-point concentration response curve. The curves were then transferred to 384-well pla...

Claims

1. Compound of formula (I), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula: G １ teeth, 【Chemistry 2】 And, X １ NR ５ , O, or CR ５Ａ R ５Ｂ And; X ２ CR ６ or N; R １ and R ３ are each independently hydrogen, halogen, cyano, C １－４ alkyl, C １－４ fluoroalkyl, -OC １－４ alkyl, or -OC １－４ fluoroalkyl; R ２ G ２ , -NR ｂ R ｃ , C １－６ Haloalkyl, halogen, cyano, NO ２ , C １－６ Alkyl, C ２－６ Alkenil, -OR ｂ , -NR ｃ C(O)R ｂ , -NR ｃ SO ２ R ａ , -N=S(O)(R ａ ) ２ , -P(O)(R ａ ) ２ , -C １－３ Alkilen-G ２ , -C ２－４ Alkenylene-G ２ , or hydrogen; R ａ Each time it appears, C １－６ Alkyl, C １－６ Haloalkyl, G ２ , or -C １－３ Alkilen-G ２ And; Here, by choice, -N = S(O)(R ａ ) ２ or -P(O)(R ａ ) ２ The two R's ａ They bond as straight alkylene chains, forming a 5-7 membered heterocycle; R ｂ and R ｃ 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 5-12 membered heteroaryl, a 6-12 membered aryl, a 4-12 membered heterocyclyl, or a 3-12 membered carbocyclyl, where each heteroaryl and heterocyclyl contains 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S, and G ２ These are halogen, cyano, and C １－６ Alkyl, C １－６ Haloalkyl, oxo, -OR ｘ , -N(R ｘ ) ２ , -SR ｘ , -SO ２ R ｘ , -C(O)R ｘ , -C(O)OR ｘ , -C(O)N(R ｘ ) ２ , -C １－６ Alkylene-OR ｘ , -C １－６ Alkylene-N(R) ｘ ) ２ G ２ａ , and -C １－３ Alkilen-G ２ａ It is optionally substituted with a first substituent selected from the group consisting of halogens, cyanosides, and C12. １－６ Alkyl, C １－６ Haloalkyl and -OR ｘ They are further optionally substituted with 1 to 4 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 Haloalkyl, C ３－６ Cycloalkyl, -C １－３ Alkylene-C ３－６ Cycloalkyl, phenyl, or -C １－３ Alkylene-phenyl, where each cycloalkyl or phenyl is a halogen, C １－４ Alkyl and C １－４ They are optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl groups; G ２ａ is phenyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms, 4- to 8-membered heterocyclyl containing 1 or 2 heteroatoms, or 3- to 8-membered carbocyclyl, where the heteroatoms are independently selected from the group consisting of O, N, and S, and G ２ａ is, independently each time it appears, halogen, cyano, C １－４ alkyl, C １－４ haloalkyl, -C １－６ alkylene-OH, oxo, OH, -OC １－４ alkyl, -OC １－４ haloalkyl, C ３－４ cycloalkyl, and -C １－３ alkylene-C ３－４ cycloalkyl and is optionally substituted with 1 to 5 substituents independently selected from the group consisting of; 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; 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 Alkyl, 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, G ５ , or -C １－３ Alkilen-G ５ And; G ５ This includes phenyl, a 5-6 member heteroaryl containing 1-3 heteroatoms, a 4-8 member heterocyclyl containing 1-2 heteroatoms, or C ３－８ It is a cycloalkyl, 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 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, OH, and oxo; Or, R ４Ａ and R ４Ｂ C ３－６ Forms a cycloalkyl group; or R ４Ｂ and R ５ Together with the atoms to which they are attached, they form a 5- to 7-membered heterocycle that optionally contains one additional heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; R ６ is hydrogen, halogen, cyano, C １－４ Alkyl, C １－４ Fluoroalkyl, C ２－４ Alkenil, -OR ６ａ , -N(R ６ａ ) ２ , -C １－３ Alkylene-OR ６ａ , or C ３－６ It is a 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 a cycloalkyl; Alternatively, two R's ６ａ Along with the nitrogen to which they are attached, R ６ａ A 4-8 membered heterocycle is formed, containing nitrogen attached to the element and one or two additional heteroatoms that are optionally and independently O, N, or S, wherein the heterocycle is a halogen, C １－２ Alkyl and C １－２ It is 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, -OR ７ａ , -C １－３ Alkylene-OR ７ａ , or G ７ And; Or, R ６ and R ７ Together with the atoms to which they are attached, they form a 5-7 membered heterocycle or 5-7 membered carbon ring containing one heteroatom, where the heteroatom is independently selected from the group consisting of N, O, and S, and the heterocycle and carbon ring are C １－４ Alkyl, halogen, -OC １－４ Alkyl, C １－４ Fluoroalkyl, C ３－４ Cycloalkyl, and C １－２ Alkylene-C ３－４ It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl groups; 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 a cycloalkyl; G ７ This includes phenyl, a 5-6 member heteroaryl containing 1-3 heteroatoms, a 4-8 member heterocyclyl containing 1-2 heteroatoms, or C ３－６ It is a cycloalkyl, 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 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, OH, and oxo; R ８ Each time it appears, halogen, C １－４ Alkyl, C １－４ Fluoroalkyl, or C ３－４ It is a cycloalkyl; n is 0, 1, 2, 3, or 4. Here, R ６ , R ６ａ , R ７ , R ７ａ , and R ８ Each cycloalkyl group in is either unsubstituted or C １－４ (The molecule is substituted with 1 to 4 substituents independently selected from alkyl and halogen compounds.)

2. R １ However, hydrogen or C １－４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

3. R ３ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

4. R ２ However, G ２ , -NR ｂ R ｃ , C １－６ Haloalkyl, C ２－６ Alkenyl, cyano, hydrogen, or -C ２－４ Alkenylene-G ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. R ２ However, C １－６ The compound according to claim 4, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

6. R ２ However, G ２ The compound according to claim 4, or a pharmaceutically acceptable salt thereof.

7. G ２ The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a 5- to 12-membered heteroaryl substituted by any choice.

8. G ２ The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein the substituted 6- to 12-membered aryl is optionally replaced.

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

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

11. G ２ but, (a) 【Transformation 3】 Five- to twelve-membered heteroaryls that are optionally substituted, selected from the group consisting of the following: or (b) 【Chemistry 4】 A 6- to 12-membered aryl that is optionally substituted, selected from the group consisting of the following: or (c) 【Transformation 5】 A 4- to 12-membered heterocycline that is optionally substituted, selected from the group consisting of the following: or (d) 【Transformation 6】 These are 3- to 12-membered carbocyclils that are optionally substituted. The compound according to any one of claims 6 to 10, or a pharmaceutically acceptable salt thereof.

12. R ２ However, -NR ｂ R ｃ And; R ｂ However, C １－６ Alkyl, G ２ , or -C １－３ Alkilen-G ２ And; R ｃ However, hydrogen or C １－６ It is alkyl. The compound according to claim 4, or a pharmaceutically acceptable salt thereof.

13. R ｂ However, G ２ The compound according to any one of claims 1 to 4 or 12, or a pharmaceutically acceptable salt thereof.

14. G ２ The compound according to claim 12 or 13, or a pharmaceutically acceptable salt thereof, wherein the compound is a 5- to 12-membered heteroaryl substituted by any choice.

15. G ２ The compound according to claim 12 or 13, or a pharmaceutically acceptable salt thereof, wherein the substituted 6- to 12-membered aryl is optionally replaced.

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

17. R ２ but, 【Transformation 7】 The compound according to any one of claims 12 to 16, or a pharmaceutically acceptable salt thereof.

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

19. R ５ However, hydrogen, C １－６ Alkyl, C １－６ Fluoroalkyl, -C １－６ Alkilen-R ｙ G ５ or -C １－３ Alkilen-G ５ The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

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

21. R ６ However, hydrogen, halogen, C １－４ Alkyl, C １－４ Fluoroalkyl, -OR ６ａ , or C ３－６ A compound according to any one of claims 1 to 20, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

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

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

24. G １ but, 【Transformation 8】 The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

25. X １ However, NR ５ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

26. X １ A compound according to any one of claims 1 to 18 or 21 to 24, or a pharmaceutically acceptable salt thereof, wherein the compound is O.

27. X １ However, CR ５Ａ R ５Ｂ The compound according to any one of claims 1 to 18 or 21 to 24, or a pharmaceutically acceptable salt thereof.

28. X ２ However, CR ６ The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

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

30. G １ but, 【Chemistry 9】 The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

31. R ６ and R ７ The compound according to any one of claims 1 to 20 or 23 to 30, or a pharmaceutically acceptable salt thereof, wherein, together with the atoms to which they are attached, they form a optionally substituted 5- to 7-membered heterocycle or 5- to 7-membered carbon ring. 【Request Item 32】 【Table 1】 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

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

34. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 33, 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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