Positive modulator of muscarinic acetylcholine receptor M4

Abstract

Deuterium-labeled 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine, substituted with pyrrolo[3,4-b]pyridine-5-one, flo[3,4-b]pyridine-5(7H)-one, or [1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one, are positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4) and may have use in treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 509,589 filed on 22 June 2023 and U.S. Provisional Application No. 63 / 610,220 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] background Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs) by the binding of acetylcholine (ACh), an endogenous orthosteric agonist. Conditions associated with cognitive impairment, such as Alzheimer's disease, involve a reduction in acetylcholine content in the brain. This is thought to be a result of degeneration of cholinergic neurons in the basal forebrain ganglia, which broadly innervate numerous brain regions, including the cortex and hippocampus, which are critically involved in cognitive processes. Clinical data support the idea that impaired cholinergic system function contributes to cognitive deficits in patients with schizophrenia. Efforts to increase acetylcholine levels have focused on increasing the levels of choline, 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 use in the palliative, non-disease-modifying treatment of cognitive deficits in patients with Alzheimer's disease (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 in AD patients, they are known to have frequent cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal colic, nausea, vomiting, and diarrhea. These gastrointestinal side effects are observed in approximately one-third of treated patients. In addition, some AChE inhibitors, such as tacrine, are known to cause significant hepatotoxicity due to high hepatic transaminase levels, observed in approximately 30% of patients. Due to the adverse effects of AChE inhibitors, their clinical applicability is limited. An alternative approach to pharmacologically targeting cholinergic dysfunction is the activation of mAChRs, which are widely expressed throughout the body.

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

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

[0007] Previous attempts to develop agonists highly selective for individual mAChR subtypes have failed due to the high conserved nature of the orthosteric ACh binding site. One approach to circumvent the problems associated with targeting highly conserved orthosteric ACh binding sites is to develop compounds that act at allosteric sites on mAChRs that are distant from the orthosteric site and less highly conserved. In the case of mAChRs, the primary objective was to develop allosteric ligands that selectively increase the activity of mAChR M4 or other mAChR subtypes. Allosteric activators may 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 the activation of the receptor by ACh, an endogenous orthosteric agonist. It is also possible for a single molecule to possess both allosteric enhancer and allosteric agonist activity.

[0008] More recently, muscarinic agonists, including xanomeline, have been shown to be active in animal models, possessing 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, xanomeline has been shown to reduce 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); however, the treatment induced side effects, such as gastrointestinal effects, severely limiting the clinical applicability of this compound. [Prior art documents] [Non-patent literature]

[0009] [Non-licensed document 1] Bymaster, Eur. J. Pharmacol.1998, 356, 109 [Non-licensed document 2] Bymaster, Life Sci. 1999, 64, 527 [Non-licensed document 3] Shannon, J. Pharmacol. Exp. Ther.1999, 290, 901

Non-licensed Document 4

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Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Summary of the Invention

Problems to be Solved by the Invention

[0010] Despite the progress in muscarinic acetylcholine receptor research, there is still a lack of compounds that are potent, effective, and selective activators of M4 mAChR and are effective in the treatment of neurological and psychiatric disorders associated with cholinergic activity and diseases involving the muscarinic M4 receptor.

Means for Solving the Problems

[0011] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0012]

Chemical Formula

[0013] {Wherein, G 1 is

[0014]

Chemical Formula

[0015] and X 1 is NR 5 or O, R 4A and R 4B are independently hydrogen, C 1~4 alkyl, C 3~4 cycloalkyl or -C 1~3 alkylene - OH, or R 4A and R 4B [[ID= seventy]]are such that together with the carbon to which they are attached they form C 3~6 cycloalkyl, R 5 is hydrogen, C1~6 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 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 instance of appearance is independent of hydrogen and 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 5 This includes phenyl, 4-8 membered heterocyclyls containing 1-2 heteroatoms, 5-6 membered heteroaryls containing 1-4 heteroatoms, or C 3~6 It is a cycloalkyl group, and the heteroatoms are independently selected from the group consisting of O, N, and S, G 5 C 1~4 Alkyl, halogen, oxo, -OC 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~4 Cycloalkyl and -C 1~2 Alkylene-C 3~4 Optionally substituted with 1 to 4 substituents selected from the group consisting of cycloalkyl groups, R 6 Hydrogen, 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 3~4 It is a cycloalkyl, R 6a Each instance of appearance is independent of hydrogen and C. 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 It is a cycloalkyl, Here, or two R's 6a Along with the nitrogen to which they bind, R 6a It forms a 4- to 8-membered heterocyclic ring containing a nitrogen atom bonded to it and, optionally, one additional heteroatom which is O, N, or S, and the heterocyclic ring is independently a halogen, C 1~2 Alkyl and C 1~2 Optionally substituted with 1 to 4 substituents selected from the group consisting of fluoroalkyl groups, R 7 C 1~4 Alkyl, hydrogen, halogen, cyano, C 1~4 Fluoroalkyl, C 2~4 Alkenil, -OR 7a , -C 1~3 Alkilen-OR 7a CO2R 7a COR 7a or C 3~6 It is a cycloalkyl, Alternatively, R 6 and R 7 Together with the atoms to which they are bonded, they form an aromatic or non-aromatic ring consisting of 5 to 7 carbon atoms. 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, R 8 Each instance of appearance is independent of halogen and C. 1~4 Alkyl, C 1~4 Fluoroalkyl or C 3~4 It is a cycloalkyl, n is 0, 1, 2, 3, or 4. and at least one hydrogen in the compound is a deuterium isotope (2 A compound H is disclosed.

[0016] 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.

[0017] Another embodiment provides a method for treating neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals, comprising the step of administering to a mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or composition thereof.

[0018] 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.

[0019] 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.

[0020] 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. [Brief explanation of the drawing]

[0021] [Figure 1] This graph shows the effect of compound 3 in an amphetamine-induced spontaneous motility enhancement assay. [Modes for carrying out the invention]

[0022] This specification discloses a positive modulator of the muscarinic acetylcholine receptor M4 (mAChR M4), a method for producing the same, a pharmaceutical composition comprising the same, and a method for treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the same.

[0023] The human muscarinic acetylcholine receptor M4 (mAChR M4) is a 479-amino acid protein encoded by the CHRM4 gene. The non-glycosylated protein has a molecular weight of approximately 54 kDa and is a transmembrane GPCR. As described above, mAChR M4 is a rhodopsin-like GPCR, characterized by its rhodopsin-like structural features, such as being a member of the GPCR class A family or having seven transmembrane segments. The muscarinic acetylcholine receptor has an N-terminus facing the extracellular surface of the membrane and a C-terminus located on the cytoplasmic surface.

[0024] Previous attempts to develop agonists highly selective for individual mAChR subtypes have failed due to the high conserved nature of the orthosteric ACh binding site. To circumvent the problems associated with targeting the highly conserved orthosteric ACh binding site, it is considered beneficial to develop compounds that act on allosteric sites on mAChR, which are distant from the orthosteric site and less highly conserved. The binding of the disclosed mAChR M4 positive modulator compounds to mAChR M4 is thought to involve binding to an allosteric site distinct from the orthosteric binding site, where the positive modulator of mAChR M4 may directly or indirectly enhance the activity of the mAChR M4 receptor through mechanisms that may include allosteric enhancement, allosteric upregulation, and varying degrees of agonism.

[0025] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of any conflict, the definitions in this document shall prevail. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in the practice or testing of the present invention. All publications, patent applications, patents and other references referenced herein are incorporated herein by reference in their entirety. The materials, methods and examples disclosed herein are illustrative and not intended to be limiting.

[0026] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” and “contain(s),” and their variations, when used herein, are intended to be unrestricted transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms “a,” “an,” and “the” include plural referents unless the context clearly indicates otherwise. Furthermore, this disclosure intends other embodiments “comprise,” “consist of,” and “essentially consist of,” the embodiments or elements “contain,” “consist of,” and “essentially consist of,” those described herein, whether expressly indicated or not.

[0027] The modifier "approximately" used in relation to quantity includes the value being expressed and has meanings indicated by the context (for example, it includes at least some degree of error associated with the measurement of a particular quantity). Furthermore, the modifier "approximately" should be considered to disclose a range defined by the absolute values ​​of the two endpoints. For example, the expression "approximately 2 to approximately 4" also discloses the range "2 to 4". The term "approximately" can refer to + or -10% of the expressed number. For example, "approximately 10%" may mean a range of 9% to 11%, and "approximately 1" may mean 0.9 to 1.1. Other meanings of "approximately," such as rounding, may be evident from the context, so for example, "approximately 1" may also mean 0.5 to 1.4.

[0028] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the periodic table, CAS versions, Handbook of Chemistry and Physics, 75th edition, and endpapers, and specific functional groups are defined as generally described therein. In addition, general principles of organic chemistry, as well as specific functional parts and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987, the entire contents of each of these are incorporated herein by reference.

[0029] As used herein, the term "alkoxy" refers to an alkyl group as defined herein, which is added to the parent molecule via an oxygen atom. Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0030] The term "alkyl," as used herein, means a straight-chain or branched saturated hydrocarbon chain. "Lower alkyl" or "C 1~6 The term "alkyl" refers to a straight-chain or branched-chain hydrocarbon containing 1 to 6 carbon atoms. 1~4The term "alkyl" refers to a linear or branched saturated hydrocarbon containing 1 to 4 carbon atoms. Typical examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0031] As used herein, the term "alkenyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond.

[0032] When used herein, the term "alkoxyalkyl" refers to an alkoxy group as defined herein, which is attached to the parent molecule via an alkyl group as defined herein.

[0033] When used herein, the term "alkoxyfluoroalkyl" refers to an alkoxy group as defined herein, which is attached to the parent molecule via a fluoroalkyl group as defined herein.

[0034] As used herein, the term "alkylene" refers to a divalent group derived from a linear or branched saturated hydrocarbon, for example, having 1 to 6 carbon atoms. Typical examples of alkylenes include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0035] When used herein, the term "alkylamino" means that at least one alkyl group as defined herein is attached to the parent molecule through an amino group as defined herein.

[0036] As used herein, the term "amide" means -C(O)NR- or -NRC(O)-, where R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl or heteroalkyl.

[0037] As used herein, the term "aminoalkyl" means that at least one amino group as defined herein is attached to the parent molecular moiety through an alkylene group as defined herein.

[0038] As used herein, the term "amino" means -NR x R y wherein R x and R y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl or heteroalkyl. In the case of an aminoalkyl group, or any other moiety where the amino is attached together to two other moieties, the amino may be -NR x -wherein R x may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl or heteroalkyl.

[0039] As used herein, the term "aryl" refers to phenyl, or phenyl attached to the parent molecular moiety and condensed to a cycloalkane group (e.g., aryl can be indan-4-yl), or condensed to a 6-membered arene group (i.e., aryl is naphthyl), or condensed to a non-aromatic heterocycle (e.g., aryl can be benzo[d][1,3]dioxol-5-yl). The term "phenyl" is used when referring to a substituent, and the term "6-membered arene" is used when referring to a fused ring. The 6-membered arene is monocyclic (e.g., benzene or benzo). Aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9-12 member fused bicyclic system).

[0040] As used herein, the term "cyanoalkyl" means that at least one -CN group is attached to the parent molecule via an alkylene group as defined herein.

[0041] As used herein, the term "cyanofluoroalkyl" means that at least one -CN group is attached to the parent molecule through a fluoroalkyl group as defined herein.

[0042] 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.

[0043] The terms "cycloalkyl" or "cycloalkane," as used herein, refer to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term "cycloalkyl" is used herein to refer to a cycloalkane when present as a substituent. Cycloalkyls can be monocyclic cycloalkyls (e.g., cyclopropyl), condensed bicyclic cycloalkyls (e.g., decahydronaphthalenyl), or crosslinked cycloalkyls (e.g., bicyclo[2.2.1]heptanyl) in which two non-adjacent atoms of the ring are linked by an alkylene crosslink of 1, 2, 3, or 4 carbon atoms. 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.

[0044] The terms "cycloalkenyl" or "cycloalkene," as used herein, mean a non-aromatic monocyclic or polycyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond, preferably having 5 to 10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a condensed bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl (e.g., bicyclo[2.2.1]heptenyl) in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0045] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl." The term "carbocyclic" means "cycloalkane" or "cycloalkene." The term "carbocyclyl" refers to a "carbocyclic" when it is present as a substituent.

[0046] 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. Typical examples of fluoroalkyls include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl, for example, 3,3,3-trifluoropropyl.

[0047] As used herein, the term "fluoroalkylene" means an alkylene group as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms are replaced by fluorine. Typical examples of fluoroalkylenes include, but are not limited to, -CF2-, -CH2CF2-, 1,2-difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropylene, 1,1,2,3,3-pentafluoropropylene, and perfluoropropylene, such as 1,1,2,2,3,3-hexafluoropropylene.

[0048] When used herein, the term "fluoroalkoxy" means that at least one fluoroalkyl group, as defined herein, is attached to the parent molecule via an oxygen atom. Typical examples of fluoroalkoxys include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0049] As used herein, the terms "halogen" or "halo" mean Cl, Br, I, or F.

[0050] 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.

[0051] When used herein, the term "haloalkoxy" means that at least one haloalkyl group, as defined herein, is attached to the parent molecule via an oxygen atom.

[0052] As used herein, the term "halocycloalkyl" means a cycloalkyl group as defined herein, in which one or more hydrogen atoms are replaced by halogens.

[0053] 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. Typical examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkylamines, amides, and alkyl sulfides.

[0054] The term "heteroaryl," as used herein, 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 a heteroarene when present as a substituent. A monocyclic heteroaryl is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (for example, 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). A 5-membered aromatic monocyclic ring has two double bonds, and a 6-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryls are 8- to 12-membered ring systems and include fused bicyclic heteroaromatic ring systems (i.e., 10π-electron systems), such as monocyclic heteroaryl rings fused to 6-membered arenes (e.g., quinoline-4-yl, indole-1-yl), monocyclic heteroaryl rings fused to monocyclic heteroarenes (e.g., naphthilidinyl), and phenyls fused to monocyclic heteroarenes (e.g., quinoline-5-yl, indole-4-yl). Bicyclic heteroaryl / heterearene groups include 9-membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom that provides a lone pair of electrons to a fully aromatic 10π-electron system, such as ring systems having a nitrogen atom at the ring junction (e.g., imidazopyridine) or benzoxadiazolyl. Furthermore, bicyclic heteroaryls include fused bicyclic ring 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). In bicyclic heteroaryls, the parent molecule is bonded to the aromatic ring atom.Other representative examples of heteroaryls include 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, pyridadinyl, 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, and benzimidazolyl (e.g., benzimidazole Examples include, but are not limited to, thiazolo[5,4-]pyridinyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranil, isobenzofuranil, furanil, oxazolyl, isoxazolyl, prinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazole-4-yl, indazole-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, 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.

[0055] The terms “heterocycle” or “heterocyclic formula” as used herein mean monocyclic, bicyclic, or tricyclic heterocycles. The term “heterocyclyl” is used herein to refer to a heterocycle when present as a substituent. A monocyclic heterocycle 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. A 7 and 8-membered ring contains 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 heterocyclils include azetidinil, azepanil, azilidinil, diazepanil, 1,3-dioxanil, 1,3-dioxolanil, 1,3-dithiolanil, 1,3-dithianil, imidazolinil, imidazolidinil, isothiazolinil, isothiazolidinil, isoxazolinil, isoxazolidinil, morpholinil, 2-oxo-3-piperidinil, 2-oxoazepan-3-yl, oxadiazolinil, oxadiazolidinil, oxazolinil, oxazolidinil, oxetanil, oxe Examples include, but are not limited to, panyl, 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 to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiroheterocyclic group, or a bridged monocyclic heterocycle system in which two non-adjacent atoms of a 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 the non-aromatic ring atom (e.g., indoline-1-yl). Representative examples of bicyclic heterocyclyls include croman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-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 (including 3-azabicyclo[3.1.0]hexane-3-yl). Examples include, but are not limited to, 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]furanil, 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 condensed on a six-membered arene, or bicyclic heterocycles condensed on a monocyclic cycloalkane, or bicyclic heterocycles condensed on a monocyclic cycloalkene, or bicyclic heterocycles condensed on a monocyclic heterocycle, or bicyclic heterocycles in which two non-adjacent atoms of the 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-methanocyclopent[b]furan, hexahydro-1H-1,4-methanocyclopent[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). Monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom.

[0056] As used herein, the term "hydroxyl" or "hydroxy" means an -OH group.

[0057] As used herein, the term "hydroxyalkyl" means that at least one -OH group is attached to the parent molecular moiety through an alkylene group as defined herein.

[0058] As used herein, the term "hydroxyfluoroalkyl" means that at least one -OH group is attached to the parent molecular moiety through a fluoroalkyl group as defined herein.

[0059] Terms such as "alkyl", "cycloalkyl", "alkylene", etc. may be preceded by a symbol indicating the number of atoms present in the group in a particular case (e.g., "C 1~4 alkyl", "C 3~6 cycloalkyl", "C 1~4 alkylene"). These symbols are used as generally understood by those skilled in the art. For example, the expression "C" and the following subscripted number indicate the number of carbon atoms present in the subsequent group. Thus, "C3 alkyl" is an alkyl group having three carbon atoms (i.e., n-propyl, isopropyl). When a range is indicated as in "C 1~4 ", the members of the subsequent group can have any number of carbon atoms within the recited range. For example, "C 1~4An alkyl group is an alkyl group that has 1 to 4 carbon atoms, but is arranged (i.e., linear or branched).

[0060] The term "parent molecule" or "parent molecule portion" refers to the entire portion of the molecule to which the substituent is attached, i.e., the remaining part of the molecule.

[0061] The term "sulfonamide" as used herein refers to -S(O)2NR z - or -NR z S(O)- means that in the formula, R z This can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.

[0062] The term "substituent" refers to a group, such as an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, or heterocyclic group, that is "substituted" at any atom of that group. Any atom may be substituted.

[0063] The term "substituted" refers to a group which may be further substituted by one or more nonhydrogen 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 by 1, 2, 3, 4, or 5 substituents. In some embodiments, the aryl, heteroaryl, cycloalkyl, or heterocycle may be optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, the aryl, heteroaryl, cycloalkyl, or heterocycle may independently be unsubstituted or substituted with 1, 2, or 3 substituents.

[0064] For the compounds described herein, the groups and substituents of the compounds may be selected according to the allowable valencies of the atoms and substituents, such that the selection and substitution result in a stable compound, for example, the compound does not spontaneously deform through rearrangement, cyclization, elimination, etc.

[0065] As used herein, the term "allosteric site" refers to a ligand-binding site that is topographically distinct from an orthosteric binding site.

[0066] As used herein, the term "modulator" refers to a molecular entity (e.g., ligand and / or disclosed compounds) that modulates the activity of a target receptor protein.

[0067] As used herein, the term "ligand" refers to a natural or synthetic molecular entity that has the ability to associate with or bind to a receptor to form a complex and mediate, prevent, or modify a biological effect. Thus, the term "ligand" encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substances, and analogs of natural substances.

[0068] The terms “natural ligand” and “endogenous ligand,” as used herein, are interchangeable and refer to naturally occurring ligands that bind to a receptor and are found in nature.

[0069] As used herein, the term "orthosteric site" refers to the primary binding site on a receptor that is recognized by the endogenous ligand or agonist for that receptor. For example, the orthosteric site of the mAChR M4 receptor is the site where acetylcholine binds.

[0070] The term “positive allosteric modulator of the mAChR M4 receptor” as used herein refers to any exogenously administered compound or agent that directly or indirectly enhances the activity of the mAChR M4 receptor in animals, particularly mammals, such as humans, in the presence or absence of acetylcholine or another agonist. For example, a positive allosteric modulator of the mAChR M4 receptor can increase the intracellular activity of the 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 "positive allosteric modulator of the mAChR M4 receptor" includes compounds that are "mAChR M4 receptor allosteric enhancers" or "mAChR M4 receptor allosteric agonists," as well as compounds having mixed activity encompassing the pharmacological properties of both "mAChR M4 receptor allosteric enhancers" and "mAChR M4 receptor allosteric agonists." Furthermore, the term "positive allosteric modulator of the mAChR M4 receptor" also includes compounds that are "mAChR M4 receptor allosteric enhancers."

[0071] The term "mAChR M4 receptor allosteric enhancer," as used herein, refers to any exogenously administered compound or agent that directly or indirectly enhances the response produced by an endogenous ligand (e.g., 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, an increased safety margin, higher tolerability, reduced potential for abuse, and reduced toxicity.

[0072] The term "mAChR M4 receptor allosteric enhancer," as used herein, refers to any exogenously administered compound or agent that directly or indirectly enhances the response produced by an endogenous ligand (e.g., acetylcholine) in animals, particularly mammals, such as humans. In some embodiments, the allosteric enhancer increases the affinity of the native ligand or agonist to the orthosteric site. In some embodiments, the allosteric enhancer increases the efficacy of the agonist. The mAChR M4 receptor allosteric enhancer binds to a site other than the orthosteric site, i.e., the allosteric site, and positively enhances the receptor's response to the agonist or endogenous ligand. The allosteric enhancer has no effect on the receptor itself and requires the presence of an agonist or native ligand to achieve its receptor effect.

[0073] The term "mAChR M4 receptor allosteric agonist," as used herein, refers to any exogenously administered compound or agent that directly activates the activity of the mAChR M4 receptor in animals, particularly mammals, such as humans, in the absence of an endogenous ligand (e.g., acetylcholine). mAChR M4 receptor allosteric agonists bind to a site on the mAChR M4 receptor distinct from the orthosteric acetylcholine site. Because it does not require the presence of an endogenous ligand, the activity of a compound as an mAChR M4 receptor allosteric agonist is advantageous when the cholinergic system at a given synapse is underactive.

[0074] The term "mAChR M4 receptor neutral allosteric ligand," as used herein, refers to any exogenously administered compound or agent that binds to the allosteric site in animals, particularly mammals, such as humans, without affecting the binding or function of agonists or native ligands at the orthosteric site. However, neutral allosteric ligands may block the action of other allosteric modulators acting via the same site.

[0075] In the enumeration of numerical ranges in this specification, each number in between is explicitly intended with the same degree of precision. For example, in the range of 6 to 9, the numbers 7 and 8 are intended in addition to 6 and 9, and in the range of 6.0 to 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.

[0076] Abbreviation: AcOH is acetic acid. ADDP is 1,1'-(azodicarbonyl)dipiperidine. AIBN is azobisisobutyronitrile. AQ is water-based. atm stands for atmosphere / air pressure. BINAP is 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl. Boc is tert-butoxycarbonyl Boc2O is di-tert-butyl dicarbonate B2pin2 is bis(pinacolato)diboron BrettPhos is 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl BrettPhos Pd G3 is [(2-dicyclohexylphosphino-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 cat. is catalyst CDI is 1,1'-carbonyldiimidazole CD2O is deuterated formaldehyde Celite® is diatomaceous earth CSA is (1S,4R)-10-camphorsulfonic acid DCE is 1,2-dichloroethane DCM is dichloromethane DEA is diethylamine DIAD is diisopropyl azodicarboxylate DIPEA or DIEA is diisopropylethylamine DMAP is 4-dimethylaminopyridine DMF is N,N-dimethylformamide DMP or Dess-Martin periodinane is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DMSO is dimethyl sulfoxide Dowtherm™ A is a eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxide dppp is 1,3-bis(diphenylphosphino)propane DtBAD is di-tert-butyl azodicarboxylate eq or eq. is equivalent EtOAC is ethyl acetate (4,4'-dtbbpy)NiCl2 is 4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride Et2O is diethyl ether EtOH is ethanol h or hr is hour 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 meta-chloroperoxybenzoic acid MeCN or ACN is acetonitrile MeI is iodomethane / methyl iodide MeOD is CD3OD (methanol-d4) MeOH is methanol min is minute 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 PCC is pyridinium chlorochromate [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(diphenylphosphino)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 seconds. The SCX cartridge or HF SCX cartridge is a strong cation exchange cartridge (i.e., Agilent part number 14256027). SFC is supercritical fluid chromatography. TBAC or TBACl is tetrabutylammonium chloride. t-BuXPhos is 2-di-tert-butylphosphin-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. TBACl is tetrabutylammonium chloride. TCICA is trichloroisocyanuric acid. TEA or Et3N is triethylamine. TFA is trifluoroacetic acid. THF is tetrahydrofuran TMB is trimethylboroxine. TsCl is p-toluenesulfonyl chloride. tosyl is p-toluenesulfonyl. Xantphos is 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0077] 2.Compound In one embodiment, the present invention provides a compound of formula (I), wherein R 8 , G 1 And n are as defined herein.

[0078] Unsubstituted or substituted rings (i.e., optionally substituted), such as aryls and heteroaryls, consist of both a ring system and optional substituents on the ring system. Therefore, since the ring system can be defined independently of its substituents, redefining only the ring system leaves any previously optional substituents in place. For example, a 5-12 member heteroaryl with optional substituents may be further defined by specifying that the ring system of the 5-12 member heteroaryl is a 5-6 member heteroaryl (i.e., a 5-6 member heteroaryl ring system), in which case, unless explicitly shown otherwise, the optional substituents of the 5-12 member heteroaryl still reside on the 5-6 member heteroaryl.

[0079] If a heterocyclic ring system and a heteroaromatic ring system are defined as "containing" or "having" specified heteroatoms (for example, 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S), then any ring atom of the heterocyclic ring system and the heteroaromatic ring system that is not one of the specified heteroatoms is a carbon atom.

[0080] The following numbered embodiments of the present invention are disclosed. The first embodiment is indicated as E1, and subsequent embodiments are indicated as E1.1, E1.2, E1.3, E2, E3, E3.1, E3.2, E3.3, E3.4, E4, and so on.

[0081] E1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

[0082]

化

[0083] {wherein, G 1 is

[0084]

化

[0085] and X 1 is NR 5 or O, R 4A and R 4B are independently hydrogen, C 1~4 alkyl, C 3~4 cycloalkyl or -C6] 1~3 alkylene-OH, or R 4A and R 4B together with the carbon to which they are attached form C 3~6 cycloalkyl, R 5 is hydrogen, C 1~6 alkyl, C 1~6 fluoroalkyl, -C 1~6 alkylene-R y 、-C 1~6 fluoroalkylene-R y 、G 5 or -C 1~3 alkylene-G 5 and 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 is, each time it appears, independently hydrogen, C 1~4 alkyl, C1~4 Fluoroalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 It is a cycloalkyl, G 5 This includes phenyl, 4-8 membered heterocyclyls containing 1-2 heteroatoms, 5-6 membered heteroaryls containing 1-4 heteroatoms, or C 3~6 It is a cycloalkyl group, and the heteroatoms are independently selected from the group consisting of O, N, and S, G 5 C 1~4 Alkyl, halogen, oxo, -OC 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~4 Cycloalkyl and -C 1~2 Alkylene-C 3~4 Optionally substituted with 1 to 4 substituents selected from the group consisting of cycloalkyl groups, R 6 Hydrogen, 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 3~4 It is a cycloalkyl, R 6a Each instance of appearance is independent of hydrogen and C. 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 It is a cycloalkyl, Here, or two R's 6a Along with the nitrogen to which they bind, R 6a It forms a 4- to 8-membered heterocyclic ring containing a nitrogen atom bonded to it and, optionally, one additional heteroatom which is O, N, or S, and the heterocyclic ring is independently a halogen, C 1~2 Alkyl and C 1~2 Optionally substituted with 1 to 4 substituents selected from the group consisting of fluoroalkyl groups, R 7 C 1~4 Alkyl, hydrogen, halogen, cyano, C 1~4 Fluoroalkyl, C 2~4 Alkenil, -OR 7a , -C 1~3 Alkilen-OR 7a CO2R 7a COR 7a or C 3~6 It is a cycloalkyl, Alternatively, R 6 and R 7 Together with the atoms to which they are bonded, they form an aromatic or non-aromatic ring consisting of 5 to 7 carbon atoms. 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, R 8 Each instance of appearance is independent of halogen and C. 1~4 Alkyl, C 1~4 Fluoroalkyl or C 3~4 It is a cycloalkyl, n is 0, 1, 2, 3, or 4. and at least one hydrogen in the compound is a deuterium isotope ( 2 A compound that is H.

[0086] E1.1. R 6 However, hydrogen, 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 3~4 It is a cycloalkyl, R 7 However, C 1~4 Alkyl, hydrogen, halogen, cyano, C 1~4 Fluoroalkyl, C 2~4 Alkenil, -OR 7a , -C1~3 Alkilen-OR 7a CO2R 7a COR 7a or C 3~6 It is a cycloalkyl, The compounds listed in E1 or their pharmaceutically acceptable salts.

[0087] E1.2. R 6 and R 7 The compound described in E1 or a pharmaceutically acceptable salt thereof, wherein, together with the atoms to which they are bonded, they form an aromatic or non-aromatic ring consisting of 5 to 7 carbon atoms.

[0088] E1.3. R 6 and R 7 The compounds described in E1 or E1.2, or pharmaceutically acceptable salts thereof, which, together with the atoms to which they are bonded, form a non-aromatic ring consisting of 5 to 7 carbon atoms.

[0089] E2. G 1 but,

[0090] [ka]

[0091] The compound described in any one of E1 to E1.3, or a pharmaceutically acceptable salt thereof.

[0092] E3. R 4A and R 4B However, hydrogen or C 1~4 A compound that is alkyl, as described in any one of E1 to E2, or a pharmaceutically acceptable salt thereof.

[0093] E3.1. R 4A and R 4B A compound described in E3 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

[0094] E3.2. R 4A and R 4B The hydrogen of deuterium ( 2H) The compound described in E3.1 or a pharmaceutically acceptable salt thereof.

[0095] E3.3. R 4A is hydrogen, R 4B C 1~4 A compound described in E3, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0096] E3.4. R 4A and / or R 4B C 1~4 A compound described in any one of E1-E3 or E3.3, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is methyl.

[0097] E4.X 1 NR 5 The compound described in any one of E1 to E3.4, or a pharmaceutically acceptable salt thereof.

[0098] E5.X 1 A compound listed in any one of E1 to E3.4, or a pharmaceutically acceptable salt thereof, wherein the compound is O.

[0099] E6. G 1 but,

[0100] [ka]

[0101] The compound described in any one of E1 to E1.3, or a pharmaceutically acceptable salt thereof.

[0102] E6.1. G 1 but,

[0103] [ka]

[0104] The compound described in any one of E1, E1.2-E1.3, or E6, or a pharmaceutically acceptable salt thereof.

[0105] E6.2. G 1 but,

[0106] [ka]

[0107] The compound described in any one of E1, E1.2-E1.3, or E6, or a pharmaceutically acceptable salt thereof.

[0108] E7. R 5 However, hydrogen, C 1~6 Alkyl, -C 1~6 Alkilen-R y , G 5 or -C 1~3 Alkilen-G 5 A compound described in any one of E1-E4 or E6, or a pharmaceutically acceptable salt thereof.

[0109] E7.1. R 5 A compound described in E7 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

[0110] E7.2. R 5 C 1~6 A compound described in E7, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0111] E7.3. R 5 ga-C 1~6 Alkilen-R y The compound described in E7 or a pharmaceutically acceptable salt thereof.

[0112] E7.4. R 5 -C 1~6 Alkilen-R y However, -CH2CH2-R y or -CH(CH3)CH2-R y The compound described in any one of E1-E4, E6-E7, or E7.3, or a pharmaceutically acceptable salt thereof.

[0113] E7.5. R 5 G 5 The compound described in E7 or a pharmaceutically acceptable salt thereof.

[0114] E7.6. R 5 ga-C 1~3 Alkilen-G 5 The compound described in E7 or a pharmaceutically acceptable salt thereof.

[0115] E7.7. R 5 -C 1~3 Alkilen-G 5 However, -CH2-G 5 A compound described in any one of E1-E4, E6-E7, or E7.6, or a pharmaceutically acceptable salt thereof.

[0116] E8. R 5 C 1~6 A compound described in any one of E1-E4, E6-E7, E7.2, E7.4, or E7.7, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is methyl or ethyl.

[0117] E8.1. R 5 C 1~6 A compound described in E8, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is methyl.

[0118] E8.2. R 5 A compound described in E8 or E8.1, or a pharmaceutically acceptable salt thereof, wherein the methyl group is CD3.

[0119] E9. R y ga-OR 5a The compound described in any one of E1-E4, E6-E7, E7.3-E7.4, E7.7, or E8-E8.2, or a pharmaceutically acceptable salt thereof.

[0120] E10. R 5a C 1~4A compound that is alkyl, as described in any one of E1-E4, E6-E7, E7.3-E7.4, E7.7, or E8-E9, or a pharmaceutically acceptable salt thereof.

[0121] E10.1. R 5a C 1~4 A compound described in any one of E1-E4, E6-E7, E7.3-E7.4, E7.7, or E8-E10, wherein the alkyl group is methyl, or a pharmaceutically acceptable salt thereof.

[0122] E11. G 5 A compound or pharmaceutically acceptable salt thereof described in any one of E1-E4, E6-E7, or E7.4-E10.1, which is a 4-8 membered heterocycline that optionally contains 1-2 heteroatoms and is substituted.

[0123] E11.1. G 5 A compound described in any one of E1-E4, E6-E7, or E7.4-E11, or a pharmaceutically acceptable salt thereof, wherein the 4-8 membered heterocyclyl ring system, which may be substituted in some cases, is tetrahydrofuran or morpholine.

[0124] E11.2. G 5 The compound described in E11.1 or a pharmaceutically acceptable salt thereof, wherein the 4- to 8-membered heterocyclyl ring system, which may be substituted in some cases, is tetrahydrofuran-3-yl or morpholine-2-yl.

[0125] E11.3. G 5 but,

[0126] [ka]

[0127] The compound described in E11.2 or a pharmaceutically acceptable salt thereof.

[0128] E11.4. G 5 but,

[0129] [ka]

[0130] The compound described in E11.2 or a pharmaceutically acceptable salt thereof.

[0131] E11.5. G 5 but,

[0132] [ka]

[0133] The compound described in E11.4 or a pharmaceutically acceptable salt thereof.

[0134] E12. G 5 However, C is substituted in some cases. 3~6 A cycloalkyl compound, one of those listed in E1-E4, E6-E7, or E7.4-E10.1, or a pharmaceutically acceptable salt thereof.

[0135] E12.1. G 5 C is replaced depending on the case. 3~6 A compound described in any one of E1-E4, E6-E7, E7.4-E10.1, E11.1-E11.2, or E12, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl ring system is cyclopropyl or cyclopentyl.

[0136] E12.2. G 5 The compound described in E12.1 or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl or cyclopentyl.

[0137] E13. R 6 However, hydrogen, C 1~4 Alkyl, halogen, or C 3~4 A cycloalkyl compound, one of those listed in E1-E6 or E7-E12.2, or a pharmaceutically acceptable salt thereof.

[0138] E13.1. R 6 However, hydrogen, C 1~4 A compound described in E13, or a pharmaceutically acceptable salt thereof, which is alkyl or halogenated.

[0139] E13.2. R 6 A compound described in E13.1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

[0140] E13.3. R 6 C 1~4 A compound described in E13.1, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0141] E13.4. R 6 C 1~4 A compound described in any one of E1-E6, E7-E13.1, or E13.3, wherein the alkyl group is methyl, or a pharmaceutically acceptable salt thereof.

[0142] E13.5. R 6 A compound listed in E13.1 or a pharmaceutically acceptable salt thereof, wherein the halogen is present.

[0143] E13.6. R 6 A compound described in any one of E1-E6, E7-E13.1, or E13.4-E13.5, or a pharmaceutically acceptable salt thereof, wherein the halogen is chloro.

[0144] E13.7. R 6 C 3~4 A cycloalkyl compound, as described in E13, or a pharmaceutically acceptable salt thereof.

[0145] E13.8. R 6 C 3~4 A compound described in any one of E1-E6, E7-E13.1, E13.4, or E13.6-E13.7, wherein the cycloalkyl group is cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0146] E14. R 7 C 1~4A compound that is alkyl, as described in any one of E1-E6 or E7-E13.8, or a pharmaceutically acceptable salt thereof.

[0147] E14.1. R 7 C 1~4 A compound listed in any one of E1-E6 or E7-E14, wherein the alkyl group is methyl, or a pharmaceutically acceptable salt thereof.

[0148] E15. A compound listed in any one of E1 to E14.1, or a pharmaceutically acceptable salt thereof, where n is 0.

[0149] E16. A compound listed in any one of E1 to E14.1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0150] E17. R 8 However, each appearance is independent, C 1~4 A compound that is alkyl, as described in any one of E1 to E14.1 or E16, or a pharmaceutically acceptable salt thereof.

[0151] E17.1. R 8 C 1~4 A compound listed in any one of E1 to E17, wherein the alkyl group is methyl, or a pharmaceutically acceptable salt thereof.

[0152] E18.1. The compound of formula (I) is the compound of formula (Ia)

[0153] [ka]

[0154] A compound described in any one of E1 to E17.1, or a pharmaceutically acceptable salt thereof.

[0155] E18.2. The compound of formula (I) is the compound of formula (Ib)

[0156] [ka]

[0157] A compound described in any one of E1 to E17.1, or a pharmaceutically acceptable salt thereof.

[0158] E18.3. The compound of formula (I) is the compound of formula (Ic)

[0159] [ka]

[0160] A compound described in any one of E1 to E17.1, or a pharmaceutically acceptable salt thereof.

[0161] E18.4. The compound of formula (I) is the compound of formula (Id)

[0162] [ka]

[0163] A compound described in any one of E1 to E17.1, or a pharmaceutically acceptable salt thereof.

[0164] E18.5. The compound of formula (I) is the compound of formula (Ie)

[0165] [ka]

[0166] A compound described in any one of E1 to E17.1, or a pharmaceutically acceptable salt thereof.

[0167] E19.1. The compound of formula (I) is the compound of formula (Ia-1)

[0168] [ka]

[0169] A compound described in any one of E1 to E18.1, or a pharmaceutically acceptable salt thereof.

[0170] E19.2. The compound of formula (I) is the compound of formula (Ib-1)

[0171] [ka]

[0172] A compound described in any one of E1 to E18 or E18.2, or a pharmaceutically acceptable salt thereof.

[0173] E19.3. The compound of formula (I) is the compound of formula (Ic-1)

[0174] [ka]

[0175] A compound described in any one of E1 to E18 or E18.3, or a pharmaceutically acceptable salt thereof.

[0176] E19.4. The compound of formula (I) is the compound of formula (Ic-2)

[0177] [ka]

[0178] A compound described in any one of E1 to E18 or E18.3, or a pharmaceutically acceptable salt thereof.

[0179] E19.5. The compound of formula (I) is the compound of formula (Id-1)

[0180] [ka]

[0181] A compound described in any one of E1 to E18 or E18.4, or a pharmaceutically acceptable salt thereof.

[0182] E19.6. The compound of formula (I) is the compound of formula (Ie-1)

[0183] [ka]

[0184] A compound described in any one of E1 to E18 or E18.5, or a pharmaceutically acceptable salt thereof.

[0185] E19.7. At least one additional hydrogen in the compound is an isotopic hydrogen ( 2 H) A compound listed in any one of E1 to E19.6 or a pharmaceutically acceptable salt thereof.

[0186] E20. 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl-4-d)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl-2,2,6,6-d4)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopropyl-2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopentyl-2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3-methylflu[3,4-b]pyridine-5(7H)-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3,7-dimethylflu[3,4-b]pyridine-5(7H)-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-yl-4-d)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-yl-2,2,6,6-d4)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-ethyl-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-(2-methoxyethyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; (R)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-2-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3a]pyrimidine-3(2H)-one; (S)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-2-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-(1-methoxypropan-2-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-2-((4-methylmorpholine-2-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 5-Chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 5-Cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 5-Cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-2-(methyl-d3)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-methyl-2,6,7,8-tetrahydro-1H-cyclopenta[e][1,2,4]triazolo[4,3a]pyrimidine-1-one; 5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazoline-1(2H)-one; 5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1,2,4]triazolo[4,3a]pyrimidine-1-one; 5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazoline-1(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5,6-dimethyl-2-(methyl-d3)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; A compound described in E1, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

[0187] E21. A compound described in any one of E1 to E20, or a pharmaceutically acceptable salt thereof, having at least 50% deuterium incorporation at each deuterium label.

[0188] E21.1. The compound described in E21 or a pharmaceutically acceptable salt thereof, having at least 55% deuterium incorporation at each deuterium label.

[0189] E21.2. The compounds described in E21.1 or pharmaceutically acceptable salts thereof, having at least 60% deuterium incorporation at each deuterium label.

[0190] E21.3. The compounds described in E21.2 or pharmaceutically acceptable salts thereof, having at least 70% deuterium incorporation at each deuterium label.

[0191] E21.4. The compounds described in E21.3 or pharmaceutically acceptable salts thereof, having at least 75% deuterium incorporation at each deuterium label.

[0192] E21.5. The compounds described in E21.4 or pharmaceutically acceptable salts thereof, having at least 80% deuterium incorporation at each deuterium label.

[0193] E21.6. The compounds described in E21.5 or pharmaceutically acceptable salts thereof, having at least 85% deuterium incorporation at each deuterium label.

[0194] E21.7. The compounds described in E21.6 or pharmaceutically acceptable salts thereof, having at least 90% deuterium incorporation at each deuterium label.

[0195] E21.8. The compounds described in E21.7 or pharmaceutically acceptable salts thereof, having at least 95% deuterium incorporation at each deuterium label.

[0196] E21.9. The compounds described in E21.8 or pharmaceutically acceptable salts thereof, having at least 96% deuterium incorporation at each deuterium label.

[0197] E21.10. The compounds described in E21.9 or pharmaceutically acceptable salts thereof, having at least 97% deuterium incorporation at each deuterium label.

[0198] E21.11. The compounds described in E21.10 or pharmaceutically acceptable salts thereof, having at least 98% deuterium incorporation at each deuterium label.

[0199] E21.12. The compounds described in E21.11 or pharmaceutically acceptable salts thereof, having at least 99% deuterium incorporation at each deuterium label.

[0200] E21.13. The compounds described in E21.12 or pharmaceutically acceptable salts thereof, having at least 99.5% deuterium incorporation at each deuterium label.

[0201] E21.14. The compounds described in E21.13 or pharmaceutically acceptable salts thereof, having at least 99.9% deuterium incorporation at each deuterium label.

[0202] E21.15. A compound described in any one of E21 to E21.14, or a pharmaceutically acceptable salt thereof, having 99 to 99.9% deuterium incorporation at each deuterium label.

[0203] E22. Any hydrogen atom in the compound that is not identified as deuterium represents its naturally occurring isotopic abundance of hydrogen, as described in any one of E1 to E21.15, or a pharmaceutically acceptable salt thereof.

[0204] E23. A pharmaceutical composition comprising a compound described in any one of E1 to E22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0205] E24. A method for treating neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals, comprising the step of administering to a mammal a therapeutically effective amount of any one of E1 to E22 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to E23.

[0206] E25. The method described in E24, wherein the dysfunction is associated with mAChR M4 dysfunction.

[0207] E26. The method according to E24 or E25, wherein the disorder is a neurological and / or psychiatric disorder associated with mAChR M4 dysfunction.

[0208] E27. A method according to any one of E24-E26, wherein the disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, sleep disorders, pain disorders, and cognitive impairment.

[0209] E28. The method described in E27, where the disorder is Alzheimer's disease.

[0210] E29. The method according to any one of E24-E26, wherein the disorder is selected from the group consisting of psychosis, schizophrenia, conduct disorder, destructive behavior disorder, bipolar disorder, anxiety psychotic episodes, anxiety associated with psychosis, psychotic mood disorders, such as severe major depressive disorder, mood disorders associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral signs of intellectual disability, autism spectrum disorder, motor disorders, Tourette syndrome, akinetic-rigid 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.

[0211] E30. A kit comprising one of the compounds described in any one of E1 to E22 or a pharmaceutically acceptable salt thereof, and one or more of the following: (a) at least one agent known to increase mAChR M4 activity, (b) at least one agent known to decrease mAChR M4 activity, (c) at least one agent known to treat disorders associated with cholinergic activity, (d) instructions for use for treating disorders associated with cholinergic activity, (e) instructions for use for treating disorders associated with mAChR M4 receptor activity, and (f) instructions for use for administering the compound in connection with cognitive or behavioral therapy.

[0212] E31. A compound according to any one of E1 to E22 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to E23, for use in the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0213] E32. Use of any one of the compounds described in E1 to E22 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in E23, for the preparation of a medicament for the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0214] Compounds may exist as stereoisomers containing a chiral or asymmetric center. The stereoisomers are "R" or "S" depending on the arrangement of substituents around the chiral carbon atom. The terms "R" and "S" as used herein refer to the arrangements defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45:13-30. This disclosure envisions various stereoisomers and mixtures thereof, which are particularly included within the scope of the invention. Stereoiomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of a compound may be synthesized from commercially available starting materials containing a chiral or asymmetric center, or prepared by the preparation of racemic mixtures and subsequent separation methods well known to those skilled in the art. These separation methods are exemplified by (1) binding of the enantiomer mixture to a chiral auxiliary, separation of the resulting diastereomer mixture by recrystallization or chromatography, and optional release 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, UK; or (2) direct separation of the optical enantiomer mixture in a chiral chromatography column; or (3) fractional recrystallization.

[0215] The compound may have tautomers and geometric isomers, which should be understood to also constitute embodiments of the present disclosure.

[0216] This disclosure includes isotope-labeled compounds that are identical to the compounds enumerated in formula (I), but are not identical in that one or more atoms are identified as atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, not limited to, 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 It is Cl.

[0217] The deuterium-labeled compounds disclosed herein may have certain therapeutic advantages compared to unlabeled analogs as a result of greater metabolic stability. For example, the disclosed compounds may have improved pharmacokinetic properties compared to unlabeled analogs, such as increased in vivo half-life, reduced clearance rate, and / or increased bioavailability. Improved pharmacokinetic properties may allow for reduced dose requirements, a greater therapeutic index, and / or less frequent dosing to achieve or maintain therapeutic effects.

[0218] The compound may incorporate positron emission isotopes for medical imaging and positron emission tomography (PET) studies to determine the 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.

[0219] Isotope-enriched compounds of formula (I) or any subformula can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples, using appropriate isotope-enriching reagents instead of non-isotope-enriching 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. While synthetic techniques for accessing isotope-enriched compounds may be conventional, the resulting compounds may have unexpected properties, such as those described herein.

[0220] It is understood that, depending on the origin of the materials used in synthesis, some variations in the natural isotopic abundances occur in the synthesized compounds. Despite these variations, the concentrations of naturally abundant and stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotopic substitution in the deuterated compounds described herein.

[0221] In a compound of formula (I) or any subformula, any deuterium label, for example, 2 "H", "D", or "deuterium" represents deuterium in abundances at least greater than the natural abundance of deuterium (e.g., 25%, 50%, 75%, 90%, 99% deuterium incorporation). The amount of deuterium incorporation at a specified position can be measured by analytical methods known to those skilled in the art, such as proton NMR. Any hydrogen atom not specifically designated as deuterium represents its natural isotopic abundance.

[0222] a. Pharmaceutically acceptable salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a salt or zwitterion of a compound that is suitable for treating a disorder without excessive toxicity, irritation, and allergic reactions, is commensurate with a reasonable benefit-risk ratio, and is effective for its intended use, and is water-soluble, oil-soluble, or dispersible. 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 not limited to methanol and water, and treated with at least one equivalent of an acid, such as hydrochloric acid. The resulting salt may be isolated by precipitation and filtration and dried under reduced pressure. Alternatively, the salt may be obtained by removing the solvent and excess acid under reduced pressure. Typical salts include acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivaphosphate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. Furthermore, the amino group of the compound can be quaternized by alkyl chlorides, alkyl bromides, and alkyl iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, and stearyl.

[0223] Base-added salts may be prepared during the final isolation and purification of the disclosed compounds by reacting the carboxyl group with a suitable base, such as a metal cation hydroxide, carbonate, or bicarbonate, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or with an organic primary, secondary, or tertiary amine. Quaternary amine salts, such as salts 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, etc., may be prepared.

[0224] b. General synthesis The compound of formula (I) can be prepared by a synthetic or metabolic process. The preparation of the compound by a metabolic process includes processes that occur in the body of a human or animal (in vivo) or in vitro.

[0225] The compound of formula (I) can be synthesized using the processes shown in schemes 1 to 5, preferably with deuterium-labeled intermediates and / or reagents.

[0226] [ka]

[0227] As illustrated in Scheme 1, intermediate i may be reacted with intermediate ii and a base (e.g., DIEA or TEA) in a solvent (e.g., NMP, DMF) by heating to about 120-160°C to obtain the compound of formula iii.

[0228] [ka]

[0229] As shown in Scheme 2, the intermediate compound of formula iv (wherein Y and Y 1 The compound of formula v may be obtained by reacting an amine (which is fluorine, chlorine, or bromine) with an amine i, a base (e.g., DIEA, Et3N, etc.), and a solvent (e.g., NMP, DMF) under standard nucleophilic substitution conditions, heated to about 60-75°C. The intermediate of formula v (wherein Y is a halogen) may be reacted with hydrazine in a solvent (e.g., ethanol) by heating to 70-80°C. The intermediate may be reacted with CDI (CAS number 530-62-1) in a solvent (e.g., 1,4-dioxane) by heating to 70-85°C to form the compound of formula vi. The intermediate of formula vi may be reacted with an alkylating reagent (R) in a solvent (e.g., DMF) under standard alkylation conditions generally known in the art. 5 -X (wherein X is a halogen, mesylate, or tosylate) may be reacted with a base (e.g., K2CO3) to obtain the compound of formula vii.

[0230] [ka]

[0231] As shown in Scheme 3, the intermediate of formula viii (wherein Y is a halogen) may be coupled with a boronic acid or ester under Suzuki coupling conditions generally known in the art. The coupling reaction may be carried out by heating to about 70-90°C in an organic solvent, such as DMF or a solvent mixture of 1,4-dioxane and water, with a palladium catalyst, such as Pd(dppf)Cl2, and a base (e.g., K2CO3, Cs2CO3), to form the compound of formula iii. The reaction may be accelerated by microwave irradiation.

[0232] [ka]

[0233] As shown in Scheme 4, the intermediate of formula viii (wherein Y is a halogen) may be reacted with a catalyst (e.g., Pd(PPh3)4), a cyanide source (e.g., Zn(CN)2), and a solvent (e.g., DMF) by heating to 120-140°C to obtain the compound of formula ix. The reaction may be accelerated by microwave irradiation.

[0234] [ka]

[0235] As shown in Scheme 5, the ester intermediate x (wherein Y, Y) 1 and Y 2 Compound xi may be obtained by reacting a (wherein is Cl, Br, or I) with an amine, a base (e.g., DIEA), and a solvent (e.g., THF) without heating or by heating to 40-50°C.

[0236] Boronic acids / esters, amines, and alcohols suitable for the coupling reactions described herein can be readily obtained from commercially available sources or prepared by standard methods well known to those skilled in the art.

[0237] Compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography on a solid support, such as silica gel, alumina, or silica derivatized with alkylsilane groups; recrystallization at high or low temperatures with pretreatment with optionally activated carbon; thin-layer chromatography; distillation at various pressures; sublimation under vacuum; and trituration, as described, for example, in "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Furniss, Hannaford, Smith, and Tatchell, published by Longman Scientific & Technical, Essex CM20 2JE, UK.

[0238] The disclosed compounds may have at least one basic nitrogen such that the compounds can be treated with an acid to form a desired salt. For example, the compounds may react with an acid at room temperature or at a temperature higher than room temperature to produce a desired salt, which can be deposited and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid and mandelic acid, atrolactinic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carboxylic acids, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0239] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants used and the substituents present in them. Specific procedures are shown in the Examples section. The reaction is carried out in a conventional manner, for example by removing the solvent from the residue, and may be further purified by methods generally known in the art, such as crystallization, distillation, extraction, grinding, and chromatography, without limitation. Unless otherwise indicated, the 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 the starting materials are not commercially available, they may be prepared by a method 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.

[0240] Routine experiments, including the appropriate manipulation of reaction conditions, reagents and sequences of the synthetic route, protection of any chemical functional groups that may not be compatible with the reaction conditions, and deprotection at a suitable point 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 can be found in PGM Wuts and TW Greene, Greene's book, *Protective Groups in Organic Synthesis* (4th edition), John Wiley & Sons, NY (2006), the entire literature of which is incorporated herein by reference. The synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthetic schemes and specific examples described herein.

[0241] 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 a suitable reaction step), or by decomposition of a mixture of stereoisomers of the compound or intermediate using standard procedures (e.g., chromatographic separation, recrystallization, or enzymatic decomposition).

[0242] Similarly, if a pure geometric isomer of a 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 decomposition of a mixture of geometric isomers of the compound or intermediate using a standard procedure, such as chromatographic separation.

[0243] Since the scope of this invention is defined in the accompanying claims, 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. All substitutes, modifications, and equivalents of the synthesis methods and specific examples are included within the claims.

[0244] 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 the agonist in the presence of the compound compared to the response to the agonist in the absence of the compound. The enhancement of mAChR M4 activity can be demonstrated by methods known in the art. For example, activation of mAChR M4 activity is Ca 2+ The calcium flow can be determined by measuring the response to an agonist, such as acetylcholine, in cells loaded with co-expression of a sensitive fluorescent dye (e.g., Fluo-4) and a chimeric or crossbred G protein. In some embodiments, calcium flow was measured as an increase in the fluorescence static ratio. In some embodiments, positive allosteric modulator activity is measured as EC 20 The acetylcholine response (i.e., the response of mAChR M4 at acetylcholine concentrations that produce 20% of the maximum response) was analyzed as a concentration-dependent increase.

[0245] 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 equivalent CHO-K1 cell response in the absence of the compound. In some embodiments, the disclosed compounds are present in EC concentrations of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 This activates the mAChR M4 response. In some embodiments, CHO-K1 cells transfected with mAChR M4 are transfected with human mAChR M4. In some embodiments, CHO-K1 cells transfected with mAChR M4 are transfected with rat mAChR M4.

[0246] 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 mAChR M4-transfected CHO-K1 cells in the presence of the compound compared to the response to acetylcholine in the absence of the compound. In some embodiments, the disclosed compounds are present in EC concentrations of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. 50 This exhibits positive allosteric modulation of the mAChR M4 response to acetylcholine. In some embodiments, the EC for positive allosteric modulation is shown. 50 This is determined in CHO-K1 cells transfected with mAChR M4. In some embodiments, mAChR M4 is transfected with human mAChR M4. In some embodiments, mAChR M4 is transfected with rat mAChR M4.

[0247] The disclosed compounds may exhibit selectivity for the mAChR M4 receptor to one or more of the mAChR M1, M2, M3, or M5 receptors. For example, the disclosed compounds may exhibit selectivity for the EC of one or more CHO-K1 cells transfected with mAChR M1, M2, M3, or M5. 50 e-commerce below 50 Therefore, the mAChR M4 response can be activated in CHO-K1 cells transfected with mAChR M4. In some embodiments, the disclosed compounds have an EC of mAChR M1. 50 EC less than approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or 1 / 500 50 This can activate the mAChR M4 response. In some embodiments, the disclosed compounds have an EC of mAChR M2. 50EC less than approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or 1 / 500 50 This can activate the mAChR M4 response. In some embodiments, the disclosed compounds have an EC of mAChR M3. 50 EC less than approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or 1 / 500 50 This can activate the mAChR M4 response. In some embodiments, the disclosed compounds have an EC of mAChR M5. 50 EC less than approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or 1 / 500 50 This can activate the mAChR M4 response. In some embodiments, the disclosed compounds are EC for M2-M5 receptors. 50 One-fifth, approximately one-tenth, approximately one-twentieth, approximately one-thirtieth, and EC for mAChR M1, M2, M3, or M5 receptors. 50 EC less than approximately 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or 1 / 500 50 This can activate the mAChR M4 response.

[0248] The disclosed compounds have an EC of less than approximately 10 μM. 50 Therefore, the mAChR M4 response can be activated in CHO-K1 cells transfected with M4, and the compound exhibits selectivity for the M4 receptor over one or more of the mAChR M1, M2, M3, or M5 receptors. For example, in some embodiments, the 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, less than about 100 nM, or less than about 50 nM. 50 The compound may have EC with respect to mAChR M1. 50EC less than approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or about 1 / 500 50 This can activate the mAChR M4 response. In some embodiments, the 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, less than about 100 nM, or less than about 50 nM. 50 The compound may have EC for mAChR M2. 50 EC less than approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or 1 / 500 50 This can activate the mAChR M4 response. In some embodiments, the 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, less than about 100 nM, or less than about 50 nM. 50 The compound may have EC for mAChR M3. 50 EC less than approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or 1 / 500 50 This can activate the mAChR M4 response. In some embodiments, the 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, less than about 100 nM, or less than about 50 nM. 50 The compound may have EC for mAChR M5. 50 EC less than approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or 1 / 500 50 This can activate the mAChR M4 response. In some embodiments, the 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, less than about 100 nM, or less than about 50 nM. 50 The compound may also have EC for M2-M5 receptors. 501 / 5, approximately 1 / 10, approximately 1 / 20, approximately 1 / 30, approximately 1 / 50, approximately 1 / 100, approximately 1 / 200, approximately 1 / 300, approximately 1 / 400 of M2, M3, or M5 receptors, or EC for mAChR M1, M2, M3, or M5 receptors 50 E-commerce is less than 1 / 500th of the total. 50 This can activate the mAChR M4 response.

[0249] The in vivo efficacy of the disclosed compounds can be measured in several preclinical rat behavioral models, where known clinically useful antipsychotics show similar positive responses. For example, the disclosed compounds can reverse amphetamine-induced hyperkineticism in male SD (Sprague-Dolly) rats at doses ranging from 1 to 100 mg / kg po.

[0250] 3. Pharmaceutical compositions and preparations The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a target (e.g., a patient, which may be human or non-human). The disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.

[0251] Pharmaceutical compositions and preparations may contain a “therapeutic dose” or a “preventive dose” of the drug. “Therapeutic dose” refers to the amount effective in achieving the desired therapeutic outcome in the required dosage and duration. The therapeutic dose of a 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 induce the desired response in the individual. Furthermore, the therapeutic dose is the amount in which the therapeutically beneficial effects of the compound of the present invention (e.g., the compound of formula (I)) outweigh any toxic or adverse effects. “Preventive dose” refers to the amount effective in achieving the desired preventive outcome in the required dosage and duration. Typically, since preventive doses are used in subjects before or in the early stages of disease, the preventive dose is less than the therapeutic dose.

[0252] 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 could be mg / kg to approximately 550 mg / kg, approximately 50 mg / kg to approximately 500 mg / kg, approximately 55 mg / kg to approximately 450 mg / kg, approximately 60 mg / kg to approximately 400 mg / kg, approximately 65 mg / kg to approximately 350 mg / kg, approximately 70 mg / kg to approximately 300 mg / kg, approximately 75 mg / kg to approximately 250 mg / kg, approximately 80 mg / kg to approximately 200 mg / kg, approximately 85 mg / kg to approximately 150 mg / kg, and approximately 90 mg / kg to approximately 100 mg / kg.

[0253] Pharmaceutical compositions and formulations may contain pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means any kind of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. Some examples of materials that may act 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; glyco The composition may also contain, at the discretion of the compounder, preservatives and antioxidants. These include, for example, propylene glycol; esters, for example, not limited to ethyl oleate and ethyl laurate; agar; buffers, for example, not limited to magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solution; and other non-toxic, suitable lubricants, for example, not limited to sodium lauryl sulfate and magnesium stearate; as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances.

[0254] Therefore, compositions and their pharmaceutically acceptable salts may be formulated for administration, for example, by solid dosing, eye drops; topical oil-based formulations; injection, inhalation (through either the mouth or nose), implantation, or oral, parenteral, or rectal administration. Techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under manufacturing and storage conditions.

[0255] The route of administration of the disclosed compound and the form of the composition will determine the type of carrier to be used. The composition may exist in various forms suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, oral cavity, implant, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0256] Carriers for systemic administration typically include at least one of the following: diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, antioxidants, preservatives, lubricants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the composition.

[0257] 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 typically about 50 to about 90%.

[0258] 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 oils. The amount of lubricant in the whole-body composition or topical composition is typically about 5 to about 10%.

[0259] Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starch, such as corn 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 typically about 5 to about 50%.

[0260] 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 the whole-body composition or topical composition is typically about 0.1 to about 10%.

[0261] Suitable colorants include colorants, such as FD&C dyes. When used, the amount of colorant in the whole-body composition or topical composition is typically about 0.005 to about 0.1%.

[0262] Suitable flavoring agents include menthol, peppermint, and fruit flavoring agents. When used, the amount of flavoring agent in the systemic or topical composition is typically about 0.1% to about 1.0%.

[0263] Suitable sweeteners include aspartame and saccharin. The amount of sweetener in the whole-body composition or topical composition is typically about 0.001 to about 1%.

[0264] Suitable antioxidants include butylhydroxyanisole ("BHA"), butylhydroxytoluene ("BHT"), and vitamin E. The amount of antioxidants in a systemic or topical composition is typically about 0.1 to about 5%.

[0265] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative in the systemic or topical composition is typically about 0.01 to about 5%.

[0266] A suitable lubricant is silicon dioxide. The amount of lubricant in the whole-body composition or topical composition is typically about 1 to about 5%.

[0267] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohols such as ethanol, and phosphate buffer solution. The amount of solvent in the whole-body composition or topical composition is typically about 0 to about 100%.

[0268] Suitable suspensions include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspension in the systemic or topical composition is typically about 1% to about 8%.

[0269] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, as well as TWEENS® from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Wilmington's Pharmaceutical Sciences, 15th edition, 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant in the whole-body or topical composition is typically about 0.1% to about 5%.

[0270] The amounts of components in a whole-body composition may vary depending on the type of whole-body composition being prepared, but generally, a whole-body composition contains 0.01% to 50% of the active compound (e.g., the compound of formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically contain 0.1% to 10% of the active substance and 90% to 99.9% of a carrier containing a diluent and solvent.

[0271] Compositions for oral administration may have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of the active ingredient, usually at least about 5%, and especially about 25% to about 50%. Oral administration compositions contain about 50% to about 95%, and especially about 50% to about 75% of the carrier.

[0272] Tablets may be compressed, wet-coated, enterically coated, sugar-coated, film-coated, or compressed multiple times. Tablets typically contain an active ingredient and a carrier containing components selected from diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, lubricants, and combinations thereof. Certain diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Certain binders include starch, gelatin, and sucrose. Certain disintegrants include alginic acid and croscarmellose. Certain lubricants include magnesium stearate, stearic acid, and talc. Certain colorants are FD&C dyes, which may be added for appearance. Chewable tablets preferably contain sweeteners, such as aspartame and saccharin, or flavorings, such as menthol, peppermint, fruit flavorings, or combinations thereof.

[0273] Capsules (including implants, time-release and maintenance-release formulations) typically contain an active compound (e.g., a compound of formula (I)) and a carrier containing one or more of the diluents disclosed above, within a gelatin-containing capsule. Granules typically contain the disclosed compound and, preferably, a lubricant to improve flow characteristics, such as silicon dioxide. Implants may be biodegradable or non-biodegradable implants.

[0274] The selection of components in the carrier for the oral composition depends on secondary considerations such as taste, cost, and storability, which are not important to the purpose of the present invention.

[0275] The solid composition may be coated by conventional methods, typically by pH or time-dependent coatings, so that the disclosed compound is released in the gastrointestinal tract near the desired application, or at various time points and for durations that extend the desired effect. The coatings typically comprise one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, EUDRAGIT® coating (available from Evonik Industries of Essen, Germany), waxes, and shellac.

[0276] Compositions for oral administration may be in liquid form. For example, preferred liquid forms include aqueous solutions, emulsions, suspensions, solutions restored from non-foaming granules, suspensions restored from non-foaming granules, effervescent preparations restored from effervescent granules, elixirs, tinctures, syrups, etc. Liquid oral administration compositions typically comprise the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavorings, sweeteners, preservatives, solvents, suspending agents, and surfactants. Oral liquid compositions preferably comprise one or more components selected from colorants, flavorings, and sweeteners.

[0277] Other compositions useful for obtaining systemic delivery of the subject compound include sublingual, oral, and nasal formulations. Such compositions typically contain soluble fillers such as diluents containing sucrose, sorbitol, and mannitol; and one or more binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. Such compositions may further contain lubricants, colorants, flavorings, sweeteners, antioxidants, and lubricants.

[0278] The disclosed compounds may 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, etc. A topical composition comprises the disclosed compounds (e.g., compounds of formula (I)) and a carrier. The carrier of the topical composition preferably assists the penetration of the compounds into the skin. The carrier may further comprise one or more optionally selected components.

[0279] The amount of carrier used in conjunction with the disclosed compound is sufficient to provide a composition in a practical amount for administration, with respect to a 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 and Rhodes (eds.) (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd edition, (1976).

[0280] The carrier may consist of a single component or a combination of two or more components. In a topical composition, the carrier includes a topical carrier. A suitable topical carrier contains one or more components selected from phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohol, symmetrical alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristylpropionate, dimethyl isosorbide, castor oil, and combinations thereof. In particular, carriers for skin application contain propylene glycol, dimethyl isosorbide and water, and more specifically, phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohol and symmetrical alcohol.

[0281] The carrier of the topical composition may further contain one or more components selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, dyes, and preservatives, all of which are optional.

[0282] Suitable emollients include stearyl alcohol, glyceryl monolicinolate, 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 di-n-butyl This includes sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for the skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in a skin-based topical composition is typically about 5% to about 95%.

[0283] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant in the topical composition is typically about 0% to about 95%.

[0284] 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 solvents include ethyl alcohol and homotopic alcohol. The amount of solvent in the topical composition is typically about 0% to about 95%.

[0285] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant in the topical composition is typically 0% to 95%.

[0286] The amount of thickener in a topical composition is typically between approximately 0% and 95%.

[0287] Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's earth, kaolin, starch, rubber, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder in the topical composition is typically 0% to 95%.

[0288] The amount of fragrance in topical compositions is typically about 0% to 0.5%, and especially about 0.001% to 0.1%.

[0289] A suitable pH-adjusting additive contains an amount of HCl or NaOH sufficient to adjust the pH of the topical pharmaceutical composition.

[0290] 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 Therefore, it may exhibit positive allosteric modulation of mAChR M4. 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 Therefore, it can exhibit positive allosteric modulation of mAChR M4.

[0291] a. Spray-drying 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 with 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 the solution. The use of spray drying for pharmaceutical applications can result in amorphous dispersions with increased solubility for BCS (Biopharmaceutics Classification System) Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) drugs. Formulation and process conditions are selected so that the solvent evaporates rapidly from the droplets, and therefore there is insufficient time for phase separation or crystallization. SDDs have demonstrated long-term stability and manufacturability. For example, a shelf life of over two years has been demonstrated for SDDs. The advantages of SDD include, but are not limited to, improved oral bioavailability of water-insoluble compounds, delivery using conventional solid dosage forms (e.g., tablets and capsules), renewable, controllable, and scalable manufacturing processes, and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.

[0292] Therefore, in one embodiment, the present disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I).

[0293] 4.How to use The disclosed compounds, pharmaceutical compositions, and formulations may 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 may also be used in methods for enhancing muscarinic acetylcholine receptor activity in mammals and in methods for improving cognition in mammals. The methods further include combination therapies for improving treatment outcomes related to cognitive or behavioral therapy. In the methods of use described herein, additional therapeutic agents may be administered concurrently or sequentially with the disclosed compounds and compositions.

[0294] a. Address the problem. The disclosed compounds, pharmaceutical compositions, and formulations may be used to treat disorders, such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction, or may be used in methods for treating such disorders. Methods of treatment may include administering to a subject requiring such treatment a therapeutically effective amount of the compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I).

[0295] In some embodiments, the Disclosure provides a method for improving cognition in mammals, comprising the step of administering to a 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).

[0296] The compounds and compositions disclosed herein may be useful for treating, preventing, improving, controlling, or reducing the risk of various disorders associated with selective mAChR M4 receptor activation. For example, the treatment may include selective mAChR M4 receptor activation to an extent effective in affecting cholinergic activity. The disorder may be associated with cholinergic activity, e.g., impaired cholinergic function. Accordingly, a method is provided for treating or preventing a disorder in a subject, comprising the step of administering to the subject an amount effective in treating the disorder in the subject, of at least one disclosed compound or at least one disclosed pharmaceutical composition.

[0297] Furthermore, there is a method for treating one or more impairments associated with 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 comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0298] 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.

[0299] 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 disorders associated with the mAChR M4 receptor.

[0300] In some embodiments, the Disclosure provides a method for treating disorders associated with muscarinic acetylcholine receptor dysfunction in mammals, comprising the step of administering to a mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0302] In some embodiments, the Disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0303] 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 disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0304] In some embodiments, the disclosed compounds and compositions have applicability in treating a variety of neurological, psychiatric, and cognitive disorders associated with the mAChR M4 receptor, the disorders including one or more of the following conditions or diseases: schizophrenia, psychotic disorder NOS, short-term psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic acute, delayed-onset psychosis, myxedematous psychosis (hypothyroidism-associated psychosis), occupational psychosis, menstrual psychosis, secondary psychotic disorder, type I bipolar disorder with psychotic characteristics, and substance-induced psychotic disorders. 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, neurological disorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder.

[0305] In some embodiments, the Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for treating neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, particularly the disorders described herein. 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 treating neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, particularly the disorders described herein. In some embodiments, the Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of pharmaceuticals for treating neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, particularly the disorders described herein.

[0306] 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.

[0307] 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, hebephrenic schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizotypal personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some embodiments, the psychotic disorder is due to a general health condition and is induced by a substance or drug (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine).

[0308] In some embodiments, the Disclosure provides a method for treating cognitive impairment, comprising the step of administering an effective amount of a compound or composition of the Disclosure to a patient in need of treatment. 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 systemic health 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-like-ALS dementia complex, Alzheimer's disease, age-related cognitive decline, and mild cognitive impairment.

[0309] The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Revised (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides diagnostic tools for cognitive disorders, including dementia, delirium, amnesia, and age-related cognitive decline. The 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 and associated major NCDs, mild NCDs, and their etiological subtypes. Major 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, NCD induced by substances / pharmaceuticals, NCD due to Huntington's disease, NCD due to prion diseases, NCD due to other health conditions, NCD due to multiple etiologies, and unspecified NCD. The NCD category in DSM-5 encompasses a group of disorders in which the primary clinical deficit is 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. Those skilled in the art will recognize that there are alternative nomenclature, disease classifications, and classification systems for mental disorders, and that these systems evolve with medical and scientific advances. Accordingly, the term “cognitive impairment” is intended to include disorders as described in other diagnostic sources.

[0310] In some embodiments, the Disclosure provides a method for treating schizophrenia or psychosis, comprising the step of administering an effective amount of a compound or composition of the Disclosure to a patient in need of treatment. Specific schizophrenic or psychotic pathologies include paranoid, hebephrenic, catatonic, or anaplastic schizophrenia, and substance-induced psychotic disorders. DSM-IV-TR provides a diagnostic tool encompassing paranoid, hebephrenic, catatonic, anaplastic, or residual schizophrenia, and substance-induced psychotic disorders. DSM-5 removes the subtypes of schizophrenia and instead includes a dimensional approach for grading the severity of the core symptoms of schizophrenia, capturing the heterogeneity of symptom types and severity observed among individuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the treatment of mental disorders as described in DSM-IV-TR or DSM-5. Those skilled in the art will recognize that there are alternative nomenclature, disease classifications, and classification systems for mental disorders, and that these systems evolve with advances in medicine and science. Therefore, the term “schizophrenia or psychosis” is intended to include disorders as described in other diagnostic sources.

[0311] In some embodiments, the Disclosure provides a method for treating pain, comprising the step of administering an effective amount of a compound or composition of the Disclosure to a patient in need of treatment. Specific pain embodiments include bone and joint pain (osteoarthritis), repetitive pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), surgical pain (general surgery, gynecology), chronic pain, and neuropathic pain.

[0312] Compounds and compositions may be even more useful in methods for preventing, treating, controlling, improving or reducing the risk thereof of the diseases, disorders and conditions described herein. Compounds and compositions may be even more useful in combination with other agents in methods for preventing, treating, controlling, improving or reducing the risk thereof of the diseases, disorders and conditions listed above.

[0313] In the treatment of conditions requiring activation of mAChR M4, appropriate dose levels may be approximately 0.01 to 500 mg per kg of patient body weight per day, which may be administered in single or multiple doses. Dose levels may be approximately 0.1 to 250 mg / kg per day, or approximately 0.5 to 100 mg / kg per day. Preferred dose levels may be approximately 0.01 to 250 mg / kg per day, approximately 0.05 to 100 mg / kg per day, or approximately 0.1 to 50 mg / kg per day. Within this range, doses may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the composition may be 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, for symptomatic adjustment of the dosage to the patient to be treated. The compound may be administered in a regimen of 1 to 4 times per day, preferably 1 or 2 times per day. This dosage regimen can be adjusted to provide an optimal therapeutic response. However, it is understood that specific dose levels and dosing frequencies for any particular patient may vary and depend on various factors, including the activity of the particular compound used, its metabolic stability and duration of action, age, weight, health status, sex, diet, mode and timing of administration, elimination rate, drug combinations, severity of the particular condition, and the host being treated.

[0314] 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 mammalian cell, for example, a human cell. In some embodiments, the cell is isolated from the subject before the contact step. In some embodiments, the contact step is by administration to the subject.

[0315] 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 is diagnosed for the need for mAChR M4 agonism prior to the administration step. In some embodiments, the mammal is diagnosed for the need for mAChR M4 activation prior to the administration step. In some embodiments, the method further comprises the step of identifying a subject that requires mAChR M4 agonism.

[0316] In some embodiments, the present invention relates to a method for treating a disorder associated with selective mAChR M4 activation in a mammal, for example, a disorder associated with cholinergic activity, comprising the step of administering to a mammal at least one disclosed compound or at least one product of the disclosed method in doses and amounts effective for treating a disorder in a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is diagnosed for the need to treat the disorder prior to the administration step. In some embodiments, the method further includes the step of identifying a subject that requires treatment of the disorder.

[0317] In some embodiments, the disorder may be selected from psychosis, schizophrenia, conduct disorder, destructive behavior disorder, bipolar disorder, anxiety psychotic episodes, anxiety associated with psychosis, psychotic mood disorders, such as severe major depressive disorder, mood disorders associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral signs 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.

[0318] In some embodiments, the disorder is Alzheimer's disease.

[0319] b. Enhancement of muscarinic acetylcholine receptor activity In some embodiments, the present disclosure relates to a method for enhancing muscarinic acetylcholine receptor activity 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.

[0320] In some embodiments, the Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method for enhancing muscarinic acetylcholine receptor activity in mammals. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method for enhancing muscarinic acetylcholine receptor activity in mammals.

[0321] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for enhancing muscarinic acetylcholine receptor activity in mammals.

[0322] 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 agonism of the muscarinic acetylcholine receptor. In some embodiments, enhancement of muscarinic acetylcholine receptor is positive allosteric modulation of the muscarinic acetylcholine receptor.

[0323] In some embodiments, the administered compound 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 This results in enhancement of mAChR M4. In some embodiments, the administered compound is EC2 at concentrations of approximately 10 μM to 1 nM, 1 μM to 1 nM, 100 nM to 1 nM, or 10 nM to 1 nM. 50 This exhibits enhancement of mAChR M4.

[0324] In some embodiments, the mammal is a human. In some embodiments, the mammal is diagnosed for the need for enhancement of muscarinic acetylcholine receptor activity prior to the administration step. In some embodiments, the method further includes the step of identifying a mammal that requires enhancement of muscarinic acetylcholine receptor activity. In some embodiments, enhancement of muscarinic acetylcholine receptor activity addresses a disorder associated with muscarinic acetylcholine receptor activity in the mammal. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.

[0325] In some embodiments, enhancement of muscarinic acetylcholine receptor activity in mammals is associated with neurological and / or psychiatric disorders associated with muscarinic receptor dysfunction, such as the treatment of neurological or psychiatric disorders disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4.

[0326] In some embodiments, the disclosure provides a method for enhancing muscarinic acetylcholine receptor activity in cells, comprising the step of contacting cells with at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are mammalian (e.g., human) cells. In some embodiments, the cells are isolated from the mammal before the contact step. In some embodiments, the contact step is performed by administration to the mammal.

[0327] c. Improve cognition In some embodiments, the present invention relates to a method for improving cognition 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, hydrate, solvate, or polymorph thereof.

[0328] In some embodiments, the Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for improving cognition 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 methods for improving cognition in mammals.

[0329] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for cognitive enhancement in mammals.

[0330] In some embodiments, the mammal is a human. In some embodiments, the mammal is diagnosed for a need for cognitive enhancement prior to the administration step. In some embodiments, the method further includes the step of identifying a mammal in need of 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.

[0331] In some embodiments, cognitive improvement is a statistically significant increase in performance on the Novel Object Recognition test. In some embodiments, cognitive improvement is a statistically significant increase in performance on the Wisconsin Card Classification Test.

[0332] d. Combination therapy The present invention further relates to the administration of selective mAChR M4 activators to improve treatment outcomes related to cognitive or behavioral therapy. Specifically, in some embodiments, the present invention relates to combination therapy comprising the step of administering to a mammal at least one disclosed compound or a pharmaceutically acceptable salt thereof in effective amounts and doses.

[0333] In some embodiments, the Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in adjunctive therapy 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 adjunctive therapy with cognitive or behavioral therapy in mammals.

[0334] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for adjunctive therapy with cognitive or behavioral therapies in mammals.

[0335] In some embodiments, the administration improves the treatment outcome related to cognitive or behavioral therapy. The administration related to cognitive or behavioral therapy may be continuous or intermittent. The administration does not need to be concurrent with the treatment, but may be before, during, and / or after the treatment. For example, cognitive or behavioral therapy may be provided within 1, 2, 3, 4, 5, 6, or 7 days before or after the 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 the 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.

[0336] It is understood that the disclosed combination therapies may be used in relation to the disclosed compounds, compositions, kits, and uses.

[0337] e. Combination therapy In the methods of use described herein, additional therapeutic agents may be administered simultaneously with or sequentially to the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, additional therapeutic agents or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be a time interval between the administration of the additional therapeutic agent and the disclosed compound. In some embodiments, the administration of the additional therapeutic agent and the disclosed compound may allow for lower doses of other therapeutic agents and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include compositions containing one or more other active ingredients in addition to the compound of formula (I). The above combinations include combinations of the compound of the present invention with not only one other active compound, but two or more other active compounds.

[0338] The disclosed compound can be used as a single agent or in combination with one or more other agents in the treatment, prevention, control, improvement, or reduction of the risk thereof of the diseases, disorders and conditions listed above for which the compound or other agents are available, where the combination of agents is safer or more effective than either agent alone. The other agents may be administered concurrently with or sequentially with the disclosed compound, in the routes and amounts commonly used for those agents. When the disclosed compound is used concurrently with one or more other agents, a pharmaceutical composition in unit dosage forms containing such agents and the disclosed compound may be used. However, combination therapy may also be administered on overlapping schedules. Furthermore, a combination of one or more active ingredients and the disclosed compound may be more effective than either of them as a single agent. 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.

[0339] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds, as shown herein, which are commonly used in the treatment of the pathological conditions listed above.

[0340] The above combinations include not only the disclosed compound with one other active compound, but also combinations with two or more other active compounds. Similarly, the disclosed compound may be used in combination with other drugs used in the prevention, treatment, control, improvement, or reduction of the risk thereof of diseases or conditions in which the disclosed compound is useful. Such other drugs may be administered concurrently with or sequentially with the compound of the present invention, in the routes and amounts commonly used for such drugs. When the compound of the present invention is used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the disclosed compound is preferred. Therefore, the pharmaceutical composition includes a pharmaceutical composition containing one or more other active ingredients in addition to the compound of the present invention.

[0341] The mass ratio of the disclosed compound to the second active ingredient may vary and depend on the effective dose of each component. Generally, the effective dose of each component is used. For example, when the compound of the present invention is combined with another agent, the mass ratio of the disclosed compound to the other agent is generally about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Furthermore, while the combination of the compound of the present invention with other active ingredients is generally within the range listed above, the effective dose of each active ingredient should be used in each case.

[0342] In such combinations, the disclosed compounds and other activators may be administered separately or together. In addition, the administration of one element may be before, simultaneously with, or after the administration of the other agents.

[0343] Accordingly, the disclosed compounds 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 to increase the efficacy, safety, or convenience of the disclosed compounds or to reduce their undesirable side effects or toxicity. The subject compounds and other agents may be administered concurrently in either concurrent therapy or fixed combinations.

[0344] In some embodiments, the compound can be used in combination with anti-Alzheimer's agents, beta-secretase inhibitors, cholinergic agents, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, M1 allosteric agonists, positive allosteric modulators of M1, NSAIDs including ibuprofen, vitamin E, and anti-amyloid antibodies. In other embodiments, the compound in question can be used as a sedative, hypnotic, anxiolytic, antipsychotic (typical and atypical), anxiolytic, cyclopyrrolone, imidazopyridine, pyrazolopyrimidine, mild tranquilizer, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, tranquilizers, 5HT-2 antagonists, etc., such as azinazolam, arobarbital, alonimid, alprazolam, amisulpride, and amitriptyline. Amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamin, brotizolam, bupropion, buspirone, butabarbital, butarbital, capride, carbochloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, chlorazepate, chlordiazepoxide, clorethate, clo Lupromazine, clozapine, ciprazepam, desipramine, dexclamol, diazepam, dichlorphenazone, divalproex, diphenhydramine, doxepin, estazolam, etochlorbinol, etomidate, phenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimid, harazepam, haloperidol, hydr Roxidine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, meclocalon, melatonin, mefobarbital, meprobamate, methacalon, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraaldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital,The subject compound may be used in combination with prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, leclazepam, risperidone, loletamide, secobarbital, sertraline, suproclone, 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, or the subject compound may be administered in conjunction with the use of physical methods such as phototherapy or electrical stimulation.

[0345] In some embodiments, the compound can be used in combination with levodopa (with or without a selective extraneuronal decarboxylase inhibitor, e.g., carbidopa or benserazide), anticholinergic agents, 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, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists, and dopamine receptor agonists, e.g., alentemol, bromocriptine, phenoldopam, rislide, naxagolide, pergolide and pramipexole. It is understood that dopamine agonists may exist in pharmaceutically acceptable salt forms, such as allentemol hydrobromide, bromocriptine mesylate, phenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Rislide and pramipexole are generally used in their non-salt forms.

[0346] In some embodiments, the compound can be used in combination with compounds from the classes of neuroleptics: phenothiazines, thioxanthenes, heterocyclic dibenzazepines, butyrophenones, diphenylbutylpiperidines, and indolones. Preferred examples of phenothiazines include chlorpromazine, mesolidazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifluoperazine. Preferred 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 molindolone. Other neuroleptics include roxapine, sulpiride, and risperidone. It is understood that when nerve blockers are used in combination with the compound of the subject, they may exist in pharmaceutically acceptable salt forms, such as chlorpromazine hydrochloride, mesolidazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, roxapine succinate, and morindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide, and risperidone are generally used in their non-salt forms. Therefore, the subject compound can be used in combination with acetophenazine, allentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixen, clozapine, diazepam, phenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, rislide, roxapine, mesolidazine, morindone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixen, trifluoperazine, or ziprasidone.

[0347] In some embodiments, the compound can be used in combination with norepinephrine reuptake inhibitors (including tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, α-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, particularly 5-HT1A partial agonists, and antidepressants or anxiolytics including corticotropin-releasing factor (CRF) antagonists. Specific drugs include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazide, phenelzine, tranylcypromine, and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone, and piroxazine; alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, harazepam, lorazepam, oxazepam, and prazepam; buspirone, fresinoxane, gepirone, and ipsapirone, as well as their pharmaceutically acceptable salts.

[0348] In some embodiments, the compound may be administered co-administered with an orthosteric muscarinic agonist, a muscarinic enhancer, or a cholinesterase inhibitor. In some embodiments, the compound may be administered co-administered with GlyT1 inhibitors, such as, for example, risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbital and their salts, and combinations thereof.

[0349] f. Mode of administration The administration method may include any number of forms of administration of the disclosed composition. The forms of administration may include tablets, pills, sugar-coated tablets, hard and softgel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions, e.g., oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the drug may be mixed with commonly known and used auxiliaries and excipients, e.g., gum arabic, tarcan, starch, sugars (e.g., mannitose, methylcellulose, lactose), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking binders, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g., ether oil), soluble enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g., Gelucire®). In pharmaceutical compositions, the drug may be dispersed in fine particles, such as nanoparticle compositions.

[0350] 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. Oils that may be used, but are not limited to examples, include olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil. More generally, for parenteral administration, the drug may exist in the form of an aqueous, lipid, oily, or other type of solution or suspension, or even in the form of liposomes or nanosuspensions.

[0351] As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions.

[0352] 5. Kit In one embodiment, the disclosure relates to at least one disclosed compound or a pharmaceutically acceptable salt thereof, (a) At least one agent known to increase mAChR M4 activity, (b) At least one agent known to reduce mAChR M4 activity, (c) At least one agent known to treat disorders associated with cholinergic activity, (d) Instructions for use to treat disorders associated with cholinergic activity, (e) Instructions for use to treat disorders associated with M4 receptor activity, or (f) Instructions for use for administering compounds related to cognitive or behavioral therapy A kit is provided that includes one or more of the following.

[0353] 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. The kit may also contain compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug distributor, physician, compound store, or pharmacist may provide a kit containing the disclosed compounds and / or products as well as other components for delivery to a patient.

[0354] The disclosed kit can be used in connection with the disclosed method of use.

[0355] The kit may further include information, instructions for use, or both, indicating that the use of the kit may provide treatment for a health condition in mammals (especially humans). The information and instructions for use may be in the form of words, pictures, or both. In addition or alternatively, the kit may include a compound, composition, or both, and information, instructions for use, or both, regarding how to apply the compound or composition, which has benefits such as treating or preventing a health condition in mammals (e.g., humans).

[0356] The compounds and processes of the present invention will be better understood by referring to the following examples, which are intended to be illustrative of the invention and not intended to limit the scope of the invention. [Examples]

[0357] 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 downfield in ppm, with the deuterated solvent as the internal standard. The data is 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 integration. Reverse-phase LC-MS analysis was performed using an Agilent 1200 system consisting of a binary pump with degassing equipment, high-performance autosampler, thermostat-equipped column compartment, C18 column, diode array detector (DAD), and Agilent 6150 MSD, with the following parameters: gradient conditions were aqueous phase of 0.1% TFA in 5%–95% acetonitrile and water over 1.4 minutes, retention in 95% acetonitrile for 0.1 minutes, 0.5 mL / min, 55°C ("90-second method"). The sample was separated at 0.5 mL / min on a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 x 50 mm), and the column and solvent temperature were maintained at 55°C. The DAD was set to scan from 190 to 300 nm, and the signals used were at 220 nm and 254 nm (both with a bandwidth of 4 nm). The MS detector was configured with an electrospray ionization source, and low-resolution mass spectra were acquired by scanning from 140 to 700 AMU at a step size of 0.2 AMU at 0.13 cycles / second, with a peak width of 0.008 min. The dry gas flow was set to 13 liters / min at 300°C, and the atomizer 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 acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0358] a. Preparation of intermediates

[0359] [ka]

[0360] Ethyl 5-bromo-6-hydroxy-2-methylnicotinate. N-bromosuccinimide (10.8 g, 60.7 mmol) was slowly added in small amounts to a solution of ethyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (10 g, 55.2 mmol) in DMF (185 mL) at 0°C. The ice bath was removed. After 18 hours, saturated sodium bisulfite (aq) was added to the reaction and stirred for 30 minutes. The reaction was filtered, and the collected solid was dried in a vacuum oven to obtain the title compound (14.2 g). 1 ES-MS [M+1] + : 260.0 / 262.0.

[0361] [ka]

[0362] 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 connected to 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 saturated aqueous NaHCO3 solution, maintaining a pH above 7. An additional DCM (25 mL) was added, and the mixture was stirred for 30 minutes. The organic layer was separated, and the aqueous layer was re-extracted with chloroform / IPA (3 x 20 mL) in a 3:1 ratio. The mixed organic layers were dried (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase chromatography (0-25% siRNA / hexane) to obtain the compound indicated in the title (12 g). 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.76 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); ES-MS [M+1] + : 277.9 / 279.9.

[0363] [ka]

[0364] Ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate. To a solution of ethyl 5-bromo-6-chloro-2-methylnicotinate (12 g, 43.1 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.71 g, 4.3 mmol) in carbon tetrachloride (287 mL) at 50 °C, N-bromosuccinimide (8.43 g, 47.4 mmol) was added in small amounts. After 30 minutes, the reaction was heated to 80 °C. After 18 hours, the reaction was cooled to room temperature, diluted with water, and the organic layer was separated. The aqueous layer was extracted by DCM (3 x 50 mL). The mixed organic layers were dried over (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase chromatography (0-4% Depositphotos / hexane) to obtain the title compound (13.6 g). 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 4.91 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); ES-MS [M+1] + : 357.9 / 359.9.

[0365] [ka]

[0366] 3-Bromo-2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. To a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (2.5 g, 6.99 mmol) in 140 mL of THF at 0°C, a 2.0 M solution of methylamine (17.5 mL, 35.0 mmol) was added, and the reaction was stirred for 30 minutes. The reaction was concentrated at room temperature and purified by normal-phase chromatography (0-30% Â / DCM) to obtain the title compound. 1 H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 4.50 (s, 2H), 3.09 (s, 3H); ES-MS [M+1] + : 261.1 / 263.1.

[0367] [ka]

[0368] 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 RINKAN 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% RINKAN / hexane) to obtain the title compound (668 mg). ES-MS [M+1] + : 292 / 294; 1 H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.34 (d, J = 0.5 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

[0369] [ka]

[0370] 3-Bromo-2-chloroflou[3,4-b]pyridine-5(7H)-one. Sodium borohydride (27 mg, 0.70 mmol) was added to a solution of ethyl 5-bromo-6-chloro-2-formylnicotinate (668 mg, 1.76 mmol) in THF (8.8 mL) at -40°C. The reaction was stirred at -40°C for 45 minutes. Water was added to the reaction mixture, and the reaction was warmed to room temperature. After extraction of the reaction with RINKAN (3x), the mixed organic layers were dried (MgSO4), filtered, and concentrated. The residue was taken in 1,4-dioxane (4 mL), and then hydrochloric acid (879 μL, 3.52 mmol; 4 M in 1,4-dioxane) was added, and the mixture was heated to 50°C for 18 hours. 4M HCl in an additional 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 aqueous saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4), and concentrated. The unpurified 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 (400 MHz, CDCl3) δ 8.42 (t, J = 0.5 Hz, 1H), 5.28 (d, J = 0.5 Hz, 2H).

[0371] [ka]

[0372] 3,5-Dichloro-6-methyl-2H-1,4-oxazin-2-one. To a cooled solution of oxalyl chloride (49.1 mL, 563 mmol) in chlorobenzene (75 mL) under inert gas conditions at 0°C, a solution of DL-lactonitrile (10 g, 140.7 mmol) in chlorobenzene (11 mL) was added dropwise. The solution was then heated to 90°C, where triethylamine hydrochloride (1.43 g, 10.4 mmol) was added all at once at 90°C. The resulting mixture was then stirred for 3 hours, cooled to ambient temperature, and concentrated under vacuum. The resulting solution was then diluted with Et2O (approximately 300 mL), and the solid was filtered. The filtrate was concentrated, and 16.8 g of the title compound was obtained by normal-phase column chromatography (0-15% Â / Hex) on silica gel. 1 H NMR (400 MHz, CDCl3) δ 2.38 (s, 1H).

[0373] [ka]

[0374] 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 inert gas conditions. The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated, then diluted with water and extracted by DCM (3x). After sequential washing with saturated aqueous solution of Na2S2O3 and brine, the mixed organic matter was dried to (MgSO4), filtered, and concentrated to obtain 22 g of the title compound. The material was not further purified before proceeding to the next step. 1 H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H); ES-MS [M+1] + : 272.

[0375] [ka]

[0376] Methyl 6-chloro-2-iodo-5-methylnicotinate. A solution of 5-chloro-3-iodo-6-methyl-2H-1,4-oxazin-2-one (22 g, 81.1 mmol) and methylpropiolate (21.6 mL, 243 mmol) in toluene (80 mL) was heated to 80 °C for 42 hours. The reaction was cooled to ambient temperature, and volatile substances were removed under reduced pressure. 15.0 g of the title compound was obtained by normal-phase column chromatography on silica gel (0-10% siRNA / hexane, second elution from the column). 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 0.8 Hz, 1H), 3.95 (s, 3H), 2.36 (d, J = 0.8 Hz, 3H); ES-MS [M+1] + : 312.

[0377] [ka]

[0378] Methyl 6-chloro-2-cyano-5-methylnicotinate. A solution of methyl 6-chloro-2-iodo-5-methylnicotinate (15.0 g, 48.2 mmol) and copper(I) cyanide (6.48 g, 72.3 mmol) in DMF (112 mL) was heated at 100 °C for 1 hour. After cooling to ambient temperature, the mixture was filtered through Celite® and washed with SiO2. The filtrate was added to a saturated aqueous NaHCO3 solution (approximately 150 mL) and extracted with SiO2 (3x). The mixed organic matter was then sequentially washed with a saturated aqueous solution of NH4Cl (100 mL) and brine. The organic matter was then dried (MgSO4), filtered, and concentrated. 8.1 g of the title compound was obtained by normal-phase column chromatography (0-40% SiO2 / hexane) on silica gel. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 0.9 Hz, 1H), 4.04 (s, 3H), 2.52 (d, J = 0.8 Hz, 3H); ES-MS [M+1] + : 211.

[0379] [ka]

[0380] 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 hydrogen gas (balloon) for 36 hours. The solid was removed by filtration with Celite®, washed with DCM, and the filtrate was concentrated. The residue was dissolved in MeOH, purified using an SCX cartridge, and eluted with MeOH solution to obtain the title compound. 1 H NMR(400MHz, MeOD)δ8.38(d, J=0.8Hz, 1H), 4.62(s, 2H), 3.96(s, 3H), 2.47(q, J=0.7Hz, 3H);ES-MS[M+H] + =215. Subsequently, the SCX cartridge was washed with NH3 / MeOH(7N) to obtain 3.4 g of impure 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one, which was purified using normal-phase column chromatography (with 3.5% MeOH / DCM / 1% NH4OH additive) (84.4 mg). 1 H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.11 (d, J = 0.9 Hz, 1H), 4.39 (s, 2H), 2.42 (d, J = 0.8 Hz, 3H); ES-MS [M + H] + = 183.

[0381] [ka]

[0382] 2-Chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. A solution of methylmethyl 2-(aminomethyl)-6-chloro-5-methylnicotinate (5.46 g, 25.4 mmol) and triethylamine (17.7 mL, 127 mmol) in methanol (127 mL) was added to a vial. The solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum until it was half its original volume, and the solid was removed by vacuum filtration. The mixture was then washed with MeOH to obtain 1.99 g of the desired product. 1 H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.11 (d, J = 0.9 Hz, 1H), 4.39 (s, 2H), 2.42(d, J = 0.8 Hz, 3H); ES-MS [M + H] + = 183.

[0383] [ka]

[0384] tert-butyl-4-methylsulfonyloxypiperidine-1-carboxylate. To a solution of tert-butyl-4-hydroxypiperidine-1-carboxylate (2.5 g) in 40 mL of DCM at 0°C, triethylamine (2.42 mL) was added, followed by the dropwise addition of methanesulfonyl chloride (1.35 mL). The ice bath was removed, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with 3:1 CHCl3 / IPA and water. The layers were separated, and the aqueous layer was extracted with 3:1 CHCl3 / IPA (2x). The mixed organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to obtain the title compound (3.4 g). 1H NMR (400 MHz, CDCl3) δ 4.91-4.85 (m, 1H), 3.73-3.67 (m, 2H), 3.33-3.26 (m, 2H), 3.03 (s, 3H), 1.99-1.93 (m, 2H), 1.85-1.77 (m, 2H), 1.45 (s, 9H).

[0385] [ka]

[0386] 2,3-Dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-carboaldehyde. In a 500 mL round-bottom flask, 3,4-dihydroxybenzaldehyde (21.3 g), 1,2-dibromoethane-d4 (Cambridge Isotope Laboratories, Inc., D-99%; CAS No. 22581-63-1, 14.1 mL), and potassium carbonate (65.0 g) were mixed in acetone (515 mL). The reaction was heated for 18 hours until reflux. The reaction was diluted with ELISA, filtered through Celite®, and the filtrate was concentrated under vacuum. The unpurified sample was purified by normal-phase column chromatography (0-40% ELISA / hexane) to obtain the title compound (15.4 g). 1 H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.41-7.38 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H). ES-MS [M+1] + : 169.

[0387] [ka]

[0388] 2,3-Dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol. Step 1. To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-carboaldehyde (15.4 g) in DCE (250 mL), 3-chloroperoxybenzoic acid (47.6 g, less than 77%, CAS No. 937-14-4; Sigma-Aldrich) was added. The reaction mixture was heated to 50°C for 18 hours. The reaction was diluted with DCM and saturated NaHCO3 solution. The layers were separated. The aqueous layer was extracted by DCM (2x), the mixed organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to obtain 2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4 formate (15.1 g). ES-MS[M+1] + :185. Step 2. 2,3-Dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4 formate (15.1 g) was dissolved in methanol (250 mL) and potassium carbonate (15.5 g) was added. After 3 hours, the solvent was removed and water / DCM (1:1) was added. The aqueous layer was slowly acidified to less than pH 4 by adding 6N aqueous HCl dropwise. The layers were separated, the aqueous layer was extracted by DCM (2x), the mixed organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The filtrate was purified by flash chromatography (0-40% siRNA / hexane) on silica gel. The desired fraction was concentrated and simultaneously evaporated (2x with toluene) to obtain the title compound (12.3 g). 1 H NMR (400 MHz, CDCl3) δ 6.72 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 2.9 Hz, 1H), 6.34-6.31 (dd, J = 8.7, 2.9 Hz, 1H), 4.64 (s, 1H). ES-MS [M+1] + : 157.

[0389] [ka]

[0390] tert-butyl4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-carboxylate. In a 1000 mL round-bottom flask, 18 g of tert-butyl4-methylsulfonyloxypiperidine-1-carboxylate, 6.0 g of 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol, 16.2 g of potassium carbonate, and 2.1 g of tetrabutylammonium chloride were added in 360 mL of water and 18 mL of DMF. The reaction was heated until refluxed. After 24 hours, the reaction was cooled to room temperature, diluted with phenylethylamine, and washed with water (3x) and brine (2x). The organic layer was dried over (MgSO4), filtered, and concentrated under vacuum. The unpurified residue was purified by normal-phase column chromatography (0-40% siRNA / hexane) to obtain the compound indicated in the title (3.1 g). 1 H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 8.7 Hz, 1H), 6.46 (d, J = 2.8 Hz, 1H), 6.44-6.41 (dd, J = 8.7, 2.8 Hz, 1H), 4.32-4.27 (m, 1H), 3.72-3.66 (m, 2H), 3.31-3.25 (m, 2H), 1.90-1.85 (m, 2H), 1.74-1.66 (m, 2H), 1.46 (s, 9H). ES-MS [M+1] + : 340.

[0391] [ka]

[0392] 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine. Trifluoroacetic acid (2 mL) was added to a round-bottom flask containing tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-carboxylate (760 mg) in DCM (6 mL). After 2 hours at room temperature, the solvent was removed, the unpurified residue was dissolved in DCM, and concentrated under vacuum (3x) to obtain the title compound (802 mg) as the TFA salt. 1 H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 1H), 6.45 (d, J = 2.8 Hz, 1H), 6.43-6.40 (dd, J = 8.8, 2.9 Hz, 1H), 4.51-4.50 (m, 1H), 3.44-3.37 (m, 2H), 3.28-3.25 (m, 2H), 2.16-2.07 (m, 4H). ES-MS [M+1] + : 240.

[0393] [ka]

[0394] tert-butyl4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-carboxylate-2,2,6,6-d4. In a vial, tert-butyl4-hydroxypiperidine-1-carboxylate-2,2,6,6-d4 (100 mg, 0.49 mmol) [Reference: J. of Labelled Compounds and Radiopharmaceuticals 2018, 61, 1036~1042], triphenylphosphine (180 mg, 0.68 mmol), and 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol (107 mg, 0.68 mmol) were mixed in THF (2 mL). The container was degassed, and then diisopropyl azodicarboxylate (0.13 mL, 0.68 mmol) was added. The reaction was heated at 60°C for 18 hours. The reaction was dissolved in 3:1 CHCl3:IPA and concentrated with Celite®. The solid was dried and loaded onto silica gel for purification using normal-phase column chromatography (0-25% Â / hexane). The desired fraction was concentrated to obtain the title compound (123 mg). 1 H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 8.7 Hz, 1H), 6.45 (d, J = 2.8 Hz, 1H), 6.42 (dd, J = 8.8, 2.9 Hz, 1H), 4.31-4.26 (m, 1H), 1.87-1.83 (m, 2H), 1.71-1.66 (m, 2H), 1.45 (s, 9H). ES-MS [M+1] + : 344.

[0395] [ka]

[0396] 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-2,2,6,6-d4. In a vial, tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-carboxylate-2,2,6,6-d4 (123 mg, 0.36 mmol) and trifluoroacetic acid (0.5 mL) were mixed in dichloromethane (2 mL). The reaction was stirred for 1 hour and then concentrated. The residue was purified using an SCX cartridge (5 G), washed with MeOH, and eluted with 7N NH3 / MeOH solution. The solvent was removed to obtain the title compound (55 mg). 1 H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 2.8 Hz, 1H), 6.43 (dd, J = 8.8, 2.8 Hz, 1H), 4.24-4.18 (m, 1H), 1.99 (d, J = ES-MS [M+1] + : 244. 244.

[0397] [ka]

[0398] tert-butyl-4-hydroxypiperidine-1-carboxylate-4-d. To a solution of 1-tert-butyl-4-piperidone (10 g, 50 mmol) in methanol (250 mL) at 0°C, sodium borodete (3.2 mL, 100 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated NH4Cl(aq) and extracted with ELISA(3x). The mixed organic layer was dried (MgSO4), filtered, and concentrated to obtain the title compound (10 g). 1H NMR (400 MHz, CDCl3) δ 3.85 (d, J = 12.4 Hz, 2H), 3.06-3.00 (m, 2H), 1.87-1.82 (m, 2H), 1.48-1.42 (m, 2H), 1.46 (s, 9H).

[0399] [ka]

[0400] tert-butyl 4-(tosyloxy)piperidine-1-carboxylate-4-d. To a suspension of tert-butyl 4-hydroxypiperidine-1-carboxylate-4-d (10 g) and 4-dimethyl-aminopyridine (0.6 g) in pyridine (45 mL), tosyl chloride (11.8 g) was added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with saturated NaHCO3 solution and extracted with ELISA (2x). The mixed organic layer was washed with water (2x) and brine (2x), dried, filtered, and concentrated. The unrefined oil was purified by normal-phase column chromatography (0-20% ELISA / hexane). After removal of the solvent, the desired compound was obtained (14.3 g). 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.61-3.55 (m, 2H), 3.28-3.22 (m, 2H), 2.45 (s, 3H), 1.79-1.73 (m, 2H), 1.70-1.64 (m, 2H), 1.43 (s, 9H). ES-MS [M+Na] + : 379.

[0401] [ka]

[0402] 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-4-d. In a round-bottom flask, 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol (1.0 g, 6.7 mmol), tert-butyl4-(tosyloxy)piperidine-1-carboxylate-4-d (2.0 g, 5.6 mmol), potassium carbonate (2.4 g, 16.8 mmol), and tetrabutylammonium chloride (0.31 g, 1.1 mmol) were added in water (25 mL) and DMF (1.3 mL). The reaction was heated under reflux for 18 hours. The reaction was diluted with 3:1 CHCl3 / IPA and the layers were separated. The aqueous layer was extracted with 3:1 CHCl3 / IPA (2x), the mixed organic layer was washed with water and brine, then dried (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase column chromatography (0-20% siRNA / hexane). After solvent removal, the residue was dissolved in DCM (9 mL), followed by the addition of trifluoroacetic acid (2.1 mL). After 1 hour, the solvent was removed under vacuum. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was rinsed with MeOH and 7N NH3 / MeOH solution. After solvent removal, the title compound (725 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 8.7, 1H), 6.45 (d, J = 2.8, 1H), 6.41 (dd, J = 8.8, 2.9 Hz, 1H), 3.21-3.15 (m, 2H), 2.87-2.81 (m, 2H), 2.07-2.00 (m, 2H), 1.78-1.72 (m, 2H). ES-MS [M+1] + : 241.

[0403] [ka]

[0404] tert-butyl(2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-1-carboxylate. ADDP (13.6g) was added in small increments to a mixture of 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol (8.4g), (2R,4R)-tert-butyl4-hydroxy-2-methylpiperidine-1-carboxylate (9.5g) and P(n-Bu)3 (13.5mL) in toluene (300mL). The reaction mixture was heated to 90°C. After 18 hours, the reaction was concentrated under vacuum, and the residue was dissolved in a solution of CHCl3:IPA (3:1) and saturated NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted with CHCl3:IPA(3x). The mixed organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by normal-phase column chromatography (0-30%, ethyl acetate in petroleum ether) to obtain the compound described in the title. 1 H NMR (400MHz, CDCl3) δ 6.77 (d, J = 8.8 Hz, 1H), 6.46 (s, 1H), 6.42 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 4.61 - 4.46 (m, 1H), 4.41 - 4.31 (m, 1H), 4.13 - 4.06 (m, 1H), 2.96 - 2.89 (m, 1H), 2.14 - 2.04 (m, 1H), 2.01 - 1.90 (m, 1H), 1.74-1.64 (m, 1H), 1.52-1.42 (s, 10H), 1.19 (d, J = 7.2 Hz, 3H).

[0405] [ka]

[0406] (2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine. To a solution of tert-butyl(2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-1-carboxylate (3.7g) in DCM (20mL), TFA (4mL) was added, and the reaction was stirred at 20°C for 3 hours. The reaction was quenched at 0°C with saturated aqueous solution Na2CO3 to pH 8-9, and extracted with DCM (20mL x 2). The mixed organic layer was washed with brine (20mL), dried over Na2SO4, and concentrated to obtain the title compound (2.6g, unpurified). ES-MS[M+1] + :254.2.

[0407] [ka]

[0408] 3-bromo-2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)flou[3,4-b]pyridine-5(7H)-one. To a solution of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine (170 mg, 0.36 mmol) in DMSO (5.6 mL), 3-bromo-2-chloroflou[3,4-b]pyridine-5(7H)-one (80 mg, 0.30 mmol) and N,N-diisopropylethylamine (155 μL, 0.89 mmol) were added. The mixture was stirred at ambient temperature for 18 hours. The mixture was added to water and extracted with ELISA (3x). The mixed organic matter was dried (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase column chromatography (0-30% siRNA / DCM) to obtain the title compound (131 mg). ES-MS [M+1] + : 451 / 453; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.46 (dd, J = 8.7, 2.9 Hz, 1H), 5.11 (s, 2H), 4.43 (tt, J = 7.0, 3.6 Hz, 1H), 3.81 (ddd, J = 12.2, 8.0, 3.4 Hz, 2H), 3.51 (ddd, J = 13.2, 7.4, 3.5 Hz, 2H), 2.08 (ddq, J = 10.6, 6.6, 3.3 Hz, 2H), 1.96 (dtd, J = 13.7, 7.1, 3.5 Hz, 2H).

[0409] [ka]

[0410] Ethyl 2-(1-ethoxyvinyl)-5-methylnicotinate. Tributyl(1-ethoxyvinyl)tin (1.39 mL, 4.12 mmol) was added to a solution of ethyl 2-chloro-5-methylnicotinate (500 mg, 2.5 mmol) and tetrakis(triphenylphosphine)palladium (0) (159 mg, 0.14 mmol) in toluene (8.7 mL) under nitrogen gas. The mixture was heated to 80°C for 18 hours. After cooling to ambient temperature, the crude product was purified by normal-phase column chromatography (0-50% Â / hexane) to obtain the title compound (342 mg). ES-MS [M+1] + : 235; 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 2.2, 0.8 Hz, 1H), 7.69 (dd, J = 2.2, 0.8 Hz, 1H), 4.88 (d, J = 2.4 Hz, 1H), 4.39 (d, J = 2.4 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.90 (q, J = 7.0 Hz, 2H), 2.37 (t, J = 0.7 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.0 Hz, 3H).

[0411] [ka]

[0412] Ethyl 2-acetyl-5-methylnicotinate. A mixture of ethyl 2-(1-ethoxyvinyl)-5-methylnicotinate (342 mg, 1.45 mmol) in acetone (6.5 mL) was mixed with 2 M hydrochloric acid in water (8.0 mL, 16.1 mmol), and the mixture was stirred at ambient temperature for 18 hours. The solvent was removed under vacuum. The residue was dissolved in ethyl phosphate and washed with saturated aqueous solution NaHCO3. The organic matter was isolated, and the aqueous layer was further extracted with ethyl phosphate (3x). The organic matter was pooled, dried (MgSO4), filtered, and concentrated. The process proceeded without further purification of the material. ES-MS [M+1] + : 208; 1 H NMR (400 MHz, CDCl3) δ 8.52 (dd, J = 2.1, 0.8 Hz, 1H), 7.75 (dq, J = 1.5, 0.7 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 2.43 (t, J = 0.7 Hz, 3H), 1.37 (t, J = 7.2 Hz, 3H).

[0413] [ka]

[0414] 3,7-Dimethylflou[3,4-b]pyridine-5(7H)-one. Sodium borohydride (46 mg, 1.22 mmol) was added to a solution of ethyl 2-acetyl-5-methylnicotinate (253 mg, 1.22 mmol) in THF (30 mL) at 4°C. The mixture was stirred at 4°C for 16 hours. Water (20 mL) was added, and the mixture was extracted with RINKAN (3x). The mixed organic matter was dried (MgSO4), filtered, and concentrated. The residue was then dissolved in DCM (10 mL), cooled to 4°C, and pyridinium chlorochromate (612 mg, 2.81 mmol) was added. The mixture was stirred at 4°C for 16 hours. The reaction mixture was filtered through a Celite® pad and concentrated. The crude product was purified by normal-phase column chromatography (0-20% RINKAN / DCM) to obtain the title compound (114 mg). ES-MS [M+1] + : 164; 1 H NMR (400 MHz, CDCl3) δ 8.68 (dd, J = 1.9, 0.8 Hz, 1H), 7.97 (dd, J = 2.2, 1.0 Hz, 1H), 5.52 (q, J = 6.8 Hz, 1H), 2.48 (q, J = 0.7 Hz, 3H), 1.69 (d, J = 6.8 Hz, 3H).

[0415] [ka]

[0416] 3,7-dimethyl-5-oxo-5,7-dihydroflou[3,4-b]pyridine 1-oxide. To a solution of 3,7-dimethylflou[3,4-b]pyridine-5(7H)-one (84.7 mg, 0.52 mmol) in 2.6 mL of DCM at 0°C, 3-chloroperoxybenzoic acid (108 mg, 0.62 mmol) was slowly added, and the reaction was stirred at ambient temperature for 18 hours. Then, a saturated aqueous solution of Na2S2O3 was added, and the mixture was stirred for 1 hour. The organic layer was isolated, and the aqueous layer was further extracted by DCM (3x), followed by chloroform / IPA (3:1) (2x). The organic matter was pooled, washed with 1 M NaOH, then passed through a phase separator and concentrated to obtain the title compound (46 mg). The material was not further purified before proceeding to the next step. ES-MS [M+1] + : 180; 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(t, J = 1.0 Hz, 1H), 7.55 (s, 1H), 5.68 (q, J = 6.7 Hz, 1H), 2.45 (d, J = 0.9 Hz, 3H), 1.83 (d, J = 6.7 Hz, 3H).

[0417] [ka]

[0418] 2-Chloro-3,7-dimethylflou[3,4-b]pyridine-5(7H)-one. 3,7-dimethyl-5-oxo-5,7-dihydroflou[3,4-b]pyridine-1-oxide (42 mg, 0.24 mmol) in MeCN (1.2 mL), followed by phosphorus(V) oxychloride (110 μL, 1.18 mmol), was added to a vial. The vial was sealed and the mixture was heated to 85°C for 1 hour. The mixture was cooled to ambient temperature and slowly added to a stirred solution of saturated aqueous NaHCO3, maintaining an alkaline pH. DCM was added and the mixture was stirred for 30 minutes. The organic layer was isolated, and the aqueous layer was extracted with chloroform / IPA (3:1) (3x) and returned. The mixed organic layers were passed through a phase separator and concentrated. The residue was not further purified before proceeding. ES-MS[M+1]+ :198.

[0419] [ka]

[0420] 2,4-Dichloro-6-cyclopropyl-5-methylpyrimidine. A solution of 2,4-dichloro-5-methylpyrimidine (1.0 g, 6.1 mmol), silver nitrate (521 mg, 3.1 mmol), and cyclopropanecarboxylic acid (1.47 mL, 18.4 mmol) in water (31 mL) was heated to 72 °C. Ammonium persulfate (2.1 g, 9.2 mmol) was added in small amounts over more than 15 minutes. After heating for a further 20 minutes at 72 °C, sulfuric acid (491 μL, 9.2 mmol) was added, and the mixture was heated to 90 °C for 1 hour. After cooling to ambient temperature, the reaction mixture was slowly poured into a solution of saturated aqueous bicarbonate and DCM, and stirred for a further 20 minutes. The organic layer was isolated, and the aqueous layer was further extracted with DCM (3x). The mixed organic layers were dried over (MgSO4), filtered, and concentrated. The compound in question (872 mg) was obtained by purification using normal-phase column chromatography (0-25% siRNA / hexane). ES-MS [M+1] + : 203 / 205; 1 H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H), 2.11 (tt, J = 7.9, 4.6 Hz, 1H), 1.29 - 1.23 (m, 2H), 1.18 - 1.12 (m, 2H).

[0421] [ka]

[0422] 2-Chloro-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5-methylpyrimidine. To a solution of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine (50 mg, 0.21 mmol) in DMF (1 mL), triethylamine (146 μL, 1.04 mmol) and 2,4-dichloro-5-methylpyrimidine (37.5 mg, 0.23 mmol) were added. The mixture was stirred at ambient temperature for 18 hours. The mixture was added to water (20 mL) and extracted with ELISA (3x). The organic matter was pooled, dried (MgSO4), filtered, and concentrated. The unpurified material was purified by normal-phase column chromatography (0-30% siRNA / DCM) to obtain the compound indicated in the title (26 mg). 1 H NMR (400 MHz, CDCl3) δ 7.94 (q, J = 0.8 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 2.8 Hz, 1H), 6.45 (dd, J = 8.7, 2.9 Hz, 1H), 4.41 (tt, J = 6.9, 3.6 Hz, 1H), 3.77 (ddd, J = 12.2, 7.9, 3.5 Hz, 2H), 3.46 (ddd, J = 13.4, 7.5, 3.6 Hz, 2H), 2.20 (d, J = 0.8 Hz, 3H), 2.02 (ddd, J = 16.3, 7.5, 3.8 Hz, 2H), 1.88 (dtd, J = 13.8, 7.1, 3.5 Hz, 2H). ES-MS [M+1] + : 366.

[0423] [ka]

[0424] 2-Chloro-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5,6-dimethylpyrimidine. To a solution of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine (50 mg, 0.21 mmol) in DMF (1 mL), triethylamine (146 μL, 1.04 mmol) and 2,4-dichloro-5,6-dimethylpyrimidine (41 mg, 0.23 mmol) were added. The mixture was stirred at 75°C for 18 hours. The mixture was added to water (20 mL) and extracted with ELISA (3x). The collected organic layer was dried (Na2SO4), filtered, and concentrated. The unpurified material was purified by normal-phase column chromatography (0-30% Ã / DCM) on silica gel to obtain the compound indicated in the title (54 mg). 1 H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 2.8 Hz, 1H), 6.45 (dd, J = 8.7, 2.8 Hz, 1H), 4.37 (tt, J = 7.2, 3.7 Hz, 1H), 3.62 (ddd, J = 11.9, 7.6, 3.6 Hz, 2H), 3.25 (ddd, J = 12.6, 7.9, 3.5 Hz, 2H), 2.38 (s, 3H), 2.12 (s, 3H), 2.10 - 1.97 (m, 2H), 1.87 (ddt, J = 17.1, 7.4, 3.5 Hz, 2H). ES-MS [M+1] + : 380.

[0425] [ka]

[0426] 2,4-Dichloro-6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5-methylpyrimidine. Triethylamine (352 μL, 0.35 mmol) and 2,4,6-trichloro-5,6-methylpyrimidine (110 mg, 0.56 mmol) were added to a solution of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine (121 mg, 0.50 mmol) in DMF (1.5 mL). The mixture was stirred at 70°C for 18 hours. The mixture was added to water (20 mL) and extracted with ELISA (3x). The collected organic layer was dried (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase column chromatography (0-80% Â / DCM) to obtain the compound indicated in the title (173 mg). 1 H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.7 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.44 (dd, J = 8.8, 2.8 Hz, 1H), 4.41 (tt, J = 7.0, 3.6 Hz, 1H), 3.69 (ddd, J = 12.3, 8.1, 3.5 Hz, 2H), 3.40 (ddd, J = 13.4, 7.2, 3.7 Hz, 2H), 2.23 (s, 3H), 2.08 - 1.96 (m, 2H), 1.89 (dtd, J = 13.6, 6.9, 3.5 Hz, 2H). ES-MS [M+1] + : 400.2 / 402.2.

[0427] [ka]

[0428] 4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-hydrazinyl-5-methylpyrimidine. To a solution of hydrazine (46 μL, 1.45 mmol) in ethanol (483 μL), 2-chloro-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5-methylpyrimidine (27 mg, 0.07 mmol) was added, and the mixture was stirred at 80°C for 4 hours. The mixture was cooled to ambient temperature, an additional 30 μL of hydrazine was added, and the mixture was stirred at 80°C for a further 3 hours. After cooling to ambient temperature, the mixture was concentrated and proceeded to the next step without further purification. ES-MS[M+1] + :362.

[0429] [ka]

[0430] 4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-hydrazinyl-5-methylpyrimidine. To a solution of 2-chloro-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5,6-dimethylpyrimidine (54 mg, 0.14 mmol) in ethanol (950 μL), hydrazine (89 μL, 2.83 mmol) was added, and the mixture was stirred at 80°C for 9 hours. After cooling to ambient temperature, the mixture was concentrated and proceeded to the next step without further purification. ES-MS[M+1] + :376.

[0431] [ka]

[0432] 4-Chloro-6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-hydrazinyl-5-methylpyrimidine. To a solution of hydrazine (271 μL, 8.64 mmol) in ethanol (3.0 mL), 2,4-dichloro-6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5-methylpyrimidine (173 mg, 0.43 mmol) was added, and the mixture was stirred at 80°C for 4 hours. After cooling to ambient temperature, the mixture was concentrated and proceeded to the next step without further purification. ES-MS[M+1] + :396.3.

[0433] [ka]

[0434] 5-Chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one. To a solution of 4-chloro-6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-hydrazolinyl-5-methylpyrimidine (170 mg, 0.43 mmol) in 1,4-dioxane (2.8 mL), triphosgene (127 mg, 0.43 mmol) was added. The reaction was stirred at ambient temperature for 30 minutes. The mixture was diluted with water, and the resulting precipitate was collected by vacuum filtration. The solid was dissolved in DCM (2 mL) and purified by normal-phase column chromatography (0-40% MeOH / DCM) to obtain the compound indicated in the title. 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.44 (dd, J = 8.8, 2.9 Hz, 1H), 4.41 (tt, J = 6.8, 3.5 Hz, 1H), 3.71 - 3.60 (m, 2H), 3.37 (ddd, J = 13.4, 7.2, 3.7 Hz, 2H), 2.20 (s, 3H), 2.04 (ddt, J = 12.0, 7.8, 3.6 Hz, 2H), 1.91 (dtd, J = 13.7, 6.9, 3.5 Hz, 2H). ES-MS [M+1] + : 422.3.

[0435] [ka]

[0436] 2,4,5-Trimethylpyridine-3-yltrifluoromethanesulfonate. A 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 (21 mL) 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 on Celite® and purified by normal-phase chromatography (0-15% Â / Hex) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 2.57 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H). ES-MS [M+1] + : 270.

[0437] [ka]

[0438] Ethyl 2,4,5-trimethylnicotinate. To a solution of 2,4,5-trimethylpyridine-3-yltrifluoromethanesulfonate (1.9 g, 7.06 mmol) in ethanol (12 mL) and DMSO (6 mL), 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. The mixture was placed under CO(g) (50 psi) gas and heated to 80°C for 18 hours. The reaction mixture was filtered through a Celite® pad, then washed with DCM / MeOH and concentrated. The residue was then diluted with water (approximately 150 mL) and extracted with ELISA (4x). The mixed organic layer was dried over (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase chromatography (0-60% alkyl / hexol) to obtain the compound indicated in the title. 1 ES-MS [M+1] + : 194.

[0439] [ka]

[0440] Ethyl 2-(chloromethyl)-4,5-dimethylnicotinate. Trichloroisocyanuric acid (1085 mg, 4.67 mmol) was added to a stirred 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 aqueous Na2CO3 solution. The organic layer was isolated, and the aqueous layer was further extracted by DCM (3x). The mixed organic matter was dried (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase chromatography (0-5% MeOH / DCM) to obtain the title compound. 1 ES-MS [M+1] + : 228.

[0441] [ka]

[0442] 2-(chloromethyl)-3-(ethoxycarbonyl)-4,5-dimethylpyridine 1-oxide. 3-chloroperoxybenzoic acid (285 mg, 1.65 mmol) was added in small increments to a solution of ethyl 2-(chloromethyl)-4,5-dimethylnicotinate (216 μL, 1.38 mmol) in 6.9 mL of DCM at 0°C. After removing the ice bath and allowing 18 hours at room temperature, the mixture was concentrated directly on Celite® and purified by normal-phase chromatography (0-80% Â / DCM, then 0-10% MeOH / DCM) to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 4.84 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). [M+1] + : 244.

[0443] [ka]

[0444] Ethyl 6-chloro-2-(chloromethyl)-4,5-dimethylnicotinate. To a solution of 2-(chloromethyl)-3-(ethoxycarbonyl)-4,5-dimethylpyridine 1-oxide (182 mg, 0.75 mmol) in MeCN (1.6 mL), phosphorus(V) oxychloride (348 μL, 3.73 mmol) was added. The vial was sealed and the mixture was heated to 90°C for 20 hours. After cooling to ambient temperature, the reaction mixture was slowly added to a stirred solution of saturated aqueous solution NaHCO3, maintaining an alkaline pH. DCM was added and the mixture was stirred for 30 minutes. The organic layer was isolated, and the aqueous layer was extracted with chloroform / IPA (3:1) (3x) and returned. The mixed organic layers were dried over (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase chromatography (0-15% RINKAN / hexane) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ 4.66 (s, 2H), 4.46 (q, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). ES-MS [M+1] + : 262 / 264.

[0445] [ka]

[0446] 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 was heated to 30°C for 18 hours. The reaction was concentrated in vacuum to obtain the compound described in the title. 1 H NMR (400 MHz, CDCl3) δ 4.29 (s, 3H), 3.18 (s, 2H), 2.73 (s, 3H), 2.39 (s, 3H). ES-MS [M+1] + : 211.

[0447] [ka]

[0448] 6-Hydroxy-4,5-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile. To a solution of 2-cyanoacetamide (2.0 g, 23.8 mmol) dissolved in methanol (30 mL), ethyl 2-methyl-3-oxobutanoate (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 the precipitate was observed. The solid was collected by vacuum filtration and rinsed with water to obtain the compound described in the title. 1 H NMR (400 MHz, DMSO) δ 2.23 (s, 1H), 1.90 (s, 1H). ES-MS [M+1] + : 165.

[0449] [ka]

[0450] 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 at room temperature was poured into ice water (100 mL). The precipitate was collected by vacuum filtration to obtain the compound described in the title. 1 H NMR (400 MHz, CDCl3) δ 2.58 (s, 3H), 2.39 (s, 3H). ES-MS [M+1] + : 201 / 203.

[0451] [ka]

[0452] 2,6-Dichloro-4,5-dimethylnicotinic acid. A stirred solution of 2,6-dichloro-4,5-dimethylnicotinonitrile (1.48 g, 7.36 mmol) in sulfuric acid (2.0 mL) was heated to 110°C for 1 hour. After cooling to ambient temperature, the reaction mixture was cooled to 0°C, and an aqueous solution of sodium nitrite (671 mg, 9.58 mmol) (2.6 M in water) was added dropwise over a period of 15 minutes, releasing heat and brown gas. The mixture was then heated to ambient temperature for 15 minutes, and then heated to 60°C for 18 hours. After cooling to ambient temperature, the reaction mixture was cooled again to 0°C, and an aqueous solution of sodium nitrite (186 mg, 2.66 mmol) (2.6 M in water) was added dropwise over a period of 15 minutes. The mixture was then heated to ambient temperature for 15 minutes, and then heated to 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 compound described in the title. 1 H NMR (400 MHz, DMSO) δ 2.32 (s, 3H), 2.31 (s, 3H). ES-MS [M+1] + : 220 / 222.

[0453] [ka]

[0454] Methyl 2,6-dichloro-4,5-dimethylnicotinate. Potassium carbonate (918 mg, 6.54 mmol) and iodomethane (543 μL, 8.73 mmol) were added to a solution of 2,6-dichloro-4,5-dimethylnicotinic acid (960 mg, 4.36 mmol) in DMF (14.5 mL). The mixture was stirred at ambient temperature for 1 hour, then diluted with water and extracted with RINKAN (3x). The mixed organic layer was dried (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase chromatography (0-10% RINKAN / Hex) to obtain the compound described in the title. 1 H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H). ES-MS [M+1] + : 234 / 236.

[0455] [ka]

[0456] Methyl 6-chloro-2-cyano-4,5-dimethylnicotinate. A solution of methyl 2,6-dichloro-4,5-dimethylnicotinate (868 mg, 3.71 mmol) and copper(I) cyanide (498 mg, 5.56 mmol) in NMP (4.4 mL) was stirred at 180°C for 3 hours under an inert gas. After cooling to ambient temperature, the reaction was poured into ice water, the solid was removed by filtration, and the mixture was washed with ethyl acetate. The filtrate was then extracted with ethyl acetate (3x), the mixed organic matter was dried (MgSO4), filtered, and concentrated. The unpurified residue was purified by normal-phase chromatography (0-40% ethyl acetate / Hex) to obtain the compound described in the title. ES-MS[M+1] + :225.

[0457] [ka]

[0458] 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 three times). The mixture was stirred under hydrogen gas (with a balloon) for 25 hours. The reaction mixture was filtered over Celite®, washed with DCM / MeOH, the filtrate was concentrated, and the process proceeded to the next step without further purification. ES-MS[M+1] + :229.

[0459] [ka]

[0460] 2-Chloro-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one. A solution of methyl 2-(aminomethyl)-6-chloro-4,5-dimethylnicotinate (236 mg, 0.97 mmol) and triethylamine (680 μL, 4.88 mmol) in methanol (4.9 mL) 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 (400 MHz, CDCl3) δ 6.06 (s, 1H), 4.38 (s, 2H), 2.74 (s, 3H), 2.41 (s, 3H). ES-MS [M+1] + : 197.

[0461] b. Examples of compounds of the present invention

[0462] [ka]

[0463] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 3). 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (200 mg, 1.10 mmol) and N,N-diisopropylethylamine (1.91 mL, 10.95 mmol) were added to a solution of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-ium 2,2,2-trifluoroacetate (503 mg, 1.42 mmol) in NMP (6.8 mL). The reaction mixture was heated to 160°C. After 18 hours, the unpurified material was purified by RP-HPLC (10-55% MeCN / 0.05% aqueous NH4OH). The fraction containing the desired product was concentrated and re-purified using normal-phase flash column chromatography (0-7% MeOH / DCM) to obtain the title compound (303 mg). 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 0.9 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 6.47 (dd, J = 8.7, 2.9 Hz, 1H), 6.02 (s, 1H), 4.40 - 4.30 (m, 3H), 3.55 (ddd, J = 11.5, 7.0, 3.6 Hz, 2H), 3.14 (ddd, J = 12.5, 8.4, 3.3 Hz, 2H), 2.35 (d, J = 0.9 Hz, 3H), 2.16 - 2.07 (m, 2H), 1.92 (dtd, J = 12.1, 8.0, 3.5 Hz, 2H); ES-MS [M+1] + : 386.

[0464] [ka]

[0465] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl-4-d)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 1). Prepared in a manner similar to compound 3, the title compound was obtained. ES-MS [M + H] + = 387. 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 0.9 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.46 (dd, J = 8.8, 2.9 Hz, 1H), 6.07 - 5.85 (m, 1H), 4.35 (s, 2H), 3.55 (ddd, J = 11.4, 6.9, 3.5 Hz, 2H), 3.14 (ddd, J = 18.2, 8.7, 4.5 Hz, 2H), 2.35 (d, J = 0.9 Hz, 3H), 2.16 - 2.00 (m, 2H), 1.92 (ddd, J = 12.6, 8.4, 3.5 Hz, 2H).

[0466] [ka]

[0467] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl-2,2,6,6-d4)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 2). This compound was prepared in a manner similar to compound 3 to obtain the compound of the title. 1H NMR (400 MHz, MeOD) δ 7.79 (d, J = 0.9 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.49 (d, J = 2.7 Hz, 1H), 6.47 (dd, J = 8.6, 2.9 Hz, 1H), 4.44 (tt, ES-MS [M + H] + = 390.

[0468] [ka]

[0469] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-yl-4-d)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 10). This compound was prepared in a manner similar to compound 3 to obtain the compound of the title. 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 6.91 (s, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.52 - 6.42 (m, 2H), 4.36 (s, 2H), 4.28 - 4.17 (m, 4H), 3.55 (ddd, J = 11.6, 7.0, 3.5 Hz, 2H), 3.14 (ddd, J = 12.5, 8.4, 3.3 Hz, 2H), 2.34 (s, 3H), 2.09 (ddd, J = 13.1, 7.0, 3.3 Hz, 2H), 1.96 - 1.86 (m, 2H).; ES-MS [M+1] + : 383.3.

[0470] [ka]

[0471] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-yl-2,2,6,6-d4)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 11). This compound was prepared in a manner similar to compound 3 to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.46 (dd, J = 8.7, 2.9 Hz, 1H), 4.41 - 4.33 (m, ES-MS [M+1] + : 386.3.

[0472] [ka]

[0473] 2-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 4). The compound in the title was obtained by preparing it in a manner similar to compound 3. ES-MS[M+H] + = 400.

[0474] [ka]

[0475] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3-methylflu[3,4-b]pyridine-5(7H)-one (compound 8). 3-Bromo-2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)flo[3,4-b]pyridine-5(7H)-one (131 mg, 0.25 mmol), cesium carbonate (241 mg, 0.74 mmol), trimethylboroxine (50% by mass in THF) (207 μL, 0.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol), and 1,4-dioxane (1.2 mL) were placed in a vial. The mixture was evacuated, purged with nitrogen, and stirred at 85°C for 17 hours. After cooling to ambient temperature, the reaction was filtered through a Celite® pad, thoroughly rinsed with DCM / MeOH, and then concentrated on Celite®. The crude product was purified by normal-phase column chromatography (0-70% siRNA / hexane) to obtain the title compound (71 mg). ES-MS [M+1] + : 387; 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 1.0 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.46 (dd, J = 8.8, 2.9 Hz, 1H), 5.13 (s, 2H), 4.40 (tt, J = 7.3, 3.7 Hz, 1H), 3.64 (ddd, J = 11.7, 7.4, 3.5 Hz, 2H), 3.26 (ddd, J = 12.5, 8.0, 3.4 Hz, 2H), 2.35 (d, J = 0.8 Hz, 3H), 2.14 - 2.03 (m, 2H), 2.00 - 1.78 (m, 2H).

[0476] [ka]

[0477] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3,7-dimethylflu[3,4-b]pyridine-5(7H)-one (compound 9). To a solution of 2-chloro-3,7-dimethylflu[3,4-b]pyridine-5(7H)-one (17.8 mg, 0.06 mmol) in DMSO (0.5 mL), 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine (31 mg, 0.07 mmol) and N,N-diisopropylethylamine (38 μL, 0.18 mmol) were added. The mixture was stirred at ambient temperature for 18 hours, and then at 40°C for 3 hours. The unpurified material was purified by RP-HPLC (5-70% ACN / 0.1% aqueous TFA). The fraction containing the desired product was basicized with saturated aqueous NaHCO3, and then extracted with 3:1 chloroform / IPA (3:1) (3x). The mixed organic matter was passed through a phase separation apparatus, and the solvent was concentrated to obtain the compound indicated in the title. ES-MS [M+1] + : 401; 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 1.0 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 6.47 (dd, J = 8.7, 2.9 Hz, 1H), 5.33 (q, J = 6.8 Hz, 1H), 4.40 (tt, J = 7.4, 3.7 Hz, 1H), 3.70 - 3.60 (m, 2H), 3.27 (ddd, J = 12.7, 8.0, 3.4 Hz, 2H), 2.34 (s, 3H), 2.09 (ddd, J = 10.9, 7.1, 3.5 Hz, 2H), 1.92 (qd, J = 7.9, 3.8 Hz, 2H), 1.61 (d, J = 6.7 Hz, 3H).

[0478] [ka]

[0479] 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound A1). 1,1'-carbonyldiimidazole (18.8 mg, 0.12 mmol) was added to a solution of 4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-hydrazolo[4,3-a]methylpyrimidine (compound A1). 1,1'-carbonyldiimidazole (18.8 mg, 0.12 mmol) was added to a solution of 4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-hydrazolo[4,3-a]methylpyrimidine (compound A1). The reaction was heated to 85°C for 18 hours. The reaction was cooled to ambient temperature, at which point 1.6 equivalents of CDI were added, and the mixture was stirred at 85°C for 8 hours. After cooling to ambient temperature, the mixture was diluted with water, and the resulting precipitate was collected by vacuum filtration. The solid was dissolved in DMSO (2 mL) and purified by RP-HPLC (5-50% ACN / 0.1% aqueous TFA). The fraction containing the product was basicized with saturated aqueous NaHCO3, and then extracted with chloroform / IPA (3:1) (3x). The mixed organic matter was passed through a phase separation apparatus, and the solvent was concentrated to obtain the compound described in the title. ES-MS[M+1] + :388.

[0480] [ka]

[0481] 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound A6). Iodomethane (0.22 mL, 3.5 mmol) was added to a suspension of 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (797 mg, 2.1 mmol) and potassium carbonate (577 mg, 4.1 mmol) in DMF (30 mL). The reaction was stirred at 60 °C for 18 hours. The reaction was diluted with water and 3:1 CHCl3 / IPA. The layers were separated, and the aqueous layer was extracted with CHCl3 / IPA (3x). The mixed organic layers were washed with brine (2x), dried (MgSO4), filtered, and concentrated. The unpurified sample was purified by reverse-phase chromatography (10-50% MeCN / water / 0.05% NH4OH) to obtain the title compound (472 mg). 1 H NMR (400 MHz, DMSO) δ 7.90 (d, J = 1.3 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 2.9 Hz, 1H), 6.47 (dd, J = 8.8, 2.9 Hz, 1H), 4.49 (tt, J = 7.7, 3.7 Hz, 1H), 3.77 - 3.62 (m, 2H), 3.39 (s, 3H), 3.31 - 3.25 (m, 2H), 2.16 (d, J = 1.2 Hz, 3H), 2.06 - 1.90 (m, 2H), 1.67 (dtd, J = 12.2, 8.2, 3.5 Hz, 2H). ES-MS [M+1] + : 402.1.

[0482] [ka]

[0483] 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound A9). 1,1'-carbonyldiimidazole (37 mg, 0.23 mmol) was added to a solution of 4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2-hydrazolo[4,3-a]pyrimidine (53 mg, 0.14 mmol) in 1,4-dioxane (250 μL), and the mixture was heated to 85°C for 18 hours. After cooling to ambient temperature, the mixture was diluted with water, and the resulting precipitate was collected by vacuum filtration. The solid was then dissolved in DCM / MeOH, dried (Na2SO4), filtered, and concentrated to obtain the title compound (51 mg). 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.44 (dd, J = 8.8, 2.9 Hz, 1H), 4.43 - 4.22 (m, 1H), 3.62 (ddd, J = 12.2, 7.7, 3.4 Hz, 2H), 3.27 (ddd, J = 12.6, 7.7, 3.6 Hz, 2H), 2.76 (s, 3H), 2.07 (s, 3H), 2.07 - 2.00 (m, 2H), 1.94 - 1.81 (m, 2H). ES-MS [M+1] + : 402.

[0484] [ka]

[0485] 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound A10). Potassium carbonate (1.43 g, 10.2 mmol) and then iodomethane (0.48 mL, 7.7 mmol) were added to a solution of 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (2.05 g, 5.1 mmol) in DMF (25 mL). The mixture was heated at 60°C for 18 hours. 50 mL of water was added to the reaction, the resulting precipitate was filtered, washed with water, and dried under high vacuum. The solid was purified by reverse-phase chromatography (10-60% MeCN / water / 0.05% NH4OH) to obtain the title compound (940 mg). 1 H NMR (400 MHz, DMSO) δ 6.75 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.47 (dd, J = 8.8, 2.9 Hz, 1H), 4.46 (dt, J = 7.9, 4.0 Hz, 1H), 3.59 - 3.46 (m, 2H), 3.36 (s, 3H), 3.14 (ddd, J = 12.8, 8.8, 3.2 Hz, 2H), 2.65 (s, 3H), 2.01 (s, 3H), 2.01 - 1.95 (m, 2H), 1.68 (dtd, J = 12.2, 8.2, 3.4 Hz, 2H). ES-MS [M+1] + : 416.2.

[0486] [ka]

[0487] 5-Chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound A11). A solution of 5-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (20 mg, 0.05 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (0.25 mL) was stirred at ambient temperature for 20 minutes. Subsequently, iodomethane (4 μL, 0.07 mmol) was added, and the mixture was stirred at 60°C for 18 hours. The mixture was added to water (10 mL) and extracted with ethyl acetate (3x). The collected organic layer was dried (Na2SO4), filtered, and concentrated. The unpurified material was purified by RP-HPLC (15-55% ACN / 0.1% aqueous TFA). The fraction containing the desired product was basicized with saturated aqueous NaHCO3, and then extracted with 3:1 chloroform / IPA (3x). The mixed organic matter was passed through a phase separator, and the solvent was concentrated to obtain the title compound (9 mg). 1 H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 8.7 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.44 (dd, J = 8.7, 2.8 Hz, 1H), 4.40 (tt, J = 6.8, 3.5 Hz, 1H), 3.64 (ddd, J = 12.3, 8.2, 3.4 Hz, 2H), 3.53 (s, 3H), 3.35 (ddd, J = 13.4, 7.2, 3.6 Hz, 2H), 2.19 (s, 3H), 2.03 (ddt, J = 12.1, 7.9, 3.8 Hz, 2H), 1.90 (dtd, J = 13.6, 6.9, 3.4 Hz, 2H). ES-MS [M+1] + : 436.3.

[0488] [ka]

[0489] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 12). Prepared in a manner similar to compound 3. 1 H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 6.47 (dd, J = 8.7, 2.9 Hz, 1H), 4.33 (tt, J = 7.8, 3.8 Hz, 1H), 4.21 (s, 2H), 3.44 (ddd, J = 11.2, 6.6, 3.7 Hz, 2H), 3.15 (s, 3H), 3.04 (ddd, J = 12.5, 8.8, 3.2 Hz, 2H), 2.62 (s, 3H), 2.22 (s, 3H), 2.10 (dtd, J = 12.5, 8.0, 4.6 Hz, 2H), 1.92 (dtd, J = 12.3, 8.3, 3.5 Hz, 2H). ES-MS [M+1] + : 414.

[0490] [ka]

[0491] 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one (compound 13). Prepared in a manner similar to compound 3. 1H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 6.47 (dd, J = 8.8, 2.8 Hz, 1H), 5.85 (s, 1H), 4.34 (tt, J = 7.7, 3.8 Hz, 1H), 4.28 (s, 2H), 3.52 - 3.41 (m, 2H), 3.06 (ddd, J = 12.5, 8.7, 3.2 Hz, 2H), 2.63 (s, 3H), 2.23 (s, 3H), 2.16 - 2.03 (m, 2H), 1.92 (dtd, J = 12.3, 8.2, 3.5 Hz, 2H). ES-MS [M+1] + : 400.

[0492] The compounds shown in Table 1 can be prepared using appropriate starting materials and the methods shown in the above scheme and examples.

[0493] [Table 1A]

[0494] [Table 1B]

[0495] [Table 1C]

[0496] [Table 1D]

[0497] [Table 1E]

[0498] [Table 1F]

[0499] [Table 1G]

[0500] Bioactive A. Cell lines expressing muscarinic acetylcholine receptors Human and rat M4 cDNA, and chimeric G protein G qi5 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) and G418 sulfate were used to select M4-expressing cells. qi5 Hygromycin B (500 μg / mL) was used to select expressing cells. The resulting polyclones were further screened to identify hM4-G qi5 and rM4-G qi5 Monoclones were obtained and used in compound screening assays. Stable monoclonal cells were maintained in Ham F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1X antibiotic / antifungal agent, 20 mM HEPES, 500 μg / mL G418 sulfate, and 200 μg / mL hygromycin B in a humidified incubator at 37°C in the presence of 5% CO2.

[0501] B. Cell-based functional assay of muscarinic acetylcholine receptor activity To determine the compound activity, receptor-induced intracellular calcium mobilization was measured using a high-throughput assay. 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, near-maximal (EC) mobilization was measured. 20Acetylcholine at a concentration of ) was added, and the response was measured. This kinetic assay allows for simultaneous screening and intensity determination of multiple pharmacological actions, including agonist and enhancer activity. CHO-K1 cells stably expressing muscarinic receptors were seeded at 15,000 cells / 20 μL / well in growth medium lacking G418 and hygromycin in Greiner 384-well black-walled tissue culture (TC) treated clear-bottom plates (Greiner Bio-One). 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, fluor-4-acetomethoxyester (Fluo-4-AM), and fluorescent calcium indicator dye were diluted. Using a Bravo liquid handler (Agilent, Santa Clara, CA), the compound was serially diluted 1:3 in DMSO to generate a 10-point concentration response curve. This curve was then transferred to a 384-well daughter plate using an Echo acoustic liquid handler (Beckman Coulter, Indianapolis, Indiana) and diluted in assay buffer to a 2X final concentration. By diluting in assay buffer to a 5X final concentration, the EC2 concentration was reduced. 20 and EC MAXAgonist plates were prepared using the responsive acetylcholine (ACh, Sigma-Aldrich, St. Louis, MO) concentration. A 2X dye solution (2.3 μM) was prepared by mixing 2.3 mM Fluo-4-AM stock in DMSO with 10% (w / v) pluluronic acid F-127 in a 1:1 ratio in assay buffer. Cells were washed three times with assay buffer using a microplate washer (BioTek, Winooski, VT) to remove the culture medium. After the final wash, 20 μL of assay buffer was left in the cell plate. Immediately, 20 μL of 2X dye solution (final 1.15 μM) was added to each well of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA). The cells were incubated with the dye solution at 37°C in the presence of 5% CO2 for 45 minutes. After that, the dye solution was removed and replaced with assay buffer using a microplate washer, leaving 20 μL of assay buffer in the cell plate.

[0502] The prepared compounds, agonists, and cell plates were placed in a Functional Drug Screening System μCell (FDSS μCell, Hamamatsu, Japan) and calcium flow was measured. Ca kinetics were measured using a triple dosing protocol. 20 Regarding ACh and EC 80 The ACh levels for each component are added sequentially. In short, after establishing the fluorescence baseline for 2 seconds (excitation, 480 nm; emission, 530 nm), the first addition was performed by adding 20 μL of the test compound to the cells, and the response was measured for 140 seconds. This was followed by the second addition. EC 20 10 μL (5X) of the ACh agonist concentration was added to the cells, and the cellular response was measured for 125 seconds. Immediately afterward, EC 80 A third addition was performed by adding 12 μl (5X) of concentrated ACh, and the cellular response was measured for 90 seconds. By adding 1 mM ACh as the third addition to the control well, the acetylcholine-mediated maximal response (EC) was measured. max ) was measured. ACh EC 20 , EC80 and ECmax To evaluate the response, DMSO medium was added to the control well during the first addition. Calcium fluorescence was recorded as a multiple of baseline fluorescence, and the raw data was normalized for the maximum response to the ACh agonist. Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Positive allosteric modulator activity was measured using EC 20 The antagonist activity was analyzed as a concentration-dependent increase in the acetylcholine response. 80 The acetylcholine response was analyzed as a concentration-dependent decrease. Concentration response curves were generated using the four-parameter logistic equation with GraphPad Prism (La Jolla, CA) or the Dotmatics software platform (Woburn, MA).

[0503] Furthermore, the assay described above was performed in a second configuration, where, after establishing a fluorescence baseline for approximately 3 seconds, the compound at an appropriate fixed concentration was added to the cells, and the cellular response was measured. After 140 seconds, an appropriate concentration of agonist was added, and the calcium response (maximum-local minimum response) was measured. The EC of the agonist in the presence of the test compound was also measured. 50 The values ​​were determined by nonlinear curve fitting. EC of the agonist with increasing concentration of this compound. 50 A decrease in the value (a leftward shift in the agonist concentration response curve) indicates the degree of muscarinic positive allosteric modulation at a given concentration of this compound. The EC of the agonist with increasing concentrations of this compound... 50 An increase in the value (a shift to the right of the agonist concentration response curve) indicates the degree of muscarinic antagonism at a given concentration of this compound. The second mode indicates whether this compound also affects the maximal response of muscarinic receptors to the agonist.

[0504] C. mAChR compound activity in M4 cell-based assays The compound was synthesized as described above. Activity (EC 50 and E maxThe M2 activity (EC) was determined in the M4 cell-based functional assay described above, and the data is shown in Table 2. In addition, the M2 activity (EC) was determined in the M2 cell-based functional assay. 50 and E max The selectivity in ) is shown below. The compound numbers correspond to the compound numbers used in Table 1.

[0505] [Table 2]

[0506] D. Cellular cAMP assay, Cellular cAMP G i Functional evaluation of M4 activator compounds in HTRF assays Activation of the M4 receptor is G i / o Protein coupling inhibits cAMP production. To measure the level of cAMP inhibition by M4 allosteric modulators, the Homogeneous Time-Resolved Fluorescence (HTRF®) cAMP assay was used with CHO cells stably expressing human or rat M4 receptors. The HTRF cAMP assay is a Time-Resolved Resonance Energy Transfer (TR-FRET) competitive immunoassay. Endogenous intracellular cAMP produced by cells competes with europium cryptotate-labeled cAMP (europium donor, release 665 nm) for binding to a d2-labeled cAMP antibody (d2-acceptor, release 620 nm). Therefore, the fluorescence emission ratio (665 nm / 620 nm) is inversely proportional to the amount of cAMP in the cell. Compound-mediated M4 activation results in an increase in the HTRF ratio (665 nm / 620 nm), indicating a decrease in intracellular cAMP levels. To monitor agonist activity, EC induces near-maximum intracellular cAMP levels. 80 The compound was added to M4 cells in the presence of a concentration of forskolin (adenylyl cyclase activator). To evaluate the enhancer activity, EC was used. 20In the presence of acetylcholine at a certain concentration, EC 80 The compound was added to M4 cells containing a concentration of forskolin. This functional assay showed that G i / o It became possible to determine the strength and efficacy of compounds that directly activate or enhance the conjugated M4 receptor, and representative data are shown in Table 3.

[0507] HTRF CAMP G i / o The functional agonist and enhancer activity of the compounds was determined by measuring cAMP levels in Chinese hamster ovary (CHO) cells stably expressing human or rat M4 muscarinic receptors using the kit. Cells were maintained in F12 medium containing 10% FBS, 20 mM HEPES, 1X antibiotic / antifungal agent, and G418 (500 μg / ml) in a humidified incubator at 37°C in the presence of 5% CO2. The day before the assay, the cells were trypsinized and resuspended in seeding medium (growth medium without G418). Cells were seeded in white solid flat-bottom 384-well plates at densities of 4,000 and 6,000 cells / 10 μL / well for human M4 and rat M4 cells, respectively. The cell plates were spun at 100xg for 1 minute and then immediately placed overnight in a 37°C incubator in the presence of 5% CO2.

[0508] The following day, the reagents were freshly diluted to a 2X concentration in assay buffer using F12 basal medium or stimulation buffer. All assay buffers contained 500 μM IBMX to prevent cAMP degradation. EC induces near-maximal intracellular cAMP levels. 80 We investigated compound-mediated M4 activation in cells stimulated with forskolin. (Forskolin EC) 80 The concentration was determined from the forskolin concentration response curve (CRC) and was in the range of 1.5–2.5 μM. The compound (10 mM) was prepared in 100% DMSO and further serially diluted in either 1:3 or 1:5 using a Bravo liquid handler in a 384-well microplate to obtain 13-point CRCs in DMSO.

[0509] The ability of M4 compounds to directly activate the M4 receptor in the absence of the agonist acetylcholine was evaluated using an agonist assay method. Ten serial dilutions of the compound, starting at a final concentration of 30 μM, were transferred to compound plates using the Echo plate reformatting protocol. 80 A 2X assay buffer containing a forskolin concentration was added to the compound plate. The medium (1% DMSO) was used to measure the following: baseline cAMP (without forskolin), forskolin maxima, and forskolin EC. 80 It was added to the cell plate. Using a Bravo 384-well tip liquid handler, 10 μL / well of the prepared 2X assay buffer was immediately added to the cell plate. The cell plate was immediately spun at 100xg for 30 seconds and incubated at 37°C at 50 rpm with gentle shaking for 10 minutes. Acetylcholine CRC was also added to the EC 80 The procedure is performed in the presence of forskolin at a maximum concentration (EC2). max ) and quasi-maximum (EC 20 The concentration of acetylcholine that induces cAMP inhibition was determined and prepared for the following enhancer-type assay.

[0510] In the enhancer assay, 10 sequentially diluted compounds, starting at a final concentration of 1.1 μM, were transferred to compound plates using the Echo plate reformatting protocol. 80 Forskolin and EC concentrations 20 A 2X assay buffer containing acetylcholine was added to the compound plate. The medium (1% DMSO) was added as follows: (1) For the forskolin control well, baseline cAMP (without forskolin), forskolin maxima, and forskolin EC2 80 (2) Forskolin EC 80 For the agonist control well containing the baseline (without agonist) and acetylcholine EC 20 and EC maxUsing a Bravo 384-well tip liquid handler, 10 μL / well of the prepared 2X assay buffer was immediately added to the cell plate. The cell plate was immediately spun at 100xg for 30 seconds and incubated at 37°C at 50 rpm with gentle shaking for 10 minutes. During the 10-minute incubation period, cAMP Eu-cryptate donor (20X) and anti-cAMP d2 antibody acceptor (20X) were diluted in lysis / detection buffer in separate tubes. Immediately after incubation, cells were lysed by sequentially adding 10 μL / well of cAMP Eu-cryptate solution and 10 μL / well of anti-cAMP d2 antibody solution. The cell plate was immediately spun at 100xg for 30 seconds and incubated at 25°C at 50 rpm with gentle shaking for 60 minutes. Immediately after detection incubation, TR-FRET signals were measured in two channels, 665 and 620 nm, using an EnVision plate reader (Perkin Elmer). All emission ratios (665 / 620) were normalized for the maximum acetylcholine percentage. Individual CRCs were generated using a four-parameter logistic equation with GraphPad Prism (La Jolla, CA), and the EC was fitted from the CRCs. 50 The data was extracted, and the maximum response (maximum ACh %) was determined.

[0511]

number

[0512] In the formula, A is the molar concentration of the compound, the minimum and maximum values ​​represent the low and high steady-state values ​​of the concentration response curve, the slope coefficient represents the gradient of the curve, and EC 50 This is the molar concentration of the compound required to produce half of the response between the minimum and maximum values.

[0513] [Table 3]

[0514] [Table 4]

[0515] E. Effects of compounds on amphetamine-induced hyperactivity in rats The ability of compound 3 to reverse amphetamine-induced hyperactivity, a predictive preclinical model of antipsychotic-like activity (Stanhope et al. (2001) J Pharmacol Exp Ther. 299:782~792), was evaluated in male Sprague-Dolly rats.

[0516] The drug, d-amphetamine hemisulfate, was obtained from Sigma (St. Louis, MO). Using salt correction, the exact amount of d-amphetamine hemisulfate in milligrams was determined and added to sterile water to obtain a 0.75 mg / mL solution, which could be administered at 1 mL per kg of body weight per animal. Compound 3 and the comparative compound VU0467154 (reported in mAChR M4PAM, Bubser et al. ACS Chem. Neurosci. 2014, 5(10):920~942) were formulated in volumes specific to the number of animals to be administered each day at a particular dose. For all compounds, the solution was formulated to be injected into animals at a volume equal to 10 mL per kg of body weight. The appropriate amount according to the dose was mixed in 10% Tween 80 (Sigma) in sterile water. The mixture was then vortexed and stored in an ultrasonic bath at 39°C for 1 hour until it became a solution or microsuspension (dose-dependent).

[0517] Animals used: Male Sprague Dolly rats (Harlan, Inc., Indianapolis, IN) weighing 239–300 grams and averaging 265 g were used. They were housed in an animal laboratory accredited by AALAC (American Association for the Accreditation of Laboratory Animal Care) under a 12-hour light-dark cycle (lights on at 6 AM, lights off at 6 PM), with free access to food and water. The animals used in this experiment were fasted from the evening before the experiment in preparation for oral administration of the compound / vector. The experimental protocol conducted during the light cycle was approved by the Institutional Animals Care and Use Committee at Vanderbilt University and was consistent with the guidelines established by the National Research Council's Guide for the Care and Use of Laboratory Animals.

[0518] Amphetamine-induced hyperkinetic activity: Male Harlan Sprague-Dolly rats were acclimatized to a Smart Open Field kinetic activity test chamber (Hamilton-Kinder, San Diego, CA) with a 16x16 light beam for automatic recording of kinetic activity. After 30 minutes of monitoring, the animals were administered either the medium or compound 3 or VU0467154 by forced oral administration. They were monitored for a further 30 minutes, after which the medium or 0.75 mg / kg amphetamine was administered subcutaneously. The animals were then monitored for a further 60 minutes, for a total of 120 minutes. Data were expressed as changes in walking motion, defined as the total number of beam interruptions per 5-minute interval. At the end of the study, terminal brain and plasma samples were collected and pharmacokinetic analyses were performed.

[0519] Data Analysis: Behavioral data were analyzed using a two-way ANOVA with major effects of treatment and time. Post-hoc statistical analysis was performed using Dunnett's t-test for all treatment groups compared to the medium / amphetamine (VAMP) group, using GraphPad Prism V.5.04 (GraphPad Software, San Diego, CA). Data were graphed using GraphPad Prism V.5.04 (GraphPad Software, San Diego, CA). A probability of p ≤ 0.05 was defined as the level of statistical significance. In addition, the total number of beam interruptions from amphetamine administration (65 minutes) to the end of the study (120 minutes) was calculated and graphed. Retrograde percentage was calculated using Microsoft Excel as follows: For each animal, the total walking behavior from t=65 to t=120 was summed. The mean of each sum was calculated for the VAMP group. Then, for each animal, the retrograde percentage was calculated according to the following formula. Retrograde percentage = 100 - {[(Total walking behavior of each animal from t=65 to t=120) / (Mean value of each total from t=65 to t=120 for the VAMP group)] * 100}. The mean retrograde percentage and standard error were calculated for each dose group using GraphPad Prism V5.04.

[0520] Results: Compound 3 administered at 1 mg / kg, 1.8 mg / kg, 3 mg / kg, and 5.6 mg / kg, and VU0467154 administered at 10 mg / kg, reversed amphetamine-induced hyperkinetic activity in 27.5%, 40.1%, 59.1%, 60.9%, and 56.2% of cases, respectively. The data are shown in the figure.

[0521] Conclusion: Systemic administration of M4PAM compound 3 resulted in a significant and sustained retrograde of amphetamine-induced hyperactivity, comparable to that of the control M4PAM compound VU0467154 at 10 mg / kg po, suggesting that these compounds possess antipsychotic-like effects in this animal model.

[0522] F. In vitro secondary pharmacological effects and toxicity Compound 3 was tested using Eurofins LeadProfilingScreen®, which detects potential adverse activity, additional unpredictable activity, and relative selectivity and specificity. The screening included 68 key molecular targets, including several CNS targets recommended by EMEA for assessing drug-dependent potential. Compound 3 exhibited less than 50% inhibition of each target of LeadProfilingScreen® at 10 μM (bound).

[0523] Compound 3 was further tested using the Eurofins Ames test. The Ames test is a widely used bacterial assay for identifying compounds that can induce gene mutations, and it exhibits high predictive value for rodent carcinogenicity testing. The Ames test used four strains of Salmonella with pre-existing mutations that prevent bacteria from synthesizing the essential amino acid histidine, and as a result, prevent them from growing in histidine-free media. If the compound induces mutations in these specific genes, it restores gene function, thereby allowing the cells to regain the ability to synthesize histidine and therefore grow in its absence ("reverse assay"). In this assay, compound 3 was negative at 5–100 μM.

[0524] G. In vitro and in vivo drug metabolism and pharmacokinetics (DMPK) The compounds may be tested in in vitro assays to investigate both their metabolism and pharmacokinetics. These assays may be performed according to known methods generally described in the following references: Conde-Ceide et al., ACS Med. Chem. Lett. 2015, 6, 716-720; Morris et al., J. Med. Chem. 2014, 57, 10192-10197; and Bubser et al., ACS Chem. Neurosci. 2014, 5, 920-942. The in vitro DMPK data for compound 3 are listed in the table below.

[0525] [Table 5]

[0526] The in vivo pharmacokinetic data for compound 3 listed in the table below were determined from pharmacokinetic studies in rats or dogs according to known methods generally described in the following references: Garrison et al. J. Med. Chem. 2022, 65, 6273-6286; Felts et al. J. Med. Chem 2017, 60, 5072-5085; and Yu et al. J. Med. Chem. 2021, 64, 4709-4729.

[0527] [Table 6]

[0528] The above detailed description and accompanying embodiments are merely illustrative and should not be construed as limitations on the scope of the invention, and it should be understood that the scope of the invention is defined solely by the accompanying claims and their equivalents.

[0529] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including, but not limited to, changes and modifications to the chemical structure, substituents, derivatives, intermediates, synthesis, composition, formulation or method of use of the present invention, may be made without departing from the spirit and scope of the invention.

Claims

1. Compound of formula (I) or its pharmaceutically acceptable salt 【Chemistry 1】 {In the formula, G 1 teeth, 【Chemistry 2】 And, X 1 , NR 5 or O, R 4A and R 4B These are hydrogen and C, which are independent of each other. 1～4 Alkyl, C 3～4 Cycloalkyl or -C 1～3 It is either an alkylene-OH group, or R 4A and R 4B together with the carbon to which they are attached form a C 3～6 cycloalkyl, 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 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 instance of appearance is independent of hydrogen and 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 5 This includes phenyl, 4-8 membered heterocyclyls containing 1-2 heteroatoms, 5-6 membered heteroaryls containing 1-4 heteroatoms, or C 3～6 It is a cycloalkyl group, and the heteroatoms are independently selected from the group consisting of O, N, and S, G 5 C 1～4 Alkyl, halogen, oxo, -OC 1～4 Alkyl, C 1～4 Fluoroalkyl, C 3～4 Cycloalkyl and -C 1～2 Alkylene-C 3～4 Optionally substituted with 1 to 4 substituents selected from the group consisting of cycloalkyl groups, R 6 Hydrogen, 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 3～4 It is a cycloalkyl, R 6a Each instance of appearance is independent of hydrogen and C. 1～4 Alkyl, C 1～4 Fluoroalkyl, C 3～4 Cycloalkyl or -C 1～3 Alkylene-C 3～4 It is a cycloalkyl, Here, or two R's 6a Along with the nitrogen to which they bind, R 6a It forms a 4- to 8-membered heterocyclic ring containing a nitrogen atom bonded to it and, optionally, one additional heteroatom which is O, N, or S, and the heterocyclic ring is independently a halogen, C 1～2 Alkyl and C 1～2 Optionally substituted with 1 to 4 substituents selected from the group consisting of fluoroalkyl groups, R 7 C 1～4 Alkyl, hydrogen, halogen, cyano, C 1～4 Fluoroalkyl, C 2～4 Alkenil, -OR 7a , -C 1～3 Alkilen-OR 7a CO 2 R 7a COR 7a or C 3～6 It is a cycloalkyl, Alternatively, R 6 and R 7 Together with the atoms to which they are bonded, they form an aromatic or non-aromatic ring consisting of 5 to 7 carbon atoms. 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, R 8 Each instance is independently determined by halogen and C. 1～4 Alkyl, C 1～4 Fluoroalkyl or C 3～4 It is a cycloalkyl, n is 0, 1, 2, 3, or 4. and at least one hydrogen in the compound is a deuterium isotope ( 2 A compound that is H.

2. G 1 but, 【Transformation 3】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R 4A and R 4B are each independently hydrogen or C 1～4 alkyl, a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. X 1 NR 5 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. X 1 A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is O.

6. G 1 but, 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. R 5 is hydrogen, C 1～6 alkyl, -C 1～6 alkylene-R y , G 5 or -C 1～3 alkylene-G 5 The compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof.

8. R 5 C 1～6 A compound according to any one of claims 1 to 4 or 6 to 7, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is methyl or ethyl.

9. R y ga-OR 5a The compound according to any one of claims 1 to 4 or 6 to 8, or a pharmaceutically acceptable salt thereof.

10. R 5a C 1～4 A compound according to any one of claims 1 to 4 or 6 to 9, or a pharmaceutically acceptable salt thereof, which is alkyl.

11. G 5 The compound according to any one of claims 1 to 4 or 6 to 10, or a pharmaceutically acceptable salt thereof, which is a 4 to 8-membered heterocycline substituted in the case of containing 1 to 2 heteroatoms.

12. G 5 However, C is substituted in some cases. 3～6 A compound according to any one of claims 1 to 4 or 6 to 10, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

13. R 6 However, hydrogen, C 1～4 Alkyl, halogen, or C 3～4 A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

14. R 7 C 1～4 A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, which is alkyl.

15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein n is 0.

16. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein n is 1.

17. R 8 However, each appearance is independent, C 1～4 A compound according to any one of claims 1 to 14 or 16, or a pharmaceutically acceptable salt thereof, which is alkyl.

18. A compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), or (Ie). 【Transformation 5】 The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. The compound of formula (I) is a compound of formula (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), or (Ie-1). 【Transformation 6】 The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

20. 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl-4-d)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl-2,2,6,6-d 4 )-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )oxy)-2-methylpiperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopropyl-2-(4-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 6-Cyclopentyl-2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-3-methylfl[3,4-b]pyridine-5(7H)-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-3,7-dimethylfl[3,4-b]pyridine-5(7H)-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-yl-4-d)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-yl-2,2,6,6-d 4 )-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-2-ethyl-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-2-(2-methoxyethyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; (R)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-6-methyl-2-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; (S)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-6-methyl-2-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-2-(1-methoxypropan-2-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )oxy)piperidine-1-yl)-6-methyl-2-((4-methylmorpholine-2-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 5-Chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 5-Cyclopropyl-7-(4-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 5-Cyclopropyl-7-(4-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-6-methyl-2-(methyl-d 3 )-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; 5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )oxy)piperidine-1-yl)-2-methyl-2,6,7,8-tetrahydro-1H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyrimidine-1-one; 5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-2-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazoline-1(2H)-one; 5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )oxy)piperidine-1-yl)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyrimidine-1-one; 5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazoline-1(2H)-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d 4 )Oxy)piperidine-1-yl)-5,6-dimethyl-2-(methyl-d 3 )-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

21. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, having at least 50% deuterium incorporation at each deuterium label.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier.

23. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, 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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