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

Abstract

6,7-dihydrothiazolo[5,4-c]pyridine, which has a heterocyclic substitution at position 5, is a positive allosteric modulator of the muscarinic acetylcholine receptor M4 (mAChR M4) and may be used to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 496,808, filed on April 18, 2023, and U.S. Provisional Patent Application No. 63 / 610,205, filed on December 14, 2023, each of which is hereby incorporated 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 Art

[0003] Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs) by the binding of the endogenous orthosteric agonist acetylcholine (ACh). Symptoms associated with cognitive disorders such as Alzheimer's disease are accompanied by a decrease in acetylcholine content in the brain. This is thought to be the result of the degeneration of cholinergic neurons in the basal forebrain, which widely innervate multiple regions of the brain, including the association cortex and hippocampus, which are critically involved in higher - order processes. Clinical data support that reduced cholinergic function contributes to cognitive deficits in patients with schizophrenia. Efforts to increase acetylcholine levels have focused on increasing the level of choline, a precursor of acetylcholine synthesis, and inhibiting acetylcholinesterase (AChE), an enzyme that metabolizes acetylcholine. As a result, acetylcholinesterase (AChE) inhibitors that inhibit the hydrolysis of ACh are approved for use in the United States for the alleviation of cognitive deficits (not disease - modifying treatment) in AD patients.

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

[0005] mAChRs are members of the family of AG protein-coupled receptors (GPCRs) and include five subtypes called M1-M5. The M1, M3, and M5 subtypes are primarily G q It binds to and activates phospholipase C, but the M2 and M4 subtypes mainly use G i / o They also bind to associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system, where they are widely found and expressed differently. M1-M5 have various roles in cognitive, sensory, motor, and autonomic functions. Therefore, while we do not wish to be bound by any particular theory, selective agonists of mAChR subtypes that control processes involved in cognitive function are thought to be potentially excellent therapeutic agents for psychosis, schizophrenia, and related disorders. The muscarinic M4 receptor has been shown to play an important role in cognitive processes and is thought to play a crucial role in the pathophysiology of mental disorders, including schizophrenia.

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

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

[0008] More recently, muscarinic agonists, including xanomeline, have been shown to exhibit activity in animal models with a similar profile to known antipsychotics, but without causing catalepsy (Bymaster et al., Eur.J.Pharmacol.1998,356,109; Bymaster et al., Life Sci.1999,64,527; Shannon et al., J.Pharmacol.Exp.Ther.1999,290,901; Shannon et al., Schizophrenia Res.2000,42,249). Furthermore, while xanomerin has been shown to alleviate psychotic behavioral symptoms such as delusions, paranoia, vocal outbursts, and hallucinations in patients with Alzheimer's disease (Bodick et al., Arch. Neurol. 1997, 54, 465), the clinical utility of this compound is severely limited by treatment-induced side effects, such as gastrointestinal effects.

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

Summary of the Invention

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

Chemical formula

Chemical formula

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

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

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

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

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

[0016] [Figure 1] The figure shows the effect of compound 70 in an amphetamine-induced hyperactivity assay. [Modes for carrying out the invention]

[0017] Detailed explanation This specification discloses positive allosteric modulators (i.e., enhancers) of muscarinic acetylcholine receptor M4 (mAChR M4), methods for producing the same, pharmaceutical compositions containing the same, and methods for using the same to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. These compounds include naphthyridine-substituted pyridazine compounds.

[0018] The human muscarinic acetylcholine receptor M4 (mAChR M4) is a 479-amino acid protein encoded by the CHRM4 gene. The unglycosylated protein has a molecular weight of approximately 54 kDa and is a transmembrane GPCR. As mentioned earlier, mAChR M4 is a member of the GPCR class A family, or rhodopsin-like GPCRs, characterized by rhodopsin-like structural features, such as seven transmembrane segments. Muscarinic acetylcholine receptors have their N-terminus facing the extracellular side of the membrane and their C-terminus located in the cytoplasm.

[0019] Previous attempts to develop highly selective agonists for individual mAChR subtypes have failed due to the high conservation of orthosteric ACh binding sites. To circumvent the problems associated with targeting highly conserved orthosteric ACh binding sites, it is considered important to develop compounds that act at the allosteric site of mAChR, which is removed from the orthosteric site and is not highly conserved. While we do not wish to be bound by any particular theory, the compounds disclosed and the products of the disclosed methods are expected to bind to an allosteric site different from the orthosteric binding site.

[0020] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. In case of any conflict, this specification shall prevail, including the definitions. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in the implementation or testing described herein. All publications, patent applications, patents and other references referred herein are incorporated herein by reference in their entirety. The materials, methods and examples disclosed herein are illustrative and not intended to be limiting.

[0021] The terms “include,” “contain,” “have,” “possess,” “can contain,” and their variations are intended, when used herein, to be unrestricted transitional phrases, terms, or words that do not preclude the possibility of additional actions or structures. The singular forms “a,” “an,” and “the” refer to multiple things unless otherwise explicitly indicated by the context. This disclosure also intends other embodiments that “include,” “consist of,” and “be essentially derived from” the embodiments or elements provided herein, whether expressly or not.

[0022] The modifier "approximately" used in relation to quantity includes the stated value and has a meaning determined by the context (for example, it includes the smallest degree of error associated with measuring a particular quantity). The modifier "approximately" should also be considered to reveal a range defined by the absolute values ​​of two endpoints. For example, the expression "approximately 2 to approximately 4" also reveals the range "2 to 4". The term "approximately" can refer to plus or minus 10% of a given number. For example, "approximately 10%" can indicate a range of 9% to 11%, and "approximately 1" can mean 0.9 to 1.1. Other meanings of "approximately," such as rounding, may be evident from the context, and therefore, for example, "approximately 1" can also mean 0.5 to 1.4.

[0023] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are defined as follows: Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Identification follows the Ed. (inside cover), and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional groups and reactivity, are as follows: Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rd This is described in Edition, Cambridge University Press, Cambridge, 1987 (the entire contents of each of these are incorporated herein by reference).

[0024] As used herein, the term "alkoxy" refers to an alkyl group as defined herein, which is attached to the parent molecule via an oxygen atom. Representative examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0025] The term "alkyl," as used herein, means a straight or branched saturated hydrocarbon chain. The term "lower alkyl" or "C" 1-6 "Alkyl" refers to a straight-chain or branched-chain hydrocarbon containing 1 to 6 carbon atoms. 1-4 "Alkyl" refers to a linear or branched saturated hydrocarbon containing 1 to 4 carbon atoms. Representative examples of alkyls, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0026] As used herein, the term "alkenyl" means a linear or branched hydrocarbon chain containing at least one carbon-carbon double bond.

[0027] The term "alkoxyalkyl," as used herein, refers to an alkoxy group as defined herein, which is attached to the parent molecule via an alkyl group as defined herein.

[0028] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group as defined herein that is attached to the parent molecule via a fluoroalkyl group as defined herein.

[0029] As used herein, the term "alkylene" refers to a divalent group derived, for example, from a straight-chain or branched saturated hydrocarbon consisting of 1 to 6 carbon atoms. Representative examples of alkylenes include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0030] The term "alkylamino," as used herein, means at least one alkyl group as defined herein, which is attached to the parent molecule via an amino group as defined herein.

[0031] As used herein, the term "amide" means -C(O)NR- or NRC(O)- (wherein R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl).

[0032] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, attached to the parent molecule via an alkylene group, as defined herein.

[0033] The term "amino" as used herein is -NR x R y (In the formula, R x and R y (which can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl or heteroalkyl). If aminoalkyl or amino is any other part to which two other parts are added together, amino is -NR x -(In the formula, R x (This can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.)

[0034] The term "aryl," as used herein, refers to phenyl, or phenyl that is attached to the parent molecule and condensed with a cycloalkane group (e.g., aryl may be indan-4-yl), condensed with a 6-membered allene group (i.e., aryl is naphthyl), or condensed with a non-aromatic heterocycle (e.g., aryl may be benzo[d][1,3]dioxol-5-yl). The term "phenyl" is used to refer to a substituent, and the term "6-membered allene" is used to refer to a fused ring. A 6-membered allene is monocyclic (e.g., benzene or benzo). Aryl can be monocyclic (phenyl) or bicyclic (e.g., a 9-12 member fused bicyclic system).

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

[0036] The term "cyanofluoroalkyl," as used herein, means at least one -CN group attached to the parent molecule via a fluoroalkyl group as defined herein.

[0037] 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.

[0038] As used herein, the terms “cycloalkyl” or “cycloalkane” refer to a saturated ring system containing all carbon atoms and zero double bonds as ring members. The term “cycloalkyl” is used herein to refer to cycloalkanes when present as substituents. Cycloalkyls can be monocyclic cycloalkyls (e.g., cyclopropyl), condensed bicyclic cycloalkyls (e.g., decahydronaphthalenyl), or bridged cycloalkyls (where two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0039] The terms "cycloalkenyl" or "cycloalkene," as used herein, mean a non-aromatic monocyclic or polycyclic ring system having all carbon atoms as ring members, at least one carbon-carbon double bond, and preferably 5 to 10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to cycloalkenes when present as substituents. Cycloalkenyls can be monocyclic cycloalkenyls (e.g., cyclopentenyl), fused bicyclics (e.g., octahydronaphthalenyl), or bridged cycloalkenyls (where two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0040] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl." The term "carbocyclic ring" means "cycloalkane" or "cycloalkene." The term "carbocyclyl" refers to a "carbocyclic ring" when it exists as a substituent.

[0041] As used herein, the term "fluoroalkyl" means an alkyl group as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyls include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl (such as 3,3,3-trifluoropropyl).

[0042] The term "fluoroalkylene," as used herein, means an alkylene group as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkylenes, but not limited to these, include -CF2-, -CH2CF2-, 1,2-difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropylene, 1,1,2,3,3-pentafluoropropylene, and perfluoropropylene, such as 1,1,2,2,3,3-hexafluoropropylene.

[0043] As used herein, the term "fluoroalkoxy" means at least one fluoroalkyl group, as defined herein, that is attached to the parent molecule via an oxygen atom. Representative examples of fluoroalkoxys include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0044] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0045] The term "haloalkyl," as used herein, means an alkyl group as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by halogens.

[0046] The term "haloalkoxy," as used herein, means at least one haloalkyl group as defined herein, which is attached to the parent molecule via an oxygen atom.

[0047] As used herein, the term "halocycloalkyl" means a cycloalkyl group as defined herein, in which one or more hydrogen atoms are replaced by halogens.

[0048] As used herein, the term "heteroalkyl" means an alkyl group as defined herein, in which one or more carbon atoms are replaced by heteroatoms selected from S, O, P, and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkylamines, amides, and alkyl sulfides.

[0049] As used herein, the term "heteroaryl" refers to an aromatic monocyclic heteroatom-containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term "heteroaryl" is also used herein to refer to heteroarenes when present as substituents. A monocyclic heteroaryl is a five- or six-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (for example, one, two, three, or four heteroatoms independently selected from the group consisting of O, S, and N). A five-membered aromatic monocyclic ring has two double bonds, and a six-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryl groups are 8-12 membered ring systems, including fused bicyclic heteroaromatic ring systems (i.e., 10π electron systems), such as monocyclic heteroaryl rings fused with 6-membered allenes (e.g., quinoline-4-yl, indole-1-yl), monocyclic heteroaryl rings fused with monocyclic heteroarenes (e.g., naphthilidinyl), and phenyl groups fused with monocyclic heteroarenes (e.g., quinoline-5-yl, indole-4-yl). Bicyclic heteroaryl / heteralene groups include 9-membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom that donates a lone pair of electrons to a fully aromatic 10π electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) and benzoxadiazolyl. Bicyclic heteroaryls also include fused bicyclic systems consisting of one heteroaromatic ring and one nonaromatic ring, such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydroflu[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecule at the aromatic ring atom.Other typical examples of heteroaryls include, but are not limited to, indolyl (e.g., indole-1-yl, indole-2-yl, indole-4-yl), pyridinyl (including pyridine-2-yl, pyridine-3-yl, pyridine-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazole-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazole-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazolyl-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., Examples include benzimidazole-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranil, isobenzofuranil, furanil, oxazolyl, isoxazolyl, prinyl, isoindolyl, quinoxalinil, indazolyl (e.g., indazole-4-yl, indazole-5-yl), quinazolinil, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinil, quinolinil, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridinyl), naphthilidinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridinyl, and thiazolo[5,4-d]pyrimidine-2-yl.

[0050] The terms “heterocyclic” or “heterocyclic” as used herein mean monocyclic, bicyclic, or tricyclic heterocyclic rings. The term “heterocyclyl” is used herein to refer to a heterocyclic ring when it exists as a substituent. A monocyclic heterocyclic ring is a 3, 4, 5, 6, 7, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3 or 4-membered ring contains 0 or 1 double bond and 1 heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains 0 or 1 double bond and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains 0, 1, or 2 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain 0, 1, 2, or 3 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles, though not limited to them, include azetidinyl, azepanyl, azilidinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, ox Examples include cetanyl, oxepanil, oxocanil, piperazinil, piperidinil, pyranil, pyrazolinil, pyrazolidinil, pyrrolinil, pyrrolidinil, tetrahydrofuranil, tetrahydropyranil, tetrahydropyridinil, tetrahydrothienyl, thiadiazolinil, thiadiazolidinil, 1,2-thiadinil, 1,3-thiadinil, thiazolinil, thiazolidinil, thiomorpholinil, 1,1-dioxidethiomorpholinil (thiomorpholine sulfone), thiopyranil, and trithianil.A bicyclic heterocycle is a monocyclic heterocycle fused with a 6-membered allene, or a monocyclic heterocycle fused with a monocyclic cycloalkane, or a monocyclic heterocycle fused with a monocyclic cycloalkene, or a monocyclic heterocycle fused with a monocyclic heterocycle, or a monocyclic heteroelene, or a spiroheterocyclic group, or a bridging monocyclic heterocycle system (where two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms). In bicyclic heterocyclyls, the parent molecule is bonded at a non-aromatic ring atom (e.g., indoline-1-yl). Representative examples of bicyclic heterocyclils, though not limited to them, include croman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzotin-2-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), and azabicyclo[3.1.0]hexanyl (3-azabicyclo[3.1.0]hexane). Examples include (including -3-yl), 2,3-dihydro-1H-indole-1-yl, isoindorin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-1-yl, and 3-oxabicyclo[3.1.0]hexane-6-yl. Tricyclic heterocycles are exemplified by bicyclic heterocycles fused with a 6-membered allene, or bicyclic heterocycles fused with a monocyclic cycloalkane, or bicyclic heterocycles fused with a monocyclic cycloalkene, or bicyclic heterocycles fused with a monocyclic heterocycle, or bicyclic heterocycles in which two non-adjacent atoms of a bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms.Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). These monocyclic, bicyclic, and tricyclic heterocyclines are linked to the parent molecule at the non-aromatic ring atom.

[0051] The term "hydroxyl" or "hydroxy" as used herein means the -OH group.

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

[0053] The term "hydroxyfluoroalkyl," as used herein, means at least one -OH group attached to the parent molecule via a fluoroalkyl group as defined herein.

[0054] Terms such as "alkyl," "cycloalkyl," and "alkylene" are symbols that indicate the number of atoms present in the group in a specific example (for example, "C"). 1~4 Alkyl," "C 3~6 Cycloalkyl, C 1~4 The term "alkylene" may be preceded by "C". These symbols are used in the same way as is generally understood by those skilled in the art. For example, the expression "C" followed by a subscript number indicates the number of atoms present in the following group. Thus, "C3 alkyl" is an alkyl group containing three carbon atoms (i.e., n-propyl, isopropyl). 1~4 When a range is given, as in "C", the members of the subsequent group may have any number of carbon atoms within the indicated range. 1~4"Alkyl" refers to an alkyl group having 1 to 4 carbon atoms, regardless of its configuration (i.e., linear or branched).

[0055] The term "parent molecule" or "parent molecule portion" refers to the entire part of the molecule to which the substituent is attached, that is, the remaining part of the molecule.

[0056] The term "sulfonamide" as used herein means -S(O)2NR z - or -NR z S(O)-(wherein, R z (This can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.)

[0057] The term "substituent" refers to a group in which any atom of the group is "substituted," such as an alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, cycloalkyl group, heteroalkyl group, or heterocyclic group. Any atom can be substituted.

[0058] The term "substituted" refers to a group that may be further substituted with one or more non-hydrogen substituents. Substituents include, but are not limited to, halogens, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl. In some embodiments, the group is optionally substituted. In some embodiments, the group is optionally substituted with one, two, three, four, or five substituents. In some embodiments, the aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, the aryl, heteroaryl, cycloalkyl, or heterocycle may independently be unsubstituted or substituted with 1, 2, or 3 substituents.

[0059] With respect to the compounds described herein, the groups and substituents can be selected and substituted according to the recognized valencies of the atoms and substituents, such that a stable compound (for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination) is obtained.

[0060] As used herein, the term "allosteric site" refers to a ligand-binding site that is tissue-distributed differently from an orthosteric binding site.

[0061] As used herein, the term "modulator" refers to a molecular entity that modulates the activity of a target receptor protein (e.g., ligands and the disclosed compounds, but not limited to these).

[0062] As used herein, the term "ligand" refers to a natural or synthetic molecular entity that can associate with or bind to a receptor to form a complex, thereby mediating, preventing, or modifying a biological effect. Therefore, the term "ligand" encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates, and analogues of natural substrates.

[0063] The terms “natural ligand” and “endogenous ligand” are used interchangeably as herein and refer to naturally occurring ligands that bind to receptors.

[0064] As used herein, the term "orthosteric site" refers to the primary binding site on a receptor that is recognized by its endogenous ligand or agonist. For example, the orthosteric site of the mAChR M4 receptor is the site where acetylcholine binds.

[0065] The term “mAChR M4 receptor positive allosteric modulator” as used herein refers to an exogenously administered compound or agent that directly or indirectly enhances the activity of the mAChR M4 receptor in animals, particularly mammals, such as humans, in the presence or absence of acetylcholine or another agonist. For example, an mAChR M4 receptor positive allosteric modulator can enhance the activity of the intracellular mAChR M4 receptor in the presence of extracellular acetylcholine. The cells may be Chinese hamster ovary (CHO-K1) cells transfected with human mAChR M4. The cells may be Chinese hamster ovary (CHO-K1) cells transfected with rat mAChR M4 receptor. The cells may be Chinese hamster ovary (CHO-K1) cells transfected with mammalian mAChR M4. The term "mAChR M4 receptor positive allosteric modulator" includes compounds that are either "mAChR M4 receptor allosteric enhancers" or "mAChR M4 receptor allosteric agonists," as well as compounds with mixed activity that includes the pharmacological effects of both "mAChR M4 receptor allosteric enhancers" and "mAChR M4 receptor allosteric agonists." The term "mAChR M4 receptor positive allosteric modulator" also includes compounds that are "mAChR M4 receptor allosteric enhancers."

[0066] The term “mAChR M4 receptor allosteric enhancer” as used herein refers to an exogenously administered compound or agent that directly or indirectly enhances the response mediated by an endogenous ligand (such as acetylcholine) when the endogenous ligand binds to the orthosteric site of the mAChR M4 receptor in animals, particularly mammals, such as humans. mAChR M4 receptor allosteric enhancers bind to a site other than the orthosteric site, i.e., the allosteric site, and positively enhance the receptor's response to an agonist or endogenous ligand. In some embodiments, allosteric enhancers do not induce receptor desensitization, and the activity of a compound as an mAChR M4 receptor allosteric enhancer offers advantages over the use of a pure mAChR M4 receptor orthosteric agonist. Such advantages may include, for example, increased safety margins, improved tolerability, reduced potential for abuse, and reduced toxicity.

[0067] The term "mAChR M4 receptor allosteric enhancer," as used herein, refers to an exogenously administered compound or agent that directly or indirectly enhances the response induced by an endogenous ligand (such as acetylcholine) in animals, particularly mammals, such as humans. In some embodiments, the allosteric enhancer increases the affinity of a native ligand or agonist to the orthosteric site. In some embodiments, the allosteric enhancer enhances the potency of the agonist. The mAChR M4 receptor allosteric enhancer binds to a site other than the orthosteric site, i.e., the allosteric site, and positively enhances the receptor's response to the agonist or endogenous ligand. The allosteric enhancer does not affect the receptor by itself and requires the presence of an agonist or native ligand to achieve its receptor effect.

[0068] The term "mAChR M4 receptor allosteric agonist," as used herein, refers to an exogenously administered compound or agent that directly activates the activity of the mAChR M4 receptor in animals, particularly mammals, such as humans, in the absence of an endogenous ligand (such as acetylcholine). mAChR M4 receptor allosteric agonists bind to a site on the mAChR M4 receptor distinct from the orthosteric acetylcholine site. Because they do not require the presence of an endogenous ligand, the activity of a compound as an mAChR M4 receptor allosteric agonist offers advantages when cholinergic tone is low at a given synapse.

[0069] The term "mAChR M4 receptor neutral allosteric ligand," as used herein, refers to an exogenously administered compound or agent that binds to the allosteric site in animals, particularly mammals, such as humans, without affecting the binding or function of agonists or native ligands at the orthosteric site. However, neutral allosteric ligands may block the action of other allosteric modulators acting via the same site.

[0070] In the enumeration of numerical ranges described herein, the numbers within each range are explicitly intended to be of equal precision. For example, in the range 6–9, the numbers 7 and 8 are intended in addition to 6 and 9, and in the range 6.0–7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly intended.

[0071] Abbreviation: AQ is water-based. BINAP is 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl Boc is tert-butyloxycarbonyl Boc2O is a di-tert-butyl dicarbonate. BrettPhos is 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl BrettPhos-Pd-G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. n-BuLi is n-butyllithium. t-BuOH is tert-butanol. CDI is 1,1'-carbonylimidazole. Celite® is diatomaceous earth. DCE is 1,2-dichloroethane. DCM is dichloromethane. DEA is diethylamine. DIAD is diisopropyl azodicarboxylate. DIPEA or DIEA is diisopropylethylamine. DMA is N,N-dimethylacetamide. DMAP is 4-dimethylaminopyridine. DMF is N,N-dimethylformamide. DMP, or Des Martin periodinane, is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one. DMSO is dimethyl sulfoxide. Dowtherm® A is a eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxide. DtBAD is di-tert-butyl azodicarboxylate. eq or eq. is equivalent. HCl is ethyl acetate. (4,4'-dtbbpy)NiCl2 is 4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride. EtOH is ethanol. h or hr is time. HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. Hex is hexane. IPA is isopropyl alcohol. Ir[dF(CF3)ppy]2(dtbpy))PF6 is [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate. KOAc is potassium acetate. Lawson's reagent is 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (CAS number 19172-47-5). LAH is lithium aluminum hydride. mCPBA is metachloroperbenzoic acid. Me is methyl MeCN or ACN is acetonitrile. MeOH is methanol. min is minutes MW stands for microwave (referring to a microwave reactor). NaOAc is sodium acetate. NaOMe is sodium methoxide. NBS is N-bromosuccinimide. NCS is N-chlorosuccinimide. NMP is N-methyl-2-pyrrolidone. [Pd(allyl)(tBuBrettPhos)]OTf is trifluoromethanesulfonate allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 is [1,1'-bis(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. Rxn is a reaction sat. is saturated. sec is seconds. SCX cartridges or HF SCX cartridges are strong cation exchange cartridges (e.g., Agilent part number 14256027). SFC is supercritical fluid chromatography. TBAC or TBACl is tetrabutylammonium chloride. t-BuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl. TEA or Et3N is triethylamine. TFA is trifluoroacetic acid. THF is tetrahydrofuran TosCl is p-toluenesulfonyl chloride. Tosyl is p-toluenesulfonyl. Xantphos is 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0072] 2.Compound In one embodiment, the present invention provides a compound of formula (I), where R 1 , R 2 , R 8 , and o are as defined herein.

[0073] Unsubstituted or substituted rings (i.e., may be substituted), such as aryl and heteroaryl rings, consist of a ring system and any substituents on the ring system. Therefore, since a ring system can be defined independently of its substituents, redefining only the ring system allows any previous substituents to remain. For example, a 5- to 12-membered heteroaryl with any substituent can be further defined by explicitly stating that the ring system of the 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., a 5- to 6-membered heteroaryl ring system), in which case, unless otherwise indicated, any substituents on the 5- to 12-membered heteroaryl still exist on the 5- to 6-membered heteroaryl.

[0074] If a heterocyclic and heteroaromatic ring system is defined as "containing" or "having" certain heteroatoms (for example, 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S), then all ring atoms in the heterocyclic and heteroaromatic ring system that are not one of the certain heteroatoms are carbon atoms.

[0075] The following numbered embodiments of the present invention are disclosed. The first embodiment is indicated by E1, and subsequent embodiments are indicated by E1.1, E1.2, E2, E3, E4, E5, E6, E7, E7.1, and so on.

[0076] E1. Compounds of formula (I), or pharmaceutically acceptable salts thereof. [ka] (In the formula: R 1 teeth, [ka] and; X 1 is N or CR 1a and; R 1a is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, or C1-4 It is a fluoroalkyl group; X 2 is N or CR 1b and; R 1b These are cyano, halogen, and C 1-4 Alkyl, C 1-4 Fluoroalkyl or hydrogen; R 1c and R 1e is hydrogen, C 1-4 Alkyl, halogen, C 1-4 Fluoroalkyl, C 3-6 Cycloalkyl, or -OC 1-4 It is alkyl; R 1d and R 1f is hydrogen, C 1-4 Alkyl, halogen, C 1-4 Fluoroalkyl, or C 3-6 It is a cycloalkyl; Alternatively, R 1a and R 1b Each atom is attached together with the atom to which it is attached, or R 1c and R 1d Each atom, together with the atom to which it is attached, forms a 6-membered allene, a 5-6 membered heteroarene containing 1-3 heteroatoms, a 5-7 membered heterocycle containing 1 heteroatom, or a 5-7 membered carbon ring, where the heteroatoms are independently selected from the group consisting of N, O, and S, and where the optional substitution is C 1-4 Alkyl, halogen, -OC 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, and C 1-2 Alkylene-C 3-4 One to three optional substituents independently selected from the group consisting of cycloalkyl groups; G 1 Z is a 5-6 member aromatic or partially unsaturated heterocyclic ring system containing 1-3 nitrogen atoms, where Z 1 is N or C, Z 2 is N or C, Z 1 and Z 2 Both are not N; R 10 C 1-4 Alkyl, C 1-4 Fluoroalkyl, halogen, C 3-4 Cycloalkyl, C 1-2 Alkylene-C 3-4 Cycloalkyl, -C(O)OC 1-4 Alkyl and -C(O)NR a R b Selected from the group consisting of; R 11 Each time it appears, C 1-6 Alkyl, C 1-6 Fluoroalkyl, halogen, -C 1-6 Alkilen-R y , -C 1-6 Fluoroalkylene-R y , G 11 , or -C 1-3 Alkilen-G 11 Selected from the group consisting of; R 12 It is oxo; m is either 0 or 1; n is 0, 1, or 2; p is either 0 or 1; R a 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 b is hydrogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, G 10 , or -C 1-3 Alkilen-G 10 and; Alternatively, R a and R b Along with the nitrogen to which they are attached, R a and R b A 4-10 membered heterocycle is formed, containing nitrogen attached to the atom and 1-2 additional heteroatoms which are optionally and independently O, N, or S, wherein the heterocycle consists of halogens, cyanocarbons, and C13 1-4Alkyl, C 1-4 Fluoroalkyl, oxo, -OR 50 , -N(R 50 )2, G 10a , and -C 1-3 Alkilen-G 10a It is optionally substituted with a first substituent selected from the group consisting of; independently of a halogen or C 1-4 It is further optionally substituted with 1 to 3 alkyl substituents; G 10 This includes phenyl, a 5-6 membered heteroaryl containing 1-3 heteroatoms, a 4-8 membered heterocyclyl containing 1-2 heteroatoms, or C 3-6 It is a cycloalkyl group, where the heteroatom is independently selected from the group consisting of O, N, and S, and G 10 These are halogen, cyano, and C 1-4 Alkyl, C 1-4 Fluoroalkyl, oxo, -OR 50 , -N(R 50 )2, G 10a , and -C 1-3 Alkilen-G 10a The first substituent is optionally substituted with one selected from the group consisting of the following, and is independently a halogen or C 1-4 It is further optionally substituted with 1 to 3 alkyl substituents; G 10a This is a phenyl, a 5-6 member heteroaryl containing 1-3 heteroatoms, a 4-8 member heterocyclyl containing 1-2 heteroatoms, or a 3-8 member carbocyclyl, where the heteroatoms are independently selected from the group consisting of O, N, and S, and G 10a These are halogen, cyano, and C 1-4 Alkyl, C 1-4 Fluoroalkyl, oxo, OH, -OC 1-4 Alkyl, -OC 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, and -C 1-3 Alkylene-C 3-4 It is optionally substituted with 1 to 5 substituents independently selected from the group consisting of cycloalkyl groups; R 50Each time they appear, hydrogen and C appear independently. 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-6 Cycloalkyl, or -C 1-3 Alkylene-C 3-6 It is a cycloalkyl, where each cycloalkyl is a halogen, C 1-4 Alkyl and C 1-4 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl groups; R y は-OR c , -N(R c )2, -C(O)R c , -C(O)OR c , or -C(O)N(R c )2; R c Each time they appear, hydrogen and C appear independently. 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, or -C 1-3 Alkylene-C 3-4 It is cycloalkyl, or two R c Along with the nitrogen to which they are attached, R c It forms a 4- to 8-membered heterocycle containing nitrogen attached to it and one additional heteroatom which is optionally O, N, or S, and the heterocycle is a halogen, C 1-2 Alkyl and C 1-2 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl groups; G 11 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, where the heteroatom is independently selected from the group consisting of O, N, and S, and G 11 C 1-4 Alkyl, halogen, cyano, oxo, -OC 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, and -C 1-2 Alkylene-C3-4 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl groups; R 2 is G 2 , -NR 2a R 2b , halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 2a , -NR 2a C(O)R 2b , -C(O)OR 2a -C(O)NR 2a R 2b , or hydrogen; R 2a and R 2b These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, G 2 , or -C 1-3 Alkilen-G 2 However, R 2 This is not -N(CH3)2; G 2 Each instance is independently a 5-6 member heteroaryl, phenyl, 4-7 member heterocyclyl, or 3-7 member carbocyclyl containing 1-4 heteroatoms, where the heteroatoms are independently selected from the group consisting of O, N, and S. 2 These are halogen, cyano, and C 1-4 Alkyl, C 1-4 Fluoroalkyl, oxo, -OR x , -N(R x )2, -C(O)R x , -C(O)OR x ,-C(O)N(R x )2, -C 1-6 Alkilen-OR x , -C 1-6 Alkylene-N(R) x )2, G 2a , and -C 1-3 Alkilen-G 2a It is optionally substituted with a first substituent selected from the group consisting of halogens, cyanos, and C 1-4 Alkyl and C 1-4It is further optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl groups; R x Each time they appear, hydrogen and C appear independently. 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-6 Cycloalkyl, or -C 1-3 Alkylene-C 3-6 It is a cycloalkyl; G 2a C 3-6 It is a cycloalkyl; R 8 Each time it appears, halogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, or C 3-4 It is a cycloalkyl; o is 0, 1, 2, 3, or 4; Here is the G 2a and R 8 Each cycloalkyl group in is independently either unsubstituted or C 1-4 It is substituted with 1 to 4 substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., fluoro) elements; However, the compound is 4,5,6,7-Tetrahydro-5-(2-pyridinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(4-pyrimidinyl)-thiazolo[5,4-c]pyridine-2-amine; 5-(6-chloro-2-cyclopropyl-5-methyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-2-methyl-thiazolo[5,4-c]pyridine; 2-[2-(4-ethyl-piperazine-1-yl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-yl]quinoline; 4,5,6,7-Tetrahydro-5-[5-(trifluoromethyl)-thiazolo[5,4-c]pyridine-2-amine; N-(2-aminophenyl)-4,5,6,7-tetrahydro-5-[5-(trifluoromethyl)-2-pyridinyl]-thiazolo[5,4-c]pyridine-2-carboxamide; 5-(2,5-dimethyloxazolo[5,4-d]pyrimidine-7-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-(2-cyclopentyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-4-yl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-amine; 5-(5,6-dimethylthieno[2,3-d]pyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-thieno[2,3-d]pyrimidine-4-ylthiazolo[5,4-c]pyridine-2-amine; 5-[2,6-bis(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 7-(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-2-(trifluoromethyl)-thiazolo[5,4-d]pyrimidine; 4,5,6,7-tetrahydro-5-(2-pyridinyl)-thiazolo[5,4-c]pyridine-2-carboxylic acid, or a salt thereof; 4-(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-[1,2,5]thiadiazolo[3,4-c]pyridine; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]-thiazolo[5,4-c]pyridine-2-amine; 5-(4-chloro-2-pyridinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 5-[2-(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-[6-(1,1-dimethylethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-(2-ethyl-7-methylthieno[3,2-d]pyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine-2-amine; 5-(6-cyclopentyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-[3-(trifluoromethyl)-1,2,4-Triazolo[4,3-b]pyridazin-6-yl]thiazolo[5,4-c]pyridine-2-amine; 6-(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-2-(trifluoromethyl)-9H-purine; 5-(2,6-dicyclopropyl-4-pyrimidinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(5-iodo-2-pyridinyl)-thiazolo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-(7-methylthieno[3,2-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(2-methyl-4-pyrimidinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(4-quinazolinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-(3-pyridazinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylethyl)-4-pyrimidinyl]-thiazolo[5,4-c]pyridine-2-amine; 5-(6-ethyl-5-fluoro-4-pyrimidinyl)-4,5,6,7-thiazolo[5,4-c]pyridine-2-amine; 5-(7-chloro-4-quinazolinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-(5-bromo-2-pyridinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-(2-methylthieno[3,2-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(1H-pyrrolo[2,3-b]pyridine-6-yl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(2-methyl-6-propyl-4-pyrimidinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(5-methylthieno[2,3-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine-2-amine; 5-(6-cyclohexyl-4-pyrimidinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]-thiazolo[5,4-c]pyridine; or (Not 5-(6-bromo-4-quinazolinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine).

[0077] E1.1.G 11 However, C 1-4 Alkyl, halogen, oxo, -OC 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, and -C 1-2 Alkylene-C3-4 The compound described in E1, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyls.

[0078] E1.2.R 11 However, each time it appears, C 1-4 Alkyl, C 1-4 Fluoroalkyl, halogen, C 3-4 Cycloalkyl, and C 1-2 Alkylene-C 3-4 Compounds selected from the group consisting of cycloalkyls, as described in E1 or E1.1, or pharmaceutically acceptable salts thereof.

[0079] E2.R 1 but, [ka] The compound described in any of E1 to E1.2, or a pharmaceutically acceptable salt thereof.

[0080] E3.X 1 However, the compound is N, as described in any of E1 to E2, or a pharmaceutically acceptable salt thereof.

[0081] E4.X 1 However, CR 1a The compound described in any of E1 to E2, or a pharmaceutically acceptable salt thereof.

[0082] E5.X 2 However, the compound is N, one of the compounds listed in E1 to E4, or a pharmaceutically acceptable salt thereof.

[0083] E6.X 2 However, CR 1b The compound described in any of E1 to E4, or a pharmaceutically acceptable salt thereof.

[0084] E7.R 1a However, hydrogen or C 1-4A compound that is alkyl, as described in any of E1-E2 or E4-E6, or a pharmaceutically acceptable salt thereof.

[0085] E7.1.R 1a However, the compounds listed in E7, or pharmaceutically acceptable salts thereof, are hydrogen.

[0086] E7.2.R 1a However, C 1-4 A compound described in E7 that is alkyl, or a pharmaceutically acceptable salt thereof.

[0087] E7.3.R 1a However, the compounds listed in E7.2, or pharmaceutically acceptable salts thereof, are methyl.

[0088] E8.R 1b However, the compound is cyano, as described in any of E1-E4 or E6-E7.3, or a pharmaceutically acceptable salt thereof.

[0089] E9.R 1a and R 1b The compounds described in any of E1-E2, E4, or E6, or pharmaceutically acceptable salts thereof, which form a 6-membered allene, a 5-6 membered heteroallene containing 1-3 heteroatoms, a 5-7 membered heterocycle containing 1 heteroatom, or a 5-7 membered carbon ring, each optionally substituted with the atom to which it is attached.

[0090] E9.1.R 1a and R 1b The compounds described in E9, or pharmaceutically acceptable salts thereof, which each form a 5-6 membered heteroallene that is optionally substituted with the atom to which it is attached.

[0091] E9.2.R 1a and R 1b A compound according to any of E1 to E9.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of 5-6 membered heteroalenes formed together with the atoms to which each is attached is an imidazole, pyrazole, pyrrole, furan, thiophene, or pyrazine.

[0092] E9.3.R 1 but, [ka] And R 10a , R 11a , and R 11b These are, independently, hydrogen and C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, or C 1-2 Alkylene-C 3-4 A cycloalkyl compound as described in E9.2, or a pharmaceutically acceptable salt thereof.

[0093] E9.4.R 1 but, [ka] And R 11a and R 11b These are, independently, hydrogen and C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, or C 1-2 Alkylene-C 3-4 A cycloalkyl compound as described in E9.2, or a pharmaceutically acceptable salt thereof.

[0094] E9.5.R 10a , R 11a , and R 11b However, the compound described in E9.3 or E9.4, which is hydrogen, or a pharmaceutically acceptable salt thereof.

[0095] E10.R 1c However, hydrogen, C 1-4 A compound described in any of E1 to E9.5, which is alkyl or halogenated, or a pharmaceutically acceptable salt thereof.

[0096] E10.1.R 1cHowever, the compounds listed in E10, or pharmaceutically acceptable salts thereof, are hydrogen.

[0097] E10.2.R 1c However, C 1-4 A compound listed in E10 that is alkyl, or a pharmaceutically acceptable salt thereof.

[0098] E10.3.R 1c However, the compounds listed in E10.2, or pharmaceutically acceptable salts thereof, are methyl.

[0099] E10.4.R 1c However, the compounds listed in E10 that are halogens, or pharmaceutically acceptable salts thereof.

[0100] E10.5.R 1c However, the compounds listed in E10.4, or pharmaceutically acceptable salts thereof, are chloro.

[0101] E11.R 1d However, hydrogen or C 1-4 A compound that is alkyl, as described in any of E1 to E10.5, or a pharmaceutically acceptable salt thereof.

[0102] E11.1.R 1d However, the compounds listed in E11, or pharmaceutically acceptable salts thereof, are hydrogen.

[0103] E11.2.R 1d However, C 1-4 A compound listed in E11 that is alkyl, or a pharmaceutically acceptable salt thereof.

[0104] E11.3.R 1d However, the compounds listed in E11.2, or pharmaceutically acceptable salts thereof, are methyl.

[0105] E12.R 1c and R 1dThe compounds described in any of E1 to E8, or pharmaceutically acceptable salts thereof, which form a 6-membered allene, a 5-6 membered heteroallene containing 1-3 heteroatoms, a 5-7 membered heterocycle containing 1 heteroatom, or a 5-7 membered carbon ring, each optionally substituted with the atom to which it is attached.

[0106] E12.1.R 1c and R 1d The compound described in E12, or a pharmaceutically acceptable salt thereof, wherein each atom, together with the atom to which it is attached, forms a 6-membered allene that is optionally substituted.

[0107] E12.2.R 1c and R 1d Compounds described in any of E1-E8 or E12-E12.1, or pharmaceutically acceptable salts thereof, wherein the six-membered allenes formed together with the atoms to which each is attached are optionally substituted with methyl, fluoro, chloro, or methoxy.

[0108] E12.3.R 1 but, [ka] The compounds described in E12.1, or pharmaceutically acceptable salts thereof.

[0109] E12.4.R 1 but, [ka] The compounds described in E12.2 or E12.3, or pharmaceutically acceptable salts thereof.

[0110] E12.5.R 1c and R 1d The compounds described in E12, or pharmaceutically acceptable salts thereof, which each form a 5-6 membered heteroallene that is optionally substituted with the atom to which it is attached.

[0111] E12.6.R 1c and R 1d A compound according to any one of E1 to E12 or E12.5, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5-6 membered heteroalene ring system formed by is furan, thiophene, pyrrole, or isoxazole.

[0112] E12.7.R 1c and R 1d The 5-6 member heteroalene formed by C 1-4 Compounds described in any of E1-E12 or E12.5-E12.6, which are optionally substituted with alkyl groups, or pharmaceutically acceptable salts thereof.

[0113] E12.8.R 1c and R 1d The compounds described in E12.7, or pharmaceutically acceptable salts thereof, wherein the 5-6 membered heteroallene formed by is optionally substituted with methyl.

[0114] E12.9.R 1 but, [ka] The compounds described in E12.7, or pharmaceutically acceptable salts thereof.

[0115] E12.10.R 1 but, [ka] The compounds described in E12.8 or E12.9, or pharmaceutically acceptable salts thereof.

[0116] E12.11.R 1c and R 1d The compound described in E12, or a pharmaceutically acceptable salt thereof, wherein each atom, together with the atom to which it is attached, forms a 5- to 7-membered heteroarene that is optionally substituted and contains one heteroatom.

[0117] E12.12.R 1 but, [ka] The compounds described in E12.11, or pharmaceutically acceptable salts thereof.

[0118] E12.13.R 1c and R 1d The compounds described in E12, or pharmaceutically acceptable salts thereof, each forming a 5- to 7-membered carbon ring that is optionally substituted with the atom to which it is attached.

[0119] E12.14.R 1 but, [ka] The compounds described in E12.13, or pharmaceutically acceptable salts thereof.

[0120] E13.R 1 but, [ka] [ka] The compound described in any of E1 to E12.9, or a pharmaceutically acceptable salt thereof.

[0121] E14.R 1 but, [ka] The compound described in any of E1 to E1.2, or a pharmaceutically acceptable salt thereof.

[0122] E15.Z 1 However, N is Z 2However, C is a compound listed in any of E1 to E1.2 or E14, or a pharmaceutically acceptable salt thereof.

[0123] E16.Z 1 However, C is Z 2 However, the compound is N, as described in any of E1 to E1.2 or E14, or a pharmaceutically acceptable salt thereof.

[0124] E17.Z 1 However, C is Z 2 However, C is a compound listed in any of E1 to E1.2 or E14, or a pharmaceutically acceptable salt thereof.

[0125] E18.G 1 However, the compound is a five-membered aromatic heterocyclic ring system, as described in any of E1-E1.2 or E14-E17, or a pharmaceutically acceptable salt thereof.

[0126] E18.1.G 1 A compound described in any of E1-E1.2 or E14-E18, or a pharmaceutically acceptable salt thereof, wherein the 5-6 membered heterocyclic ring system is imidazole, pyrazole, pyrrole, furan, or thiophene.

[0127] E18.2.R 1 but, [ka] [ka] And R 10a , R 11a , and R 11b These are, independently, hydrogen and C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, or C 1-2 Alkylene-C 3-4 A cycloalkyl compound as described in E18.1, or a pharmaceutically acceptable salt thereof.

[0128] E19.G 1 However, the compounds described in E1-E1.2 or E14-E17, which are five-membered partially unsaturated heterocyclic ring systems, or pharmaceutically acceptable salts thereof.

[0129] E19.1.R 1 but, [ka] And R 11a However, hydrogen, C 1-6 Alkyl, C 1-6 Fluoroalkyl, -C 1-6 Alkilen-R y , -C 1-6 Fluoroalkylene-R y , G 11 , or -C 1-3 Alkilen-G 11 The compound described in E19, or a pharmaceutically acceptable salt thereof.

[0130] E19.2.R 11a However, hydrogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, or C 1-2 Alkylene-C 3-4 A cycloalkyl compound as described in E19.1, or a pharmaceutically acceptable salt thereof.

[0131] E19.3.R 11a However, the compound is hydrogen, as described in E19.1 or E19.2, or a pharmaceutically acceptable salt thereof.

[0132] E19.4.R 11a However, C 1-4 A compound that is alkyl, as described in E19.1 or E19.2, or a pharmaceutically acceptable salt thereof.

[0133] E19.5.R 11a However, the compounds listed in E19.4, or pharmaceutically acceptable salts thereof, are methyl.

[0134] E19.6.R 11a The compound described in E19.5, or a pharmaceutically acceptable salt thereof, wherein the methyl group in is CD3.

[0135] E19.7.R 11a However, -C 1-6 Alkilen-R y The compounds described in E19.1, or pharmaceutically acceptable salts thereof.

[0136] E19.8.R 11a -C in 1-6 Alkilen-R y However, -CH2CH2-R y or -CH(CH3)CH2-R y The compounds described in E19.1 or E19.7, or pharmaceutically acceptable salts thereof.

[0137] E19.9.R 11a However, G 11 The compounds described in E19.1, or pharmaceutically acceptable salts thereof.

[0138] E19.10.R 11a However, -C 1-3 Alkilen-G 11 The compounds described in E19.1, or pharmaceutically acceptable salts thereof.

[0139] E19.11.R 11a -C in 1-3 Alkilen-G 11 However, -CH2-G 11 The compounds described in E19.1 or E19.10, or pharmaceutically acceptable salts thereof.

[0140] E19.12.R y However, -OR c The compounds described in E19.1, E19.7-E19.8, or E19.11, or pharmaceutically acceptable salts thereof.

[0141] E19.13.R c However, C 1-4 A compound that is alkyl, as described in E19.1, E19.7-E19.8, or E19.11-E19.12, or a pharmaceutically acceptable salt thereof.

[0142] E19.14.R c C in 1-4 A compound described in any of E19.1, E19.7-E19.8, or E19.11-E19.13, wherein the alkyl group is methyl, or a pharmaceutically acceptable salt thereof.

[0143] E19.15.G 11 However, the compounds described in any of E19.1 or E19.8 to E19.14, which are optionally substituted 4 to 8 membered heterocyclines containing 1 to 2 heteroatoms, or pharmaceutically acceptable salts thereof.

[0144] E19.16.G 11 A compound described in any of E19.1 or E19.8 to E19.15, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 8-membered heterocyclyl ring system in is tetrahydrofuran or morpholine.

[0145] E19.17.G 11 The compounds described in E19.16, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 4- to 8-membered heterocyclyl ring system in is tetrahydrofuran-3-yl or morpholine-2-yl.

[0146] E19.18.G 11 but, [ka] The compounds described in E19.17, or pharmaceutically acceptable salts thereof.

[0147] E19.19.G 11 but, [ka] The compounds described in E19.17, or pharmaceutically acceptable salts thereof.

[0148] E19.20.G 11 but, [ka] The compounds described in E19.19, or pharmaceutically acceptable salts thereof.

[0149] E19.21.G 11 However, C is replaced by arbitrary selection. 3-6 A cycloalkyl compound as described in E19.1 or E19.8-E19.14, or a pharmaceutically acceptable salt thereof.

[0150] E19.22.G 11 C is replaced by arbitrary choice in the above. 3-6 A compound described in any of E19.1, E19.8-E19.14, E19.16-E19.17, or E19.21, wherein the cycloalkyl ring system is cyclopropyl or cyclopentyl, or a pharmaceutically acceptable salt thereof.

[0151] E19.23.G 11 C is replaced by arbitrary choice in the above. 3-6 A compound described in any of E19.1, E19.8-E19.14, E19.16-E19.17, or E19.21, wherein the cycloalkyl ring system is cyclobutyl, or a pharmaceutically acceptable salt thereof.

[0152] E19.24.G 11 However, the compounds described in E19.22, which are cyclopropyl or cyclopentyl, or pharmaceutically acceptable salts thereof.

[0153] E19.25.G 11 C in 3-6 Cycloalkyls are halogens, cyanos, and C1-4 Compounds described in any of E19.1, E19.8-E19.14, E19.16-E19.17, or E19.21, or pharmaceutically acceptable salts thereof, which are optionally substituted with one or two substituents independently selected from the group consisting of alkyl groups.

[0154] E19.26.G 11 C in 3-6 The compounds described in E19.25, or pharmaceutically acceptable salts thereof, wherein the cycloalkyl group is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, cyano, and methyl.

[0155] E19.27.G 11 but, [ka] The compounds described in E19.26, or pharmaceutically acceptable salts thereof.

[0156] E20.G 1 However, the compounds described in E1-E1.2 or E14-E17, which are six-membered partially unsaturated heterocyclic ring systems, or pharmaceutically acceptable salts thereof.

[0157] E20.1.R 1 but, [ka] And R 10a However, hydrogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, halogen, C 3-4 Cycloalkyl, C 1-2 Alkylene-C 3-4 Cycloalkyl, -C(O)OC 1-4 Alkyl and -C(O)NR a R b Selected from the group consisting of; R 11a However, hydrogen, C 1-4 Alkyl, C 1-4Fluoroalkyl, halogen, C 3-4 Cycloalkyl, and C 1-2 Alkylene-C 3-4 A compound selected from the group consisting of cycloalkyls, as described in E20, or a pharmaceutically acceptable salt thereof.

[0158] E20.2.R 10a However, hydrogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -C(O)OC 1-4 Alkyl and -C(O)NR a R b Selected from the group consisting of R 11a However, hydrogen, C 1-4 Compounds described in E20.1, selected from the group consisting of alkyls and halogens, or pharmaceutically acceptable salts thereof.

[0159] E20.3.R 10a However, hydrogen, methyl, CHF2, -CO2CH2CH3, and -C(O)NR a R b Selected from the group consisting of; R 11a However, the compounds described in E20.2, selected from the group consisting of hydrogen, methyl, and fluoro, or pharmaceutically acceptable salts thereof.

[0160] E20.4.R a However, the compound is hydrogen, as described in any of E1-E1.2, E14-E18.1, E19, or E20-E20.3, or a pharmaceutically acceptable salt thereof.

[0161] E20.5.R b However, G 10 or -C 1-3 Alkilen-G 10 (For example, -CH2-G 10 ) a compound described in any of E1-E1.2, E14-E18.1, E19, or E20-E20.4, or a pharmaceutically acceptable salt thereof.

[0162] E20.6.G 10However, it is optionally substituted with a 5-6 member heteroaryl (e.g., thiazolyl) or C 3-6 Compounds described in any of E1-E1.2, E14-E18.1, E19, or E20-E20.5, which are cycloalkyl (e.g., cyclopropyl, cyclobutyl), or pharmaceutically acceptable salts thereof.

[0163] E20.7.G 10 However, cyano or C 1-4 Compounds described in any of E1-E1.2, E14-E18.1, E19, or E20-E20.6, or pharmaceutically acceptable salts thereof, optionally substituted with a fluoroalkyl group (e.g., 2,2,2-trifluoroethyl).

[0164] E20.8.R b but, [ka] The compounds described in E20.7, or pharmaceutically acceptable salts thereof.

[0165] E20.9.R a and R b Compounds described in any of E1-E1.2, E14-E18.1, E19, or E20-E20.3, or pharmaceutically acceptable salts thereof, which form a 4- to 10-membered heterocycle that is optionally substituted together with the nitrogen to which they are attached.

[0166] E20.10.R a and R b Compounds described in any of E1-E1.2, E14-E18.1, E19, E20-E20.3, or E20.9, or pharmaceutically acceptable salts thereof, wherein the 4-10 membered heterocyclic ring system formed by is azetidine, pyrrolidine, or 2-oxa-6-azapyrro[3.3[heptane].

[0167] E20.11.R a and R bThe 4-10 membered heterocycle formed by this process is a halogen (e.g., fluorocarbon), C 1-4 Alkyl (e.g., methyl), -OR 50 (For example, OCH3), and G 10a It is optionally substituted with a first substituent selected from the group consisting of (e.g., pyridinyl such as pyridine-3-yl); halogen (e.g., fluoro) or C 1-4 Compounds described in any of E1-E1.2, E14-E18.1, E19, E20-E20.3, or E20.9-E20.10, or pharmaceutically acceptable salts thereof, which are optionally further substituted with one alkyl substituent (e.g., methyl).

[0168] E20.12.R a and R b The 4- to 10-membered complex rings formed by the following, which are substituted by any choice, [ka] The compounds described in any of E1-E1.2, E14-E18.1, E19, E20-E20.3, or E20.9-E20.11, or pharmaceutically acceptable salts thereof.

[0169] E20.13.R 1 but, [ka] And R 11a and R 11b However, independently, hydrogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, halogen, C 3-4 Cycloalkyl, and C 1-2 Alkylene-C 3-4 A compound selected from the group consisting of cycloalkyls, as described in E20, or a pharmaceutically acceptable salt thereof.

[0170] E20.14.R 11aHowever, hydrogen is a compound listed in E20.13, or a pharmaceutically acceptable salt thereof.

[0171] E20.15.R 11b However, hydrogen, C 1-4 Alkyl (e.g., methyl), and C 1-4 Compounds described in E20.13 or E20.14, selected from the group consisting of fluoroalkyls (e.g., CHF2, CF3), or pharmaceutically acceptable salts thereof.

[0172] E21.G 1 However, the compound described in any of E1 to E1.2, E14, or E17, which is a six-membered aromatic heterocyclic ring system, or a pharmaceutically acceptable salt thereof.

[0173] E21.1.G 1 A compound described in any of E1-E1.2, E14, E17, or E21, or a pharmaceutically acceptable salt thereof, wherein the six-membered aromatic ring heterocyclic ring system in the compound is pyrazine.

[0174] E21.2.R 1 but, [ka] And R 11a and R 11b These are, independently, hydrogen and C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 3-4 Cycloalkyl, or C 1-2 Alkylene-C 3-4 A cycloalkyl compound as described in E21.1, or a pharmaceutically acceptable salt thereof.

[0175] E21.3.R 11a and R 11b However, hydrogen is a compound listed in E21.2, or a pharmaceutically acceptable salt thereof.

[0176] E22.R 1e However, hydrogen or C 1-4A compound that is alkyl, as described in E1-E1.2 or E14-E21.3, or a pharmaceutically acceptable salt thereof.

[0177] E22.1.R 1e However, the compounds listed in E22, or pharmaceutically acceptable salts thereof, are hydrogen.

[0178] E22.2.R 1e However, C 1-4 A compound described in E22 that is alkyl, or a pharmaceutically acceptable salt thereof.

[0179] E22.3.R 1e However, the compounds listed in E22.2, or pharmaceutically acceptable salts thereof, are methyl.

[0180] E23.R 1f However, C 1-4 The compounds described in E1 to E1.2 or E14 to E22.3, or pharmaceutically acceptable salts thereof.

[0181] E23.1.R 1f However, the compounds listed in E23, or pharmaceutically acceptable salts thereof, are methyl.

[0182] E24.R 1 but, [ka] [ka] [ka] The compounds described in E1-E1.2 or E14-E23.1, or pharmaceutically acceptable salts thereof.

[0183] E24.1.R 1 but, [ka] [ka] [ka] The compound described in E24, or a pharmaceutically acceptable salt thereof.

[0184] E24.2.R 1 but, [ka] [ka] [ka] The compounds described in E24 or E24.1, or pharmaceutically acceptable salts thereof.

[0185] E25.R 2 However, G 2 , -NR 2a R 2b , halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 2a , -C(O)OR 2a -C(O)NR 2a R 2b A compound described in any of E1 to E24.2, or a pharmaceutically acceptable salt thereof, which is hydrogen.

[0186] E26.R 2 However, G 2 The compounds described in E25, or pharmaceutically acceptable salts thereof.

[0187] E27.G 2However, the compounds described in any of E1 to E26, or pharmaceutically acceptable salts thereof, are 3- to 7-membered carbocyclyls that are optionally substituted.

[0188] E27.1. The 3- to 7-membered carbocyclyl ring system that is optionally substituted is C 3-6 A cycloalkyl compound as described in any of E1 to E27, or a pharmaceutically acceptable salt thereof.

[0189] E27.2.C 3-6 A compound described in E27.1, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl ring system is cyclopropyl.

[0190] E27.3.C 3-6 A compound described in E27.1, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl ring system is cyclobutyl.

[0191] E27.4.G 2 The compounds described in any of E1 to E27.3, or pharmaceutically acceptable salts thereof, are optionally substituted with one or two substituents independently selected from methyl and fluoro.

[0192] E27.5.G 2 but, [ka] The compounds described in E27.4, or pharmaceutically acceptable salts thereof.

[0193] E27.6.G 2 but, [ka] The compounds described in E27.4, or pharmaceutically acceptable salts thereof.

[0194] E27.7.G 2 but, [ka] The compounds described in E27.4, or pharmaceutically acceptable salts thereof.

[0195] E28.G 2 However, the compound described in any of E1 to E26, or a pharmaceutically acceptable salt thereof, is a 5-6 member heteroaryl compound that is optionally substituted.

[0196] E28.1.G 2 Compounds described in E1 to E26 or E28, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 5-6 membered heteroaryl ring system in is thiophenyl, thiazolyl, pyrazolyl, pyrrolyl, or pyridinyl.

[0197] E28.2.G 2 However, C 1-4 Alkyl (e.g., methyl) or C 3-4 It is optionally substituted with a cycloalkyl group, and contains 1-2 C atoms. 1-4 Compounds described in any of E1-E26 or E28-E28.1, or pharmaceutically acceptable salts thereof, which are further optionally substituted with alkyl groups.

[0198] E28.3.G 2 but, [ka] The compounds described in E28.2, or pharmaceutically acceptable salts thereof.

[0199] E29.G 2 However, the compound is one of those listed in E1 to E26, or a pharmaceutically acceptable salt thereof, which is a phenyl compound substituted by any choice.

[0200] E30.G 2 but, [ka] The compound described in any of E1 to E29, or a pharmaceutically acceptable salt thereof.

[0201] E30.1.G 2 but, [ka] The compound described in any of E1 to E30, or a pharmaceutically acceptable salt thereof.

[0202] E30.2.G 2 but, [ka] The compounds described in E30.1, or pharmaceutically acceptable salts thereof.

[0203] E31.R 2 However, -NR 2a R 2b The compounds described in E25, or pharmaceutically acceptable salts thereof.

[0204] E32.R 2 However, -C(O)NR 2a R 2b The compounds described in E25, or pharmaceutically acceptable salts thereof.

[0205] E33.R 2b However, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, G 2 , or -C 1-3 Alkilen-G 2 The compounds described in any of E1-E25 or E31-E32, or pharmaceutically acceptable salts thereof.

[0206] E33.1.R 2b However, the compounds listed in E33, or pharmaceutically acceptable salts thereof, are hydrogen.

[0207] E33.2.R 2b However, G2 The compound described in E33, or a pharmaceutically acceptable salt thereof.

[0208] E33.3.R 2b However, -C 1-3 Alkilen-G 2 The compound described in E33, or a pharmaceutically acceptable salt thereof.

[0209] E33.4.R 2b However, -CH2-G 2 The compounds described in E33.3, or pharmaceutically acceptable salts thereof.

[0210] E33.5.G 2 However, the compounds described in E1-E25, E31-E33, or E33.2-E33.4, which are 5-6 member heteroaryl compounds that are optionally substituted, or pharmaceutically acceptable salts thereof.

[0211] E33.6.G 2 However, the compounds described in E1-E25, E31-E33, or E33.2-E33.4, which are phenyl compounds to which phenyl compounds are optionally substituted, or pharmaceutically acceptable salts thereof.

[0212] E33.7.G 2 The compounds described in any of E1-E25, E31-E33, or E33.2-E33.6, or pharmaceutically acceptable salts thereof, are optionally substituted with 1-3 halogens independently selected from the group consisting of fluoro and chloro.

[0213] E33.8.G 2 However, the compounds described in E33.7, or pharmaceutically acceptable salts thereof, are 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

[0214] E34.R 2 However, -C(O)OR 2a The compounds described in E25, or pharmaceutically acceptable salts thereof.

[0215] E35.R 2 However, -OR 2a The compounds described in E25, or pharmaceutically acceptable salts thereof.

[0216] E36.R 2a However, hydrogen or C 1-6 A compound that is alkyl, as described in any of E1-E25 or E31-E35, or a pharmaceutically acceptable salt thereof.

[0217] E36.1.R 2a However, the compounds listed in E36, or pharmaceutically acceptable salts thereof, are hydrogen.

[0218] E36.2.R 2a However, C 1-4 A compound described in E36 that is alkyl, or a pharmaceutically acceptable salt thereof.

[0219] E36.3.R 2a The compounds described in E36.2, or pharmaceutically acceptable salts thereof, which are methyl or ethyl.

[0220] E37.R 2 However, C 1-6 A compound that is alkyl, as described in E25, or a pharmaceutically acceptable salt thereof.

[0221] E37.1.R 2 However, C 1-4 A compound described in E37 that is alkyl, or a pharmaceutically acceptable salt thereof.

[0222] E37.2.R 2 The compounds described in E37.1, or pharmaceutically acceptable salts thereof, are methyl (e.g., CD3), isopropyl, or tert-butyl.

[0223] E38.R 2 However, the compounds listed in E25 that are halogens, or pharmaceutically acceptable salts thereof.

[0224] E38.1.R 2However, the compounds described in E38, which are chloro or bromo, or pharmaceutically acceptable salts thereof.

[0225] E39.R 2 However, hydrogen is a compound listed in E25, or a pharmaceutically acceptable salt thereof.

[0226] E40.R 2 However, C 1-6 A compound described in E25 that is a haloalkyl, or a pharmaceutically acceptable salt thereof.

[0227] E40.1.R 2 However, CF3 is a compound listed in E40, or a pharmaceutically acceptable salt thereof.

[0228] E41.R 2 However, the compounds listed in E25, or pharmaceutically acceptable salts thereof, are cyano compounds.

[0229] A compound listed in any of E1 to E41, or a pharmaceutically acceptable salt thereof, wherein E42.o is 0.

[0230] E43.

[0231] [Table 1]

[0232] [Table 2]

[0233] [Table 3]

[0234] [Table 4]

[0235] [Table 5]

[0236] [Table 6]

[0237] [Table 7]

[0238] [Table 8]

[0239] A compound described in E1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

[0240] A pharmaceutical composition comprising a compound described in any of E44.E1 to E43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0241] E454. A method for treating neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals, comprising administering to a mammal a therapeutically effective amount of any of the compounds described in E1 to E43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in E44.

[0242] E46. The method described in E45, wherein the disorder is related to mAChR M4 dysfunction.

[0243] E47. The method according to E454 or E46, wherein the disorder is a neurological and / or psychiatric disorder associated with mAChR M4 dysfunction.

[0244] E48. The method according to any of E45-E47, wherein the disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, sleep disorders, pain disorders, and cognitive impairment.

[0245] E49. The method described in E48, where the disorder is Alzheimer's disease.

[0246] E50. The method according to any one of E45 to E47, wherein the disorder is selected from the group consisting of psychotic mood disorders such as psychosis, schizophrenia, conduct disorder, destructive behavior disorder, bipolar disorder, psychotic anxiety episode, anxiety associated with psychosis, and severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral symptoms of intellectual disability, autism spectrum disorder, motor disorders, Tourette syndrome, akinesia-rigidity syndrome, motor disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0247] A kit comprising one of the compounds described in E51.E1 to E43, or a pharmaceutically acceptable salt thereof, and one or more instructions for administering compounds related to cognitive therapy or behavioral therapy: (a) at least one agent known to increase mAChR M4 activity; (b) at least one agent known to decrease mAChR M4 activity; (c) at least one agent known to treat disorders related to cholinergic activity; (d) instructions for treating disorders related to cholinergic activity; (e) instructions for treating disorders related to mAChR M4 receptor activity; and (f) instructions for administering compounds related to cognitive therapy or behavioral therapy.

[0248] E52. A compound according to any of E1 to E43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to E44, for use in the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0249] E53. Use of any compound described in E1 to E43, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in E44, for the preparation of a medicament for the treatment of neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in mammals.

[0250] Compounds may exist as stereoisomers containing a chiral or asymmetric center. The stereoisomers are designated "R" or "S" depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S" as used herein refer to the configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45:13-30. This disclosure intends for a variety of stereoisomers and mixtures thereof, which are clearly included within the scope of the invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Each stereoisomer of this compound can be prepared from commercially available starting materials containing a chiral or asymmetric center by synthesis or by preparation of racemic mixtures followed by division methods well known to those skilled in the art. These separation methods are exemplified by (1) attachment of the mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product from the auxiliary (as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England), or (2) direct separation of the mixture of optically enantiomers in a chiral chromatography column, or (3) fractional recrystallization methods.

[0251] It should be understood that this compound may have tautomers and geometric isomers, and that these also constitute embodiments of the present disclosure.

[0252] In compounds of formula (I) and any subformula, any "hydrogen" or "H", whether explicitly or implicitly indicated in the structure, is a hydrogen isotope. 1 H (protium) and 2 It contains H (deuterium).

[0253] The present invention also includes isotope-labeled compounds identical to those described in formula (I), but in which one or more atoms are replaced with atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl is one example. Deuterium, that is 2 Substitution with heavier isotopes, such as H, may be preferable in some situations because it can lead to certain therapeutic benefits resulting from greater metabolic stability, such as an extended in vivo half-life or a reduced need for dosage. This compound can incorporate positron emission isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron emission isotopes that can be incorporated into the compound of formula (I) are: 11 C, 13 N, 15 O and 18 It is F.

[0254] Isotope-enriched forms of compounds of formula (I), or any subformula, can generally be prepared by the prior art known to those skilled in the art, or by processes similar to those described in the appended examples, using appropriate isotope-enriched reagents instead of non-isotope-enriched reagents. The degree of isotope enrichment can be characterized as the percentage of a particular isotope incorporated into the isotope-labeled atom (e.g., deuterium incorporation %) in deuterium labeling.

[0255] a. Pharmaceutically acceptable salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a water- or oil-soluble or dispersible salt or zwitterion of the compound that is suitable for the treatment of a disorder without excessive toxicity, irritation, and allergic reactions, and is effective for its intended use, with a reasonable benefit-risk ratio. These salts may be prepared during the final isolation and purification of the compound or separately by reacting the amino group of the compound with a suitable acid. For example, the compound may be dissolved in a suitable solvent such as methanol and water, but is not limited to, and treated with at least one acid equivalent such as hydrochloric acid. The resulting salt may be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Typical salts include acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, and phosphate. The amino group of this compound can also be quaternized by chlorination, bromide, and alkyl iodide, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, and stearyl.

[0256] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reacting a carboxyl group with a hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or with a suitable base such as a primary, secondary, or tertiary organic amine. Quaternary amine salts can also be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0257] b. General synthesis The compound of formula (I) can be prepared by synthetic or metabolic processes. Metabolic preparations of this compound include processes that occur in the human or animal body (in vivo) or in vitro.

[0258] The compound of formula (I) can be synthesized as shown in schemes 1 to 11.

[0259] Scheme 1 [ka] As shown in Scheme 1, tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate of formula (i) is converted under appropriate conditions to R 2 By reacting with a substituted thioamide, tert-butyl6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (ii) can be obtained, followed by treatment under appropriate acidic Boc deprotection conditions (e.g., TFA, HCl, etc.) to obtain 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (iii).

[0260] Scheme 2 [ka] As shown in Scheme 2, the tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate of formula (iv) is appropriate R 2 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(iii) can be formed by using a substituted boronic acid or ester reagent and a palladium catalyst (e.g., Pd(PPh3)4, Pd(dppf)Cl2) under Suzuki reaction conditions in the presence of a base (e.g., sodium carbonate, cesium carbonate), followed by Boc deprotection under acidic conditions (e.g., TFA, HCl).

[0261] Scheme 3 [ka] As shown in Scheme 3, tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate of formula (iv) is converted under appropriate conditions R 2 -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(iii) can be obtained by reacting it with substituted (1,10-phenanthroline)copper (e.g., trifluoromethyl(1,10-phenanthroline)copper) followed by Boc deprotection under acidic conditions (e.g., TFA, HCl).

[0262] Scheme 4 [ka] As shown in Scheme 4, tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate of formula (iv) is subjected to a metalling reagent (e.g., n-BuLi, -78°C), followed by R 2Reacting with a substituted halide (e.g., CD3I) can yield tert-butyl 6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(ii).

[0263] Scheme 5 [ka] As shown in Scheme 5, the R of equation (va) or (vb) (where X is a halogen) 1 The substituted halide is reacted with 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(iii) under appropriate nucleophilic substitution conditions, e.g., an amine, a base (e.g., DIEA, Et3N, etc.), and a solvent (e.g., NMP), while heating to approximately 70-110°C, to form R of formula (vi). 1 Substituting 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine can be obtained.

[0264] Scheme 6 [ka] As shown in Scheme 6, the intermediate of formula (vii) can be subjected to hydrazine in ethanol and heated to 70-80°C to obtain the intermediate of formula (viii).

[0265] Scheme 7 [ka] As shown in Scheme 7, the intermediate of formula (viii) can be subjected to a solvent (e.g., 1,4-dioxane, THF, etc.) and CDI (CAS No. 530-62-1), and heated to 60-80°C to form the compound of formula (ix).

[0266] Scheme 8 [ka] As shown in Scheme 8, intermediate (x) can be coupled with an amine under Buchwald coupling conditions commonly known in the art to obtain product (xi). A similar reaction can be carried out using intermediate (iv) to obtain -NR 2a R 2b Substitutive intermediate compounds may be obtained.

[0267] Scheme 9 [ka] As shown in Scheme 9, intermediate (x) can be coupled with an alkoxide-type reagent in a suitable solvent to obtain product (xii). A similar reaction can be carried out using intermediate (iv) to obtain -OR 2a Substitutive intermediate compounds may be obtained.

[0268] Scheme 10 [ka] As shown in Scheme 10, intermediate (x) may be reacted with zinc metal and Zn(CN)2 using a palladium catalyst (e.g., Pd(dppf)Cl2), and heated in a suitable solvent to obtain (xiii). A similar reaction may be carried out using intermediate (iv) to obtain a cyano-substituted intermediate compound.

[0269] Scheme 11 [ka] As shown in Scheme 11, the intermediate of formula (ix) is a base (e.g., K2CO3, Cs2CO3, etc.), R 11a The material can be subjected to -X (wherein X is a halogen, mesylate, etc.) and heated to 45-50°C to form the compound of formula (xiv).

[0270] Boronic acids / esters, amines, and alcohols suitable for the coupling reactions described herein can be readily obtained from commercial sources or prepared by standard methods well known to those skilled in the art.

[0271] Compounds and intermediates can be isolated and purified by methods well known to those skilled in the field of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography, thin-layer chromatography, distillation at various pressures, sublimation in vacuum, and trituration on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups by recrystallization at high or low temperatures, with optional pretreatment with activated carbon, as described in "Vogel's Textbook of Practical Organic Chemistry" 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0272] The disclosed compounds may have at least one basic nitrogen (so that the compound can be treated with an acid to form a desired salt). For example, the compound can be reacted with an acid at room temperature or above room temperature to provide a desired salt (which precipitates and is collected by filtration after cooling). Examples of acids suitable for this reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, phosphoric acid of hydrogen bromide, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0273] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants used and the substituents present in the reactants. Specific procedures are provided in the Examples section. The reaction can be post-treated in a conventional manner, for example, by removing the solvent from the residue, and further purified according to methodologies commonly known in the art, including but not limited to crystallization, distillation, extraction, polishing, and chromatography. Unless otherwise stated, starting materials and reagents are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature. If not commercially available, starting materials can be prepared by procedures selected from standard organic chemistry techniques, techniques similar to the synthesis of known structurally similar compounds, or techniques similar to the schemes or synthesis examples described above.

[0274] Conventional experimental methods, including reaction conditions, reagents and the order of the synthesis route, and appropriate handling of the protection and deprotection of any chemical functionalities that are not compatible with the reaction conditions and the appropriate timing of deprotection in the reaction sequence of the method, are within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art, and examples thereof are incorporated herein by reference in Protective Groups in Organic Synthesis (4) th This can be referenced in Greene's book titled (ed.) PGM Wuts and TW Greene, John Wiley & Sons, NY (2006). The synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthesis schemes described above and in the specific examples.

[0275] If an optically active form of the disclosed compound is required, it can be obtained by performing one of the procedures described herein using an optically active starting material (e.g., prepared by asymmetric induction of the appropriate reaction step), or by dividing a mixture of stereoisomers of the compound or intermediate using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0276] Similarly, if a pure geometric isomer of this compound is required, it can be obtained by performing one of the above procedures using the pure geometric isomer as a starting material, or by dividing a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0277] It should be understood that the described synthesis schemes and specific examples are illustrative and should not be construed as limiting the scope of the invention as defined in the appended claims. All alternative forms, modifications, and equivalents of the synthesis methods and specific examples are included within the scope of the claims.

[0278] c. Muscarinic acetylcholine receptor M4 activity In some embodiments, the disclosed compounds enhance the agonist response of mAChR M4 (e.g., acetylcholine). In some embodiments, the disclosed compounds increase the mAChR M4 response to non-maximal concentrations of agonists in the presence of the compound compared to the response to agonists in the absence of the compound. The enhancement of mAChR M4 activity can be demonstrated by methodologies known in the art. For example, activation of mAChR M4 activity is Ca 2+ The activity can be determined by measuring the calcium flux in response to an agonist, such as acetylcholine, in cells loaded with a sensitive fluorescent dye (e.g., Fluo-4), and by co-expression of a chimeric or promiscuous G protein. In some embodiments, the calcium flux was measured as an increase in the fluorescence resting ratio. In some embodiments, positive allosteric modulator activity is measured by EC 20This is analyzed as a concentration-dependent increase in the acetylcholine response (i.e., the mAChR M4 response at the acetylcholine concentration that produces 20% of the maximum response).

[0279] In some embodiments, the disclosed compounds activate the mAChR M4 response as an increase in calcium fluorescence in mAChR M4-transfected CHO-K1 cells in the presence of the compound, compared to the response of equivalent CHO-K1 cells in the absence of the compound. In some embodiments, the disclosed compounds are present in concentrations of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM of EC. 50 This activates the mAChR M4 reaction. In some embodiments, mAChR M4-transfected CHO-K1 cells are transfected with human mAChR M4. In some embodiments, mAChR M4-transfected CHO-K1 cells are transfected with rat mAChR M4.

[0280] The disclosed compounds may exhibit positive allosteric modulation of the mAChR M4 response to acetylcholine, as an increase in the response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with mAChR M4 in the presence of the compounds, compared to the response to acetylcholine in the absence of the compounds. In some embodiments, the disclosed compounds exhibit positive allosteric modulation of the mAChR M4 response to acetylcholine, and EC 50 These are less than approximately 10 μM, less than approximately 5 μM, less than approximately 1 μM, less than approximately 500 nM, or less than approximately 100 nM. In some embodiments, positive allosteric regulation of EC is observed in CHO-K1 cells transfected with mAChR M4. 50 This is determined. In some embodiments, mAChR M4 was transfected with human mAChR M4. In some embodiments, mAChR M4 was transfected with rat mAChR M4.

[0281] The disclosed compounds may exhibit selectivity for the mAChR M4 receptor to one or more mAChR M1, M2, M3, or M5 receptors. For example, the disclosed compounds may exhibit selectivity for EC in one or more mAChR M1, M2, M3, or M5 transfected CHO-K1 cells. 50 e-commerce below 50 This may activate the mAChR M4 response in mAChR M4-transfected CHO-K1 cells.

[0282] The disclosed compounds may exhibit selectivity for the mAChR M4 receptor to one or more mAChR M1, M2, M3, or M5 receptors. For example, the disclosed compounds may exhibit selectivity for EC in one or more mAChR M1, M2, M3, or M5 transfected CHO-K1 cells. 50 e-commerce below 50 This can activate the mAChR M4 reaction in mAChR M4-transfected CHO-K1 cells. In some embodiments, the disclosed compounds have an EC of about 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower, about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that for mAChR M2. 50 The mAChR M4 reaction can be activated. In some embodiments, the disclosed compounds have an EC of about 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower, about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that of mAChR M3. 50 The mAChR M4 reaction can be activated. In some embodiments, the disclosed compounds have an EC of about 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower, about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that of mAChR M5. 50The mAChR M4 reaction can be activated. In some embodiments, the disclosed compounds have an EC that is 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower than that for M2-M5 receptors, and about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than 500 times lower than that for mAChR M1, M2, M3 or M5 receptors. 50 This can activate the mAChR M4 reaction.

[0283] The disclosed compounds have an EC of less than approximately 10 μM. 50 This can activate the mAChR M4 reaction in M4-transfected CHO-K1 cells and exhibit selectivity for the M4 receptor over one or more mAChR M1, M2, M3, or M5 receptors. For example, in some embodiments, the compound may have an EC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have an EC of approximately 5 times, 10 times, 20 times, 30 times, 50 times, 100 times, 200 times, 300 times, 400 times, or more than 500 times lower than that of mAChR M1. 50 The mAChR M4 reaction can also be activated. In some embodiments, the compound is EC2 less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have an EC of approximately 5 times lower, 10 times lower, 20 times lower, 30 times lower, 50 times lower, 100 times lower, 200 times lower, 300 times lower, 400 times lower, or more than 500 times lower than that of mAChR M2. 50 The mAChR M4 reaction can also be activated. In some embodiments, the compound is EC2 less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50The compound may have an EC of approximately 5 times lower, 10 times lower, 20 times lower, 30 times lower, 50 times lower, 100 times lower, 200 times lower, 300 times lower, 400 times lower, or more than 500 times lower than that of mAChR M3. 50 The mAChR M4 reaction can also be activated. In some embodiments, the compound is EC2 less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have an EC of approximately 5 times lower, 10 times lower, 20 times lower, 30 times lower, 50 times lower, 100 times lower, 200 times lower, 300 times lower, 400 times lower, or more than 500 times lower than that of mAChR M5. 50 The mAChR M4 reaction can also be activated. In some embodiments, the compound is EC2 less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have an EC that is approximately 5 times lower, 10 times lower, 20 times lower, 30 times lower than that for M2-M5 receptors, approximately 50 times lower, 100 times lower, 200 times lower, 300 times lower, 400 times lower than that for M2, M3, or M5, or more than 500 times lower than that for mAChR M1, M2, M3, or M5 receptors. 50 Therefore, the mAChR M4 reaction can also be activated.

[0284] The in vivo potency of the disclosed compounds can be measured in numerous preclinical rat behavioral models in which known clinically useful antipsychotics exhibit similar positive responses. For example, the disclosed compounds can reverse amphetamine-induced hyperactivity in male Sprague-Dawley rats at doses ranging from 1 to 100 mg / kg at post-occlusion (PO).

[0285] 2. Pharmaceutical compositions and preparations The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to subjects (such as patients, which may be human or non-human). The disclosed compounds can also be provided as formulations such as spray-dried dispersions.

[0286] These pharmaceutical compositions and formulations may contain a “therapeutic dose” or a “preventive dose.” “Therapeutic dose” refers to the amount effective in the dosage and duration required to achieve the desired therapeutic outcome. The therapeutic dose of this composition can be determined by those skilled in the art and may vary depending on factors such as the individual’s disease state, age, sex, and weight, as well as the composition’s ability to elicit the desired response in the individual. The therapeutic dose is also the amount in which the therapeutically beneficial effects of any of the compounds of the present invention (e.g., compounds of formula (I)) outweigh any toxic or harmful effects. “Preventive dose” refers to the amount effective in the dosage and duration required to achieve the desired preventive outcome. Generally, since preventive doses are used for targets before or in the early stages of disease, the preventive dose will be lower than the therapeutic dose.

[0287] For example, the therapeutically effective doses of the compound of formula (I) are approximately 1 mg / kg to 1000 mg / kg, 5 mg / kg to 950 mg / kg, 10 mg / kg to 900 mg / kg, 15 mg / kg to 850 mg / kg, 20 mg / kg to 800 mg / kg, 25 mg / kg to 750 mg / kg, 30 mg / kg to 700 mg / kg, 35 mg / kg to 650 mg / kg, 40 mg / kg to 600 mg / kg, and 45 mg / kg. It may be approximately mg / kg to 550 mg / kg, approximately 50 mg / kg to 500 mg / kg, approximately 55 mg / kg to 450 mg / kg, approximately 60 mg / kg to 400 mg / kg, approximately 65 mg / kg to 350 mg / kg, approximately 70 mg / kg to 300 mg / kg, approximately 75 mg / kg to 250 mg / kg, approximately 80 mg / kg to 200 mg / kg, approximately 85 mg / kg to 150 mg / kg, and approximately 90 mg / kg to 100 mg / kg.

[0288] This pharmaceutical composition and formulation may contain pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier” as used herein means any non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid of any kind. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and Soybean oil; glycols; for example, propylene glycol; esters, for example, ethyl oleate and ethyl laurate (but not limited); agar; buffers, for example, magnesium hydroxide and aluminum hydroxide (but not limited); alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer; and other non-toxic, suitable lubricants, for example, sodium lauryl sulfate and magnesium stearate (but not limited), as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants may also be present in the composition at the discretion of the compounder.

[0289] Therefore, this compound and its pharmaceutically acceptable salts can be formulated, for example, in solid tablets, eye drops, oil-based topical preparations, injection, inhalation (through the mouth or nose), implantable tablets, or for oral, buccal, parenteral, or rectal administration. The techniques and formulations can generally be referenced in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions should generally be sterile and stable under manufacturing and storage conditions.

[0290] The route by which the disclosed compound is administered and the form of the composition determine the type of carrier used. The composition may be in various forms suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implantable, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0291] Carriers for systemic administration generally include at least one of the following: diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, fluidizers, solvents, suspending agents, wetting agents, surfactants, or combinations thereof. All carriers are optional within the composition.

[0292] Suitable diluents include sugars, such as glucose, lactose, dextrose, and sucrose; diols, such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent in a systemic or topical composition is generally about 50-90%.

[0293] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil. The amount of lubricant in a composition for whole-body or topical use is generally about 5 to about 10%.

[0294] Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starch, such as sorghum starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder in the whole composition is generally about 5 to 50%.

[0295] Suitable disintegrants include agar, alginic acid and its sodium salts, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clay, and ion exchange resins. The amount of disintegrant in a whole-body or topical composition is generally about 0.1 to about 10%.

[0296] Suitable colorants include FD&C dyes. When used, the amount of colorant in a whole-body or topical composition is generally about 0.005 to 0.1%.

[0297] Suitable flavors include menthol, peppermint, and fruit flavors. When used, the amount of flavor in a systemic or topical composition is generally about 0.1 to 1.0%.

[0298] Suitable sweeteners include aspartame and saccharin. The amount of sweetener in a whole-body or topical composition is generally about 0.001% to about 1%.

[0299] Suitable antioxidants include butylhydroxyanisole ("BHA"), butylhydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant in a systemic or topical composition is generally about 0.1 to 5%.

[0300] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative in a systemic or topical composition is generally about 0.01 to 5%.

[0301] A suitable fluidizing agent is silicon dioxide. The amount of fluidizing agent in a whole-body or topical composition is generally about 1 to 5%.

[0302] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, castor oil hydroxide, alcohols such as ethanol, and phosphate buffer. The amount of solvent in a whole-body or topical composition is generally about 0 to 100%.

[0303] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent in a systemic or topical composition is generally about 1 to 8%.

[0304] Suitable surfactants include lecithin, polysorbate 80, sodium lauryl sulfate, and TWEENS (from Atlas Powder Company of Wilmington, Delaware). Other suitable surfactants are disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Wilmington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant in a systemic or topical composition is generally about 0.1% to about 5%.

[0305] The amounts of components in a systemic composition may vary depending on the type of systemic composition being prepared, but generally, a systemic composition contains 0.01% to 50% of an active compound (e.g., a compound of formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration generally contain 0.1% to 10% of an active substance and 90% to 99.9% of a carrier (including diluents and solvents).

[0306] Compositions for oral administration may have various dosage forms. For example, solid dosage forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of the active substance, usually at least about 5%, more specifically about 25% to about 50%. These oral medication compositions contain about 50% to about 95%, more specifically about 50% to about 75% of the carrier.

[0307] Tablets can be compressed, wet-coated (tablet triturate), enteric-coated, sugar-coated, film-coated, or multi-compressed. Tablets generally contain an active ingredient and a carrier containing an ingredient selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, fluidizers, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are FD&C dyes that can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or combinations thereof.

[0308] Capsules (including implantable tablets, sustained-release and sustained-release formulations) generally comprise an active compound (e.g., a compound of formula (I)) and a carrier containing one or more of the disclosed diluents in a gelatin-containing capsule. Granules generally comprise the disclosed compound and a fluidizing agent, preferably silicon dioxide, to improve flowability. Implantable tablets may be biodegradable or non-biodegradable.

[0309] The selection of components in the carrier for oral compositions depends on auxiliary considerations such as taste, cost, and storage stability, which are not important to the purpose of the present invention.

[0310] The solid composition can be conventionally coated with a pH or time-dependent coating so that the disclosed compound is released into the gastrointestinal tract or near the desired site of application, or at various locations and times, in order to maintain the desired effect. The coating generally comprises one or more components selected from the group consisting of cellulose phthalate acetate, vinyl polyphthalate acetate, hydroxypropyl methylcellulose phthalate, ethylcellulose, EUDRAGIT® coating (available from Evonik Industries of Essen, Germany), wax, and shellac.

[0311] Compositions for oral administration can take the form of a liquid. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-foaming granules, suspensions reconstituted from non-foaming granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, and syrups. Liquid compositions for oral administration generally comprise the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Oral liquid compositions preferably contain one or more components selected from colorants, flavors, and sweeteners.

[0312] Other compositions useful for achieving systemic delivery of the target compound include sublingual, buccal, and nasal dosage forms. These compositions generally contain diluents, including sucrose, sorbitol, and mannitol; and one or more soluble fillers, such as gum arabic, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. These compositions may further contain lubricants, colorants, flavors, sweeteners, antioxidants, and fluidizers.

[0313] The disclosed compounds can be administered topically. Topical compositions that can be applied topically to the skin may be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-in and rinse-off hair conditioners, emulsions, cleansers, moisturizers, sprays, skin patches, and the like. A topical composition comprises the disclosed compound (e.g., the compound of formula (I)) and a carrier. The carrier of the topical composition preferably facilitates the penetration of the compound into the skin. The carrier may further comprise one or more optional components.

[0314] The amount of carrier used with the disclosed compound is sufficient to provide a composition of a useful dose for administration per unit dose of the compound. Techniques and compositions for producing useful dosage forms in the method of the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0315] The carrier may consist of a single component or a combination of two or more components. In topical compositions, this carrier includes a topical carrier. Suitable topical carriers include one or more components selected from phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, and combinations thereof. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, and even more specifically, phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0316] The carrier for the topical composition may further include one or more components selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, dyes, and preservatives (all of which are optional).

[0317] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, and sebaci. Examples include di-n-butyl phosphate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for the skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in topical compositions for skin use is generally about 5% to about 95%.

[0318] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant in a topical composition is generally about 0% to about 95%.

[0319] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific examples of solvents include ethyl alcohol and homotopic alcohol. The amount of solvent in a topical composition is generally about 0% to about 95%.

[0320] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. A specific example of a humectant is glycerin. The amount of humectant in a topical composition is generally between 0% and 95%.

[0321] The amount of thickener in topical compositions is generally between approximately 0% and 95%.

[0322] Suitable powders include β-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's clay, kaolin, starch, rubber, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, aluminum silicate hydrate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder in a topical composition is generally 0% to 95%.

[0323] The amount of fragrance in topical compositions is generally about 0% to 0.5%, and especially about 0.001% to 0.1%.

[0324] Suitable pH-adjusting additives include HCl or NaOH in sufficient quantities to adjust the pH of the topical pharmaceutical composition.

[0325] The pharmaceutical composition or preparation has an EC of less than approximately 10 μM, less than approximately 5 μM, less than approximately 1 μM, less than approximately 500 nM, or less than approximately 100 nM. 50 Positive allosteric modulation of mAChR M4 can be observed. The pharmaceutical composition or formulation has an EC of about 10 μM to about 1 nM, about 1 μM to about 1 nM, about 100 nM to about 1 nM, or about 10 nM to about 1 nM. 50 This demonstrates the positive allosteric modulation of mAChR M4.

[0326] a. Spray-dried dispersion formulation The disclosed compounds can be formulated as spray-dried dispersions (SDDs). An SDD is a single-phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution containing a compound molecularly "dissolved" in a solid matrix. SDDs are obtained by dissolving the drug and polymer in an organic solvent and then spray-drying this solution. The use of spray-drying for pharmaceutical applications can result in amorphous dispersions with increased solubility for Biopharmaceutical Classification System (BCS) Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) drugs. Formulation and operating conditions are selected so that the given time is insufficient for phase separation or crystallization due to the rapid evaporation of the solvent from the droplets. SDDs exhibit long-term stability and manufacturability. For example, SDDs have demonstrated a shelf life exceeding two years. The advantages of SDD include, but are not limited to, enhanced oral bioavailability of water-soluble compounds, delivery using conventional solid dosage forms (e.g., tablets and capsules), a reproducible, controllable, and scalable manufacturing process, and broad applicability to structurally different insoluble compounds with a wide range of properties.

[0327] Therefore, in one embodiment, the present disclosure can provide a spray-dried dispersion formulation comprising a compound of formula (I).

[0328] 3.How to use The disclosed compounds, pharmaceutical compositions, and formulations can be used in methods for the treatment of disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions can also be used in methods for enhancing muscarinic acetylcholine receptor activity in mammals and for enhancing cognitive abilities in mammals. These methods further include co-therapeutic methods for improving treatment outcomes in the context of cognitive therapy or behavioral therapy. In the methods of use described herein, further therapeutic agents may be administered simultaneously with or sequentially with the disclosed compounds and compositions.

[0329] a. Treatment of the disability The disclosed compounds, pharmaceutical compositions, and formulations may be used for the treatment of or in methods for the treatment of disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. Methods of treatment may include administering a therapeutically effective amount of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of formula (I), to a subject requiring such treatment.

[0330] In some embodiments, the present disclosure provides a method for enhancing the cognitive abilities of a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I).

[0331] The compounds and compositions disclosed herein may be useful for treating, preventing, improving, controlling, or mitigating the risk of various disorders associated with selective mAChR M4 receptor activation. For example, treatment may include selective mAChR M4 receptor activation to an extent effective in affecting cholinergic activity. The disorder may be associated with cholinergic activity, e.g., impaired cholinergic function. Accordingly, a method is provided for treating or preventing a disorder in a subject, the method comprising the step of administering to the subject at least one disclosed compound or at least one disclosed pharmaceutical composition in an amount effective in treating the disorder in the subject.

[0332] Furthermore, a method is provided for treating one or more impairments related to mAChR M4 receptor activity in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0333] 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.

[0334] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for the treatment of disorders associated with the mAChR M4 receptor.

[0335] In some embodiments, the present disclosure provides a method for treating disorders associated with muscarinic acetylcholine receptor dysfunction in mammals, comprising the step of administering to a mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0336] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for treating disorders associated with dysfunction of muscarinic acetylcholine receptors in mammals.

[0337] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for treating disorders associated with dysfunction of muscarinic acetylcholine receptors in mammals.

[0338] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for the treatment of disorders associated with dysfunction of muscarinic acetylcholine receptors in mammals.

[0339] In some embodiments, the disclosed compounds and compositions are useful for treating a variety of neurological, psychiatric, and cognitive disorders associated with the mAChR M4 receptor, including one or more of the following conditions or diseases: schizophrenia, psychotic disorder not otherwise specified, short-term psychotic disorder, schizophrenic disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic seizures, delayed-onset psychosis, myxedema psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar type I disorder with psychotic features, and substance-induced psychotic disorder. In some embodiments, the psychotic disorder is a psychosis associated with a disease selected from major depressive disorder, affective disorder, bipolar disorder, electrolyte disorder, Alzheimer's disease, neuropathy, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder.

[0340] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for the treatment of neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, in particular, as described herein. In some embodiments, the Disclosure provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for the treatment of neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, in particular, as described herein. In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for the treatment of neurological, psychiatric, or cognitive disorders associated with the mAChR M4 receptor, in particular, as described herein.

[0341] 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.

[0342] In some embodiments, the disorder is a psychotic disorder selected from schizophrenia, brief psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder. In some embodiments, schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disintegrative schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizoid personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some embodiments, the mental disorder is due to a general medical condition and is substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine).

[0343] In some embodiments, the Disclosure provides a method for treating cognitive impairment, comprising administering an effective amount of a compound or composition of the Disclosure to a patient in need thereof. In some embodiments, cognitive impairment includes dementia (associated with Alzheimer's disease, ischemia, polyinfarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other common medical conditions or substance abuse), delirium, amnesia, substance-induced persistent delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinson's disease-ALS dementia complex, Alzheimer's type dementia, age-related cognitive decline, and mild cognitive impairment.

[0344] The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides diagnostic tools for cognitive impairments, including dementia, delirium, amnesic disorders, and age-related cognitive decline. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (2013, American Psychiatric Association, Washington DC) provides diagnostic tools for neurocognitive disorders (NCDs), including delirium, followed by severe NCDs, mild NCDs, and syndromes of their etiological subtypes. Severe or mild NCD subtypes include NCD due to Alzheimer's disease, vascular NCD, Lewy body NCD, NCD due to Parkinson's disease, frontotemporal NCD, NCD due to traumatic brain injury, NCD due to HIV infection, substance / drug-induced NCD, NCD due to Huntington's disease, NCD due to prion disease, NCD due to other medical conditions, NCD due to multiple etiologies, and NCD of unknown origin. The NCD category in DSM-5 encompasses a group of disorders in which the primary clinical deficit lies in cognitive function and is acquired rather than developmental. As used herein, the term “cognitive impairment” includes the treatment of cognitive and neurocognitive disorders as described in DSM-IV-TR or DSM-5. Skilled technicians recognize that there are alternative nomenclature, disease taxonomy, and classification systems for mental disorders, and these systems evolve with advances in medicine and science. Therefore, the term “cognitive impairment” is intended to include similar disorders as described in other diagnostic sources.

[0345] In some embodiments, the Disclosure provides a method for treating schizophrenia or psychosis, comprising administering an effective amount of a compound or composition of the Disclosure to a patient in need thereof. Specific schizophrenic or psychotic conditions include paranoid, disorganized, catatonic, or anaplastic schizophrenia and substance-induced psychotic disorders. The DSM-IV-TR provides diagnostic tools including paranoid, disorganized, catatonic, anaplastic, or residual schizophrenia and substance-induced psychotic disorders. The DSM-5 eliminates the subtypes of schizophrenia and instead includes a dimensional approach to assess the severity of the core symptoms of schizophrenia, capturing the diversity of symptom types and severity present among individuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the treatment of mental disorders as described in the DSM-IV-TR or DSM-5. Experienced technicians recognize that mental disorders have alternative nomenclature, disease classifications, and classification systems, and that these systems evolve with advances in medicine and science. Therefore, the term “schizophrenia or psychosis” is intended to include similar disorders described in other diagnostic sources.

[0346] In some embodiments, the Disclosure provides a method for treating pain, comprising administering an effective amount of the compound or composition of the Disclosure to a patient in need thereof. Specific forms of pain include bone and joint pain (osteoarthritis), pain from repetitive movements, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, and neuropathic pain.

[0347] This compound and composition may be even more useful in preventing, treating, controlling, improving, or reducing the risk of the diseases, disorders, and conditions referred to herein. This compound and composition may be even more useful in combination with other agents in methods for preventing, treating, controlling, improving, or reducing the risk of the aforementioned diseases, disorders, and conditions.

[0348] In the treatment of conditions requiring mAChR M4 activation, appropriate dose levels may range from approximately 0.01 to 500 mg / kg patient body weight / day, which can be administered as a single or multiple dose. Preferred dose levels may range from approximately 0.1 to approximately 250 mg / kg / day or approximately 0.5 to approximately 100 mg / kg / day. Preferred dose levels may range from approximately 0.01 to 250 mg / kg / day, approximately 0.05 to 100 mg / kg / day, or approximately 0.1 to 50 mg / kg / day. Within this range, doses may range from 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg / day. For oral administration, the composition is provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient, allowing for symptomatic adjustment of the dosage to the patient being treated. The compound can be administered 1 to 4 times daily, preferably in a regimen of once or twice daily. This dosage regimen can be adjusted to provide an optimal therapeutic response. However, it will be understood that the specific dose level and frequency for any particular patient can vary and depend on various factors, including the activity of the particular compound used, its metabolic stability and duration of action, age, weight, general health, sex, diet, mode and timing of administration, excretion rate, drug combinations, severity of the particular condition, and the host being treated.

[0349] Accordingly, in some embodiments, the present disclosure relates to a method for activating mAChR M4 receptor activity in at least one cell, comprising the step of contacting at least one cell with at least one disclosed compound or at least one product of the disclosed method in an amount effective to activate mAChR M4 in at least one cell. In some embodiments, the cell is a mammal, for example, human. In some embodiments, the cell is isolated from the subject before the contact step. In some embodiments, the contact is via administration to the subject.

[0350] In some embodiments, the present invention relates to a method for activating mAChR M4 activity in a subject, comprising the step of administering to the subject at least one disclosed compound or at least one product of the disclosed method in doses and amounts effective for activating mAChR M4 activity in the subject. In some embodiments, the subject is a mammal, for example, a human. In some embodiments, the mammal has been diagnosed as requiring mAChR M4 agonism prior to the administration step. In some embodiments, the mammal has been diagnosed as requiring mAChR M4 activity prior to the administration step. In some embodiments, the method further comprises the step of identifying a subject requiring mAChR M4 agonism.

[0351] In some embodiments, the present invention relates to a method for treating a disorder in a mammal associated with selective mAChR M4 activation, for example, a disorder associated with cholinergic activity, comprising the step of administering to a mammal at least one compound disclosed or at least one product of the disclosed method in a dosage and amount effective for treating the disorder in the mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as needing treatment for the disorder prior to the administration step. In some embodiments, the method further includes the step of identifying a subject that needs treatment for the disorder.

[0352] In some embodiments, the disorder may be selected from psychotic mood disorders such as psychosis, schizophrenia, conduct disorder, destructive behavior disorder, bipolar disorder, psychotic anxiety episodes, anxiety associated with psychosis, and severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral symptoms of intellectual disability, autism spectrum disorder, motor disorders, Tourette syndrome, akinesia-rigidity syndrome, motor disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0353] In some embodiments, the disorder is Alzheimer's disease.

[0354] b. Enhancement of muscarinic acetylcholine receptor activity In some embodiments, the present disclosure relates to a method for enhancing muscarinic acetylcholine receptor activity in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for enhancing the activity of muscarinic acetylcholine receptors in mammals. In some embodiments, the disclosure provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for enhancing the activity of muscarinic acetylcholine receptors in mammals.

[0356] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals that enhance the activity of muscarinic acetylcholine receptors in mammals.

[0357] In some embodiments, enhancement of muscarinic acetylcholine receptor activity increases muscarinic acetylcholine receptor activity. In some embodiments, enhancement of muscarinic acetylcholine receptor activity is partial activation of muscarinic acetylcholine receptors. In some embodiments, enhancement of muscarinic acetylcholine receptor activity is positive allosteric regulation of muscarinic acetylcholine receptors.

[0358] In some embodiments, the administered compound has an EC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. 50This shows enhancement of mAChR M4. In some embodiments, the administered compound is EC at approximately 10 μM to approximately 1 nM, approximately 1 μM to approximately 1 nM, approximately 100 nM to approximately 1 nM, or approximately 10 nM to approximately 1 nM. 50 This demonstrates the enhancement of mAChR M4.

[0359] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as needing enhancement of muscarinic acetylcholine receptor activity before the administration step. In some embodiments, the method further includes the step of identifying the mammal that needs enhancement of muscarinic acetylcholine receptor activity. In some embodiments, enhancement of muscarinic acetylcholine receptor activity treats a disorder related to muscarinic acetylcholine receptor activity in the mammal. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.

[0360] In some embodiments, enhancement of muscarinic acetylcholine receptor activity in mammals is related to the treatment of neurological and / or psychological disorders associated with muscarinic receptor dysfunction, such as the neurological or psychological disorders disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4.

[0361] In some embodiments, the present disclosure provides a method for enhancing muscarinic acetylcholine receptor activity in cells, comprising the step of contacting cells with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are mammalian (e.g., human). In some embodiments, the cells are isolated from the mammal before the contact step. In some embodiments, the contact is via administration to the mammal.

[0362] c. Improvement of cognitive abilities In some embodiments, the present invention relates to a method for enhancing the cognitive abilities of a mammal, the method comprising the step of administering to a mammal an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0363] In some embodiments, the Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for improving the cognitive abilities of mammals. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods for improving the cognitive abilities of mammals.

[0364] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for improving cognitive abilities in mammals.

[0365] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as needing cognitive enhancement prior to the administration step. In some embodiments, the method further includes the step of identifying the mammal that needs cognitive enhancement. In some embodiments, the need for cognitive enhancement is associated with muscarinic receptor dysfunction. In some embodiments, the muscarinic receptor is mAChR M4.

[0366] In some embodiments, the improvement in cognitive ability is a statistically significant increase in novel object recognition. In some embodiments, the improvement in cognitive ability is a statistically significant improvement in performance on the Wisconsin Card Sorting Test.

[0367] d.Co-treatment method The present invention further relates to the administration of selective mAChR M4 activators for improving therapeutic outcomes in the context of cognitive therapy or behavioral therapy. Specifically, in some embodiments, the present invention relates to a co-therapeutic method comprising the step of administering at least one disclosed compound or a pharmaceutically acceptable salt thereof in effective amounts and doses to a mammal.

[0368] In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a co-therapeutic method with cognitive or behavioral therapy in mammals. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a co-therapeutic method with cognitive or behavioral therapy in mammals.

[0369] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of pharmaceuticals for co-therapeutic methods with cognitive or behavioral therapy in mammals.

[0370] In some embodiments, the administration improves treatment outcomes in conjunction with cognitive or behavioral therapy. Administration in conjunction with cognitive or behavioral therapy may be continuous or intermittent. Administration does not need to be simultaneous with therapy and may be before, during, and / or after therapy. For example, cognitive or behavioral therapy may be provided within 1, 2, 3, 4, 5, 6, or 7 days before or after administration of the compound. As a further example, cognitive or behavioral therapy may be provided within 1, 2, 3, or 4 weeks before or after administration of the compound. As yet another example, cognitive or behavioral therapy may be provided before or after administration within the 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the compound being administered.

[0371] It is understood that the disclosed co-therapeutic methods may be used in connection with the disclosed compounds, compositions, kits, and their use.

[0372] e. Combination therapy In the methods of use described herein, further therapeutic agents may be administered simultaneously with or consecutively with the disclosed compound and composition. Consecutive administration includes administration before or after the disclosed compound and composition. In some embodiments, the additional therapeutic agent may be administered in the same composition as the disclosed compound. In other embodiments, there may be a time interval between the administration of the additional therapeutic agent and the administration of the disclosed compound. In some embodiments, administration of the additional therapeutic agent with the disclosed compound may allow for administration of other therapeutic agents at lower doses and / or at less frequent intervals. When used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used at lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compound of formula (I). The above combinations include not only combinations of the compound of the present invention with one other active compound, but also combinations with two or more other active compounds.

[0373] The disclosed compound may be used as a single agent or in combination with one or more other agents in the treatment, prevention, control, improvement or reduction of risk of the aforementioned diseases, disorders and conditions in which the compound or other agents are useful, where the combination of agents is safer or more effective than either agent alone. The other agents may be administered simultaneously with or immediately following the disclosed compound, in the routes and amounts commonly used for such administration. When the disclosed compound is used simultaneously with one or more other agents, a pharmaceutical composition in unit dosage form containing such agents and the disclosed compound may be used. However, combination therapy may also be administered on overlapping schedules. It is also conceivable that a combination of one or more active ingredients and the disclosed compound may be more effective than any of them as single agents. Therefore, when used in combination with one or more other active ingredients, the disclosed compound and the other active ingredients may be used at lower doses than when each is used alone.

[0374] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutic compounds described herein that are typically applied to the treatment of the above-mentioned pathological conditions.

[0375] The above combinations include not only combinations of the disclosed compound with one other active compound, but also combinations with two or more other active compounds. Similarly, the disclosed compound can be used in combination with other drugs used in the prevention, treatment, control, improvement, or reduction of risk of diseases or conditions in which the disclosed compound is useful. Such other drugs can be administered simultaneously with or sequentially to the compound of the present invention in the routes and amounts commonly used for that purpose. When the compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing these other drugs in addition to the disclosed compound is preferred. Therefore, such pharmaceutical compositions may include those containing one or more other active ingredients in addition to the compound of the present invention.

[0376] The weight ratio of the disclosed compound to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, the effective dose of each is used. For example, when the compound of the present invention is combined with another agent, the weight ratio of the disclosed compound to the other agent is generally in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. The combination of the compound of the present invention with other active ingredients is also generally within the range described above, but the effective dose of each active ingredient should be used in each case.

[0377] In such combinations, the disclosed compound and other active agents can be administered separately or together. Furthermore, the administration of one element may occur before, simultaneously with, or after the administration of the other agent.

[0378] Therefore, the disclosed compound may be used alone or in combination with other agents known to be beneficial for the target indication, or with other agents that affect receptors or enzymes, thereby increasing the efficacy, safety, or convenience of the disclosed compound, or reducing undesirable side effects or toxicity. The target compound and other agents may be administered simultaneously in combination therapy or in certain amounts.

[0379] In some embodiments, the compound can be used in combination with anti-Alzheimer's drugs, β-secretase inhibitors, cholinergics, γ-secretase inhibitors, HMG-CoA reductase inhibitors, M1 allosteric agonists, M1 positive allosteric modulators, NSAIDs including ibuprofen, vitamin E, and anti-amyloid antibodies. In other embodiments, the compound in question can be used with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), anxiolytics, cyclopyrrolone, imidazopyridine, pyrazolopyrimidine, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, barbiturates, 5HT-2 antagonists, such as azinazolam, arobarbital, aronimide, alprazolam, amisulpride, amitriptyline, amobarbital. Tar, amoxapine, aripiprazole, bentazepam, benzothamine, brotizolam, bupropion, buspirone, butabarbital, butarbital, capride, carbochloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, chlorate, chlorpromazine, clozapine, siprazepam, desipramine, dexcramol, diazepam, dichlor Luphenazone, divalproex, diphenhydramine, doxepin, estazolam, etochlorbinol, etomidate, phenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimid, harazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, meclocalon, melatonin, mefobarbital, meprobamate Metacaron, Midaflul, Midazolam, Nefazodone, Nisobamate, Nitrazepam, Nortriptyline, Olanzapine, Oxazepam, Paraaldehyde, Paroxetine, Pentobarbital, Perlapine, Perphenazine, Phenelzine, Phenobarbital, Prazepam, Promethazine, Propofol, Protriptyline, Quazepam, Quetiapine, Leclazepam, Risperidone, Lorethamide, Secobarbital, Sertraline, Suprocron, Temazepam,Thioridazine, thiothixen, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimethodine, trimipramine, urdazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and their salts, and combinations thereof, etc., can be used in combination with these, or the target compound can be administered in combination with the use of physical methods such as phototherapy or electrical stimulation.

[0380] In some embodiments, the compound can be used in combination with levodopa (with or without a selective extraneurodecarboxylase inhibitor such as carbidopa or benserazide), anticholinergics (e.g., biperiden (optionally as its hydrochloride or lactate) and trihexyphenidyl (benzhexol) hydrochloride), COMT inhibitors (e.g., entacapone), MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, choline agonists, NMDA receptor antagonists, serotonin receptor antagonists, and dopamine receptor agonists (e.g., allentemol, bromocriptine, phenoldopam, rislide, naxagolide, pergolide, and pramipexole). It is understood that dopamine agonists may be in the form of pharmaceutically acceptable salts, such as alentemol hydrobromide, bromocriptine mesylate, phenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Lithulide and pramipexole are typically used in their non-salt forms.

[0381] In some embodiments, the compound can be used in combination with compounds from the classes of nerve relaxants: phenothiazines, thioxanthenes, heterocyclic dibenzoazepines, butyrophenones, diphenylbutylpiperidines, and indolones. Suitable examples of phenothiazines include chlorpromazine, mesolidazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is morindron. Other nerve blockers include roxapine, sulpiride, and risperidone. It should be understood that when nerve relaxants are used in combination with the target compound, they may be in pharmaceutically acceptable salt forms, such as chlorpromazine hydrochloride, mesolidazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, flurphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, roxapine succinate, and morindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide, and risperidone are commonly used in non-salt forms. Therefore, the compounds of the present invention can be used in combination with acetophenazine, allentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixen, clozapine, diazepam, phenoldopam, fluphenazine, haloperidol, levodopa, levodopa and benserazide, levodopa and carbidopa, rislid, roxapine, mesolidazine, morindron, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixen, trifluoperazine, or ziprasidone.

[0382] In some embodiments, the compound can be used in combination with antidepressants or anxiolytics, including norepinephrine reuptake inhibitors (including tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, α-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, particularly 5-HT1A partial agonists, and corticotropin-releasing factor (CRF) antagonists. Specific drugs include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazide, phenelzine, tranylcypromine, and selegiline; moclobemide; venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone, and piroxazine; alprazolam, chlordiazepoxide, clonazepam, clorazepic acid, diazepam, harazepam, lorazepam, oxazepam, and prazepam; buspirone, fresinoxane, gepirone, and ipsapirone, as well as their pharmaceutically acceptable salts.

[0383] In some embodiments, the compound can be administered co-administered with an orthosteric muscarinic agonist, a muscarinic enhancer, or a cholinesterase inhibitor. In some embodiments, the compound can be administered co-administered with GlyT1 inhibitors, including but not limited to risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and their salts, as well as combinations thereof.

[0384] f. Mode of administration The therapeutic method may include any number of forms of administration of the disclosed composition. Forms of administration may include tablets, pills, sugar-coated tablets, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the drug may be mixed with commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (e.g., mannitose, methylcellulose, lactose, etc.), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g., etheric oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol), or bioavailability enhancers (e.g., Gelucire®). In pharmaceutical compositions, the drug may also be dispersed in fine particles, such as nanoparticle compositions.

[0385] For parenteral administration, the drug may be dissolved or suspended in a physiologically acceptable diluent, such as water, a buffer, an oil with or without a solubilizer, a surfactant, a dispersant, or an emulsifier. Examples of oils that can be used include, but are not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil. More generally, for parenteral administration, the drug may be in the form of an aqueous, lipid, oily, or other type of solution or suspension, or it may be administered in the form of liposomes or nanosuspensions.

[0386] As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions.

[0387] 4. Kit In one embodiment, the present disclosure provides a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof and one or more of the following: (a) At least one agent known to increase mAChR M4 activity; (b) At least one drug known to reduce mAChR M4 activity; (c) At least one drug known to treat disorders related to cholinergic activity; (d) Instructions for the treatment of disorders related to cholinergic activity; (e) Instructions for the treatment of disorders related to M4 receptor activity; or (f) Instructions for administering compounds related to cognitive therapy or behavioral therapy.

[0388] In some embodiments, at least one disclosed compound and at least one drug are co-formulated. In some embodiments, at least one disclosed compound and at least one drug are co-packaged. These kits may also include compounds and / or products that are co-packaged, co-formulated and / or co-delivered together with other components. For example, a drug manufacturer, drug distributor, physician, pharmacy or pharmacist may provide a kit containing the disclosed compound and / or product and another component for delivery to a patient.

[0389] The disclosed kit can be used in conjunction with the disclosed method of use.

[0390] These kits may include information, descriptions, or both indicating that the use of the kit may provide treatment for a medical condition in mammals (especially humans). This information and descriptions may be in the form of words, images, or both. The kits may further or selectively include information, descriptions, or both indicating a compound, composition, or both that has the benefit of treating or preventing a medical condition in mammals (e.g., humans); and a method of applying the compound or composition.

[0391] The compounds and processes of the present invention will be better understood by referring to the following examples, which are intended to illustrate but not limit the scope of the invention. [Examples]

[0392] 5. Examples All NMR spectra were recorded using a 400 MHz AMX Bruker NMR spectrometer. 1 The H chemical shift is reported as a δ value at ppm (low field) using a deuterated solvent as an internal standard. The data are reported as follows: chemical shift, multiplicity (s=single line, bs=broad single line, d=double line, t=triple line, q=quadruple line, dd=double line of double lines, m=multiple line, ABq=AB quadruple line), coupling constant, and integral value. Reverse-phase LC-MS analysis was performed using an Agilent 1200 system consisting of a binary pump with degasser, high-performance autosampler, thermostat-equipped column compartment, C18 column, diode array detector (DAD), and Agilent 6150 MSD, with the following parameters. The gradient conditions were 5% to 95% acetonitrile over 1.4 minutes (aqueous phase: 0.1% TFA (in water)), held in 95% acetonitrile for 0.1 min, 0.5 mL / min, 55°C ("90-second method"). The sample was separated at 0.5 mL / min using a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 × 50 mm) while maintaining the column and solvent temperature at 55°C. The DAD was set to scan at 190–300 nm, and the signals used were at 220 nm and 254 nm (both using a 4 nm wide band). The MS detector was set up with an electrospray ionization source, and low-resolution mass spectra were obtained by scanning at 140–700 AMU with a step size of 0.2 AMU and a peak width of 0.008 min at 0.13 cycles / second. The drying gas flow was set to 13 liters / min at 300°C, and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set to 3000 V, and the fragmenter voltage was set to 100 V. Data was acquired using Agilent Chemstation and Analytical Studio Reviewer software.

[0393] a. Preparation of intermediates [ka] 1-Methylcyclopropanecarbothioamide. Lawson's reagent (4.5 g, 11.1 mmol) was added to a suspension of 1-methylcyclopropanecarboxamide (1.1 g, 11.1 mmol) and sodium carbonate (1.2 g, 11.1 mmol) in THF (55 mL), and the reaction mixture was heated to 70°C. After 2 hours, the reaction mixture was concentrated, and the resulting residue was diluted with SiO2 and washed with water (2x) and brine. The organic layer was concentrated and dried under high vacuum to obtain the title compound (1.2 g). ES-MS[M+1] + :116.9.

[0394] [ka] 1-Fluorocyclopropane-1-carbothioamide. Lawson's reagent (1.96 g, 4.85 mmol) was added to a suspension of 1-fluorocyclopropanecarboxamide (500 mg, 4.85 mmol) and sodium carbonate (524 mg, 4.85 mmol) in THF (24 mL). The resulting mixture was heated to 70°C. After 36 hours, the reaction mixture was concentrated, and the resulting residue was diluted with ELISA and washed with water (2x) and brine. The organic layer was concentrated to obtain the target compound, which was then proceeded to the next step without further purification. 1 H NMR(400MHz,DMSO)δ 9.74(d,J=194.7Hz,2H),1.63(td,J=8.7,5.2Hz,2H),1.49-1.38(m,2H).

[0395] [ka] 2-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. N-Boc-3-bromo-4-oxopiperidine (2.5 g, 9.0 mmol) was added to a suspension of 1-methylcyclopropanecarbothioamide (1.0 g, 9.0 mmol) in ethanol (46 mL), and the reaction mixture was heated at 80 °C for 48 hours. The crude reaction mixture was concentrated under vacuum. DCM (25 mL) and TFA (6.9 mL) were added to the residue. After 1 hour at rt, the reaction mixture was concentrated. The residue was dissolved in toluene and saturated Na2CO3 solution. The mixture was separated, and the aqueous layer was extracted with toluene (2x). The combined organic layers were dried in (MgSO4), filtered, and concentrated. The residue was purified by normal-phase column chromatography (0-70% toluene / hexane, followed by a 0-10% DCM:MeOH:1% NH4OH gradient) to obtain the title compound (1.59 g). 1 H NMR (400MHz, CDCl3)δ 4.00(t,J=1.8Hz,2H),3.71(t,J=5.8Hz,2H),2.80-2.76(m,2H),1.54(s,3H),1.23(dd,J=6.8,4.4Hz,2H),0.91(dd,J=6.5,4.1Hz,2H);ES-MS[M+1] + :295.1 and 195.1.

[0396] [ka] 2-Cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride. Cyclopropanecarbothioamide (1.8 g, 18.0 mmol) and N-Boc-3-bromo-4-oxopiperidine (5.0 g, 18.0 mmol) were stirred in ethanol (30 mL) at 80°C for 2 hours. The solution was concentrated, and then 1,4-dioxane (8 mL) and a 4 M hydrochloric acid solution in 1,4-dioxane (40 mL) were added. After 1 hour at rt, the solution was concentrated under vacuum to obtain the title compound (4.0 g). 1H NMR(400MHz,DMSO-d6)δ 4.30(s,2H),2.91(t,J=6.0Hz,2H),2.59(t,J=6.5Hz,2H),2.41-2.35(m,1H),1.13-1.08(m,2H),0.95-0.91(m,2H);ES-MS[M+1] + :181.4.

[0397] [ka] 2-(2,2-dimethylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. In a vial, 2,2-dimethylcyclopropanecarbothioamide (232 mg, 1.8 mmol) and N-Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) were combined in ethanol (2 mL). After 2 hours at 80°C, the reaction mixture was concentrated. DCM (2 mL) and trifluoroacetic acid (1.38 mL) were added to the crude residue. After 1 hour at rt, the solution was concentrated, diluted with saturated Na2CO3 aqueous solution, and extracted with DCM (3x). The combined organic layer was passed through a hydrophobic phase separator and concentrated to obtain the title compound (195 mg). 1 H NMR(400MHz,DMSO)δ 3.83(d,J=1.8Hz,2H),2.96(t,J=5.8Hz,2H),2.61(t,J=4.1.2H),2.14(dd, J=8.4,5.6Hz,1H),1.17(s,3H),1.11-1.01(m,2H),0.97(s,3H);ES-MS[M+1] + :209.3.

[0398] [ka] 2-Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. A vial containing 2-methylpropanethioamide (185 mg, 1.8 mmol) and N-Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) in ethanol (2 mL) was heated at 80°C for 2 hours. The reaction mixture was concentrated. DCM (2 mL) and trifluoroacetic acid (1.38 mL) were added to the crude residue. After 1 hour, the solution was concentrated and diluted with saturated Na2CO3 solution, and the aqueous layer was extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to obtain the title compound (372 mg). 1 H NMR(400MHz,CDCl3)δ 4.40(s,2H),3.53(t,J=6.1Hz,2H),3.29(p,J=6.9Hz,1H),3.17(t,J=5.8Hz,2H),1.38(d,J=6.9Hz,6H);ES-MS[M+1] + :183.2.

[0399] [ka] 2-(tert-butyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. A vial containing 2,2-dimethylpropanethioamide (211 mg, 1.8 mmol) and N-Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) in ethanol (2 mL) was heated at 80°C for 2 hours. The solution was concentrated. DCM (2 mL) and trifluoroacetic acid (1.38 mL) were added to the crude residue. After 1 hour at rt, the reaction mixture was concentrated and purified using an SCX cartridge. After elution with 2N NH3 / MeOH solution, the solvent was removed to obtain the title compound (238 mg). 1 H NMR(400MHz,DMSO)δ 3.83(t,J=1.9Hz,2H),2.96(t,J=5.8Hz,2H),2.61(t,J=5.8,1.9Hz,2H),1.34(s,9H);ES-MS[M+1] + :197.1.

[0400] [ka] 2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. 1-fluorocyclopropane-1-carbothioamide (114 mg, 0.72 mmol) and N-Boc-3-bromo-4-oxopiperidine (200 mg, 0.72 mmol) were heated in ethanol (2.3 mL) at 80°C for 18 hours. The reaction mixture was concentrated, and the residue was purified by normal-phase column chromatography (0-80% siRNA / hexane). DCM and trifluoroacetic acid (2.0 mL; 2:1) were added to the residue at room temperature. After 3 hours, the solution was concentrated, and the substance was purified using an SCX cartridge. After elution with 2N NH3 / MeOH solution, the solvent was removed to obtain the title compound. ES-MS[M+1] + :199; 1 H NMR(400MHz,DMSO)δ 3.92(t,J=1.9Hz,2H),2.99(t,J=5.8Hz,2H),2.63(tt,J=5.9,1.9Hz,2H),1.70-1.55(m,2H),1.40-1.28(m,2H).

[0401] [ka] 2-Cyclobutyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. Cyclobutanecarbothioamide (203 mg, 1.76 mmol) and N-boc-3-bromo-4-oxopiperidine (490 mg, 1.76 mmol) were stirred in ethanol (4.5 mL) at 80°C for 2 hours. The solution was concentrated, and then DCM (4.0 mL) and trifluoroacetic acid (1.35 mL) were added over 1 hour at room temperature. The solution was concentrated, and then diluted with toluene and saturated Na2CO3 solution. The layers were separated, and the aqueous layer was extracted with toluene (2x). The combined organic layers were dried over (MgSO4), filtered, and concentrated to obtain the title compound (300 mg). ES-MS[M+1] + :195; 1H NMR(400MHz,CDCl3)δ 4.21(s,2H),3.83-3.72(m,2H),3.33(t,J=6.0Hz,2H),2.94(t,J=5.8Hz,2H),2.49-2.37(m,2H),2.37-2.24(m,2H),2.12-1.84(m,2H).

[0402] [ka] 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2,2,2-trifluoroacetate. A vial containing 6-Boc-2-bromo-4,5,6,7-tetrahydro-6-azabenzothiazole (170 mg, 0.53 mmol) and trifluoromethyl(1,10-phenanthroline)copper (200 mg, 0.64 mmol) in DMA (2 mL) was heated at 100 °C for 18 hours. The reaction product was diluted with water and ethyl acetate. The organic matter was extracted with water (3x) and brine (3x), dried, filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-30% toluene / hexane) to obtain Boc-protected 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine, which was dissolved in DCM (2 mL) and trifluoroacetic acid (0.49 mL) and stirred for 2 hours. The reaction product was concentrated to obtain the title compound (58 mg). 1 H NMR(400MHz,CDCl3)δ 4.52(s,2H),3.60(t,J=6.0Hz,2H),3.28(t,J=5.9Hz,2H);ES-MS[M+1] + :209.1.

[0403] [ka] tert-butyl 2-(methyl-d3)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate. At -78°C, n-BuLi (150 μL, 0.38 mmol) was added to a solution of tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (100 mg, 0.31 mmol) in THF (3.1 mL). After 10 minutes at -78°C, iodomethane-d3 (97.5 μL, 1.57 mmol) was added. After another 1 hour, water was added to the reaction mixture and the mixture was warmed to ambient temperature. The mixture was extracted with ELISA (1x), then with chloroform / IPA (3:1) (2x). The organic phases were combined, dried (MgSO4), filtered, and concentrated. The crude substance was purified using normal-phase column chromatography (0-50% toluene / hexane) to obtain the title compound (49 mg). ES-MS[M+H] + =358.

[0404] [ka] 2-(methyl-d3)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. 49.3 mg, 0.19 mmol of tert-butyl 2-(methyl-d3)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate () (tert-butyl 2-(methyl-d3)-6,7-di + = 158.

[0405] [ka] 2-Chloro-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine, 2,2,2-trifluoroacetate. Trifluoroacetic acid (0.7 mL, 9.1 mmol) was added to a 5 mL solution of 6-Boc-2-chloro-4,5,6,7-tetrahydro-6-azabenzothiazole (250 mg, 0.91 mmol) in DCM. After 1 hour, the reaction product was concentrated to obtain the title compound (195 mg). ES-MS[M+1] + :175.0.

[0406] [ka] 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-amine, 2,2,2-trifluoroacetate. Trifluoroacetic acid (0.3 mL, 3.92 mmol) was added to a solution of 6-Boc-2-amino-4,5,6,7-tetrahydro-6-azabenzothiazole (100 mg, 0.39 mmol) in DCM (5 mL). After 1 hour, the reaction product was concentrated to obtain the title compound (48 mg). ES-MS[M+1] + :156.1.

[0407] [ka] 2-(thiophen-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. In a vial, thiophen-2-boronic acid (105 mg, 0.82 mmol), 6-Boc-2-bromo-4,5,6,7-tetrahydro-6-azabenzothiazole (175 mg, 0.55 mmol), sodium carbonate (148 mg, 1.37 mmol), and tetrakis(triphenylphosphine)palladium (0) were combined in 1,4-dioxane (2 mL) and water (0.5 mL). The reaction mixture was purged with nitrogen (3x) and then heated at 80°C for 2 hours. The reaction mixture was filtered through Celite® and washed with Celite® in DCM (2 × 25 mL). The reaction mixture was concentrated, and the filtrate was purified by normal-phase chromatography (0-40% siRNA / hexane) to obtain the desired Boc amine. The above residue was dissolved in DCM (2 mL) and trifluoroacetic acid (0.59 mL). After 1 hour, the reaction product was concentrated, basicized with saturated Na2CO3, extracted with DCM (3x), passed through a hydrophobic phase separator, and concentrated to obtain the title compound (112 mg). 1 H NMR(400MHz,CDCl3)δ 7.44(dd,J=3.7,1.2Hz,1H),7.36(dd,J=5.1,1.2Hz,1H),7.06(dd,J=5.1,3.7Hz,1H ),4.10(s,2H),3.24(t,J=5.9Hz,2H),2.90(ddd,J=6.0,4.1,1.8Hz,2H);ES-MS[M+1] + :223.1.

[0408] [ka] 2-(1-methyl-1H-pyrazole-5-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. 6-Boc-2-bromo-4,5,6,7-tetrahydro-6-azabenzothiazole (300 mg, 0.94 mmol), cesium carbonate (924 mg, 2.82 mmol), Pd(dppf)Cl2 (69 mg, 0.09 mmol), and 1-methylpyrazole-5-boronic acid pinacol ester (391 mg, 1.88 mmol) were heated at 105°C for 18 hours in 1,4-dioxane (2.3 mL) and water (0.4 mL). The mixture was filtered through a Celite® pad, and the filtrate was concentrated. The residue was purified by normal-phase chromatography (0-40% toluene / hexane) to obtain Boc-amine, which was dissolved in DCM (2 mL) and trifluoroacetic acid (1.1 mL). After 1 hour, the reaction mixture was concentrated, basicized with saturated Na2CO3 solution, extracted with DCM (3x), passed through a hydrophobic phase separator, and concentrated to obtain the title compound (162 mg). 1 H NMR(400MHz,CDCl3)δ 7.47(d,J=2.0Hz,1H),6.60(d,J=2.1Hz,1H),4.26(d,J=1.6Hz,2H),4.22(s,3H),3.39(t,J=5.9Hz,2H),3.10-3.01(m,2H);ES-MS[M+1] + :221.2.

[0409] [ka] tert-butyl 2-carbamoyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate. 5-(tert-butyl)2-ethyl 6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate (300 mg, 0.96 mmol) was dissolved in ethanol (5 mL) and then NaOH aqueous solution (0.38 mL, 5 M) was added. The mixture was stirred at rt for 3 hours. The reaction mixture was concentrated and the process proceeded without further purification. DIEA (1.67 mL), HATU (1.1 g), and NH4Cl (285 mg) were added to the reaction mixture in THF (3.2 mL). The reaction mixture was heated to 75°C. After 18 hours, water (2 mL) was added and the mixture was extracted with chloroform / IPA (3:1) (3x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude substance was purified using normal-phase column chromatography (0-2% MeOH / DCM) to obtain the title compound. 1 H NMR(400MHz,CDCl3)δ 7.01(s,1H),5.46(s,1H),4.71(s,2H),3.77(t,J=5.3Hz,2H),2.90(t,J=5.1Hz,2H),1.49(s,9H);ES-MS[M+H] + =284.

[0410] [ka] 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide. The title compound was obtained by preparation in the same manner as 2-(methyl-d3)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. 1 H NMR(400MHz,DMSO-d6)δ 7.15(s,1H),6.80(s,1H),3.05(t,J=1.7Hz,2H),2.10(t,J=5.8Hz,2H),1.83(ddd,J=7.4,3.8,1.5Hz,2H);ES-MS[M+H] + =184.

[0411] [ka] 6-Chloro-5-methylpyridine-2,3-diamine. Iron powder (1.79 g, 32.0 mmol) was added to an isopropanol (34 mL) / water (17 mL) suspension of 6-chloro-5-methyl-3-nitropyridine-2-amine (2.0 g, 10.7 mmol) and ammonium chloride (1.05 g, 21.3 mmol). The resulting mixture was stirred at 90°C for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate, filtered through a Celite® pad, and washed with ethyl acetate. The filtrate was successively washed with water (3x) and brine. The pooled aqueous washings were extracted with ethyl acetate (2x), the combined organic layers were dried (MgSO4), filtered, and concentrated. The process was carried out without further purification of the material. ES-MS[M+1] + :158.

[0412] [ka] 6-Chloro-7-methylpyrido[2,3-b]pyrazine. 6-Chloro-5-methylpyridine-2,3-diamine (1.68 g, 10.7 mmol) was dissolved in THF (53 mL), and glyoxal (3.0 mL, 26.7 mmol) (40% w / w aqueous solution) was added. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified using normal-phase column chromatography (0-45% siRNA / DCM) on silica gel to obtain the title compound (1.15 g). 1 H NMR(400MHz,MeOD)δ 9.02(d,J=1.9Hz,1H),9.00(d,J=1.9Hz,1H),8.47(q,J=1.1Hz,1H),2.66(d,J=1.0Hz,3H).ES-MS[M+1] + :180.

[0413] Synthesis of 7-chloro-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one. [ka] (i) 5-(((6-chloro-4-methylpyridazin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione. To a solution of 6-chloro-4-methylpyridazin-3-amine (100 mg) in ethanol (1.2 mL), triethyl orthoformate (0.174 mL) and isopropylidene malonate (151 mg) were added at ambient temperature. The reaction mixture was then heated at 60°C for 18 hours. The reaction mixture was filtered, and the cake was washed with ethanol (3 x 5 mL) to obtain the title compound, which was then removed without further purification. ES-MS[M+1] + :298.

[0414] (ii) 7-Chloro-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (title compound). A solution of 5-(((6-chloro-4-methylpyridazin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione in Dowtherm™ A (1 mL) was stirred at 220 °C for 1 hour. After cooling to rt, the mixture was added to water and acidified with 1 M HCl. The aqueous layer was extracted with hexane (3 × 125 mL). The aqueous layer was neutralized with aqueous NaHCO3 solution and the mixture was extracted with chloroform / IPA (4:1) (3x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to obtain the title compound. 1 H NMR(400MHz,CD3OD)δ 8.34(d,J=6.4Hz,1H),7.68(q,J=1.3Hz,1H),6.69(d,J=6.4Hz,1H),2.60(d,J=1.3Hz,3H);ES-MS[M+1] + :196.

[0415] [ka] 7-Chloro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one. 1 g of 6-chloro-3-amino-5-methylpyridazine was dissolved in 5 mL of polyphosphate, to which 1.76 mL of ethyl acetoacetate was added. The mixture was heated at 120°C for 18 hours. While still hot, the mixture was slowly added to 150 mL of a stirred solution of saturated NaHCO3. The aqueous layer was extracted three times with chloroform:IPA (4:1). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by normal-phase column chromatography (0-70% siRNA / DCM) on silica gel to obtain 1.34 g of the title compound. 1 H NMR(400MHz,CDCl3)δ 7.59(q,J=1.3Hz,1H),6.50(s,1H),2.50(d,J=1.3Hz,3H),2.43(d,J=0.7Hz,3H).ES-MS[M+1] + :210.

[0416] [ka] 7-Chloro-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one. 6-Chloro-3-amino-5-methylpyridazine (500 mg) was dissolved in polyphosphate (5 mL) and ethyl 4,4,4-trifluoroacetoacetate (1.02 mL) was added. The mixture was heated at 120°C for 18 hours. While still hot, the mixture was slowly added to a saturated solution of NaHCO3 (150 mL) and 50 mL of chloroform / IPA (4:1) while maintaining the pH at approximately 7. After the addition was complete, the mixture was stirred for 15 minutes and the organic layer was separated. The aqueous layer was further extracted three times with chloroform:IPA (4:1). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in 15 mL of DMSO, and the filtrate was purified by RP-HPLC (5-45% MeCN / 0.05% NH4OH aqueous solution). The fraction containing the product was concentrated to obtain the title compound. 1H NMR(400MHz,CDCl3)δ 7.79(q,J=1.3Hz,1H),6.98(s,1H),2.56(d,J=1.3Hz,3H).ES-MS[M+1] + :264.

[0417] [ka] 7-Chloro-3-fluoro-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one. To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (550 mg) in Dowtherm® A (4 mL), ethyl 2-fluoro-3-oxobutanoate (0.53 mL) was added, and the reaction mixture was heated at 150°C for 18 hours. An additional ethyl 2-fluoro-3-oxobutanoate (0.53 mL) was added, and the reaction mixture was stirred at 150°C for a further 18 hours. The reaction mixture was directly purified by normal-phase column chromatography on silica gel (0-20% hexane / Depositphotos; followed by 0-30% Depositphotos / DCM) to obtain 243 mg of the title compound. 1 H NMR(400MHz,CDCl3)δ 2.62(d,J=0.9Hz,3H),2.51(d,J=3.6Hz,3H),2.48(t,J=0.9Hz,3H).ES-MS[M+1] + :268.

[0418] [ka] 7-Chloro-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one. To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in Dowtherm® A (2 mL), ethyl 2-methyl-3-oxobutanoate (0.59 mL) was added, and the reaction mixture was heated at 150°C for 18 hours. Further addition of ethyl 2-methyl-3-oxobutanoate (0.59 mL) was added, and the reaction mixture was irradiated in a microwave reactor at 180°C for 15 minutes. The solution was directly purified by normal-phase column chromatography (100% Hex, followed by 0-80% siRNA / DCM) on silica gel to obtain 442 mg of the title compound. 1 H NMR(400MHz,CDCl3)δ 7.53(q,J=1.3Hz,1H),2.47(d,J=1.3Hz,3H),2.45(s,3H),2.26(s,3H).ES-MS[M+1] + :224.

[0419] [ka] 7-Chloro-2-(difluoromethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (I-13). To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in polyphosphate (PPA) (5 mL), ethyl 4,4-difluoroacetoacetate (0.91 mL) was added. The mixture was heated at 120 °C for 2 hours. While still hot, the mixture was slowly added to a beaker containing 125 mL of saturated NaHCO3 and 50 mL of chloroform / IPA (4:1), while maintaining the pH at approximately 7. After the addition was complete, the mixture was stirred for 15 minutes, and the organic layer was separated. The aqueous layer was further extracted three times with chloroform:IPA (4:1). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in DMSO (15 mL) and purified by RP-HPLC (0-45% MeCN / 0.05% NH4OH aqueous solution). The fraction containing the product was concentrated to obtain 640 mg of the title compound. 1H NMR(400MHz,CDCl3)δ 7.73(q,J=1.3Hz,1H),6.90(s,1H),6.46(t,J=54.8Hz,1H),2.55(d,J=1.3Hz,3H).ES-MS[M+1] + :246.

[0420] [ka] 7-Chloro-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one. Ethyl 2-fluoroacetate (0.96 mL) was added to a solution of 6-chloro-3-amino-5-methylpyridazine (550 mg) in polyphosphate (5.5 mL). The mixture was heated at 120°C for 2 hours. The mixture was quenched by slowly adding the reactants to a solution of saturated sodium bicarbonate (150 mL) and 4:1 chloroform / IPA (50 mL) at rt. After the addition was complete, the mixture was stirred for 15 minutes, and the organic layer was separated. The aqueous layer was further extracted three times with chloroform:IPA (4:1). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by RP-HPLC (0-45% MeCN / 0.05% NH4OH aqueous solution). The fraction containing the product was concentrated to obtain 627 mg of the title compound. 1 H NMR(400MHz,CDCl3)δ 7.60(q,J=1.3Hz,1H),2.52-2.47(m,6H).ES-MS[M+H] + =228.

[0421] [ka] Ethyl 7-chloro-8-methyl-4-oxo-4H-pyrimido[1,2-b]pyridazine-2-carboxylate. A mixture of diethyl ethoxymethylene malonate (641 μL) and 6-chloro-3-amino-5-methylpyridazine (500 mg) in Dowtherm® A (6 mL) was heated at 200 °C for 18 hours. The reaction mixture was cooled to room temperature and purified by normal-phase chromatography (0-55% Â / DCM). The fraction containing the desired product was concentrated and further purified by reverse-phase HPLC (5-50% ACN / 0.05% NH4OH aqueous solution). The fraction containing the product was concentrated to obtain the title compound (250 mg). 1 H NMR(400MHz,CDCl3)δ 8.93(s,1H),7.75(s,1H),4.42(q,J=7.1Hz,2H),2.57(d,J=0.9Hz,3H),1.41(t,J=7.1Hz,3H).ES-MS[M+1] + :268.

[0422] [ka] 7-chloro-8-methyl-4-oxo-4H-pyrimido[1,2-b]pyridazin-2-carboxylic acid. To a solution of ethyl 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-8-methyl-4-oxo-4H-pyrimido[1,2-b]pyridazin-2-carboxylate (134 mg, 0.30 mmol) in THF (0.30 mL), sodium hydroxide (293 μL, 0.60 mmol; 2 M aqueous solution) was added at ambient temperature. After 3 hours, the solution was cooled in an ice bath and diluted with water (0.30 mL). The pH was adjusted to 5-6 by adding 1 M HCl dropwise, and the product was extracted with CHCl3 / IPA (3:1) (3x). The combined organic layers were dried (MgSO4) and concentrated under vacuum to obtain the title compound (114 mg). ES-MS[M+H] + = 422 / 424.

[0423] [ka] 7-Chloro-8-methyl-2H-pyrimido[1,2-b]pyridazin-2-one. 6-chloro-5-methylpyridazin-3-amine (300 mg, 2.1 mmol) and ethyl propiolate (212 μL, 2.1 mmol) in ethanol (3.1 mL) were added to a microwave vial. The vial was sealed and heated at 80°C for 18 hours. The reaction mixture was concentrated with Celite®, and the crude product was purified using a Teledyne ISCO Combi-Flash system (0-8% MeOH / DCM / 1% NH4OH) to obtain the title compound (181 mg). 1 H NMR(400MHz,DMSO)δ 8.39(dd,J=7.8,0.6Hz,1H),7.67-7.62(m,1H),6.38(d,J=7.8Hz,1H),2.37(d,J=1.3Hz,3H).ES-MS[M+1] + :196.

[0424] [ka] 7-Chloro-4,8-dimethyl-2H-pyrimido[1,2-b]pyridazin-2-one. 6-chloro-5-methylpyridazin-3-amine (300 mg, 2.1 mmol) and ethyl 2-butinoate (581 μL, 5.0 mmol) in 1-butanol (6 mL) were added to a microwave vial. The vial was sealed and heated at 100°C for 72 hours. The reaction mixture was then concentrated, and the crude residue was purified using reversed-phase column chromatography (0-30% ACN / 0.05% NH4OH aqueous solution). The fraction containing the product was concentrated to obtain the title compound (167 mg). 1 H NMR(400MHz,DMSO)δ 7.64(q,J=1.3Hz,1H),6.39(d,J=1.1Hz,1H),2.43(d,J=1.0Hz,3H),2.38(d,J=1.3Hz,3H).ES-MS[M+1] + :210.

[0425] [ka] 7-Chloro-8-methyl-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyridazin-2-one. 6-Chloro-5-methylpyridazin-3-amine (300 mg, 2.1 mmol) and ethyl 4,4,4-trifluorobuto-2-inoate (478 μL, 3.34 mmol) were added to a vial in ethanol (6 mL). The mixture was stirred at ambient temperature for 18 hours, after which a precipitate was observed. The solid was collected by vacuum filtration and washed with EtOH to obtain the title compound (318 mg). 1 H NMR(400MHz,DMSO)δ 7.77(q,J=1.3Hz,1H),7.02(s,1H),2.40(d,J=1.3Hz,3H).ES-MS[M+1] + :264.

[0426] [ka] 5-(2-chloro-5-methylpyrimidine-4-yl)-2-cyclobutyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. To a solution of 2-cyclobutyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (100 mg, 0.51 mmol) in DMF (1.56 mL), triethylamine (0.36 mL, 2.57 mmol) and 2,4-dichloro-5-methylpyrimidine (92 mg, 0.57 mmol) were added. After 18 hours at rt, water was added to the reaction mixture. The reaction mixture was extracted with HCl (2x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by normal-phase column chromatography (0-80% HCl / DCM) to obtain the title compound. ES-MS[M+1] + :321.

[0427] [ka] 2-Cyclobutyl-5-(2-Hydrazinyl-5-methylpyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. 5-(2-Chloro-5-methylpyrimidine-4-yl)-2-cyclobutyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine (88 mg, 0.27 mmol) was dissolved in ethanol (1.8 mL) and hydrazine (172 μL) was added. The mixture was stirred at 80°C for 6 hours. After cooling to room temperature, the mixture was concentrated. The crude residue was not further purified before proceeding. ES-MS[M+1] + :317.

[0428] [ka] 5-(2-chloro-5,6-dimethylpyrimidine-4-yl)-2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. 2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (1.19 g, 6.0 mmol) was dissolved in DMF (15 mL) and triethylamine (4.2 mL, 30.1 mmol) and 2,4-dichloro-5,6-dimethylpyrimidine (1.49 g, 8.4 mmol) were added. The mixture was stirred at 70 °C for 18 hours. Water and ethyl acetate were added to the reaction product. The layers were separated and the aqueous layer was re-extracted with ethyl acetate (2x). The combined organic matter was washed with water (3x) and brine (2x), dried, filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-70% siRNA / DCM) to obtain the title compound (1.32 g). 1 H NMR(400MHz,CDCl3)δ 4.62(s,2H),3.65(t,J=5.7Hz,2H),3.03(ddt,J=5.7,3.7,1.9Hz,2H),2. 42(s,3H),2.19(s,3H),1.64-1.53(m,2H),1.50-1.40(m,2H).ES-MS[M+1] + :339.

[0429] [ka] 2-(1-fluorocyclopropyl)-5-(2-hydrazinyl-5,6-dimethylpyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. Hydrazine (2.4 mL, 77.9 mmol) was added to a solution of 5-(2-chloro-5,6-dimethylpyrimidine-4-yl)-2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (1.32 g, 3.9 mmol) in ethanol (15 mL), and the mixture was stirred at 80°C for 18 hours. After cooling, the mixture was concentrated and proceeded to the next step without further purification (1.3 g). ES-MS[M+1] + :335.

[0430] b. Typical synthesis of the compounds of the present invention [ka] 6-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-5-methylnicotinonitrile (compound 1). To a solution of 6-chloro-5-methylnicotinonitrile (150 mg, 0.98 mmol) in NMP (4.8 mL), N,N-diisopropylethylamine (514 μL, 2.95 mmol) and 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride (327 mg, 1.28 mmol) were added. The mixture was stirred at 110 °C for 18 hours, then cooled to room temperature, diluted with water (60 mL), and extracted with  (3 × 50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was purified using normal-phase flash column chromatography (0-50%  / Hex) to obtain the title compound (110 mg). 1 H NMR(400MHz,CDCl3)δ 8.38(d,J=2.2Hz,1H),7.61(dt,J=2.2,1.0Hz,1H),4.56(q,J=1.6Hz,3H),3.63(t, ES-MS[M+H]+ = 335 / 337.

[0431] [ka] 5-Methyl-6-(2-(methyl-d3)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)nicotinonitrile (compound 20). The title compound was obtained by preparing it in the same manner as compound 1. 1 H NMR(400MHz,CDCl3)δ 8.40(d,J=2.1Hz,1H),7.61(dd,J=2.3,0.9Hz,1H),4.59(t,J=1.9Hz,2H),3.66( t,J=5.7Hz,2H),3.05(tt,J=5.6,1.9Hz,2H),2.38(t,J=0.7Hz,3H);ES-MS[M+H] + =374.

[0432] [ka] 4-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-5-methylfl[2,3-d]pyrimidine (compound 22). To a solution of 4-chloro-5-methylfl[2,3-d]pyrimidine (12 mg, 0.07 mmol) in NMP (0.3 mL), N,N-diisopropylethylamine (51 μL, 0.29 mmol) and 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride (15 mg, 0.06 mmol) were added. The mixture was stirred at 90°C for 18 hours and then cooled to room temperature. The crude product was purified by RP-HPLC (20-70% MeCN / 0.05% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with chloroform / IPA in a 3:1 ratio. The organic layer was concentrated to obtain the title compound (7.9 mg). 1H NMR(400MHz,CDCl3)δ 8.45(s,1H),7.38(d,J=1.4Hz,1H),4.75(t,J=1.9Hz,2H),3.96(t,J=5.7Hz,2H),3.11(t,J=5.7Hz,2H),2.40(d,J=1.4Hz,3H);ES-MS[M+H] + = 351 / 353.

[0433] [ka] 2-Bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (compound 28). The title compound was obtained by preparing it in the same manner as compound 22. 1 H NMR(400MHz,CDCl3)δ 8.75(s,1H),7.96(dd,J=9.1,5.4Hz,1H),7.61-7.47(m,2H),4.85(t,J=1.9Hz,2H),4.03(t,J=5.7Hz,2H),3.21(tt,J=5.7,1.9Hz,2H);ES-MS[M+H] + = 365 / 367.

[0434] [ka] 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (compound 34). 7-chloro-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (15 mg, 0.08 mmol) and 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinide hydrochloride (29 mg, 0.12 mmol) were dissolved in tert-butanol (1 mL), to which N,N-diisopropylethylamine (67 μL, 0.38 mmol) was added. The mixture was stirred at 120 °C for 18 hours and then cooled to room temperature. The crude substance was purified by RP-HPLC (30-70% MeCN / 0.05% NH4OH aqueous solution) to obtain the title compound (2.9 mg). 1H NMR(400MHz,CDCl3)δ 8.14(d,J=6.4Hz,1H),7.58(q,J=1.2Hz,1H),6.57(d,J=6.4Hz,1H),4.67(t,J=1.9Hz,2H ),3.58(t,J=5.7Hz,2H),3.12(tt,J=5.6,1.9Hz,2H),2.51(d,J=1.2Hz,3H);ES-MS[M+H] + =378 / 380.

[0435] [ka] 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-8-methyl-2H-pyrimido[1,2-b]pyridazin-2-one (compound 50). The title compound was obtained by preparing it in the same manner as compound 34. 1 H NMR(400MHz,CDCl3)δ 7.88(d,J=7.7Hz,1H),7.34(d,J=1.4Hz,1H),6.50(d,J=7.7Hz,1H),4.44(t,J=1.8Hz,2H ),3.54(t,J=5.8Hz,2H),3.07(td,J=5.8,2.9Hz,2H),2.45(d,J=1.3Hz,3H);ES-MS[M+H] + =378 / 380.

[0436] [ka] Ethyl 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-8-methyl-4-oxo-4H-pyrimido[1,2-b]pyridazine-2-carboxylate (compound 52). To a solution of ethyl 7-chloro-8-methyl-4-oxo-4H-pyrimido[1,2-b]pyridazine-2-carboxylate (100 mg, 0.37 mmol) and 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinide hydrochloride (143 mg, 0.56 mmol) in tert-butanol (4.9 mL), N,N-diisopropylethylamine (325 μL, 1.87 mmol) was added. The mixture was stirred at 120 °C for 18 hours and then cooled to room temperature. 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride (143 mg, 0.56 mmol) and N,N-diisopropylethylamine (325 μL, 1.87 mmol) were added to the reaction mixture, and the mixture was heated at 120°C for a further 6 hours. The reaction mixture was concentrated. The residue was dissolved in MeOH and purified using an SCX cartridge eluted with MeOH solution. The solvent was removed to obtain the title compound (166 mg). 1 H NMR(400MHz,CDCl3)δ 8.90(s,1H),7.66(q,J=1.1Hz,1H),4.68(d,J=1.9Hz,2H),4.41(q,J=7.1Hz,2H),3.64(t,J=5.7Hz ,2H),3.13(ddt,J=5.8,4.3,2.0Hz,2H),2.56(d,J=1.2Hz,3H),1.41(t,J=7.1Hz,3H);ES-MS[M+H] + = 450 / 452.

[0437] [ka] 5-Methyl-6-(2-(2-methylpyridine-4-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)nicotinonitrile (Compound 2). A mixture of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (19.6 mg, 0.090 mmol), cesium carbonate (43.7 mg, 0.13 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.3 mg, 0.005 mmol), and 6-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-5-methylnicotinonitrile (15.0 mg, 0.045 mmol) was added to a vial, followed by the addition of degassed 1,4-dioxane (1.1 mL) and water (0.03 mL). The vial was sealed, and the reaction mixture was heated at 80°C for 18 hours. The reaction mixture was filtered through a Celite® pad, and the pad was washed with DCM / MeOH. The solvent was removed, and the residue was dissolved in DMSO (1 mL). The crude substance was purified by RP-HPLC (30-70% MeCN / 0.05% NH4OH aqueous solution) to obtain the title compound (5 mg). 1 H NMR(400MHz,CDCl3)δ 8.60(dd,J=5.2,0.8Hz,1H),8.42(dd,J=2.2,0.6Hz,1H),7.74-7.66(m,1H),7.66-7.61(m,1H),7.63-7.56(m,1H),4.7 2(t,J=1.8Hz,2H),3.72(t,J=5.7Hz,2H),3.17(tt,J=5.6,1.7Hz,2H),2.65(s,3H),2.42(t,J=0.7Hz,3H);ES-MS[M+H] + =348.

[0438] [ka] 5-(6-cyano-4,5-dimethylpyridazin-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonitrile (compound 13). To a solution of zinc powder (1 mg, 0.015 mmol) and Pd(dppf)Cl2 (3.14 mg, 0.0043 mmol) in DMF (1.3 mL), 6-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4,5-dimethylpyridazin-3-carbonitrile (15 mg, 0.043 mmol) and zinc cyanide (5.0 mg, 0.043 mmol) were added. The mixture was stirred at 160 °C for 4 hours, then cooled to ambient temperature and partitioned into water (8 mL) and ethyl acetate (8 mL). The organic layer was separated, and the aqueous layer was further extracted twice with ethyl acetate. The organic matter was pooled, washed with brine, dried (MgSO4), filtered, and concentrated. The crude substance was purified by RP-HPLC (25-70% MeCN / 0.05% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA. The solvent was concentrated to obtain the title compound (3.3 mg). 1 H NMR(400MHz,CDCl3)δ 4.85(t,J=1.6Hz,2H),3.67(t,J=5.7Hz,2H),3.17(t,J=5.8Hz,2H),2.50(s,3H),2.34(s,3H);ES-MS[M+H] + =297.

[0439] [ka] 6-(2-((4-fluorophenyl)amino)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4,5-dimethylpyridazine-3-carbonitrile (compound 7). In a vial under an inert atmosphere, 1,4-dioxane (1 mL) was used to add 6-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4,5-dimethylpyridazine-3-carbonitrile (15 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium (0) (3.9 mg, 0.004 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (3.7 mg, 0.01 mmol), 4-fluoroaniline (7.3 μL, 0.09 mmol), and cesium carbonate (42.1 mg, 0.13 mmol). The resulting mixture was heated at 110°C for 2 hours. The reaction mixture was filtered through a Celite® pad, and the pad was washed with ELISA / DCM. The solvent was removed, and the residue was dissolved in DMSO (1.5 mL). The crude substance was purified by RP-HPLC (30-70% MeCN / 0.05% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA. The solvent was concentrated to obtain the title compound (4.0 mg). ES-MS[M+H] + =381.

[0440] [ka] 6-(2-methoxy-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4,5-dimethylpyridazine-3-carbonitrile (compound 8). A microwave vial containing 6-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-4,5-dimethylpyridazine-3-carbonitrile (10 mg, 0.03 mmol) in methanol (1 mL) was mixed with sodium methoxide solution (76 μL, 25 wt% in methanol). The vial was sealed, and the reaction mixture was microwaved at 100°C for 10 minutes, followed by heating at 110°C for 1 hour. The reaction mixture was filtered and concentrated. The crude product was purified by RP-HPLC (30-70% MeCN / 0.05% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA. The combined organic layers were concentrated to obtain the title compound (3.7 mg). 1 H NMR(400MHz,CDCl3)δ 4.55(t,J=2.1Hz,2H),4.06(s,3H),3.64(t,J=5.7Hz,2H),2.94(td,J=5.6,2.8Hz,2H),2.46(s,3H),2.33-2.28(m,3H);ES-MS[M+H] + =302.

[0441] [ka] 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-8-methyl-4-oxo-N-(thiazole-5-ylmethyl)-4H-pyrimido[1,2-b]pyridazine-2-carboxamide (compound 42). 7-chloro-8-methyl-4-oxo-4H-pyrimido[1,2-b]pyridazine-2-carboxylic acid (10 mg, 0.024 mmol) and HATU (46.7 mg, 0.12 mmol) were dissolved in DMF (1 mL) and stirred for 15 minutes. N,N-diisopropylethylamine (36 μL, 0.20 mmol) and thiazole-5-ylmethaneamine hydrochloride (3.5 mg, 0.020 mmol) were added, and the mixture was stirred for 2 hours. The reaction mixture was filtered and concentrated. The residue was purified by RP-HPLC (5-60% MeCN / 0.05% TFA aqueous solution). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA. The combined organic layers were concentrated to obtain the title compound (7.1 mg). 1 H NMR(400MHz,CDCl3)δ 9.65(t,J=5.7Hz,1H),9.23(s,1H),8.73(d,J=0.7Hz,1H),7.84(q,J=0.7Hz,1H),7.73(q,J=1.1Hz,1H),4.88(dd,J=5. 8,0.9Hz,2H),4.68(t,J=1.9Hz,2H),3.65(t,J=5.7Hz,2H),3.14(t,J=5.8Hz,2H),2.58(d,J=1.2Hz,3H).;ES-MS[M+H] + = 518 / 520.

[0442] [ka] 2-(1-methylcyclopropyl)-5-(7-methylpyrido[2,3-b]pyradi-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (compound 55). 2-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (19 mg, 0.1 mmol) was added to a solution of 6-chloro-7-methylpyrido[2,3-b]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL). The reaction mixture was heated at 120 °C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (9.4 mg). 1 H NMR(400MHz,CDCl3)δ 8.81(d,J=2.0Hz,1H),8.66(d,J=2.0Hz,1H),8.07(d,J=1.2Hz,1H),4.79(t,J=1.9Hz,2H),3.72(t,J=5.7Hz,2H),3.1 0(tt,J=5.6,1.9Hz,2H),2.58(d,J=1.0Hz,3H),1.57(s,3H),1.29(q,J=4.2Hz,2H),0.96(q,J=4.3Hz,2H);ES-MS[M+1] + :338.0.

[0443] [ka] 2-Cyclopropyl-5-(7-methylpyrido[2,3-b]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (Compound 54). 2-Cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine hydrochloride (21 mg, 0.10 mmol) was added to a solution of 6-chloro-7-methylpyrido[2,3-b]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL). The reaction mixture was heated at 120 °C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH). The desired fraction was concentrated to obtain the title compound (7.4 mg).1 H NMR(400MHz,CDCl3)δ 8.82(d,J=2.0Hz,1H),8.68(d,J=2.0Hz,1H),8.08(d,J=1.2Hz,1H),4.78(s,2H),3.72(t,J=5.7Hz,2H) ,3.14(d,J=6.0Hz,2H),2.59(d,J=1.0Hz,3H),2.38(s,1H),1.26-1.15(m,2H),1.11(s,2H);ES-MS[M+1] + :324.0.

[0444] [ka] 2-(2,2-dimethylcyclopropyl)-5-(7-methylpyrido[2,3-b]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (compound 63). 2-(2,2-dimethylcyclopropyl)-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (23 mg, 0.11 mmol) was added to a solution of 6-chloro-7-methylpyrido[2,3-b]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) in DMSO (0.8 mL). The reaction mixture was heated at 120 °C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (2.7 mg). 1 H NMR(400MHz,DMSO)δ 8.84(d,J=2.0Hz,1H),8.72(d,J=2.0Hz,1H),8.16(d,J=1.1Hz,1H),4.68(d,J=1.5Hz,2H),3.73(t,J=5.8Hz,2H),2.99(t ,J=4.7Hz,2H),2.59-2.51(m,3H),2.19(dd,J=8.3,5.6Hz,1H),1.18(s,3H),1.16-1.09(m,2H),0.99(s,3H);ES-MS[M+1] + :352.2.

[0445] [ka] 2-(tert-butyl)-5-(7-methylpyrido[2,3-b]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (compound 65). 2-tert-butyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (21 mg, 0.11 mmol) was added to a 0.8 mL NMP solution of 6-chloro-7-methylpyrido[2,3-b]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol). The reaction mixture was heated at 160°C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (10-50% MeCN / water / 0.1% TFA). The fraction containing the desired product was made basic with saturated NaHCO3 aqueous solution and then extracted with 3:1 chloroform / IPA. The combined organic layers were concentrated to obtain the title compound (10.7 mg). 1 H NMR(400MHz,CDCl3)δ 8.81(d,J=2.0Hz,1H),8.66(d,J=2.0Hz,1H),8.07(d,J=1.1Hz,1H),4.81(s,2H),3.7 4(t,J=5.6Hz,2H),3.15(td,J=5.6,2.8Hz,2H),2.59(s,3H),1.45(s,9H);ES-MS[M+1] + :340.4.

[0446] [ka] 5-(7-methylpyrido[2,3-b]pyrazine-6-yl)-2-(thiophen-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (compound 56). 2-(thiophen-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (17 mg, 0.08 mmol) was added to a solution of 6-chloro-7-methylpyrido[2,3-b]pyrazine (9.6 mg, 0.05 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.33 mmol) in DMSO (0.8 mL). The reaction mixture was heated at 120 °C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (7.4 mg). 1 H NMR(400MHz,CDCl3)δ 8.82(d,J=2.0Hz,1H),8.67(d,J=2.0Hz,1H),8.09(d,J=1.1Hz,1H),7.48(dd,J=3.7,1.1Hz,1H),7.38(dd,J=5.1,1.1Hz,1H),7.07( dd,J=5.1,3.7Hz,1H),4.86(t,J=1.8Hz,2H),3.76(t,J=5.7Hz,2H),3.19(tt,J=5.6,1.8Hz,2H),2.61(d,J=1.0Hz,3H);ES-MS[M+1] + :366.0.

[0447] [ka] 2-(1-methyl-1H-pyrazole-5-yl)-5-(7-methylpyrido[2,3-b]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (compound 59). 2-(2-methylpyrazole-3-yl)-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (22 mg, 0.1 mmol) was added to a DMSO (0.8 mL) solution of 6-chloro-7-methylpyrido[2,3-b]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol). The reaction mixture was heated at 120 °C for 18 hours. The reaction product was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (5.2 mg). 1 H NMR(400MHz,CDCl3)δ 8.83(d,J=2.0Hz,1H),8.68(d,J=2.0Hz,1H),8.10(d,J=1.2Hz,1H),7.47(d,J=2.0Hz,1H),6.62(d,J=2.0Hz,1H),4.8 9(t,J=1.8Hz,2H),4.24(s,3H),3.79(t,J=5.7Hz,2H),3.21(tt,J=5.6,1.8Hz,2H),2.62(d,J=1.0Hz,3H);ES-MS[M+1] + :364.3.

[0448] [ka] 2-Chloro-5-(7-methylpyrido[2,3-b]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (compound 61). 2-Chloro-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (17 mg, 0.1 mmol) was added to a solution of 6-chloro-7-methylpyrido[2,3-b]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL). The reaction mixture was heated at 120 °C for 18 hours. The reaction mixture was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (2.1 mg). 11H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 1.2 Hz, 1H), 4.68 (t, J = 1.9 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 3.01 (tt, J = 5.6, 1.9 Hz, 2H), 2.50 (d, J = 1.0 Hz, 3H); ES-MS [M+1] + : 318.2.

[0449]

Chem.

[0450]

Chem.

[0451] [ka] 5-(7-methylpyrido[2,3-b]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (compound 53). N,N-diisopropylethylamine (0.06 mL, 0.34 mmol) was added to a vial containing 6-chloro-7-methylpyrido[2,3-b]pyrazine (12 mg, 0.07 mmol) and 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (9 mg, 0.07 mmol) in NMP (1 mL). The mixture was heated at 175 °C for 16 hours. After cooling to rt, the reaction product was purified by reverse-phase HPLC (5-45% MeCN / water / 0.05% NH4OH) to obtain the title compound (8.5 mg). 11H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 0.7 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 4.90 (s, 2H), 3.77 (t, J = 5.7 Hz, 2H), 3.27 - 3.19 (m, 2H), 2.61 (s, 3H); ES-MS [M+1] + : 284.0.

[0452]

Chem.

[0453]

Chem.

[0454] [ka] 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound 69). 1,1'-carbonyldiimidazole (0.71 g, 4.4 mmol) was added to a solution of 2-(1-fluorocyclopropyl)-5-(2-hydrazinyl-5,6-dimethylpyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (1.3 g, 4.0 mmol) in 1,4-dioxane (40 mL). The reaction mixture was heated at 85°C for 18 hours. CDI (515 mg) was added again to the reaction mixture and heated at 85°C for 4 hours. The reaction mixture was diluted with water and extracted with 3:1 CHCl3 / IPA (3x). The organic matter was combined, dried, filtered, and concentrated. The crude product was purified by normal-phase chromatography (0-5% MeOH / DCM) to obtain the title compound (0.6g). ES-MS[M+1] + :361; 1 H NMR(400MHz,DMSO)δ 4.57(s,2H),3.60(t,J=5.6Hz,2H),2.93(t,J=5.7Hz,2H),2.68(s,3H),2.07(s,3H),1.71-1.57(m,2H),1.42-1.31(m,2H).

[0455] [ka] 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound 70). A solution of 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (0.6 g, 1.7 mmol) and potassium carbonate (0.47 g, 3.4 mmol) in DMF (16 mL) was stirred at room temperature for 20 min. Then, iodomethane (157 μL, 2.5 mmol) was added, and the mixture was stirred at 50 °C for 18 h. The reaction product was purified by reverse-phase chromatography (10-50% ACN / 0.05% NH4OH) to obtain the title compound (390 mg). ES-MS[M+1] + :375; 1 H NMR(400MHz,DMSO)δ 4.59(s,2H),3.62(t,J=5.6Hz,2H),3.36(s,3H),2.93(td,J=5.5,2.7Hz,2H),2.68(s,3H),2.08(s,3H),1.73-1.56(m,2H),1.44-1.29(m,2H).

[0456] [ka] 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-5,6-dimethyl-2-(methyl-d3)-[1,2,4]triazolo[4,3-a]pyrimidine-3(2H)-one (compound 71). The title compound was obtained by preparation in the same manner as compound 70. ES-MS[M+1] + :378.2; 1H NMR(400MHz,DMSO)δ 4.59(d,J=1.8Hz,2H),3.62(t,J=5.7Hz,2H),2.93(t,J=5.7Hz,2H),2.68(d,J=0.9Hz ,3H),2.08(d,J=1.0Hz,3H),1.74-1.64(m,1H),1.64-1.57(m,1H),1.42-1.31(m,2H).

[0457] [Table 9]

[0458] The compounds shown in Table 1 can be prepared using appropriate starting materials and the methods described in the scheme and examples above.

[0459] [Table 10]

[0460] [Table 11]

[0461] [Table 12]

[0462] [Table 13]

[0463] [Table 14]

[0464] [Table 15]

[0465] [Table 16]

[0466] [Table 17]

[0467] [Table 18]

[0468] biological activity A. Cell lines expressing muscarinic acetylcholine receptors Human (h) and rat (r) M4 cDNA were used to create a chimeric G protein G qi5 Along with this, Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection were transfected with lipofectamine 2000. The transfected cells were subjected to antibiotic selection treatment to generate stable cell lines; G418 sulfate (1 mg / ml) was used to select M4-expressing cells. qi5 Hygromycin B (500 μg / mL) was used to select expression cells. The resulting polyclones were further screened for hM4-G compound screening assays. qi5 and rM4-G qi5 Monoclonal cells were obtained. Stable monoclonal cells were maintained in a 37°C humidified incubator in the presence of 5% CO2 in Ham's F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1X antibiotic / antifungal agent, 20 mM HEPES, 500 μg / mL G418 sulfate, and 200 μg / mL hygromycin B.

[0469] B. Cell-based functional assay of muscarinic acetylcholine receptor activity To determine the activity of the compound, a high-throughput assay was employed to measure the receptor-induced recruitment of intracellular calcium. The test compound was added to cells expressing muscarinic receptors loaded with a calcium-sensitive fluorescent dye. After an incubation period of approximately 2.5 minutes, the maximum (EC) was measured. 20 Acetylcholine at a concentration of ) was added, and the response was measured. This kinetic assay allows for simultaneous screening and efficacy measurement of multiple pharmacological mechanisms of action, including the activity of agonists and enhancers. CHO-K1 cells stably expressing muscarinic receptors were seeded at 15,000 cells / 20 μL / well in a Greiner 384-well blackwall tissue culture (TC) treated clear-bottom plates (Greiner Bio-One) at a growth medium lacking G418 and hygromycin. The cells were incubated overnight at 37°C and 5% CO2. The following day, a calcium assay buffer (Hanks equilibrium salt solution (HBSS), 20 mM HEPES, 2.5 mM probenecid, 4.16 mM sodium bicarbonate (Sigma-Aldrich, St. Louis, MO)) was prepared, and the compound, agonist, and the fluorescent calcium indicator dye Fluo-4-acetomethoxyester (Fluo-4-AM) were diluted. The compounds were serially diluted 1:3 in DMSO using a Bravo Liquid Handler (Agilent, Santa Clara, CA) to create a 10-point concentration response curve. The curves were then transferred to 384-well plates using an Echo Acoustic Liquid Handler (Beckman Coulter, Indianapolis, Indiana) and diluted to twice the final concentration with assay buffer. The agonist plates were then subjected to EC (Earthquake-Chilling). 20 and EC MAXAcetylcholine (ACh, Sigma-Aldrich, St. Louis, MO) at the response concentration was used and diluted 5-fold to the final concentration in assay buffer to prepare the solution. The 2X dye solution (2.3 μM) was prepared by mixing 2.3 mM Fluo-4-AM stock in DMSO and 10% (w / v) pluronic acid F-127 in a 1:1 ratio in assay buffer. The cells were washed three times with assay buffer using a microplate washer (BioTek, Winooski, VT) to remove the culture medium. After the final wash, 20 μL of assay buffer remained in the cell plate. Immediately, 20 μL of the 2X dye solution (final concentration 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 for 45 minutes in the presence of 5% CO2. The dye solution was then removed using a microplate washer and replaced with assay buffer, leaving 20 μL of assay buffer in the cell plate.

[0470] The prepared compounds, agonists, and cell plates were placed in a Functional Drug Screening System uCell (FDSS uCell, Hamamatsu, Japan), and the calcium flux was measured. A three-step addition protocol was used to measure Ca dynamics. 20 for ACh, EC 80 The ACh compounds were added sequentially. Briefly, the first addition was performed by adding 20 μL of the test compound to the cells after establishing a fluorescence baseline for 2 seconds (excitation 480 nm; emission 530 nm), and the response was measured for 140 seconds. The second addition was then performed. EC 20 10 μL (5X) of the specified concentration of ACh agonist 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 ACh at a concentration, and the cellular response was measured for 90 seconds. Acetylcholine-mediated maximal response (EC) max The measurement was performed by adding 1 mM ACh as a third addition to the control well. ACh EC20 , EC80, and EC max To evaluate the response, DMSO solvent was added to the control well with the initial addition. Calcium fluorescence was recorded as a multiple of the baseline fluorescence, and the raw data were normalized to the maximum response to the ACh agonist. Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Positive allosteric modulator activity was measured using EC 20 Antagonist activity was analyzed as a concentration-dependent increase in the acetylcholine response. 80 The acetylcholine response was analyzed as a concentration-dependent decrease. Concentration-response curves were generated using the four-parameter logistic equation with GraphPad Prism (La Jolla, CA) or the Dotmatics software platform (Woburn, MA).

[0471] The above assay also operated in a second mode, where, after establishing a fluorescence baseline for approximately 3 seconds, the compound was added to cells at an appropriate fixed concentration, and the response in the cells was measured. After 140 seconds, an appropriate concentration of agonist was added, and the calcium response (maximum-minimum response) was measured. EC of the agonist in the presence of the test compound. 50 The values ​​were determined by nonlinear curve fitting. The EC of the agonist as the concentration of the compound of the present invention increases. 50 A decrease in the value (a leftward shift in the agonist concentration-reaction curve) is an indicator of the degree of muscarinic positive allosteric regulation at a given concentration of the compound of the present invention. The EC of the agonist by the compound increases with increasing concentration. 50 An increase in the value (a rightward shift in the agonist concentration response curve) is an indicator of the degree of muscarinic antagonism at a given concentration of this compound. The second mode also indicates whether this compound also affects the maximal response of muscarinic receptors to the agonist.

[0472] Compound activity in C.mAChR M4 cell-based assays The compound was synthesized as described above. Activity (EC 50 and E maxThe compound numbers were measured using a functional assay based on M4 cells, as described above. The data are shown in Table 2. The compound numbers correspond to those used in Table 1.

[0473] [Table 19]

[0474] [Table 20]

[0475] [Table 21]

[0476] D. Functional evaluation of M4-activating compounds in cell cAMP assays. Cell cAMP G i HTRF assay Activation of the M4 receptor is G i / o Coupling with proteins leads to inhibition of cAMP production. To measure the level of cAMP inhibition by M4 allosteric modulators, a homogeneous time-resolved fluorescence (HTRF®) cAMP assay was employed using CHO cells stably expressing human or rat M4 receptors. The HTRF cAMP assay is a time-resolved resonance energy transfer (TR-FRET) competitive immunoassay. Endogenous intracellular cAMP produced by cells competes with europium cryptotate-labeled cAMP (europium donor, emission 665 nm) for binding to a d2-labeled cAMP antibody (d2 acceptor, emission 620 nm). Therefore, the fluorescence emission ratio (665 nm / 620 nm) is inversely proportional to the amount of intracellular cAMP. Compound-mediated M4 activation increases the HTRF ratio (665 nm / 620 nm), indicating a decrease in intracellular cAMP levels. To monitor agonist activity, EC induces submaximal intracellular cAMP levels. 80The compound was added to M4 cells in the presence of a concentration of forskolin (adenylyl cyclase activator). To evaluate the activity of the enhancer, EC 20 In the presence of acetylcholine at a certain concentration, EC 80 The compound was added to M4 cells along with a concentration of forskolin. This functional assay showed that G i / o The potency and effects of compounds that directly activate or enhance the binding M4 receptor can be determined; representative data are shown in Table 3.

[0477] HTRF cAMPG 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 37°C humidified incubator in the presence of 5% CO2. The day before the assay, cells were trypsinized and resuspended in plating medium (growth medium without G418). Human M4 cells and rat M4 cells were seeded at densities of 4,000 cells / 10 μL / well and 6,000 cells / 10 μL / well in white solid flat-bottom 384-well plates. Cell plates were spun at 100 x g for 1 min and then immediately placed overnight in a 37°C incubator in the presence of 5% CO2.

[0478] The following day, the reagents were freshly diluted to 2-fold concentration with assay buffer using F12 basal medium or stimulating buffer. All assay buffers contained 500 μM IBMX to inhibit cAMP degradation. EC 80 In cells stimulated with forskolin to induce submaximal intracellular cAMP levels, the activation of M4 by a compound was investigated. (Forskolin EC) 80The concentration was determined from the forskolin concentration-response curve (CRC) and ranged from 1.5 to 2.5 μM. The compound (10 mM) was prepared in 100% DMSO and then serially diluted in DMSO at a ratio of 1:3 or 1:5 in a 384-well microplate using a Bravo Liquid Handler to prepare 13-point CRCs.

[0479] The agonist assay mode was used to evaluate the ability of the M4 compound to directly activate the M4 receptor in the absence of the agonist acetylcholine. Starting at a final concentration of 30 μM, the compound was serially diluted 10 points and transferred to compound plates using the Echo plate reformatting protocol. 80 A 2X assay buffer containing a specified concentration of forskolin was added to the compound plate. Baseline cAMP (without forskolin), maximum forskolin level, and forskolin EC were measured. 80 The solvent (1% DMSO) was added to the control well. 10 μL / well of the prepared 2X assay buffer was immediately added to the cell plate using a Bravo384 well-tip liquid handler. The cell plate was immediately spun at 100xg for 30 seconds and incubated at 37°C for 10 minutes with gentle shaking at 50 rpm. Also, EC 80 Perform acetylcholine CRC in the presence of forskolin concentration to prepare for subsequent enhancement mode assays, up to 100% (EC2). max ) and maximum lower (EC 20 The concentration of acetylcholine, which induces cAMP inhibition, was measured.

[0480] In the enhancer assay mode, compounds were transferred to compound plates using the Echo plate reformatting protocol, starting at a final concentration of 1.1 μM and serially diluted 10 points. 80 Forskolin and EC concentrations 20A 2X assay buffer containing a concentration of acetylcholine was added to the compound plate. The solvent (1% DMSO) was then added as follows: (1) For the forskolin control well - baseline cAMP (without forskolin), forskolin max, and forskolin EC 80 (2) Forskolin EC 80 Regarding the agonist control well containing - base (without agonist), and acetylcholine EC 20 and EC max 10 μL / well of prepared 2X assay buffer was immediately added to the cell plate using a Bravo384 well-tip liquid handler. The cell plate was immediately spun at 100xg for 30 seconds and incubated at 37°C for 10 minutes with gentle shaking at 50 rpm. During the 10-minute incubation period, cAMP Eu-cryptate donor (20x) and anti-cAMP d2 antibody 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 for 60 minutes with gentle shaking at 50 rpm. Immediately after detection incubation, TR-FRET signals were measured in two channels, 665 and 620 nm, using an EnVision plate reader (Perkin Elmer). All release ratios (665 / 620) were normalized to the maximum acetylcholine concentration. Individual CRCs were generated using a 4-parameter logistic equation with GraphPad Prism (La Jolla, CA) and fitted from EC 50 The following was extracted, and the maximum response (%ACh Max) was determined:

number

[0481] [Table 22]

[0482] [Table 23]

[0483] E. Effects of compounds on amphetamine-induced hyperactivity in rats The ability of 70 compounds to reverse amphetamine-induced hyperactivity, a preclinical model used to predict antipsychotic-like effects (Bubser et al

[2014] ACS Chemical Neuroscience 5:920-942), was evaluated in male Sprague-Dawley rats.

[0484] Drug: d-amphetamine hemisulfate (AMP) was obtained from Sigma (St. Louis, MO). Using salt correction, the amount of d-amphetamine hemisulfate to add to sterile water was determined in mg, and a solution containing d-amphetamine (free base) at a concentration of 0.25 mg / mL was obtained. This solution was administered subcutaneously at a volume of 1 mL / kg body weight. On each experimental day, compound 70 and comparative compound VU0467154, M4PAM (Bubser et al.

[2014] ACS Chem. Neurosci. 5:920-942) were freshly compounded into separate vials with solvent (10% Tween 80, 90% water, v / v) to obtain compound concentrations of 20 mg / mL (compound 70) or 1 mg / mL (VU0467154). The resulting mixture was vigorously vortexed and hyperhomogenized for 2-3 minutes using a handheld tissue homogenizer, and then sonicated for 60 minutes in a 39°C sonication bath to obtain a microsuspension. These formulations were administered intraperitoneally (ip) at a volume of 5 mL / kg body weight (solvent and compound 70) or orally (po) at a volume of 10 mL / kg body weight (VU0467154).

[0485] Animals: This study used male Sprague-Dawley rats (Harlan, Inc., IN) weighing 268–343 grams, with an average weight of 290 grams. After transport, all rats were given a minimum 72-hour acclimatization period in the animal housing facility before the experiment. The animals were housed in groups under a 12-hour light-dark cycle (lights on: 6 a.m., lights off: 6 p.m.) in an animal care facility certified by the American Association for Accreditation in Laboratory Animal Care (AAALAC), with free access to food and water. The rats used in this experiment were fasted the night before the experiment in order to receive oral administration of the test compound / solvent. The experimental procedures performed during the light-dark cycle were approved by the Animal Experimentation Committee of Vanderbilt University and complied with the National Research Council's Guide for the Care and Use of Laboratory Animals.

[0486] Amphetamine-Induced Hyperactivity: Male rats were tested in a Smart Open Field spontaneous motility test chamber (Hamilton-Kinder, San Diego, CA) equipped with a 16×16 photobeam for automatic recording of spontaneous motility activity. All rats were acclimatized in a motility enclosure for 30 minutes, after which they were administered either the solvent or compound 70 intraperitoneally (ip) or VU0467154 by post-administration (po). After 30 minutes, all rats were subcutaneously (sc) injected with 0.25 mg / kg of amphetamine and then monitored for a further 60 minutes. Changes in spontaneous motility activity were recorded for a total of 120 minutes. Data were expressed as the number of walking movements, defined as the total number of beam breaks per 5-minute interval. At the end of this behavioral study, terminal plasma and brain samples were collected to assess exposure levels of compound 70 and VU0467154 by pharmacokinetic analysis.

[0487] Data Analysis and Statistics: Behavioral data (beam breaks per 5 minutes) were analyzed using GraphPad Prism10, version 1 (GraphPad Software, San Diego, CA) with a two-way ANOVA for the main effects of treatment and time. A statistical significance level of p ≤ 0.05 was adopted. Furthermore, the total number of beam breaks from amphetamine administration (65-minute bin) to the end of the study (120-minute bin) was calculated and graphed. The reversal rate (%) was calculated using Microsoft Excel. For each rat in each treatment group, the total walking movement from t=65 to t=120 was summed. The mean of each sum was calculated for the solvent group. Next, the reversal rate (%) for each rat was calculated using the following formula: Reversal rate (%) = 100 - {[(Total walking movement of each animal from t=65 to t=120) / (Average walking movement of the solvent group from t=65 to t=120)] * 100}. The mean reversal rate (%) ± SEM for each dose group was calculated and expressed using GraphPad Prism10 version 1.

[0488] Results: When compound 70 was administered systemically at 100 mg / kg (ip) and the positive control compound VU0467154 was administered at 10 mg / kg (po), amphetamine-induced hyperactivity was reversed (p<0.001), with reversal rates of 61.1% and 52.7%, respectively. The data are shown in the figure.

[0489] Conclusion: Systemic administration of compound 70 at a dose of 100 mg / kg ip resulted in a marked and sustained reversal of amphetamine-induced hyperactivity, a preclinical model predicting antipsychotic-like activity. This effect was similar in magnitude to that observed with the comparative M4PAM compound, VU0467154, administered at a dose of 10 mg / kg po.

[0490] F. Secondary pharmacological effects and toxicity in vitro Compound 70 was tested using Eurofins LeadProfilingScreen®, which detects potential off-target activity and determines relative selectivity. This screening includes 68 key molecular targets, including several CNS targets recommended by EMEA (European Medicines Agency) for assessing the potential for drug dependence. Compound 70 showed less than 50% inhibition of each target at 10 μM (bound) on LeadProfilingScreen®, with the exception of human muscarin 2 (58% inhibition at 10 μM).

[0491] G. In vitro and in vivo drug metabolism and pharmacokinetics Compound 70 was tested in several in vitro assays to investigate both its metabolism and pharmacokinetics. These assays can be performed according to known methods commonly 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 assays include those listed in the following table.

[0492] [Table 24]

[0493] Compound 70 has been tested in several in vivo assays, and the pharmacokinetic parameters listed in the following table may be determined from pharmacokinetic studies in rats, dogs, or cynomolgus monkeys 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.

[0494] [Table 25]

[0495] The above detailed description and attached examples are for illustrative purposes only and should not be considered as limitations to the scope of the invention as defined solely by the attached claims and their equivalents.

[0496] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those relating to chemical structure, substituents, derivatives, intermediates, synthesis, composition, formulation, or method of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

1. Compound of formula (I), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula: R １ teeth, 【Chemistry 2】 And; G １ is a 5-6 membered partially unsaturated or aromatic heterocyclic ring system containing 1-3 nitrogen atoms, where Z １ is C or N, Z ２ is N or C, Z １ and Z ２ Both are not N; R １０ is selected from the group consisting of C １－４ alkyl, C １－４ fluoroalkyl, halogen, C ３－４ cycloalkyl, C １－２ alkylene-C ３－４ cycloalkyl, -C(O)OC １－４ alkyl, and -C(O)NR ａ R ｂ ; and is selected from the group consisting of R １１ Each time it appears, C １－６ Alkyl, C １－６ Fluoroalkyl, halogen, -C １－６ Alkilen-R ｙ , -C １－６ Fluoroalkylene-R ｙ G １１ , or -C １－３ Alkilen-G １１ Selected from the group consisting of; R １２ It is oxo; m is either 0 or 1; n is 1, 0, or 2; p is either 1 or 0; R ａ 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 ｂ is hydrogen, C １－４ Alkyl, C １－４ Fluoroalkyl, G １０ , or -C １－３ Alkilen-G １０ And; Or, R ａ and R ｂ Along with the nitrogen to which they are attached, R ａ and R ｂ A 4- to 10-membered heterocycle is formed, containing nitrogen attached to the atom and one or two additional heteroatoms that are optionally and independently O, N, or S, wherein the heterocycle is a halogen, cyano, or C １－４ Alkyl, C １－４ Fluoroalkyl, oxo, -OR ５０ , -N(R ５０ ) ２ G １０ａ , and -C １－３ Alkilen-G １０ａ It is optionally substituted with a first substituent selected from the group consisting of; independently of a halogen or C １－４ It is further optionally substituted with 1 to 3 alkyl substituents; G １０ This includes phenyl, a 5-6 member heteroaryl containing 1-3 heteroatoms, a 4-8 member heterocyclyl containing 1-2 heteroatoms, or C ３－６ It is a cycloalkyl, where the heteroatom is independently selected from the group consisting of O, N, and S, and G １０ These are halogen, cyano, and C １－４ Alkyl, C １－４ Fluoroalkyl, oxo, -OR ５０ , -N(R ５０ ) ２ G １０ａ , and -C １－３ Alkilen-G １０ａ The first substituent is optionally substituted with one selected from the group consisting of the following, and is independently a halogen or C １－４ It is further optionally substituted with 1 to 3 alkyl substituents; G １０ａ This is a phenyl, a 5-6 member heteroaryl containing 1-3 heteroatoms, a 4-8 member heterocyclyl containing 1-2 heteroatoms, or a 3-8 member carbocyclyl, where the heteroatoms are independently selected from the group consisting of O, N, and S, and G １０ａ These are halogen, cyano, and C １－４ Alkyl, C １－４ Fluoroalkyl, oxo, OH, -OC １－４ Alkyl, -OC １－４ Fluoroalkyl, C ３－４ Cycloalkyl and -C １－３ Alkylene-C ３－４ It is optionally substituted with 1 to 5 substituents independently selected from the group consisting of cycloalkyl groups; R ５０ Each time they appear, hydrogen and C appear independently. １－４ Alkyl, C １－４ Fluoroalkyl, C ３－６ Cycloalkyl, or -C １－３ Alkylene-C ３－６ It is a cycloalkyl, where each cycloalkyl is a halogen, C １－４ Alkyl and C １－４ It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl groups; R ｙ ha-OR ｃ , -N(R ｃ ) ２ , -C(O)R ｃ , -C(O)OR ｃ , or -C(O)N(R ｃ ) ２ And; R ｃ is, each time it appears independently, hydrogen, C １－４ alkyl, C １－４ fluoroalkyl, C ３－４ cycloalkyl, or -C １－３ alkylene-C ３－４ cycloalkyl, or two Rs ｃ together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic ring containing the nitrogen to which R ｃ is attached and one additional heteroatom which is optionally O, N, or S, said heterocyclic ring being optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C １－２ alkyl, and C １－２ fluoroalkyl; G １１ This includes phenyl, a 4-8 membered heterocyclyl containing 1-2 heteroatoms, a 5-6 membered heteroaryl containing 1-4 heteroatoms, or C ３－６ It is a cycloalkyl, where the heteroatom is independently selected from the group consisting of O, N, and S, and G １１ C １－４ Alkyl, halogen, cyano, oxo, -OC １－４ Alkyl, C １－４ Fluoroalkyl, C ３－４ Cycloalkyl and -C １－２ Alkylene-C ３－４ It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl groups; X １ is N or CR １ａ And; R １ａ is hydrogen, C １－４ Alkyl, C ３－６ Cycloalkyl, or C １－４ It is a fluoroalkyl; X ２ is N or CR １ｂ And; R １ｂ These are cyano, halogen, and C １－４ Alkyl, C １－４ Fluoroalkyl or hydrogen; R １ｃ and R １ｅ C １－４ Alkyl, hydrogen, halogen, C １－４ Fluoroalkyl, C ３－６ Cycloalkyl, or -OC １－４ It is alkyl; R １ｄ and R １ｆ C １－４ Alkyl, hydrogen, halogen, C １－４ Fluoroalkyl, or C ３－６ It is a cycloalkyl; Or, R １ａ and R １ｂ Each atom is attached together with the atom to which it is attached, or R １ｃ and R １ｄ Each of these forms a 6-membered allene, a 5-6 membered heteroallene containing 1-3 heteroatoms, a 5-7 membered heterocycle containing 1 heteroatom, or a 5-7 membered carbon ring, together with the atom to which it is attached, wherein the heteroatom is independently selected from the group consisting of N, O, and S, and the optional substitution is C １－４ Alkyl, halogen, -OC １－４ Alkyl, C １－４ Fluoroalkyl, C ３－４ Cycloalkyl, and C １－２ Alkylene-C ３－４ One to three optional substituents independently selected from the group consisting of cycloalkyl groups; R ２ is G ２ , -NR ２ａ R ２ｂ , halogen, cyano, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２ａ , -NR ２ａ C(O)R ２ｂ , -C(O)OR ２ａ , -C(O)NR ２ａ R ２ｂ , or hydrogen; R ２ａ and R ２ｂ These are, independently, hydrogen and C １－６ Alkyl, C １－６ Haloalkyl, G ２ , or -C １－３ Alkilen-G ２ However, R ２ is -N(CH ３ ) ２ Rather; G ２ Each instance is independently a 3-7 membered carbocyclyl, a 5-6 membered heteroaryl containing 1-4 heteroatoms, a phenyl, or a 4-7 membered heterocyclyl containing 1-2 heteroatoms, where the heteroatoms are independently selected from the group consisting of O, N, and S, and G ２ These are halogen, cyano, and C １－４ Alkyl, C １－４ Fluoroalkyl, oxo, -OR ｘ , -N(R ｘ ) ２ , -C(O)R ｘ , -C(O)OR ｘ , -C(O)N(R ｘ ) ２ , -C １－６ Alkylene-OR ｘ , -C １－６ Alkylene-N(R) ｘ ) ２ G ２ａ , and -C １－３ Alkilen-G ２ａ It is optionally substituted with a first substituent selected from the group consisting of halogens, cyanosides, and C12. １－４ Alkyl and C １－４ It is further optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl groups; R ｘ Each time they appear, hydrogen and C appear independently. １－４ Alkyl, C １－４ Fluoroalkyl, C ３－６ Cycloalkyl, or -C １－３ Alkylene-C ３－６ It is a cycloalkyl; G ２ａ C ３－６ It is a cycloalkyl; R ８ Each time it appears, halogen, C １－４ Alkyl, C １－４ Fluoroalkyl, or C ３－４ It is a cycloalkyl; o is 0, 1, 2, 3, or 4; Here, G ２ａ and R ８ Each cycloalkyl group in is independently either unsubstituted or C １－４ It is substituted with 1 to 4 substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., fluoro) elements; However, the compound is 4,5,6,7-tetrahydro-5-(2-pyridinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(4-pyrimidinyl)-thiazolo[5,4-c]pyridine-2-amine; 5-(6-chloro-2-cyclopropyl-5-methyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-2-methyl-thiazolo[5,4-c]pyridine; 2-[2-(4-ethyl-piperazine-1-yl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-yl]quinoline; 4,5,6,7-tetrahydro-5-[5-(trifluoromethyl)-thiazolo[5,4-c]pyridine-2-amine; N-(2-aminophenyl)-4,5,6,7-tetrahydro-5-[5-(trifluoromethyl)-2-pyridinyl]-thiazolo[5,4-c]pyridin-2-carboxamide; 5-(2,5-dimethyloxazolo[5,4-d]pyrimidine-7-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-(2-cyclopentyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-(5,6-dimethylthieno[2,3-d]pyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-thieno[2,3-d]pyrimidine-4-ylthiazolo[5,4-c]pyridine-2-amine; 5-[2,6-bis(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 7-(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-2-(trifluoromethyl)-thiazolo[5,4-d]pyrimidine; 4,5,6,7-tetrahydro-5-(2-pyridinyl)-thiazolo[5,4-c]pyridine-2-carboxylic acid, or a salt thereof; 4-(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-[1,2,5]thiadiazolo[3,4-c]pyridine; 4,5,6,7-tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]-thiazolo[5,4-c]pyridine-2-amine; 5-(4-chloro-2-pyridinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 5-[2-(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-[6-(1,1-dimethylethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-(2-ethyl-7-methylthieno[3,2-d]pyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 4,5,6,7-tetrahydro-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine-2-amine; 5-(6-cyclopentyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-[3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]thiazolo[5,4-c]pyridine-2-amine; 6-(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)-2-(trifluoromethyl)-9H-purine; 5-(2,6-dicyclopropyl-4-pyrimidinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(5-iodo-2-pyridinyl)-thiazolo[5,4-c]pyridine; 4,5,6,7-tetrahydro-5-(7-methylthieno[3,2-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(2-methyl-4-pyrimidinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(4-quinazolinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine; 4,5,6,7-tetrahydro-5-(3-pyridazinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-[6-methyl-2-(1-methylethyl)-4-pyrimidinyl]thiazolo[5,4-c]pyridine-2-amine; 5-(6-ethyl-5-fluoro-4-pyrimidinyl)-4,5,6,7-thiazolo[5,4-c]pyridine-2-amine; 5-(7-chloro-4-quinazolinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine; 5-(5-bromo-2-pyridinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 4,5,6,7-tetrahydro-5-(2-methylthieno[3,2-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(1H-pyrrolo[2,3-b]pyridine-6-yl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(2-methyl-6-propyl-4-pyrimidinyl)-thiazolo[5,4-c]pyridine-2-amine; 4,5,6,7-tetrahydro-5-(5-methylthieno[2,3-d]pyrimidine-4-yl)-thiazolo[5,4-c]pyridine-2-amine; 5-(6-cyclohexyl-4-pyrimidinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 4,5,6,7-tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]thiazolo[5,4-c]pyridine; or (Not 5-(6-bromo-4-quinazolinyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine).

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

3. Z １ However, C is Z ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein N is present.

4. Z １ However, N is Z ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein C is C.

5. Z １ However, C is Z ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein C is C.

6. G １ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is a five-membered partial unsaturated heterocyclic ring system.

7. G １ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is a six-membered partially unsaturated heterocyclic ring system.

8. G １ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is a five-membered aromatic ring heterocyclic ring system.

9. G １ The compound according to any one of claims 1, 2, or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is a six-membered aromatic ring heterocyclic ring system.

10. R １ｅ However, C １－４ A compound according to any one of claims 1 to 9, wherein the compound is alkyl or hydrogen, or a pharmaceutically acceptable salt thereof.

11. R １ｆ However, C １－４ A compound according to any one of claims 1 to 10, which is alkyl, or a pharmaceutically acceptable salt thereof.

12. R １ but, 【Chemistry 4】 【Transformation 5】 【Transformation 6】 The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R １ but, 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. X １ The compound according to claim 1 or 13, or a pharmaceutically acceptable salt thereof, wherein N is present.

15. X １ However, CR １ａ The compound according to claim 1 or 13, or a pharmaceutically acceptable salt thereof.

16. X ２ The compound according to any one of claims 1 or 13 to 15, wherein N is present, or a pharmaceutically acceptable salt thereof.

17. X ２ However, CR １ｂ The compound according to any one of claims 1 or 13 to 15, or a pharmaceutically acceptable salt thereof.

18. R １ａ However, hydrogen or C １－４ A compound according to any one of claims 1, 13, or 15-17, which is alkyl, or a pharmaceutically acceptable salt thereof.

19. R １ｂ A compound according to any one of claims 1, 13-15, or 17-18, or a pharmaceutically acceptable salt thereof, which is cyano.

20. R １ａ and R １ｂ The compound according to any one of claims 1, 13, 15, or 17, or a pharmaceutically acceptable salt thereof, wherein each atom, together with the atom to which it is attached, forms a optionally substituted six-membered allene, a five- to six-membered heteroallene containing one to three heteroatoms, a five- to seven-membered heterocycle containing one heteroatom, or a five- to seven-membered carbon ring.

21. R １ｃ However, hydrogen, C １－４ A compound according to any one of claims 1 or 13 to 20, which is alkyl or halogen, or a pharmaceutically acceptable salt thereof.

22. R １ｄ However, hydrogen or C １－４ A compound according to any one of claims 1 or 13 to 21, which is alkyl, or a pharmaceutically acceptable salt thereof.

23. R １ｃ and R １ｄ The compound according to claim 1 or any one of claims 13 to 19, or a pharmaceutically acceptable salt thereof, wherein each atom, together with the atom to which it is attached, forms a optionally substituted six-membered allene, a five- to six-membered heteroallene containing one to three heteroatoms, a five- to seven-membered heterocycle containing one heteroatom, or a five- to seven-membered carbon ring.

24. R １ teeth, 【Transformation 8】 【Chemistry 9】 The compound according to any one of claims 1 or 13 to 23, or a pharmaceutically acceptable salt thereof.

25. R ２ However, G ２ , -NR ２ａ R ２ｂ , halogen, cyano, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２ａ , -C(O)OR ２ａ , -C(O)NR ２ａ R ２ｂ A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, which is hydrogen.

26. R ２ However, G ２ The compound according to claim 25, or a pharmaceutically acceptable salt thereof.

27. G ２ The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein the compound is a 3- to 7-membered carbocyclyl that is optionally substituted.

28. G ２ The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein the compound is a 5-6 member heteroaryl substituted by optional choice.

29. G ２ The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein the phenyl is optionally substituted.

30. G ２ but, 【Chemistry 10】 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

31. R ２ However, -NR ２ａ R ２ｂ The compound according to claim 25, or a pharmaceutically acceptable salt thereof.

32. R ２ However, -C(O)NR ２ａ R ２ｂ The compound according to claim 25, or a pharmaceutically acceptable salt thereof.

33. R ２ｂ However, hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, G ２ , or -C １－３ Alkilen-G ２ The compound according to any one of claims 1 to 25 or 31 to 32, or a pharmaceutically acceptable salt thereof.

34. R ２ However, -C(O)OR ２ａ The compound according to claim 25, or a pharmaceutically acceptable salt thereof.

35. R ２ However, -OR ２ａ The compound according to claim 25, or a pharmaceutically acceptable salt thereof.

36. R ２ａ However, hydrogen or C １－６ A compound according to any one of claims 1 to 25 or 31 to 35, which is alkyl, or a pharmaceutically acceptable salt thereof.

37. R ２ However, C １－６ The compound according to claim 25, or a pharmaceutically acceptable salt thereof, which is alkyl.

38. R ２ However, the compound according to claim 25, or a pharmaceutically acceptable salt thereof, is a halogen.

39. R ２ The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

40. R ２ However, C １－６ The compound according to claim 25, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

41. R ２ The compound according to claim 25, or a pharmaceutically acceptable salt thereof, which is cyano.

42. A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein o is 0. 【Request Item 43】 【Table 1】 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

45. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44, 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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