7-(Piperidin-1-yl)-4H-pyrimido[1,2-B]pyridazin-4-one derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor M4

Abstract

Disclosed herein are analogs of 6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine, i.e., 7-(4-((phenyl or pyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one derivatives of Formula (I), which may be useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. [Formula 1] JPEG2023534803000154.jpg57170

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to U.S. Patent Application No. 63 / 052,085, filed July 15, 2020, which is incorporated herein by reference in its entirety.

[0002] Technical Field The present invention relates to compounds, compositions and methods for treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. [Background technology]

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

[0004] Attempts to enhance central cholinergic function by administering choline or phosphatidylcholine have been unsuccessful. Although AChE inhibitors have demonstrated 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. In addition, some AChE inhibitors, such as tacrine, have been shown to cause significant hepatotoxicity due to elevated hepatic transaminases observed in approximately 30% of patients. The side effects of AChE inhibitors significantly limit their clinical usefulness. An alternative approach to pharmacologically targeting cholinergic hypofunction is activation of mAChRs, which are widely expressed throughout the body.

[0005] mAChRs are members of the GPCR family and include five subtypes, designated M1 to M5. The M1, M3, and M5 subtypes are primarily G q M2 and M4 subtypes bind to and activate phospholipase C, whereas M2 and M4 subtypes primarily bind to G i / o and associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system, where they are differentially expressed and prevalent. M1-M5 play diverse roles in cognitive, sensory, motor, and autonomic functions. Therefore, without wishing to be bound by any particular theory, it is believed that selective mAChR subtype agonists that modulate processes involved in cognitive function may prove to be excellent therapeutic agents for the treatment of psychosis, schizophrenia, and related disorders. The muscarinic M4 receptor has been shown to play a key role in cognitive processing and is believed to play a key role in the pathophysiology of psychotic disorders, including schizophrenia.

[0006] Evidence suggests that the most prominent side effects of AChE inhibitors and other cholinergic agonists are mediated by activation of peripheral M2 and M3 mAChRs and include bradycardia, gastrointestinal distress, excessive salivation, and sweating. In contrast, M4 has been identified as the subtype most likely to mediate the effects of muscarinic acetylcholine receptor dysfunction in psychotic disorders such as schizophrenia, cognitive impairment, and neuropathic pain. For this reason, considerable efforts have been devoted to developing selective M4 agonists for the treatment of these disorders. Unfortunately, these efforts have been largely unsuccessful due to the inability to develop compounds highly selective for the M4 mAChR. Therefore, mAChR agonists tested in clinical trials induce various side effects through 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 psychiatric diseases, including schizophrenia, cognitive impairment, and other disorders, it may be important to develop compounds that are highly selective activators of mAChR M4 and other individual mAChR subtypes.

[0007] Previous attempts to develop 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 the highly conserved orthosteric ACh binding site, researchers have attempted to develop compounds that act at less highly conserved allosteric sites on mAChRs. This approach has improved the development of selective ligands for multiple GPCR subtypes. In the case of mAChRs, the primary goal has been to develop allosteric ligands that selectively increase the activity of mAChR M4 or other mAChR subtypes. Allosteric activators include allosteric agonists, which act at sites distinct from the orthosteric site and directly activate the receptor in the absence of ACh, as well as positive allosteric modulators (PAMs), which do not directly activate the receptor but potentiate its activation by the endogenous orthosteric agonist ACh. It is also possible for a single molecule to have both allosteric potentiator and allosteric agonist activity.

[0008] Recently, muscarinic agonists, including xanomeline, have been shown to have a profile similar to that of known antipsychotic drugs but without causing catalepsy and are active in animal models (Bymaster et al., Eur. J. Pharmacol. 1998, 356, 109; Bymaster et al., Life Sci. 1999, 64, 527; Shannon et al., J. Pharmacol. Exp. Ther. 1999, 290, 901; Shannon et al., Schizophrenia Res. 2000, 42, 249). Furthermore, xanomeline has also been shown to reduce psychotic behavioral symptoms, such as delusions, distrust, sudden screaming, and hallucinations, in patients with Alzheimer's disease (Bodick et al., Arch. Neurol. 1997, 54, 465). However, treatment-induced side effects, such as gastrointestinal effects, significantly limit the clinical usefulness of this compound.

[0009] WO 2018 / 118736 discloses 6,5-fused heteroarylpiperidine ethers that are allosteric modulators of the M4 muscarinic acetylcholine receptor.

[0010] Despite advances in muscarinic acetylcholine receptor research, compounds that are potent, effective, and selective activators of M4 mAChRs and that are also effective in treating neurological and psychiatric disorders associated with cholinergic activity, as well as diseases involving the muscarinic M4 receptor, remain scarce. Summary of the Invention

[0011] In a first aspect, the present invention provides a compound of formula (I) [ka] (In the formula, X is CR 5a Or N; R 1 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C3-C6-cycloalkyl, -L 1 -C3~C6-cycloalkyl, halo, -L 1 OR a and OR a Selected from; R 2 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, halo, -L 2 OR b , OR b , NHR b , and N(R b )2 is selected; R 3 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, halo, -L 3 OR c , and OR c Selected from; Each R 4 is C1-C4 alkyl, ORd , -L 4 OR d and halo; Each R 5 is C1-C4-alkyl, C1-C4-haloalkyl, OR e , -L 5 OR e , 5- or 6-membered heteroaryl, phenyl, C3-C6-cycloalkyl, and halo; or Here, two R 5 together with the carbon atom to which they are attached form a 5-8 membered fused monocyclic heterocycle containing 1-2 heteroatoms independently selected from O, N, and S, and the fused monocyclic heterocycle is 6 may be substituted with; R 5a is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, OR e , -L 5 OR e and halo; Each R 5b are independently selected from C1-C2-alkyl, C1-C2-fluoroalkyl, C3-C4-cycloalkyl, —O—C1-C2-alkyl, —O—C1-C2-fluoroalkyl, cyano, and halo; Each R 6 is oxo, C1-C4-alkyl, OR f , -L 6 OR f and halo; R 7 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, halo, -L 2 OR b , OR b , NHR b , and N(R b )2 is selected; o is 0, 1 or 2; m is 0, 1 or 2; n is 0, 1 or 2; L 1 , L 2 , L3 , L 4 , L 5 , and L 6 is independently at each occurrence C1-C3-alkylene; R a , R b , R c , R d , R e , and R f each occurrence is independently selected from C1-C4-alkyl, C1-C4-haloalkyl, and C3-C6-cycloalkyl, wherein two R b together with the nitrogen atom to which they are attached, optionally form a 4- to 7-membered monocyclic heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halo, C1-C4-alkyl, and C1-C4-haloalkyl. or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides a method of treating a neurological and / or psychiatric disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0013] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a neurological and / or psychiatric disorder.

[0014] In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for the preparation of a medicament for the treatment of a neurological and / or psychiatric disorder. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows a schematic diagram of the ligand binding site, including the orthosteric and allosteric sites, in the muscarinic acetylcholine receptor. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description Disclosed herein are positive allosteric modulators (i.e., potentiators) of the muscarinic acetylcholine receptor M4 (mAChR M4), methods for making them, pharmaceutical compositions containing them, and methods for using them to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The compounds include analogs of 6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine.

[0017] The human muscarinic acetylcholine receptor M4 (mAChR M4) is a 479-amino acid protein encoded by the CHRM4 gene. The molecular weight of the non-glycosylated protein is approximately 54 kDa, and it is a transmembrane GPCR. As previously mentioned, mAChR M4 is a member of the GPCR class A family, or rhodopsin-like GPCR, and is characterized by structural features similar to those of rhodopsin, such as seven transmembrane segments. Muscarinic acetylcholine receptors have an N-terminus facing the extracellular surface of the membrane and a C-terminus located on the cytoplasmic surface. A schematic diagram of the mAChR M4 structure is shown in Figure 1, where the transmembrane segment is shown as a cylinder (spanning the lipid bilayer of the plasma membrane). Orthosteric binding of the natural ligand for mAChR, i.e., acetylcholine, occurs within a pocket located within the transmembrane segment, as shown in Figure 1.

[0018] Previous attempts to develop highly selective agonists for individual mAChR subtypes have failed due to the high degree of conservation of the orthosteric ACh binding site. To circumvent the problems associated with targeting the highly conserved orthosteric ACh binding site, it has been proposed to develop compounds that act on less highly conserved allosteric sites on mAChRs that are removed from the orthosteric site. While not wishing to be bound by any particular theory, it is believed that the compounds of the present invention and the products of the disclosed methods bind to an allosteric site that is different from the orthosteric binding site. For example, the disclosed compounds can bind at a binding site as illustrated in FIG. 1.

[0019] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0020] The terms "comprise," "include," "having," "having," "can," "containing," and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The present invention also contemplates other embodiments that "comprise," "consist," and "consist essentially of" the embodiments or elements provided herein, whether or not explicitly stated.

[0021] The modifier "about" used in connection with a quantity is inclusive of the stated value and has a meaning dictated by context and the understanding of one of ordinary skill in the art.

[0022] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this specification, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th (back cover), and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry and specific functional groups and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and 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 Edition, Cambridge University Press, Cambridge, 1987, the contents of each of which are incorporated herein by reference in their entirety.

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

[0024] The term "alkyl," as used herein, means a straight or branched saturated hydrocarbon chain containing from 1 to 10 carbon atoms. 1-6 The term "C-alkyl" means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. 1-3 "-Alkyl" means a straight or branched chain hydrocarbon containing 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 4,4-dimethylpentan-2-yl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0025] The term "alkenyl," as used herein, means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and from 2 to 10 carbon atoms.

[0026] The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. An alkoxyalkyl group can be represented by the general formula LOR, where L is a C group, such as CH. 1~3 -alkylene, and R is C 1~3 Representative examples include, but are not limited to, -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3.

[0027] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0028] The term "alkylene," as used herein, refers to a saturated divalent group derived from a straight or branched chain hydrocarbon of 1 to 10 carbon atoms, for example, 2 to 5 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH-, -CHCH-, -CHCHCH-, -CHCH(CH)CH-, -CHCHCHCHCH-, -CHCH(CH)CHCH-, and -CHCHCHCHCHCH-.

[0029] The term "alkylamino," as used herein, means at least one alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.

[0030] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0031] The term "amino" as used herein refers to -NR x R y (In the formula, R x and R y is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl, or R x and R y may form a heterocycle together with the N to which they are attached. In the case of an aminoalkyl group, or any other moiety where amino attaches two other moieties together, amino is represented by -NR x -(In the formula, R x can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl).

[0032] The term "aryl," as used herein, refers to a phenyl group, or a bicyclic or tricyclic fused ring system. A bicyclic fused ring system is exemplified by a phenyl group attached to the parent molecular moiety and fused to a phenyl group, a cycloalkyl group, as defined herein, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. A tricyclic fused ring system is exemplified by a phenyl group attached to the parent molecular moiety and fused to a bicyclic fused ring system, as defined herein. Representative examples of aryl include, but are not limited to, the following: phenyl, naphthyl, anthracenyl, indolyl (e.g., 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, and 1H-indol-7-yl), benzodioxolyl (e.g., benzo[d][1,3]dioxol-4-yl and benzo[d][1,3]dioxol-5-yl), chromanyl (e.g., chroman-5-yl, chroman-6-yl, chroman-7-yl, and chroman-8-yl), and tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 1,2,3,4-tetrahydroquinolin-7-yl, and 1,2,3,4-tetrahydroquinolin-8-yl).

[0033] The term "cycloalkoxy," as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0034] The term "cycloalkyl," as used herein, refers to a carbocyclic ring system containing 3 to 10 carbon atoms, zero heteroatoms, and zero double bonds. Cycloalkyls can be monocyclic, bicyclic, bridged, fused, or spirocyclic. 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. "Cycloalkyl" also includes carbocyclic ring systems in which a cycloalkyl group is appended to a parent molecular moiety and is fused to an aryl group (e.g., a phenyl group), a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Representative examples of such cycloalkyl groups include, but are not limited to, 2,3-dihydro-1H-indenyl (e.g., 2,3-dihydro-1H-inden-1-yl and 2,3-dihydro-1H-inden-2-yl), 6,7-dihydro-5H-cyclopenta[b]pyridinyl (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl), oxaspiro[3.3]heptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), and 5,6,7,8-tetrahydroquinolinyl (e.g., 5,6,7,8-tetrahydroquinolin-5-yl).

[0035] The term "cycloalkenyl," as used herein, refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms per ring. Cycloalkenyls can be monocyclic, bicyclic, bridged, fused, or spirocyclic. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, cycloheptenyl, and bicyclo[2.2.1]heptenyl.

[0036] The term "fluoroalkyl," as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl (such as 3,3,3-trifluoropropyl).

[0037] The term "fluoroalkoxy," as used herein, means at least one fluoroalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0038] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0039] The term "haloalkyl," as used herein, means an alkyl group, as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms are replaced by halogen.

[0040] The term "haloalkoxy," as used herein, means at least one haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0041] The term "halocycloalkyl," as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms has been replaced by halogen.

[0042] The term "heteroalkyl," as used herein, means an alkyl group, as defined herein, in which one or more carbon atoms is replaced by a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0043] The term "heteroaryl," as used herein, refers to an aromatic monocyclic or aromatic bicyclic ring system. An aromatic monocyclic ring is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, S, and N). A 5-membered aromatic monocyclic ring has two double bonds, and a 6-membered aromatic monocyclic ring has three double bonds. A bicyclic heteroaryl group is exemplified by a monocyclic heteroaryl ring attached to a parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Representative examples of heteroaryl include, but are not limited to, the following: indolyl, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, Examples include benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl, quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, 6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2-yl.

[0044] The term "heterocycle" or "heterocyclic" as used herein refers to a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 7- and 8-membered ring contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, 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, oxa azolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. A bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a spiro heterocyclic group, or a bridged monocyclic heterocyclic ring system (wherein two non-adjacent atoms of the ring are joined by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms).Representative examples of bicyclic heterocycles include, but are not limited to, the following: benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (2-azabicyclo[2.2.1]heptyl), 2-azabi ... -2-yl), oxabicyclo[2.2.1]heptanyl (such as 7-oxabicyclo[2.2.1]heptan-3-yl), azabicyclo[3.1.0]hexanyl (such as 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. A tricyclic heterocycle is exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-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). Monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring, and can be unsubstituted or substituted.

[0045] The terms "hydroxyl" or "hydroxy," as used herein, refer to an --OH group.

[0046] The term "hydroxyalkyl," as used herein, means at least one --OH group, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0047] The term "hydroxyfluoroalkyl," as used herein, means at least one --OH group, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0048] In some cases, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl or cycloalkyl) is indicated by the prefix "C x ~C y -" where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, "C1-C3-alkyl" refers to an alkyl substituent containing from 1 to 3 carbon atoms.

[0049] The term "substituent" refers to a group (non-hydrogen) "substituted" for a group such as an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, or heterocyclic group at any atom of that group. Any atom can be substituted.

[0050] 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, halogen, ═O (oxo), ═S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, 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, a group may be substituted. In some embodiments, a group may be substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, an aryl, heteroaryl, cycloalkyl, or heterocycle can be substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, an aryl, heteroaryl, cycloalkyl, or heterocycle can be independently unsubstituted or substituted with 1, 2, or 3 substituents.

[0051] For the compounds described herein, and in accordance with the permitted valences of atoms and substituents, groups and substituents can be selected such that selection and substitution results in stable compounds (e.g., which do not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc.).

[0052] As used herein, the term "allosteric site" refers to a ligand binding site that is topographically distinct from the orthosteric binding site.

[0053] As used herein, the term "modulator" refers to a molecular entity (for example, but not limited to, ligands and disclosed compounds) that modulates the activity of a target receptor protein.

[0054] The term "ligand," as used herein, refers to a natural or synthetic molecular entity that can associate with or bind to a receptor to form a complex and mediate, prevent, or modify a biological effect. Thus, the term "ligand" encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates, and analogs of natural substrates.

[0055] As used herein, the terms "natural ligand" and "endogenous ligand" are used interchangeably and refer to a natural ligand found in nature that binds to a receptor.

[0056] As used herein, the term "orthosteric site" refers to the primary binding site on a receptor that is recognized by the endogenous ligand or agonist for that receptor. For example, the orthosteric site on the mAChR M4 receptor is the site to which acetylcholine binds.

[0057] As used herein, the term "mAChR M4 receptor-positive allosteric modulator" refers to any exogenously administered compound or agent that directly or indirectly enhances the activity of the mAChR M4 receptor in animals, particularly mammals, e.g., humans, in the presence or absence of acetylcholine or another agonist. For example, an mAChR M4 receptor-positive allosteric modulator can increase the activity of the intracellular mAChR M4 receptor in the presence of extracellular acetylcholine. The cell can be a Chinese hamster ovary (CHO-K1) cell transfected with human mAChR M4. The cell can be a Chinese hamster ovary (CHO-K1) cell transfected with rat mAChR M4 receptor. The cell can be a Chinese hamster ovary (CHO-K1) cell transfected with mammalian mAChR M4. The term "mAChR M4 receptor positive allosteric modulator" encompasses compounds that are "mAChR M4 receptor allosteric potentiators" or "mAChR M4 receptor allosteric agonists," as well as compounds that have mixed activity, including the pharmacology of both "mAChR M4 receptor allosteric potentiators" and "mAChR M4 receptor allosteric agonists." The term "mAChR M4 receptor positive allosteric modulator" also includes compounds that are "mAChR M4 receptor allosteric enhancers."

[0058] As used herein, the term "mAChR M4 receptor allosteric potentiator" refers to any exogenously administered compound or agent that directly or indirectly enhances the response produced by an endogenous ligand (such as acetylcholine) when the endogenous ligand binds to the orthosteric site of the mAChR M4 receptor in an animal, particularly a mammal, e.g., a human. The mAChR M4 receptor allosteric potentiator binds to a site other than the orthosteric site, i.e., an allosteric site, thereby enhancing the receptor's response to an agonist or endogenous ligand. In some embodiments, the allosteric potentiator does not induce receptor desensitization, and the activity of the compound as an mAChR M4 receptor allosteric potentiator may provide advantages over the use of pure mAChR M4 receptor orthosteric agonists. Such advantages may include, for example, an increased safety margin, better tolerability, reduced abuse potential, and reduced toxicity.

[0059] As used herein, the term "mAChR M4 receptor allosteric enhancer" refers to any exogenously administered compound or agent that directly or indirectly enhances the response produced by an endogenous ligand (such as acetylcholine) in an animal, particularly a mammal, e.g., a human. In some embodiments, the allosteric enhancer increases the affinity of a natural ligand or agonist for the orthosteric site. In some embodiments, the allosteric enhancer increases agonist potency. The mAChR M4 receptor allosteric enhancer binds to a site other than the orthosteric site, i.e., an allosteric site, thereby enhancing the receptor's response to an agonist or endogenous ligand. The allosteric enhancer does not affect the receptor by itself and requires the presence of an agonist or natural ligand to achieve its receptor effect.

[0060] As used herein, the term "mAChR M4 receptor allosteric agonist" refers to any exogenously administered compound or agent that directly activates the mAChR M4 receptor in animals, particularly mammals, e.g., humans, in the absence of endogenous ligands (such as acetylcholine). mAChR M4 receptor allosteric agonists bind to a site on the mAChR M4 receptor that is distinct from the orthosteric acetylcholine site. Because the presence of an endogenous ligand is not required, the activity of a compound as an mAChR M4 receptor allosteric agonist offers advantages when the cholinergic potential at a given synapse is low.

[0061] As used herein, the term "mAChR M4 receptor neutral allosteric ligand" refers to any exogenously administered compound or drug that binds to the allosteric site in animals, particularly mammals, e.g., humans, without affecting the binding or function of agonists or natural ligands at the orthosteric site. However, neutral allosteric ligands can block the action of other allosteric modulators that act through the same site.

[0062] For the recitation of numerical ranges herein, each intervening number is specifically contemplated to the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are specifically contemplated.

[0063] 2. Embodiments of the present invention The following describes embodiments of the present invention, where the first embodiment is designated as E1, the second embodiment as E2, and so on.

[0064] E1. Formula (I) [ka] (In the formula, X is CR 5aOr N; R 1 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C3-C6-cycloalkyl, -L 1 -C3~C6-cycloalkyl, halo, -L 1 OR a and OR a Selected from; R 2 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, halo, -L 2 OR b , OR b , NHR b , and N(R b )2 is selected; R 3 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, halo, -L 3 OR c , and OR c Selected from; Each R 4 is C1-C4 alkyl, OR d , -L 4 OR d and halo; Each R 5 is C1-C4-alkyl, C1-C4-haloalkyl, OR e , -L 5 OR e , 5- or 6-membered heteroaryl, phenyl, C3-C6-cycloalkyl, and halo; or Here, two R 5 together with the carbon atom to which they are attached form a 5-8 membered fused monocyclic heterocycle containing 1-2 heteroatoms independently selected from O, N, and S, and the fused monocyclic heterocycle is 6 may be substituted with; R 5a is hydrogen, C1-C4-alkyl, C1-C4-cycloalkyl, C3-C6-cycloalkyl, OR e , -L 5 OR e and halo; Each R 5b are independently selected from C1-C2-alkyl (e.g., methyl), C1-C2-fluoroalkyl (e.g., trifluoromethyl, difluoromethyl), C3-C4-cycloalkyl (e.g., cyclopropyl), —O—C1-C2-alkyl (e.g., methoxy), —O—C1-C2-fluoroalkyl (e.g., trifluoromethoxy, difluoromethoxy), cyano, and halo (e.g., fluoro, chloro); Each R 6 is oxo, C1-C4-alkyl, OR f , -L 6 OR f and halo; R 7 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, halo, -L 2 OR b , OR b , NHR b , and N(R b )2 is selected; o is 0, 1 or 2; m is 0, 1 or 2; n is 0, 1 or 2; L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is independently at each occurrence C1-C3-alkylene; R a , R b , R c , R d , R e , and R f each occurrence is independently selected from C1-C4-alkyl, C1-C4-haloalkyl, and C3-C6-cycloalkyl, where two R b together with the nitrogen atom to which they are attached, optionally form a 4- to 7-membered monocyclic heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halo, C1-C4-alkyl, and C1-C4-haloalkyl. or a pharmaceutically acceptable salt thereof.

[0065] E2.Formula (IA) [ka] (In the formula, Each R 5c is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, OR e , -L 5 OR e , 5- or 6-membered heteroaryl, phenyl, C3-C6-cycloalkyl, and halo; or Here, two R 5c together with the carbon atom to which they are attached form a 5-8 membered fused monocyclic heterocycle containing 1-2 heteroatoms independently selected from O, N, and S, and the fused monocyclic heterocycle is 6 (which may be substituted with or a pharmaceutically acceptable salt thereof.

[0066] E3. The Two Rs 5 or R 5c together with the carbon atoms to which they are attached form a fused 5-8 membered monocyclic heterocycle; or a pharmaceutically acceptable salt thereof.

[0067] E4.R 5 or R 5c and the 5- to 8-membered fused monocyclic heterocycle formed together contains 1 to 2 heteroatoms independently selected from O and N, and 1 to 2 R 6 The compound of any of embodiments E1-E3, or a pharmaceutically acceptable salt thereof, optionally substituted with:

[0068] E5.Formula (IB) [ka] (In the formula, G 1 teeth, [ka] and; each q is independently 0, 1, 2, 3, or 4 A compound of any one of embodiments E1 to E3, or a pharmaceutically acceptable salt thereof.

[0069] E6.G 1 but, [ka] and; R 5a A compound of embodiment E5, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, C1-C4-alkyl, or halo.

[0070] E7.G 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0071] E8.Formula (Ia) [ka] A compound of any one of embodiments E1 to E5, or a pharmaceutically acceptable salt thereof.

[0072] E9.Formula (Ib) [ka] A compound of any one of embodiments E1 to E5, or a pharmaceutically acceptable salt thereof.

[0073] E10. The compound of any one of embodiments E1 to E9, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0074] E11.Each R 5 or R 5c is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, OR e , -L 5 OR e , 5- or 6-membered heteroaryl, phenyl, C3-C6-cycloalkyl, and halo, or a pharmaceutically acceptable salt thereof.

[0075] E12.Each R 5 or R 5c is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, OR e , -L 5 OR e or a pharmaceutically acceptable salt thereof.

[0076] E13.Formula (IB) [ka] (In the formula, G 1 teeth, [ka] is) A compound of embodiment E12, or a pharmaceutically acceptable salt thereof.

[0077] E14.G 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0078] E15.G 1 but, [ka] The compound of embodiment E14, wherein:

[0079] E16.R 3 is hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, or -L 3 OR c The compound of any one of embodiments E1 to E15, wherein:

[0080] E17.R 3 The compound of embodiment E16, wherein is C1-C4-alkyl, or a pharmaceutically acceptable salt thereof.

[0081] E18.R 3 The compound of embodiment E17, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0082] E19.R 1 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, -L 1 -C3-C6-cycloalkyl, or -L 1 OR a The compound of any one of embodiments E1 to E18, wherein:

[0083] E20.R 1 A compound of embodiment E19, or a pharmaceutically acceptable salt thereof, wherein is C1-C4-alkyl.

[0084] E21.R 1 A compound of embodiment E19, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0085] E22.R 1 The compound of embodiment E19, or a pharmaceutically acceptable salt thereof, wherein is C1-C4-fluoroalkyl.

[0086] E23.R 1 The compound of embodiment E22, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl.

[0087] E24.R 1 The compound of embodiment E22, or a pharmaceutically acceptable salt thereof, wherein is difluoromethyl.

[0088] E25.R 2 is hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, -L 2 OR b , OR b , NHR b , and N(R b )2; or a pharmaceutically acceptable salt thereof.

[0089] E26.R 2 The compound of embodiment E25, or a pharmaceutically acceptable salt thereof, wherein is C1-C4-alkyl.

[0090] E27.R 2 The compound of embodiment E25, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0091] E28.R 2 The compound of embodiment E25, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0092] E29.R 4 A compound of any one of embodiments E1 to E28, or a pharmaceutically acceptable salt thereof, wherein is C1-C4-alkyl or halo.

[0093] E30. The compound of any one of embodiments E1 to E29, or a pharmaceutically acceptable salt thereof, wherein o is 0.

[0094] E31. The compound of any one of embodiments E1 to E29, or a pharmaceutically acceptable salt thereof, wherein o is 1.

[0095] E32.R 7 is selected from hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, halo, and N(R b)2; or a pharmaceutically acceptable salt thereof.

[0096] E33.R 7 A compound of embodiment E32, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, methyl, cyclopropyl, fluoro, chloro, and azetidin-1-yl.

[0097] E34.R 7 The compound of embodiment E33, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0098] E35. The compound of any one of embodiments E1 to E5 or E8 to E34, wherein X is N; or a pharmaceutically acceptable salt thereof.

[0099] E36.X, CR 5a The compound of any one of embodiments E1 to E34, wherein:

[0100] E37.R 5a The compound of embodiment E36, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0101] E38. Below: 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-fluorophenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-8-methyl-7-(4-((8-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-((8-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-fluoro-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-(azetidin-1-yl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-(benzo[d][1,3]dioxol-5-yloxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-3-fluoro-4-(isochroman-6-yloxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzofuran-5-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-(chroman-7-yloxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-2-(difluoromethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-methoxy-5-methylpyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-(methoxymethyl)pyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-(p-tolyloxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-chlorophenoxy)piperidin-1-yl)-2-(difluoromethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-8,9-dimethyl-7-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-fluorophenoxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-(4-fluorophenoxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-8,9-dimethyl-7-(4-(p-tolyloxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(3-fluoro-4-methylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-ethylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-isopropylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-(4-propylphenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-(p-tolyloxy)piperidin-1-yl-4-d)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-(methoxymethyl)-5-methylpyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(cyclopentylmethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-(methoxymethyl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-(methoxymethyl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-9-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(( 2nd race, 4th race )-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-9-(methylamino)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-9-methoxy-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-(azetidin-1-yl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-2,2,6,6-d4)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one or a pharmaceutically acceptable salt thereof.

[0102] E39. A pharmaceutical composition comprising a compound of any one of embodiments E1-E38 and a pharmaceutically acceptable carrier.

[0103] E40. A method for treating a neurological and / or psychiatric disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to any one of embodiments E1-E39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0104] E41. The method of embodiment E40, wherein said disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, borderline personality disorder, Tourette's syndrome, bipolar disorder, tardive dyskinesia, Huntington's disease, a pain disorder, and a cognitive disorder.

[0105] E42. The method of embodiment E40, wherein said disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episode of anxiety, anxiety associated with psychosis, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, autistic disorder, movement disorder, Tourette's syndrome, akinetic-rigid syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative-based dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0106] E43. The method of any one of embodiments E40-E42, wherein said disorder is associated with muscarinic acetylcholine receptor M4 dysfunction.

[0107] E44. A compound according to any one of embodiments E1 to E38, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0108] E45. A compound according to any one of embodiments E1-E39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of a disorder selected from Alzheimer's disease, schizophrenia, a sleep disorder, borderline personality disorder, Tourette's syndrome, bipolar disorder, tardive dyskinesia, Huntington's disease, a pain disorder, and a cognitive disorder.

[0109] E46. A compound of any one of embodiments E1-E39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in treating a disorder selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, autistic disorder, movement disorder, Tourette's syndrome, akinetic rigidity syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative-based dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0110] E47. Use of a compound or pharmaceutical composition according to any one of embodiments E1 to E39, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder selected from Alzheimer's disease, schizophrenia, borderline personality disorder, Tourette's syndrome, bipolar disorder, tardive dyskinesia, Huntington's disease, a sleep disorder, a pain disorder, and a cognitive disorder.

[0111] E48. Use of a compound or pharmaceutical composition according to any one of embodiments E1 to E39, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, autistic disorder, movement disorders, Tourette's syndrome, akinetic rigidity syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative-based dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0112] Compound names can be assigned using the Struct=Name naming algorithm as part of CHEMDRAW® version 18.0.

[0113] This compound can exist as stereoisomers where asymmetric or chiral centers exist. Stereoisomers are "R" or "S," depending on the configuration of substituents around the chiral carbon atom. As used herein, the terms "R" and "S" refer to the configurations as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45:13-30. The present invention contemplates various stereoisomers and mixtures thereof, which are expressly included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of this compound can be prepared from commercially available starting materials containing asymmetric or chiral centers, either by synthesis or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of 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 a mixture of optical enantiomers on a chiral chromatographic column, or (3) fractional recrystallization methods.

[0114] It is to be understood that the compounds of the present invention may have tautomeric forms, stereoisomers, geometric isomers, solvates, as well as polymorphs, which also constitute embodiments of the present disclosure.

[0115] In the compounds of formula (I) and any subformula, all "hydrogen" or "H", whether explicitly stated or included in the structure, is a hydrogen isotope. 1H (protium) and 2 Includes H (deuterium).

[0116] The present invention also includes isotopically labeled compounds that are identical to those recited in Formula (I) except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes suitable for inclusion in compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, including, but not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 2 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Cl. Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may be preferable in some circumstances, as it may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. The compounds may incorporate positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that can be incorporated into compounds of formula (I) include: 11 C. 13 N, 15 O and 18 F. Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples, substituting appropriate isotopically labeled reagents for non-isotopically labeled reagents.

[0117] a. Pharmaceutically acceptable salts The compounds of the present invention can 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 suitable for treating disorders without undue toxicity, irritation, or allergic reactions, at a reasonable benefit / risk ratio and effective for its intended use. These salts can 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 can be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one acid equivalent, such as hydrochloric acid. The resulting salt can be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid can be removed under reduced pressure to provide the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

[0118] Base addition salts can be prepared during the final isolation and purification of the compounds of the invention by reaction of the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or 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.

[0119] b. General synthesis The compounds of formula (I) or salts thereof can be prepared by synthetic processes or metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or in vitro. The schemes are representative of methods useful for synthesizing the compounds of the present invention. They are not intended to limit the scope of the present invention in any way.

[0120] Abbreviations used in the following schemes include: DCE is 1,2-dichloroethane; DCM is dichloromethane; DMF is N,N-dimethylformamide; DMP or Dess-Martin periodinane is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DtBAD is di-tert-butyl azodicarboxylate; LAH is lithium aluminum hydride. mCPBA is metachlorobenzoic acid; MeOH is methanol; MW is microwave (refers to microwave reactor); Pd(OAc)2 is palladium(II) acetate; PPA is polyphosphoric acid; Rxn is reactant; TBAC is tetrabutylammonium chloride; t-BuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; THF is tetrahydrofuran.

[0121] Compounds of formula (I) can be synthesized as shown in Schemes 1-7.

[0122] [ka] As shown in Scheme 1, reaction of analogs of 6-chloropyridazin-3-amine with triethyl orthoformate and isopropylidene malonate can give compounds of type S1, which can be cyclized to give compounds of type S2. Reaction of compound S2 with an appropriately substituted 4-piperidine ether of type S3 in the presence of a base can give compounds S4.

[0123] [ka] As shown in Scheme 2, the reaction product of 6-chloropyridazin-3-amine analogs with β-keto acids can be cyclized with acid (i.e., PPA) to give compounds of type S2. Reaction of compound S2 with an appropriately substituted 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine of type S3 in the presence of a base gives compounds S4.

[0124] [ka] As shown in Scheme 3, intermediates such as compound S3 can be prepared by displacing tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate with an appropriate alcohol (i.e., compound i) to give intermediate S5, which can be deprotected under acidic conditions to give intermediate S3.

[0125] [ka] As shown in Scheme 4, intermediates such as compound S3 can be prepared via a Mitsunobu reaction between an analog of tert-butyl 4-hydroxypiperidine-1-carboxylate and an appropriate alcohol (i.e., compound i) to give intermediate S5, which can be deprotected under acidic conditions to give intermediate S3.

[0126] [ka] As shown in Scheme 5, reaction of 3,4-dihydroxybenzaldehyde with 1,2-dibromoethane-1,1,2,2-d4 in the presence of base (i.e., KCO) provides intermediate S6. In a two-step procedure, intermediate S6 is treated with m-CPBA followed by base and methanol to provide alcohol S7, which is carried forward as shown in Scheme 4 to provide intermediate S8.

[0127] [ka] As shown in Scheme 6, analogs of 6-chloropyridazin-3-amines S14 and S15 can be prepared by radical-based addition of the appropriate carboxylic acid to give intermediate S13, which can be transformed into the desired intermediates S14 and S15.

[0128] The compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography on 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, for example, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England; thin-layer chromatography; distillation at various pressures; sublimation and trituration in vacuo.

[0129] The disclosed compounds can 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 or above room temperature to provide the desired salt, which precipitates and is collected by filtration after cooling.

[0130] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants employed and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reactions can be worked up 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, trituration, and chromatography. Unless otherwise specified, starting materials and reagents are commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. When not commercially available, starting materials can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known structurally similar compounds, and procedures similar to those described in the schemes or synthetic examples section above.

[0131] Routine experimentation, including appropriate manipulation of the reaction conditions, reagents, and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the method, is 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, examples of which can be found in Greene's "Protective Groups in Organic Synthesis" (4), the entire contents of which are incorporated herein by reference. th 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 synthetic schemes described above and in the specific examples.

[0132] When an optically active form of a disclosed compound is required, this can be obtained by carrying out one of the procedures described herein using optically active starting materials (prepared, for example, by asymmetric induction in an appropriate reaction step), or by resolution of a stereoisomeric mixture of the compound or intermediate using standard procedures (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0133] Similarly, if a pure geometric isomer of this compound is required, this can be obtained by performing one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0134] It will be understood that the synthetic schemes and specific examples described are illustrative and should not be construed as limiting the scope of the invention, which is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0135] c. Muscarinic acetylcholine receptor M4 activity In one embodiment, the compounds of the present invention enhance the agonist response (e.g., acetylcholine) of mAChR M4. In some embodiments, the compounds of the present invention increase the mAChR M4 response to non-maximal concentrations of agonist in the presence of the compounds of the present invention compared to the response to the agonist in the absence of the compounds of the present invention. Enhancement of mAChR M4 activity can be demonstrated by methods known in the art. For example, activation of mAChR M4 activity can be demonstrated by Ca 2+ Positive allosteric modulator activity can be determined by measuring calcium flux in response to an agonist, e.g., acetylcholine, in cells loaded with a sensitive fluorescent dye (e.g., Fluo-4) and co-expression of a chimeric or promiscuous G-protein. In one embodiment, calcium flux was measured as an increase in the fluorescence static ratio. In one embodiment, positive allosteric modulator activity is measured by measuring the EC 20The concentration-dependent increase in the acetylcholine response (ie, the response of mAChR M4 at the concentration of acetylcholine that produces 20% of the maximal response) was analyzed.

[0136] In one embodiment, a compound of the invention activates the mAChR M4 response as an increase in calcium fluorescence in mAChR M4-transfected CHO-K1 cells in the presence of a compound of the invention compared to the response of equivalent CHO-K1 cells in the absence of a compound of the invention.

[0137] The compounds of the present invention may exhibit positive allosteric modulation of the mAChRM4 response to acetylcholine as an increased response to non-maximal concentrations of acetylcholine in mAChRM4-transfected CHO-K1 cells in the presence of the compound compared to the response to acetylcholine in the absence of the compound.

[0138] The in vivo efficacy of compounds of the present invention can be measured in several preclinical rat behavioral models in which known clinically useful antipsychotics show similar positive responses. For example, compounds of the present invention can reverse amphetamine-induced hyperlocomotion in male Sprague-Dawley rats at doses of 1-100 mg / kg po.

[0139] 3. Pharmaceutical Compositions The compounds of the invention can be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which can be human or non-human). The compounds of the invention can also be provided as a formulation, such as a spray-dried dispersion formulation.

[0140] These pharmaceutical compositions may contain a "therapeutically effective amount" or a "prophylactically effective amount" of the agent. A "therapeutically effective amount" refers to an amount effective, at single or multiple dosages and for periods of time necessary, to achieve the desired therapeutic result. The therapeutically effective amount of the composition can be determined by one of ordinary skill in the art and may vary depending on factors such as the individual's disease state, age, sex, and weight, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which the therapeutically beneficial effects of any of the compounds of the present invention (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) outweigh any toxic or harmful effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Generally, because a prophylactic dose is used in subjects prior to or at an early stage of disease, the prophylactically effective amount may be lower than the therapeutically effective amount.

[0141] The pharmaceutical composition may include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars, such as, but not limited to, lactose, glucose, and sucrose; starches, such as, but not limited to, corn starch and potato starch; cellulose and its derivatives, such as, but not limited to, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as, but not limited to, cocoa butter and suppository wax; oils, such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols; for example, propylene glycol; esters, for example, but not limited to, ethyl oleate and ethyl laurate; agar; buffers, for example, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer; and other non-toxic compatible lubricants, for example, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0142] Thus, the compounds of the invention can be formulated, for example, in solid dosages, eye drops, oil-based topical preparations, by injection, inhalation (through the mouth or nose), administration by implant, or for oral, buccal, parenteral, or rectal administration. Techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must generally be sterile and stable under the conditions of manufacture and storage.

[0143] The route by which the compound of the present invention is administered and the form of its composition will determine the type of carrier used. The composition may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implanted, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0144] Carriers for systemic administration generally include at least one diluent, lubricant, binder, disintegrant, colorant, flavor, sweetener, antioxidant, preservative, flow agent, solvent, suspending agent, wetting agent, surfactant, combinations thereof, etc. All carriers are optional within the composition.

[0145] 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 to about 90% by weight of the total composition.

[0146] 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 systemic or topical composition is generally about 5 to about 10% by weight of the total composition.

[0147] Suitable binders include polyvinylpyrrolidone, magnesium aluminum silicate, starches such as corn starch and potato starch, gelatin, tragacanth, and cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder in a systemic composition is generally about 5 to about 50% by weight of the total composition.

[0148] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant in a systemic or topical composition is generally from about 0.1 to about 10% by weight of the total composition.

[0149] Suitable coloring agents include coloring agents such as the FD&C dyes. If used, the amount of coloring agent in a systemic or topical composition is generally from about 0.005 to about 0.1% by weight of the total composition.

[0150] Suitable flavors include menthol, peppermint, and fruit flavors. If used, the amount of flavor in a systemic or topical composition is generally from about 0.1 to about 1.0% by weight of the total composition.

[0151] Suitable sweeteners include aspartame and saccharin. The amount of sweetener in a systemic or topical composition is generally from about 0.001 to about 1% by weight of the total composition.

[0152] Suitable antioxidants include butylhydroxyanisole ("BHA"), butylhydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant in a systemic or topical composition is generally from about 0.1 to about 5% by weight of the total composition.

[0153] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative in a systemic or topical composition is generally from about 0.01 to about 5% by weight of the total composition.

[0154] Suitable glidants include silicon dioxide. The amount of glidant in a systemic or topical composition is generally from about 1 to about 5% by weight of the total composition.

[0155] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, castor oil hydroxide, alcohols such as ethanol, and phosphate buffers. The amount of solvent in a systemic or topical composition is generally from about 0 to about 100% by weight of the total composition.

[0156] 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 from about 1 to about 8% by weight of the total composition.

[0157] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, and TWEENS (from Atlas Powder Company of Wilmington, Delaware). Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 22nd Ed. 2013; 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% by weight of the total composition.

[0158] The amounts of components in a systemic composition can vary depending on the type of systemic composition being prepared, but generally, a systemic composition comprises 0.01-50% by weight of the active compound (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) and 50-99.99% by weight of one or more carriers based on the total composition weight. Compositions for parenteral administration typically comprise 0.1-10% by weight of the active compound and 90-99.9% by weight of the carriers (diluents, solvents, etc.) based on the total composition weight.

[0159] Compositions for oral administration can be in 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 an active ingredient, typically at least about 5% by weight of the total composition, more specifically about 25% to about 50% by weight of the total composition. These oral dosage compositions contain about 50% to about 95% by weight of the total composition, more specifically about 50% to about 75% by weight of the total composition.

[0160] Tablets can be compressed, tablet triturated, enteric coated, sugar coated, film coated, or multiple compressed. Tablets generally contain an active ingredient and a carrier containing components selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, flow agents, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific coloring agents are FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, and fruit flavors, or combinations thereof.

[0161] Capsules (including implants, sustained-release, and sustained release formulations) generally contain an active compound (e.g., a compound of Formula (I) or a) and a carrier comprising one or more diluents disclosed above in a gelatin-containing capsule. Granules generally contain a disclosed compound and preferably a glidant, such as silicon dioxide, to improve flow properties. Implants can be biodegradable or non-biodegradable.

[0162] The selection of ingredients in a carrier for an oral composition depends on secondary considerations such as taste, cost, and shelf stability, which are not critical for purposes of this invention.

[0163] The solid compositions can be coated by conventional methods, typically with pH or time-dependent coatings, to release the disclosed compounds in the gastrointestinal tract or near the desired site of application, or at various locations and times to maintain the desired effect. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, EUDRAGIT® coating (available from Evonik Industries of Essen, Germany), wax, and shellac.

[0164] The composition for oral administration can be in liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc. The liquid composition for oral administration generally comprises the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavorants, sweeteners, preservatives, solvents, suspending agents, and surfactants. The oral liquid composition preferably comprises one or more components selected from colorants, flavorants, and sweeteners.

[0165] Other compositions useful for achieving systemic delivery of target compounds include sublingual, buccal and nasal dosage forms.These compositions generally comprise one or more soluble fillers, such as diluents including sucrose, sorbitol and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.These compositions can also comprise lubricants, colorants, flavors, sweeteners, antioxidants and flow agents.

[0166] The compounds of the present invention can be administered topically. Topical compositions that can be applied topically to the skin can 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. The topical composition comprises a disclosed compound (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) and a carrier. The carrier of the topical composition preferably facilitates penetration of the compound into the skin. The carrier may further comprise one or more optional components.

[0167] The amount of carrier used with the disclosed compound is sufficient to provide a useful amount of the composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods 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).

[0168] The carrier may comprise a single component or a combination of two or more components. In topical compositions, the carrier comprises 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, more specifically phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0169] The carrier of the topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, dyes, and preservatives, all of which are optional.

[0170] 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, sebacillus acidophilus, sorbitan ol ... Examples of emollients for skin 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 oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in a topical composition for skin application is generally about 5% to about 95% by weight of the total composition.

[0171] 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 from about 0% to about 95% by weight of the total composition.

[0172] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent in a topical composition is generally about 0% to about 95% by weight of the total composition.

[0173] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant in a topical composition is generally 0% to 95% by weight of the total composition.

[0174] The amount of thickener in a topical composition is generally from about 0% to about 95% by weight of the total composition.

[0175] Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, Fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder in a topical composition is generally 0% to 95% by weight of the total composition.

[0176] The amount of fragrance in the topical composition is generally from about 0% to about 0.5% by weight, particularly from about 0.001% to about 0.1% by weight of the total composition.

[0177] Suitable pH-adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0178] 4.How to use The compounds and pharmaceutical compositions of the present invention can be used in methods for treating disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.The compounds and pharmaceutical compositions of the present invention can also be used in methods for enhancing muscarinic acetylcholine receptor activity in patients and for improving cognitive function in patients.The methods also include co-treatment methods for improving the therapeutic results of cognitive or behavioral therapy.In the methods of use described herein, additional therapeutic agents can be administered simultaneously or sequentially with the compounds and compositions of the present invention.

[0179] Treatment of the disorder The compounds, pharmaceutical compositions, and formulations of the present invention can be used in methods for treating disorders, such as neurological and / or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction. The methods of treatment can include administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the present invention provides a method of improving cognitive function in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0181] The compounds of the present invention and compositions disclosed herein may be useful for treating, preventing, ameliorating, controlling, or reducing the risk of various disorders associated with selective mAChR M4 receptor activation. For example, treatment may involve selective mAChR M4 receptor activation to an extent effective to affect cholinergic activity. The disorder may be associated with cholinergic activity, e.g., cholinergic hypofunction. Accordingly, provided are methods for treating or preventing a disorder in a subject, comprising administering to the subject at least one compound of the present invention or at least one disclosed pharmaceutical composition in an amount effective to treat the disorder in the subject.

[0182] Also provided is a method for treating one or more disorders associated with mAChR M4 receptor activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treating a disorder associated with the mAChR M4 receptor. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treating a disorder associated with the mAChR M4 receptor.

[0184] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disorder associated with the mAChR M4 receptor.

[0185] In some embodiments, the present invention provides a method for treating a disorder associated with muscarinic acetylcholine receptor dysfunction in a patient, comprising administering to the patient 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.

[0186] In some embodiments, the compounds and compositions of the present invention are useful for treating various neurological, psychiatric, and cognitive disorders associated with the mAChR M4 receptor, including one or more of the following conditions or diseases: schizophrenia, psychotic disorder NOS, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic episodes, late-onset psychosis, myxedema psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder. In some embodiments, the psychotic disorder is psychosis associated with a disease selected from major depressive disorder, affective disorder, bipolar disorder, electrolyte disorder, Alzheimer's disease, neurological disorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder.

[0187] In some embodiments, the disorder is schizophrenia.

[0188] In some embodiments, the disorder is psychotic depression.

[0189] In some embodiments, the disorder is agitation and psychosis in Alzheimer's disease.

[0190] In some embodiments, the disorder is bipolar disorder.

[0191] In some embodiments, the disorder is a neurological disorder selected from the following: brain tumor, dementia with Lewy bodies, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, and anti-NMDA receptor encephalitis.

[0192] In some embodiments, the disorder is a psychotic disorder and is selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder. In some embodiments, the schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disorganized schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizotypal personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some embodiments, the psychotic disorder is due to a general medical condition and is substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other psychostimulants, and cocaine).

[0193] In some embodiments, the present invention provides a method for treating a neurodevelopmental disorder, comprising administering to a patient in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt, or pharmaceutical composition of the present invention. In some embodiments, the neurodevelopmental disorder is Fragile X Syndrome.

[0194] In some embodiments, the present invention provides methods for treating cognitive disorders, including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular disease 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, amnesic disorders, 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 disease, age-associated cognitive decline, and mild cognitive impairment.

[0195] In some embodiments, the cognitive disorder is Huntington's disease.

[0196] 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 disorders such as dementia, delirium, amnestic 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, subsequent syndromes of major NCDs, minor NCDs, and their etiological subtypes. Major and minor NCD subtypes include Alzheimer's disease-related NCD, vascular NCD, Lewy body NCD, Parkinson's disease-related NCD, frontotemporal NCD, traumatic brain injury-related NCD, HIV infection-related NCD, substance / drug-induced NCD, Huntington's disease-related NCD, prion disease-related NCD, other pathological condition-related NCD, multiple etiology NCD, and unspecified NCD. The DSM-5 NCD category encompasses a group of disorders in which the primary clinical impairment is cognitive function and is acquired rather than developmental. As used herein, the term "cognitive disorder" includes those cognitive and neurocognitive disorders as described in DSM-IV-TR or DSM-5. Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for mental illness exist and that these systems evolve with medical and scientific advances. Thus, the term "cognitive disorder" is intended to include disorders as described in other diagnostic sources.

[0197] In some embodiments, the present invention provides a method for treating a sleep disorder, comprising administering to a patient in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0198] In some embodiments, the sleep disorder is associated with sleep disorders in patients with schizophrenia.

[0199] In some embodiments, the present invention provides a method for treating schizophrenia or psychosis, comprising administering to a patient in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition. Specific schizophrenia or psychosis conditions are paranoid, disorganized, catatonic, or undifferentiated schizophrenia, and substance-induced psychotic disorder. DSM-IV-TR provides diagnostic tools including paranoid, disorganized, catatonic, undifferentiated, or residual schizophrenia, and substance-induced psychotic disorder. DSM-5 eliminates subtypes of schizophrenia and instead includes a dimensional approach to assessing the severity of core symptoms of schizophrenia to capture the heterogeneity in the type and severity of symptoms expressed across individuals with psychotic disorders. As used herein, the term "schizophrenia or psychosis" includes treatment of those mental disorders as described in DSM-IV-TR or DSM-5. Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for mental illness exist, and that these systems evolve with medical and scientific advances. Thus, the term "schizophrenia or psychosis" is intended to include disorders as described in other diagnostic sources.

[0200] In some embodiments, the present invention provides a method for treating pain comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition of the present invention. Specific pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, and neuropathic pain.

[0201] The compounds and compositions may further be useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions mentioned herein. The compounds and compositions of the present invention may further be useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.

[0202] For the treatment of conditions requiring activation of mAChR M4, a suitable dosage level is about 0.001 mg / kg to about 100 mg / kg of patient body weight per day, which can be administered in single or multiple doses. In particular, the daily dosage may range from 0.01 mg / kg to about 50 mg / kg of body weight per day. Suitable dosage levels may be about 0.1 to about 30 mg / kg / day, or particularly about 1 to about 10 mg / kg / day. Suitable dosage levels may be about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, dosages may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg / day. For oral administration, the composition may be provided in the form of a tablet containing 1.0 to 1000 milligrams of 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, allowing the dosage to be adjusted symptomatically to the patient being treated. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen may be adjusted to provide the optimal therapeutic response. However, it will be understood that the specific dose level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and length of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0203] Thus, in some embodiments, the present invention relates to a method for activating mAChR M4 receptor activity in at least one cell, comprising contacting at least one cell with any one of the compounds or pharmaceutical compositions of the present invention in an amount effective to activate mAChR M4 in the at least one cell. In some embodiments, the cell is a mammalian, e.g., human, cell. In some embodiments, the cell is isolated from a subject prior to the contacting step. In some embodiments, the contacting is performed by administration to the subject.

[0204] In some embodiments, the present invention relates to a method for activating mAChR M4 activity in a subject, the method comprising administering to the subject at least one compound of the present invention or at least one product of the disclosed method in a dosage and amount effective to activate mAChR M4 activity in the subject. In some embodiments, the subject is a patient. In some embodiments, the patient has been diagnosed with a need for mAChR M4 agonism prior to the administering step. In some embodiments, the patient has been diagnosed with a need for mAChR M4 activation prior to the administering step. In some embodiments, the method further comprises identifying a subject in need of mAChR M4 agonism.

[0205] In some embodiments, the present invention relates to a method for treating a disorder associated with selective mAChR M4 activation, e.g., a disorder associated with cholinergic activity, in a patient, comprising administering to the patient at least one compound of the present invention or at least one product of the disclosed method in a dosage and amount effective to treat the patient's disorder. In some embodiments, the patient is human. In some embodiments, the patient has been diagnosed with a need for treatment of the disorder prior to the administering step. In some embodiments, the method further comprises identifying a subject in need of treatment of the disorder.

[0206] In some embodiments, the disorder may be selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic mood disorders such as psychotic episodes of anxiety, anxiety associated with psychosis, 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 mental retardation, autistic disorders, movement disorders, Tourette's syndrome, akinetic rigidity syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative based dyskinesia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, cognitive disorders, dementia, and memory disorders.

[0207] In some embodiments, the disorder is Alzheimer's disease.

[0208] In some embodiments, the disorder is Tourette's syndrome.

[0209] In some embodiments, the disorder is tardive dyskinesia.

[0210] In some embodiments, the disorder is obsessive-compulsive disorder.

[0211] In some embodiments, the disorder is bipolar disorder.

[0212] b. Enhancement of muscarinic acetylcholine receptor activity In some embodiments, the invention relates to a method of enhancing muscarinic acetylcholine receptor activity in a patient, comprising administering to the patient 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.

[0213] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of enhancing muscarinic acetylcholine receptor activity in a patient. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of enhancing muscarinic acetylcholine receptor activity in a patient.

[0214] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for potentiating muscarinic acetylcholine receptor activity in a patient.

[0215] In some embodiments, potentiating muscarinic acetylcholine receptor activity increases muscarinic acetylcholine receptor activity. In some embodiments, potentiating muscarinic acetylcholine receptor activity is partial agonism of the muscarinic acetylcholine receptor. In some embodiments, potentiating muscarinic acetylcholine receptor activity is positive allosteric modulation of the muscarinic acetylcholine receptor.

[0216] In some embodiments, enhancing muscarinic acetylcholine receptor activity in a patient is associated with treating a neurological and / or psychiatric disorder associated with muscarinic receptor dysfunction, e.g., a neurological or psychiatric disorder disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4.

[0217] c.Improvement of cognitive function In some embodiments, the present invention relates to a method of improving cognitive function in a patient, comprising administering to the patient an effective amount of at least one disclosed compound of the present invention.

[0218] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of improving cognitive function in a patient. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of improving cognitive function in a patient.

[0219] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for enhancing cognitive function in a patient.

[0220] In some embodiments, the patient has been diagnosed with a need for cognitive enhancement prior to the administering step. In some embodiments, the method further comprises identifying a patient in need of cognitive enhancement. In some embodiments, the need for cognitive enhancement is associated with muscarinic receptor dysfunction. In some embodiments, the muscarinic receptor is mAChR M4.

[0221] Cognitive deficits or disorders include declines in cognitive functions or cognitive domains, such as working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving (such as executive function, processing speed, and / or social cognition). In particular, cognitive deficits or disorders may manifest as poor attention, disorganized thinking, slow thinking, difficulty comprehending, poor concentration, impaired problem-solving, poor memory, difficulty expressing thoughts and / or integrating thoughts, emotions, and behaviors, or difficulty eliminating irrelevant thoughts. The terms "cognitive deficit" and "cognitive disorder" are intended to refer to the same thing and are used interchangeably.

[0222] As previously mentioned, cognitive function is often impaired in patients with schizophrenia. Studies have also concluded that cognitive function is associated with occupational functioning in schizophrenia [Schizophrenia Res., 45, 175-184, 2000]. In one embodiment, the patient to be treated for cognitive impairment is a patient with schizophrenia.

[0223] Those skilled in the art are familiar with various tests for measuring cognitive enhancement. Examples of tests for measuring cognitive enhancement include, but are not limited to, the Novel Object Recognition Test and the Wisconsin Card Sorting Test.

[0224] d. Combination treatment methods The present invention further relates to the administration of selective mAChR M4 activators to improve therapeutic outcomes associated with cognitive or behavioral therapy. Thus, in some embodiments, the present invention relates to combination treatment methods comprising administering to a patient an effective amount and dosage of a compound of the present invention.

[0225] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a combination treatment method that includes cognitive therapy or behavioral therapy in a patient. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a combination treatment method that includes cognitive therapy or behavioral therapy in a patient.

[0226] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for a combination treatment method comprising cognitive therapy or behavioral therapy in a patient.

[0227] In some embodiments, administration improves therapeutic results in conjunction with cognitive or behavioral therapy. Administration associated with cognitive or behavioral therapy can be continuous or intermittent. Administration does not have to be simultaneous with therapy, but can occur before, during, and / or after therapy. For example, cognitive or behavioral therapy can 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 can be provided within 1, 2, 3, or 4 weeks before or after administration of the compound. As a still further example, cognitive or behavioral therapy can be provided before or after administration within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.

[0228] It is understood that the disclosed co-treatment methods can be used in conjunction with the compounds, compositions, kits and uses of the present invention.

[0229] e. Combination therapy In the methods of use described herein, the additional therapeutic agent may be administered simultaneously or sequentially with the compounds and compositions of the present invention. Sequential administration includes administration before or after the compounds and compositions of the present invention. In some embodiments, the additional therapeutic agent may be administered in the same composition as the compounds of the present invention. In other embodiments, there may be a time interval between the administration of the additional therapeutic agent and the administration of the compounds of the present invention. In some embodiments, administration of the additional therapeutic agent with the disclosed compounds may allow for lower doses of the other therapeutic agent and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used alone. Thus, pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compound of Formula (I) or a pharmaceutically acceptable salt thereof. The above combinations include combinations of the compounds of the present invention with not only one other active compound but also two or more other active compounds.

[0230] The compounds of the present invention can be used as a single agent or in combination with one or more other drugs in the treatment, prevention, control, amelioration, or risk reduction of the aforementioned diseases, disorders, and conditions for which the compounds or other drugs have utility, where the drug combination is safer or more effective than either drug alone. The other drugs can be administered simultaneously or sequentially with the disclosed compounds by a route and in an amount commonly used therefor. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the compounds of the present invention can be used. However, the combination therapy can also be administered on an overlapping schedule. It is also contemplated that the combination of one or more active ingredients with the compounds of the present invention may be more effective than either of them as a single agent. Thus, when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used in lower doses than when each is used alone.

[0231] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds as described herein that are commonly applied in the treatment of the above-mentioned pathological conditions.

[0232] The above combinations include not only combinations of the disclosed compounds with one other active compound, but also combinations of two or more other active compounds.Similarly, the compounds of the present invention can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of diseases or conditions for which the compounds of the present invention are useful.Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention, by a route and in an amount commonly used therefor.Thus, in embodiments, the pharmaceutical composition contains one or more other active ingredients in addition to the compounds of the present invention.

[0233] The weight ratio of the disclosed compound to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the compound of the present invention is combined with another drug, the weight ratio of the disclosed compound to the other drug is generally in the range of about 200:1 to about 1:200. The combination of the compound of the present invention with the other active ingredient is also generally within the above-mentioned range, but each time, an effective dose of each active ingredient should be used.

[0234] In such combinations, the compounds of the present invention and the other active agent may be administered separately or together. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.

[0235] Thus, the compounds of the present invention can be used alone or in combination with other agents known to be beneficial in the target indications or other drugs that affect receptors or enzymes to increase the efficacy, safety, or convenience of the compounds of the present invention, or to reduce undesirable side effects. The compounds of the present invention and other agents can be co-administered in combination therapy or in fixed dose combinations.

[0236] In some embodiments, the compounds may be used in combination with NSAIDs, such as Alzheimer's therapeutics, beta-secretase inhibitors, cholinergic agents, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, M1 allosteric agonists, M1 positive allosteric modulators, ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, the compounds may be used in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), anxiolytics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT2 antagonists, and the like, such as: adinazolam, allobarbital, alobital, alonimide, alprazolam, amisulpride, amitriptyline, amyloid Mobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprion, butabarbital, butalbital, brexpiprazole, capride, carbochloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, chloretate, chlorpromazine, clozapine, ciprazepam, desipramine, dextromethorphan Sucramol, diazepam, dichloralphenazone, divalproex, diphenhydramine, donepezil, menanthine, galantamine, doxepin, estazolam, eschlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine amine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol,The compounds may be used in combination with protriptyline, quazepam, quetiapine, levazepam, risperidone, loretamide, secobarbital, sertraline, suproclon, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, urdazepam, zaleplon, ziprasidone, zolazepam, zolpidem, and the like, and salts thereof, and combinations thereof, or the compounds may be administered in conjunction with the use of physical methods such as phototherapy or electrical stimulation.

[0237] In some embodiments, the compounds of the invention may be used in combination with anticholinergics such as levodopa (with or without a non-brain selective decarboxylase inhibitor such as carbidopa or benserazide), biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl hydrochloride (benzhexol), COMT inhibitors such as entacapone, MOA-B inhibitors such as azilect, antioxidants, A2a adenosine receptor antagonists such as istradefylline, cholinergic agonists, NMDA receptor antagonists such as ketamine, serotonin receptor antagonists, and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide, and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, such as alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Lisuride and pramipexole are commonly used in their non-salt form.

[0238] In some embodiments, the compounds of the present invention can be used in combination with compounds from the neuroleptic classes of phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine, and indolone. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, 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 molindron. Other neuroleptics include loxapine, sulpiride, and risperidone. It will be understood that the neuroleptic agents used in combination with the present compounds may be in the form of a pharmaceutically acceptable salt, such as chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enanthate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate, and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide, and risperidone are generally used in their non-salt form. Thus, the compounds may be used in combination with acetophenazine, alentemol, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa-benserazide, levodopa-carbidopa, lisuride, loxapine, mesoridazine, molindrone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, deutetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine, or ziprasidone.

[0239] In some embodiments, the compounds of the invention can be used in combination with antidepressants or anti-anxiety agents, such as norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, alpha-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT 1A These include 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, vortioxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazid, phenelzine, escitalopram, tranylcypromine, and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone, and viloxazine; alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam; buspirone, flesinoxan, gepirone, and ipsapirone, and pharmaceutically acceptable salts thereof.

[0240] In some embodiments, the compounds of the present invention can be co-administered with an orthosteric muscarinic agonist, a muscarinic enhancer, or a cholinesterase inhibitor. In some embodiments, the compounds can be co-administered with a GlyT1 inhibitor, such as, but not limited to, risperidone, quetiapine, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof, and combinations thereof.

[0241] f. Mode of administration Therapeutic methods may include any number of modes of administering the compounds or compositions of the present invention. Modes of administration may include tablets, pills, dragees, 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 agent may be mixed with commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (e.g., mannitol, methylcellulose, lactose, etc.), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersing agents, emulsifiers, lubricants, preservatives, flavoring agents (e.g., ethereal 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 microparticles, such as nanoparticle compositions.

[0242] For parenteral administration, the drug may be dissolved or suspended in a physiologically acceptable diluent, such as water, a buffer, an oil with or without a solubilizer, a surfactant, a dispersant, or an emulsifier. Oils that 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 may even be administered in the form of a liposome or nanosuspension.

[0243] The term "parenteral," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[0244] The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended to illustrate, but not limit, the scope of the invention. [Example]

[0245] 5. Working Example All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer, a 400 MHz Bruker Avance AV-III-400 spectrometer, or a Varian MR400 spectrometer. 1H chemical shifts are reported in δ values ​​(ppm) relative to residual protic solvent as an internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, and integration. Reversed-phase LCMS analysis was performed using an Agilent 1200 system consisting of a binary pump equipped with a degasser, a high-performance autosampler, a thermostatted column compartment, a C18 column, a diode array detector (DAD), and an Agilent 6150 MSD, with the following parameters: gradient conditions: 5% to 95% acetonitrile with aqueous 0.1% TFA over 1.4 minutes, holding at 95% acetonitrile for 0.1 minutes at 0.5 mL / min at 55°C ("90-second method"). Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 × 50 mm) at 0.5 mL / min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nm, with signals at 220 nm and 254 nm (both with 4 nm bands). The MS detector was set with an electrospray ionization source, and low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU and a peak width of 0.008 min at 0.13 cycles / sec. 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 fragmentor voltage was set to 100 V. Data acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0246] Abbreviations used in the examples and reaction schemes below are as follows: aq is aqueous; Boc is tert-butyloxycarbonyl; BrettPhos is 2-(di-cyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; BrettPhos-Pd-G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; t-BuOH is tert-butanol; DCE is 1,2-dichloroethane; DCM is dichloromethane DMF is N,N-dimethylformamide; DMP or Dess-Martin periodinane is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DIAD is diisopropyl azodicarboxylate; DIPEA or DIEA is diisopropylethylamine; DMAP is 4-dimethylaminopyridine; DMSO is dimethyl sulfoxide; Dowtherm A is a eutectic mixture of 26.5% diphenyl and 73.5% diphenyloxide; DtBAD is di-tert-butyl-azodicarboxylate; eq. or eq.are equivalents; EtOAc is ethyl acetate; EtOH is ethanol; h is hour; Hex is hexane; IPA is isopropyl alcohol; KOAc is potassium acetate; LAH is lithium aluminum hydride; mCPBA is meta-chloroperoxybenzoic acid; MeCN or ACN is acetonitrile; MeOH is methanol; min is minutes; NaOAc is sodium acetate; NaOMe is sodium methoxide; NCS is N-chlorosuccinimide; NMP is N-methyl-2-pyrrolidone; Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(OAc)2 is palladium(II) acetate; PPA is polyphosphoric acid; PPh3 is triphenylphosphine; PPTS is pyridinium p-toluenesulfonate; rt is room temperature; sat. is saturated; sec is seconds; SCX cartridge or HF SCX cartridge is a strong cation exchange cartridge (i.e., Agilent part #14256027); SFC is supercritical fluid chromatography; TBAC or TBACl is tetrabutylammonium chloride; t-BuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TosCl is para-toluenesulfonyl chloride; and tosyl is para-toluenesulfonyl.

[0247] a. Preparation of intermediates [ka] 5-(((6-chloro-5-methylpyridazin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate A): To a solution of 6-chloro-5-methylpyridazin-3-amine (1 g) in ethanol (12 mL) was added triethyl orthoformate (1.16 mL) and isopropylidene malonate (1.04 g) at ambient temperature. The mixture was then heated to 60° C. for 18 hours. The mixture was filtered and the cake was washed with ethanol (5 mL×3) to give the intermediate 5-[[(6-chloro-5-methyl-pyridazin-3-yl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (1.59 g, 77% yield). ES-MS [M+1] + :298.2

[0248] 7-Chloro-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate B): A solution of 5-[[(6-chloro-5-methyl-pyridazin-3-yl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (1.59 g) in Dowsome A (8 mL) was stirred at 220 °C for 1 h. After cooling, the mixture was added to water and acidified with 1 M HCl. The aqueous layer was extracted with hexane (3 × 125 mL) to remove Dowsome A. After neutralizing the aqueous layer with aq. NaHCO3, the mixture was extracted with chloroform / IPA (4:1) (3 ×). The combined organic layers were dried over magnesium sulfate and concentrated to give the title compound (908 mg, 67% yield). 1 H NMR(400MHz,DMSO)δ 8.23(d,J=6.5Hz,1H),8.03(q,J=1.3Hz,1H),6.54(d,J=6.4Hz,1H),2.44(d,J=1.3Hz,3H).ES-MS[M+1] + :196. [ka]

[0249] 7-Chloro-8,9-dimethyl-pyrimido[1,2-b]pyridazin-4-one (Intermediate C): A mixture of 6-chloro-3-amino-4,5-dimethylpyridazine (550 mg), ethyl 3,3-diethoxypropionate (1.02 mL), and polyphosphoric acid (5 mL) was added to a sealed tube. The mixture was stirred at 85° C. for 5 hours and then allowed to cool to room temperature, at which point additional ethyl 3,3-diethoxypropionate (1.02 mL) was added to the reaction mixture. The vial was sealed and the mixture was heated to 85° C. for 18 hours. The reaction mixture was then slowly added to a stirred solution of 150 mL of saturated aqueous NaHCO and 100 mL of DCM. After the addition was complete, the mixture was stirred for 20 minutes, the organic layer was separated, and the aqueous layer was further extracted with chloroform / IPA (4:1) (×3). The organic layers were pooled, dried over MgSO, filtered, and concentrated. The crude product was purified using a Teledyne ISCO Combi-Flash system (liquid loading with DCM, 40 G column, 0-70% EtOAc / Hex, 35 min run) to give the title compound as a solid (366 mg, 50% yield). 1 H NMR(400MHz,CDCl3)δ 8.22-8.20(d,J=6.5Hz,1H),6.64-6.62(d,J=6.5Hz,1H),2.62(d,J=0.6Hz,3H),2.51(d,J=0.6Hz,3H).ES-MS[M+1] + :210. [ka]

[0250] 7-Chloro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate D): To a solution of 6-chloro-3-amino-5-methylpyridazine (1 g) in polyphosphoric acid (5 mL) was added ethyl acetoacetate (1.76 mL). The mixture was heated to 120 °C for 18 h. While still hot, the mixture was slowly added to a stirred solution of 150 mL of saturated NaHCO3. The aqueous layer was extracted three times with chloroform:IPA (4:1). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a Teledyne ISCO Combi-Flash system (DCM, 80G column, liquid loading with 0–70% EtOAc / DCM, 42 min run). Fractions containing the desired product were concentrated to give the title compound as a solid (1.34 g, 92% yield). 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. [ka]

[0251] 7-Chloro-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate E): To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in Dowtherm A (2 mL) was added ethyl 2-methyl-3-oxobutanoate (591 μL) and the reaction was heated at 150 °C for 18 h. Additional ethyl 2-methyl-3-oxobutanoate (591 μL) was added and the reaction was microwaved at 180 °C for 15 min. This solution was loaded directly onto a Teledyne ISCO Combi-Flash system (120 G column, 100% Hex, 6 min; then 0–80% EtOAc / DCM, 15 min run) to afford the title compound as a solid (442 mg, 57% yield). 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. [ka]

[0252] 7-Chloro-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate F): To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (500 mg) in polyphosphoric acid (4.5 mL) was added ethyl acetoacetate (803 μL). The mixture was heated to 120 °C for 1 h. While hot, the mixture was slowly added to 125 mL of saturated NaHCO3 and 50 mL of chloroform / IPA (4:1). Upon completion of the addition, the mixture was stirred for 15 min and the organic layer was isolated. The aqueous layer was further extracted with chloroform:IPA (4:1) (×3). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in 5 mL of MeOH, sonicated, and the precipitate was collected by vacuum filtration and washed with hexane. The solid was dried under nitrogen to give the title compound as a solid (472 mg, 67% yield). 1 H NMR(400MHz,CDCl3)δ 6.49(s,1H),2.60(d,J=0.8Hz,3H),2.48(q,J=0.7Hz,3H),2.44(q,J=0.5Hz,3H).ES-MS[M+1] + :224. [ka]

[0253] 7-Chloro-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate G): To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in polyphosphoric acid (5 mL) was added ethyl 4,4,4-trifluoroacetoacetate (1.02 mL). The mixture was heated to 120 °C for 18 h. While 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 a pH of approximately 7. Upon completion of the addition, the mixture was stirred for 15 min and the organic layer was isolated. The aqueous layer was further extracted three times with chloroform:IPA (4:1). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in 15 mL of DMSO (all precipitated solids were collected to obtain the pure desired product), and the filtrate was purified by reverse-phase chromatography using a Gilson HPLC (50 × 250 mm column, 5–45% ACN / 0.05% NH4OH in water, 16 min run). The fractions containing the product were concentrated and combined with the previous solid to give the title compound as a solid (393 mg, 43% yield). 1 H 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. [ka]

[0254] 7-Chloro-8,9-dimethyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate H): To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (550 mg) in polyphosphoric acid (5 mL) was added ethyl 4,4,4-trifluoroacetoacetate (1.02 mL). The mixture was heated to 120 °C for 18 h. An additional 1.02 mL of ethyl 4,4,4-trifluoroacetoacetate was added, and the mixture was stirred at 120 °C for an additional 7 h. While hot, the mixture was slowly added to a beaker containing 125 mL of saturated NaHCO3 and 50 mL of chloroform / IPA (4:1), maintaining a pH of approximately 7. After the addition was complete, the mixture was allowed to stir for 15 min and the organic layer was isolated. The aqueous layer was further extracted three times with chloroform:IPA (4:1). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was dissolved in DMSO (16 mL) and purified by reverse-phase chromatography using a Gilson HPLC (50 × 250 mm column, 5–50% ACN / 0.05% NH OH in water, 16 min run). The product-containing fractions were concentrated to give the title compound (264 mg, 27% yield) as a solid. 1 H NMR(400MHz,CDCl3)δ 6.96(s,1H),2.57(q,J=0.9Hz,3H),2.48(q,J=0.9Hz,3H).ES-MS[M+1] + :278. [ka]

[0255] 7-Chloro-2-(difluoromethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate I): To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in polyphosphoric acid (5 mL) was added ethyl 4,4-difluoroacetoacetate (912 μL). The mixture was heated to 120 °C for 2 h. While 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 a pH of approximately 7. Upon completion of the addition, the mixture was allowed to stir for 15 min, and the organic layer was isolated. The aqueous layer was further extracted three times with chloroform:IPA (4:1). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in DMSO (15 mL) and purified by reverse-phase chromatography using a Gilson HPLC (50 × 250 mm column, 0–45% ACN / 0.05% NH4OH in water, 16 min run). The product-containing fractions were concentrated to give the title compound as a solid (640 mg, 75% yield). 1 H 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. [ka]

[0256] 7-Chloro-2-(difluoromethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate J): To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (1.65 g) in polyphosphoric acid (10 mL) was added ethyl 4,4-difluoroacetoacetate (2.74 mL). The mixture was heated to 120 °C for 6 h. The reaction mixture was then slowly added to a stirred saturated NaHCO solution (200 mL) while still hot. Upon reaching a pH of approximately 7, the aqueous layer was extracted with chloroform:IPA (4:1). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a Teledyne ISCO Combi-Flash system (liquid loading with DCM, 120 G column, 0–40% EtOAc / DCM, 15 min run) to afford the title compound (1.05 g, 39% yield) as a solid. 1 H NMR(400MHz,CDCl3)δ 6.90(s,1H),6.48(t,J=54.9Hz,1H),2.64(s,3H),2.53(s,3H).ES-MS[M+1] + :260. [ka]

[0257] 7-Chloro-2-cyclopropyl-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate K): In a sealed vial, a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) and ethyl 3-cyclopropyl-3-oxopropanoate (617 μL) in DOWTHERM A (5 mL) was added. The vial was sealed, and the reaction was heated to 150 °C for 18 h. Additional ethyl 3-cyclopropyl-3-oxopropanoate (617 μL) was added, and the reaction was heated to 220 °C for 3 h. The material was directly loaded onto a Teledyne ISCO Combi-Flash system (liquid loading, 120 G column, 100% Hex, 6 min run; then 0–40% EtOAc / DCM, 15 min run) to afford the title compound (44 mg; 5% yield) as a solid. 1H NMR(400MHz,CDCl3)δ 7.52(q,J=1.3Hz,1H),6.51(s,1H),2.47(d,J=1.4Hz,3H),1.97-1.86(m,1H),1.18-1.10(m,2H),1.08-0.97(m,2H).ES-MS[M+1] + :236. [ka]

[0258] 7-Chloro-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate L): To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (550 mg) in polyphosphoric acid (4 mL) was added ethyl 3-oxopentanoate (913 μL). The mixture was heated at 85°C for 1 hour, then heated to 120°C for 1 hour. While hot, the mixture was slowly transferred to a stirred solution of saturated aqueous NaHCO3 (approximately 150 mL) and chloroform / IPA (4:1) (50 mL). Upon complete addition, the mixture was stirred for 10 minutes, and the organic layer was isolated. The aqueous layer was further extracted with chloroform / IPA (4:1) (×3). The organic layers were pooled, dried over MgSO4, filtered, and concentrated in vacuo. Upon cooling, a solid precipitate was observed. Hexane was added, the suspension was sonicated, and the solid was collected by vacuum filtration and washed with hexane to give the title compound (469 mg, 57% yield) with a purity >95% clean by LCMS. 1 H NMR(400MHz,CDCl3)δ 6.50(s,1H),2.70(q,J=7.6Hz,2H),2.61(s,3H),2.48(s,3H),1.30(t,J=7.6Hz,3H).ES-MS[M+1] + :238. [ka]

[0259] 7-Chloro-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate M): To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (550 mg) in polyphosphoric acid (5 mL) was added ethyl 4-methyl-3-oxo-pentanoate (1.13 mL). The mixture was heated at 85 °C for 1 h, then heated to 120 °C for 1 h. While still hot, the mixture was slowly added to a stirred solution of saturated aqueous NaHCO3 (150 mL) and chloroform / IPA (4:1) (50 mL). Upon completion of the addition, the mixture was stirred for 10 min and the organic layer was isolated. The aqueous layer was further extracted with chloroform / IPA (4:1) (3 × 50 mL). The organic layers were pooled, dried over MgSO4, filtered, and concentrated. The crude product was purified using a Teledyne ISCO Combi-Flash system (liquid loading with DCM, 80 G column, 0–65% EtOAc / Hex, 20 min run). The column was then flushed with hexane, followed by 0-2% MeOH / DCM for 10 minutes to give the title compound (204 mg; yield 23%) as a solid. 1 H NMR(400MHz,CDCl3)δ 6.47(s,1H),3.63(hept,J=6.8Hz,1H),2.56(d,J=1.0Hz,3H),2.44(d,J=1.0Hz,3H),1.32(s,3H),1.30(s,3H).ES-MS[M+1] + :252. [ka]

[0260] 7-Chloro-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate N): To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (1 g) in polyphosphoric acid (9 mL) was added methyl 4-methoxy-3-oxobutanoate (1.23 mL). The mixture was heated at 85 °C for 1 h and then at 120 °C for 30 min. The mixture was then quenched by slow addition to a solution of saturated sodium bicarbonate (approximately 150 mL) and 4:1 chloroform / IPA (approximately 50 mL). The organic layer was isolated, and the aqueous layer was further extracted (×3). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated. The crude product was dissolved in DMSO (9 mL), and the solid was filtered off. The filtrate was purified using a Gilson (basic, 50 × 250 mm column, 5–55% ACN / 0.05% aqueous NH4OH, 16 min run). The product-containing fractions were concentrated to give the title compound (219 mg) as a solid. The solid was washed with hexane, dissolved in DCM, and purified using a Teledyne ISCO Combi-Flash system (liquid loading with DCM, 80G column, 0-2% MeOH / DCM / NH4OH, 10 min run). The product-containing fractions were concentrated to give the title compound (682 mg; 43% yield) as a solid. 1 H NMR(400MHz,CDCl3)δ 6.77(t,J=1.0Hz,1H),4.45(d,J=1.0Hz,2H),3.51(s,3H),2.59(d,J=0.9Hz,3H),2.49(d,J=1.0Hz,3H).ES-MS[M+1] + :254. [ka]

[0261] 7-Chloro-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate O): To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in polyphosphoric acid (5 mL) was added methyl 4-methoxy-3-oxobutanoate (673 μL, 5.22 mmol). The mixture was heated to 85 °C for 1 h and then at 120 °C for 30 min. The mixture was then quenched by slow addition to a solution of saturated sodium bicarbonate (approximately 150 mL) and 4:1 chloroform / IPA (approximately 50 mL). The organic layer was isolated, and the aqueous layer was further extracted (×3). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated. The crude product was dissolved in DMSO (12 mL) and purified by reverse-phase chromatography using a Gilson HPLC (50 × 250 mm column, 0–45% ACN / 0.05% aqueous NH4OH, 16 min run). The product-containing fractions were concentrated to give the title compound as a solid (690 mg, 83% yield). 1 H NMR(400MHz,CDCl3)δ 7.61(q,J=1.3Hz,1H),6.76(d,J=1.1Hz,1H),4.42(s,2H),3.50(s,3H),2.50(d,J=1.2Hz,3H).ES-MS[M+1] + :240. [ka]

[0262] Ethyl 7-chloro-8-methyl-4-oxo-4H-pyrimido[1,2-b]pyridazine-2-carboxylate (Intermediate P): A mixture of diethyl ethoxymethylenemalonate (641 μL) and 6-chloro-3-amino-4,5-dimethylpyridazine (500 mg) in Dowtherm A (6 mL) was heated to 200 °C for 18 h. The reaction mixture was cooled to room temperature and loaded directly onto a Teledyne ISCO Combi-Flash system (liquid loading, 80 G column, 0-55% EtOAc / DCM, 25 min run). Fractions containing the desired product were concentrated, which was determined to be impure by LCMS. The material was dissolved in DMSO (9 mL) and purified by reverse-phase chromatography on a Gilson HPLC (50 × 250 mm column, 5-50% ACN / 0.05% aqueous NH4OH, 16 min run). Fractions containing the product were concentrated to give the title compound as a solid (250 mg; 28% yield). 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] + :268.2. [ka]

[0263] 7-Chloro-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate Q): To a solution of 6-chloro-3-amino-5-methylpyridazine (550 mg) in polyphosphoric acid (5.5 mL) was added ethyl 2-fluoroacetoacetate (961 μL). The mixture was heated to 120° C. for 2 hours. The mixture was then quenched by slow addition to a solution of saturated sodium bicarbonate (approximately 150 mL) and 4:1 chloroform / IPA (approximately 50 mL). The organic layer was isolated, and the aqueous layer was further extracted (×3). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated. The mixture was then quenched by slow addition to a solution of saturated sodium bicarbonate (approximately 150 mL) and 4:1 chloroform / IPA (approximately 50 mL). The organic layer was isolated, and the aqueous layer was further extracted (×3). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated. The crude product was dissolved in DMSO (12 mL) and purified by reverse-phase chromatography on a Gilson HPLC (50 × 250 mm column, 0–45% ACN / 0.05% aqueous NH OH, 16 min run). The product-containing fractions were concentrated to give the title compound (627 mg; 72% yield) as a solid. 1 H NMR(400MHz,CDCl3)δ 7.60(q,J=1.3Hz,1H),2.52-2.47(m,6H).ES-MS[M+H] + =228. [ka]

[0264] 7-Chloro-3-fluoro-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate R): To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (550 mg) in Dowtherm A (4 mL) was added ethyl 2-fluoro-3-oxobutanoate (525 μL) and the reaction was heated at 150 °C for 18 h. Additional ethyl 2-fluoro-3-oxobutanoate (525 μL) was added and the reaction was stirred at 150 °C for an additional 18 h. The reaction mixture was loaded directly onto a Teledyne ISCO Combi-Flash system (liquid loading with DCM, 120 G column, 0–20% Hex / EtOAc, 6 min run; then 0–30% EtOAc / DCM, 10 min run) to obtain the title compound (243 mg; 29% yield). 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. [ka]

[0265] 3,7-Dichloro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate S): To a solution of 7-chloro-2,8-dimethyl-pyrimido[1,2-b]pyridazin-4-one (50 mg) in DMF (0.66 mL) was added N-chlorosuccinimide (33 mg). The mixture was stirred at room temperature for 18 h. Further N-chlorosuccinimide (8 mg) was added, and the mixture was stirred for 48 h. The mixture was poured into water, extracted with DCM, passed through a phase separator, and concentrated. The crude product was purified using a Teledyne ISCO Combi-Flash system (liquid loading with DCM, 12G column, 0–30% EtOAc / DCM, 10 min run). 1 H NMR(400MHz,CDCl3)δ 7.65(q,J=1.3Hz,1H),2.60(s,3H),2.51(d,J=1.3Hz,3H).ES-MS[M+1] + :244 [ka]

[0266] 3,6-Dichloro-4-(methoxymethyl)-5-methylpyridazine (Intermediate T): A stirred solution of 3,6-dichloro-4-methylpyridazine (2 g), methoxyacetic acid (2.82 mL), and silver nitrate (1.04 g) in water (100 mL) was heated to 72°C, whereupon ammonium persulfate (4.2 g) was added slowly in portions. The mixture was heated at 72°C for 30 minutes and then at 90°C for 1 hour. Additional ammonium persulfate was added in small portions (2.4 g), and the reaction was allowed to stir at 90°C for an additional hour. The mixture was allowed to cool to room temperature and slowly poured into a solution of saturated aqueous bicarbonate (approximately 150 mL) and chloroform / IPA (4:1), stirred for 20 minutes, and then extracted (x3). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated. The crude product was dissolved in DMSO (15 mL) and purified by reverse-phase chromatography on a Gilson HPLC (20 × 250 mm column, 15–60% ACN / 0.1% aqueous TFA, 16 min run). The product-containing fractions were basified with saturated NaHCO3, extracted with 3:1 chloroform / IPA, dried over magnesium sulfate, filtered, and concentrated to give the title compound (1.6 g; 62% yield). 1 H NMR(400MHz,CDCl3)δ 4.64(s,2H),3.44(s,3H),2.52(s,3H).ES-MS[M+1] + :208. [ka]

[0267] 6-Chloro-5-(methoxymethyl)-4-methylpyridazin-3-amine (Intermediate U1): 3,6-Dichloro-4-(methoxymethyl)-5-methyl-pyridazine (1.59 g) was combined with ammonium hydroxide (78 mL) and heated to 210 °C in a stainless steel pressure vessel for 24 h. The reaction was allowed to cool to room temperature, and the reaction mixture was transferred to a round-bottom flask containing DCM / MeOH and concentrated. The crude product was dissolved in DMSO (12 mL) and purified by reverse-phase chromatography on a Gilson HPLC (50 × 250 mm column, 0–35% ACN / 0.05% aqueous NH 4 OH, 16 min run) to give the title compound (364 mg; 26% yield). 1 H NMR(400MHz,CDCl3)δ 4.72(s,2H),4.59(s,2H),3.42(s,3H),2.23(s,3H).ES-MS[M+1] + :188.

[0268] 6-Chloro-4-(methoxymethyl)-5-methylpyridazin-3-amine (Intermediate U2): The intermediate was synthesized and isolated as described in the previous step (554 mg; 39% yield). 1 H NMR(400MHz,CDCl3)δ 5.27(s,2H),4.52(s,2H),3.38(s,3H),2.36(s,3H).ES-MS[M+1] + :188. [ka]

[0269] 7-Chloro-8-(methoxymethyl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate V): To a mixture of ethyl 3,3-diethoxypropionate (755 μL) and 6-chloro-5-(methoxymethyl)-4-methylpyridazin-3-amine (364 mg), polyphosphoric acid (3 mL) was added. The mixture was stirred at 120° C. for 5 hours. Additional ethyl 3,3-diethoxypropionate (755 μL) was added, and the mixture was stirred at 120° C. for an additional hour. The reaction mixture was then slowly added to a stirred solution of 100 mL of saturated aqueous NaHCO3 and 50 mL of DCM. After the addition was complete, the mixture was stirred for 20 minutes, and the organic layer was separated. The aqueous layer was further extracted with chloroform / IPA (4:1) (×3). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was dissolved in DMSO (12 mL) and purified by reverse-phase chromatography on a Gilson HPLC (50 × 250 mm column, 0–55% ACN / 0.05% aqueous NH OH, 16 min run). The product-containing fractions were concentrated to give the title compound (108 mg; 23% yield) as a solid. 1 H NMR(400MHz,CDCl3)δ 8.23(d,J=6.4Hz,1H),6.68(d,J=6.4Hz,1H),4.65(s,2H),3.49(s,3H),2.71(s,3H).ES-MS[M+1] + :240. [ka]

[0270] 7-Chloro-9-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate W): To a mixture of ethyl 3,3-diethoxypropionate (1.15 mL) and 6-chloro-5-(methoxymethyl)-4-methyl-pyridazin-3-amine (554 mg) was added polyphosphoric acid (5 mL). The mixture was stirred at 120° C. for 1 hour. Additional ethyl 3,3-diethoxypropionate (1.15 mL) was added, and the mixture was stirred at 120° C. for an additional 1 hour. The reaction mixture was then slowly added to a stirred solution of 150 mL of saturated aqueous NaHCO3 and 100 mL of DCM. After the addition was complete, the mixture was allowed to stir for 20 minutes, and the organic layer was separated. The aqueous layer was further extracted with chloroform / IPA (4:1) (×3). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was dissolved in DMSO (12 mL) and purified by reverse-phase chromatography on a Gilson HPLC (50 × 250 mm column, 0–40% ACN / 0.05% aqueous NH OH, 16 min run). The product-containing fractions were concentrated to give the title compound as a solid. 1 H NMR(400MHz,CDCl3)δ 8.22(d,J=6.4Hz,1H),6.64(d,J=6.4Hz,1H),4.95(s,2H),3.48(s,3H),2.58(s,3H).ES-MS[M+1] + :240. [ka]

[0271] 3,6-Dichloro-4-cyclopropyl-5-methylpyridazine (Intermediate X): A stirred solution of 3,6-dichloro-4-methylpyridazine (2.5 g), cyclopropanecarboxylic acid (3.66 mL), and silver nitrate (1.3 g) in water (125 mL) was heated to 72°C, whereupon ammonium persulfate (5.25 g) was added slowly in portions. The mixture was heated at 72°C for 20 minutes. Sulfuric acid (1.23 mL) was added and heated to 90°C for 1 hour. The mixture was allowed to cool to ambient temperature and then slowly poured into a solution of saturated aqueous bicarbonate (ca. 150 mL) and chloroform / IPA (4:1) (ca. 75 mL), stirred for 20 minutes, and then extracted with chloroform / IPA (4:1) (x3). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified using a Teledyne ISCO Combi-Flash system (liquid loading with DCM, 80 G column, 0-25% EtOAc / Hex, 15 min run) to give the title compound (1.95 g; 63% yield). 1 H NMR(400MHz,CDCl3)δ 2.54(d,J=0.9Hz,3H),1.88-1.75(m,1H),1.34-1.19(m,2H),0.81-0.67(m,2H).ES-MS[M+1] + :203. [ka]

[0272] 6-Chloro-4-cyclopropyl-5-methylpyridazin-3-amine (Intermediate Y1) and 6-chloro-5-cyclopropyl-4-methylpyridazin-3-amine (Intermediate Y2): 3,6-Dichloro-4-cyclopropyl-5-methyl-pyridazine (1.0 g) was mixed with ammonium hydroxide (15 mL; 28% NH3 in water) solution and 1,4-dioxane (2 mL). The solution was heated to 210 °C (140 psi) for 24 h. The reaction was allowed to cool to room temperature, and the reaction mixture was transferred to a round-bottom flask containing DCM / MeOH and concentrated. The crude product was purified using a Teledyne ISCO Combi-Flash system (solid loading, 80 G column, 0-90% EtOAc / DCM, 25 min run; then 0-10% MeOH / DCM / NH4OH, 10 min) to give a mixture of the title compounds. 1 H NMR(400MHz,CDCl3)δ 2.46(d,J=1.2Hz,3H),1.90-1.79(m,1H),1.42-1.29(m,2H),0.86-0.73(m,2H). 1 H NMR(400MHz,CDCl3)δ 2.60(d,J=1.3Hz,3H),1.80-1.55(m,1H),1.44-1.32(m,2H),0.81-0.72(m,2H).ES-MS[M+1] + :184. [ka]

[0273] 7-Chloro-9-cyclopropyl-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate Z1): To a mixture of isomers: 6-chloro-5-cyclopropyl-4-methyl-pyridazin-3-amine and 6-chloro-4-cyclopropyl-5-methyl-pyridazin-3-amine (928 mg) was added ethyl 3,3-diethoxypropionate (1.97 mL) and polyphosphoric acid (7 mL). The mixture was stirred at 120° C. for 1 hour. Additional ethyl 3,3-diethoxypropionate (1.97 mL) was added, and the mixture was stirred at 120° C. for an additional 1 hour. The reaction mixture was then slowly added to a stirred solution of 150 mL of saturated aqueous NaHCO and 100 mL of DCM. After the addition was complete, the mixture was allowed to stir for 20 minutes, and the organic layer was separated. The aqueous layer was further extracted with chloroform / IPA (4:1) (×3). The organic layers were combined, dried over MgSO, filtered, and concentrated. The crude product was dissolved in DMSO (15 mL) and purified by reverse-phase chromatography on a Gilson HPLC (50 x 250 mm column, 0-45% ACN / 0.1% aqueous TFA, 20 min run). The product-containing fractions were neutralized with saturated NaHCO3 and then extracted with 3:1 chloroform / IPA. The organic layer was concentrated to give the title compound as a solid (73 mg; 6% yield). ES-MS [M+1] + :236.

[0274] 7-Chloro-8-cyclopropyl-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate Z2): Intermediate Z2 was synthesized and isolated as described in the previous step to give the title compound as a solid (473 mg; 40% yield). ES-MS [M+1] + :236. [ka]

[0275] 4-Bromo-6-chloro-5-methylpyridazin-3-amine (Intermediate AA): A mixture of 6-chloro-5-methylpyridazin-3-amine (4 g) and NaHCO3 (4.68 g) was suspended in MeOH (40 mL) and treated with Br2 (6.68 g). The mixture was stirred at 20 °C for 4 h. The mixture was filtered, and the cake was washed with a mixture of DCM / MeOH (10:1) (100 mL). The filtrate was concentrated. The residue was diluted with saturated aqueous Na2SO3 (50 mL) and extracted with DCM (100 mL × 5). The combined organic layers were dried over Na2SO4 and concentrated to give 4-bromo-6-chloro-5-methylpyridazin-3-amine (6.07 g). 1 H NMR(400MHz,CDCl3)δ 5.86(br s,2H),2.52(s,3H). [ka]

[0276] 9-Bromo-7-chloro-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate AB): A mixture of 4-bromo-6-chloro-5-methylpyridazin-3-amine (6 g) and diethyl 2-(ethoxymethylene)malonate (11.66 g) in PPA (100 mL) was stirred at 120 °C for 2 h. The mixture was added to saturated aqueous Na2CO3 while maintaining the pH at approximately 8, and then extracted with EtOAc (50 mL × 4). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by Combi-Flash (silica gel, 0 to 70%, ethyl acetate in petroleum ether) to give 9-bromo-7-chloro-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (4.1 g). 1 H NMR(400MHz,CDCl3)δ 8.28(d,J=6.8Hz,1H),6.68(d,J=6.4Hz,1H),2.73(s,3H). [ka]

[0277] tert-Butyl 4-methylsulfonyloxypiperidine-1-carboxylate (Intermediate AC): To a solution of tert-butyl-4-hydroxypiperidine-1-carboxylate (2.5 g) in DCM (40 mL) at 0 °C was added triethylamine (2.42 mL), followed by the dropwise addition of methanesulfonyl chloride (1.35 mL). The ice bath was removed and the reaction was stirred at room temperature for 18 h. The reaction mixture was diluted with 3:1 CHCl3 / IPA and water. The layers were separated and the aqueous layer was extracted with 3:1 CHCl3 / IPA (2x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give 3.4 g of the title compound. 1 H NMR(400MHz,CDCl3)δ 4.91-4.85(m,1H),3.73-3.67(m,2H),3.33-3.26(m,2H),3.03(s,3H),1.99-1.93(m,2H),1.85-1.77(m,2H),1.45(s,9H). [ka]

[0278] tert-Butyl 4-[(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-carboxylate (Intermediate AD): To a flask was added tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.5 g), 6-hydroxy-4-oxachroman (565 mg), tetrabutylammonium chloride (207 mg), and potassium carbonate (1.6 g). After adding water (17.5 mL) and DMF (1 mL), the reaction was heated to 100 °C for 4 h. The reaction was allowed to cool to room temperature and extracted with DCM (2x). The combined extracts were washed with water and 2N NaOH, then dried (NaSO), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (20-70% EtOAc / hexanes) afforded the title compound (472 mg): 1H-NMR(400MHz,CDCl3)δ 6.76(d,J=8.7Hz,1H),6.46(d,J=2.8Hz,1H),6.42(dd,J=8.7,2.8Hz,1H),4.35-4.28(m,1H),4.25-4.18(m,4H),3.69(ddd,J=12 .9,7.3,3.5Hz,2H),3.29(ddd,J=12.5,7.9,3.8Hz,2H),1.90-1.85(m,2H),1.74-1.66(m,2H),1.46(s,9H).ES-MS[MC(CH3)3+H] + :280.4.

[0279] 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine (Intermediate AE): tert-Butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-carboxylate (315 mg) was dissolved in a 4 M HCl solution in 1,4-dioxane (14 mL). After 5 h at room temperature, the reaction was concentrated under reduced pressure. The crude product was dissolved in MeOH and then purified with an HF SCX cartridge and NH3 solution (2N in MeOH) to give the title compound (68 mg): 1 H NMR(400MHz,DMSO-d6)δ 6.77(d,J=8.8Hz,1H),6.44-6.39(m,2H),4.48-4.46(m,1H),4.24-4.19(m,4H),3.31(ddd, ES-MS[M+1] + :236.2. [ka]

[0280] 2,2,3,3-Tetradeuterio-1,4-benzodioxin-6-carbaldehyde (Intermediate AG): In a 500 mL round-bottom flask, 3,4-dihydroxybenzaldehyde (21.3 g), 1,2-dibromoethane-D4 (14.1 mL), and potassium carbonate (65.0 g) were combined in acetone (515 mL). The reaction was heated to reflux for 18 h. The reaction was diluted with EtOAc, filtered through Celite, and the filtrate was concentrated in vacuo. The crude sample was purified by flash chromatography on silica gel (0-40% EtOAc / hexanes) to afford the title compound (15.4 g). 1 H NMR(400MHz,CDCl3)δ 9.82(s,1H),7.41-7.38(m,2H),6.97(d,J=8.8Hz,1H).ES-MS[M+1] + :169. [ka]

[0281] 2,2,3,3-Tetradeuterio-1,4-benzodioxin-6-ol (Intermediate AH): Step 1. To a solution of 2,2,3,3-tetradeuterio-1,4-benzodioxin-6-carbaldehyde (15.4 g) in DCE (250 mL) was added 3-chloroperoxybenzoic acid (47.6 g, <77% CAS#937-14-4; Sigma-Aldrich). The reaction mixture was heated to 50 °C for 18 h. The reaction was diluted with DCM and saturated NaHCO solution. The layers were separated. The aqueous layer was extracted with DCM (2x), and the combined organic layers were washed with brine, dried (MgSO), filtered, and concentrated to give 2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d formate (15.1 g). ES-MS [M+1]: 185.

[0282] Step 2. 2,3-Dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4 formate (15.1 g) was dissolved in methanol (250 mL) and potassium carbonate (15.5 g) was added. After 3 h, the solvent was removed and water / DCM (1:1) was added. The aqueous layer was slowly acidified by dropwise addition of 6 N aqueous HCl until pH < 4. The layers were separated, the aqueous layer was extracted with DCM (2x), and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The filtrate was purified by flash chromatography on silica gel (0–40% EtOAc / hexanes). The desired fractions were concentrated and co-evaporated (2x with toluene) to give the title compound (12.3 g). 1 H NMR(400MHz,CDCl3)δ 6.72(d,J=8.8Hz,1H),6.39(d,J=2.9Hz,1H),6.34-6.31(dd,J=8.7,2.9Hz,1H),4.64(s,1H).ES-MS[M+1] + :157. [ka]

[0283] tert-Butyl 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (Intermediate AI): To a 1000 mL round-bottom flask was added tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (18 g), 2,2,3,3-tetradeuterio-1,4-benzodioxin-6-ol (6.0 g), potassium carbonate (16.2 g), and tetrabutylammonium chloride (2.1 g) in water (360 mL) and DMF (18 mL). The reaction was heated to reflux. After 24 h, the reaction was allowed to cool to room temperature, diluted with EtOAc, and washed with water (3×) and brine (2×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on silica gel (0–40% EtOAc / hexanes) to afford the title compound (3.1 g). 1H NMR(400MHz,CDCl3)δ 6.76(d,J=8.7Hz,1H),6.46(d,J=2.8Hz,1H),6.44-6.41(dd,J=8.7,2.8Hz,1H),4.32-4.27(m,1H),3 .72-3.66(m,2H),3.31-3.25(m,2H),1.90-1.85(m,2H),1.74-1.66(m,2H),1.46(s,9H).ES-MS[M+1] + :340.

[0284] 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (Intermediate AJ) as the TFA salt: To a round-bottom flask containing tert-butyl 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (760 mg) in DCM (6 mL) was added trifluoroacetic acid (2 mL). After 2 h at room temperature, the solvent was removed and the crude residue was dissolved in DCM and concentrated in vacuo (3x) to give the title compound (802 mg). 1 H NMR(400MHz,CDCl3)δ 6.78(d,J=8.9Hz,1H),6.45(d,J=2.8Hz,1H),6.43-6.40(dd,J=8.8,2.9Hz,1H),4.5 1-4.50(m,1H),3.44-3.37(m,2H),3.28-3.25(m,2H),2.16-2.07(m,4H).ES-MS[M+1] + :240. [ka]

[0285] tert-Butyl 2,2,6,6-tetradeuterio-4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (Intermediate AK): In a vial, tert-butyl 2,2,6,6-tetradeuterio-4-hydroxy-piperidine-1-carboxylate (100 mg, 0.49 mmol) [Reference: J. of Labeled Compounds and Radiopharmaceuticals 2018, 61, 1036-1042], triphenylphosphine (180 mg, 0.68 mmol), and 2,2,3,3-tetradeuterio-1,4-benzodioxin-6-ol (107 mg, 0.68 mmol) were combined in THF (2 mL). The vessel was degassed, followed by the addition of diisopropyl azodicarboxylate (0.13 mL, 0.68 mmol). The reaction was heated at 60 °C for 18 h. The reaction was dissolved in 3:1 CHCl3:IPA and concentrated through Celite. The solid was dry loaded and subjected to purification on silica gel (0-25% EtOAc / hexanes). The desired fractions were concentrated to give the title compound (123 mg). 1 H NMR(400MHz,CDCl3)δ 6.75(d,J=8.7Hz,1H),6.45(d,J=2.8Hz,1H),6.42(dd,J=8.8,2.9Hz,1H),4.3 1-4.26(m,1H),1.87-1.83(m,2H),1.71-1.66(m,2H),1.45(s,9H).ES-MS[M+1] + :344. [ka]

[0286] 2,2,6,6-tetradeuterio-4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (Intermediate AL): In a vial, tert-butyl 2,2,6,6-tetradeuterio-4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (123 mg, 0.36 mmol) and trifluoroacetic acid (0.5 mL) were combined in dichloromethane (2 mL). The reaction was stirred for 1 hour and concentrated. The oil was purified on an SCX cartridge (5G), washed with MeOH, and eluted with 7N NH3 / MeOH solution. The solvent was removed to give the title compound (55 mg). NMR(400MHz,CDCl3)δ 6.75(d,J=8.8Hz,1H),6.46(d,J=2.8Hz,1H),6.43(dd,J=8.8,2.8Hz,1H),4.24-4.18(m,1H),1.9 9(d,J=3.8Hz,1H),1.96(d,J=3.7Hz,1H),1.63(d,J=8.4Hz,1H)1.60(d,J=8.6Hz,1H).ES-MS[M+1] + :244. [ka]

[0287] Methyl 4-(2-hydroxypropoxy)-3-iodo-benzoate (Intermediate AM): To a 0°C solution of 1-bromo-2-propanol (1.04 mL) in DMF (22 mL) was added potassium carbonate (2.69 mL) and potassium iodide (0.59 g). After 15 minutes, methyl 4-hydroxy-3-iodobenzoate (2.44 g) was added and the reaction was heated to reflux. After 12 hours, the reaction was allowed to cool to room temperature and diluted with EtOAc and water. The layers were separated and the organic layer was washed with water (3x), Bryan (2x), dried (MgSO4), and concentrated to give the title compound (2.5 g). ES-MS [M+1] + :337.

[0288] Methyl 3-methyl-2,3-dihydro-1,4-benzodioxine-6-carboxylate (Intermediate AN): In a 250 mL round-bottom flask, methyl 4-(2-hydroxypropoxy)-3-iodobenzoate (2.5 g), cesium carbonate (4.88 g), palladium(II) acetate (0.14 g), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.47 g) were combined. The flask was evacuated and purged with anhydrous nitrogen (3x), after which degassed toluene (18 mL) was added. The reaction was sealed and heated to 110 °C. After 5 h, the reaction was cooled to room temperature and the toluene was concentrated in vacuo. The crude oil was diluted with EtOAc and water. The layers were separated, and the organic layer was washed with water (3x), brine (2x), dried over MgSO4, and concentrated. The crude oil was purified by flash chromatography on silica gel (0–20% EtOAc / hexanes) to give the title compound (0.34 g). 1 H NMR(400MHz,CDCl3)δ 7.56-7.53(m,2H),6.92-6.86(m,1H),4.36-4.22(m,2H)3.89-3.82(m,1H)3.86(s,3H),1.37(d,J=6.5Hz,3H).ES-MS[M+1] + :209. [ka]

[0289] (3-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)methanol (intermediate AO): To a 0°C suspension of lithium aluminum hydride (1.01 mL, 1 M) in THF (1.2 mL) was added methyl 3-methyl-2,3-dihydro-1,4-benzodioxine-6-carboxylate (200 mg) in THF (1.2 mL). The ice bath was removed, and after 1 h at room temperature, the reaction was cooled to 0°C and quenched with water (40 μL) and 10% aqueous NaOH (0.37 mL). After 10 min at 0°C, the suspension was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-50% EtOAc / hexanes), and the desired fractions were concentrated to give 148 mg of the title compound. ES-MS [M+1] + :182.

[0290] 3-Methyl-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (Intermediate AP): To a vial containing (3-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)methanol (148 mg) in DCM (2.7 mL) at 0 °C was added Dess-Martin periodinane (418 mg). The ice bath was removed, and after 18 h, the reaction was diluted with DCM and Celite was added. The suspension was concentrated, dry-loaded, and subjected to flash chromatography on silica gel (0–40% EtOAc / hexanes). The desired fractions were concentrated to afford the title compound (129 mg). 1 H NMR(400MHz,CDCl3)δ 9.82(s,1H),7.41-7.38(m,2H),6.99-6.95(dd,J=9.1,5.0Hz,1H),4.38-4.15(m,2H)3.92-3.82(m,1H)1.37(d,J=6.4Hz,3H).ES-MS[M+1] + :179. [ka]

[0291] 3-Methyl-2,3-dihydro-1,4-benzodioxin-6-ol (Intermediate AQ): Step 1. To a solution of 3-methyl-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (129 mg) in DCE (1.4 mL) was added 3-chloroperoxybenzoic acid (187 mg, <77% CAS#937-14-4; Sigma-Aldrich). The reaction was heated to 50 °C. After 3 h, the reaction was concentrated in vacuo, and EtOAc was added to the residue, followed by saturated aqueous NaHCO (1.5 mL). The organic layer was separated, washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The crude sample was purified by flash chromatography on silica gel (0–30% EtOAc / hexanes) to give 3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl formate (91 mg). ES-MS [M+1] + :195.

[0292] Step 2. 3-Methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl formate (78 mg) was dissolved in methanol (1.4 mL) and potassium carbonate (121 mg) was added. After 45 minutes, the methanol was concentrated in vacuo. The residue was diluted with DCM and water. The layers were separated, the aqueous layer was extracted with DCM (2x), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (71 mg). 1 H NMR(400MHz,CDCl3)δ 6.71(d,J=8.7Hz,1H),6.39-6.37(m,1H),6.34-3.30(m,1H),4.87(s,1H),4.29-4.21(m, 1H),4.15(dd,J=11.2,2.2Hz,1H),3.81-3.74(m,1H),1.33(d,J=6.5Hz,3H);ES-MS[M+1] + :167.

[0293] Separation analysis example: Chiral SFC separations were performed on a Thar (Waters) Investigator. Column: Chiral Technologies CHIRALPAK IE, 4.6 x 250 mm, 5 μm. Gradient conditions: 5% to 50% MeOH in CO2 (MeOH modified with 0.1% DEA) over 5 min, hold at 50% CO2 for 5 min. Flow rate: 3.5 mL / min. Column temperature: 40 °C. System back pressure: 100 bar. Enantiomer N1:Enantiomer N2 (1:1)

[0294] Preparative example: Chiral SFC separations were performed on a PIC Solution SFC-PICLab PREP 100. Column: Chiral Technologies CHIRALPAK IE, 20 x 250 mm, 5 m. Conditions: 10% MeOH in CO2. Flow rate: 80 mL / min. Column temperature: 40 °C. System back pressure: 100 bar. Intermediate AS1 (first eluting peak): Rt=5.06 min (preparative method); ES-MS[M+Na]+=372.0.;100%ee. Intermediate AS2 (second eluting peak): Rt=6.02 min (preparative method; ES-MS[M+Na]+=372.0; 97.3%ee.

[0295] tert-Butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidine-1-carboxylate (Intermediate AT): To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (0.2 g, 1.31 mmol) in THF (10 mL) was added tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate (340 mg, 1.58 mmol) and PPh3 (641 mg, 2.45 mmol) under N2 atmosphere with stirring at 20 °C. DIAD (399 mg, 1.97 mmol) was then added dropwise at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash silica flash column, eluent: 0–10% ethyl acetate / petroleum ether gradient at 35 mL / min) to give the desired product (102 mg). 1H NMR(400MHz,CDCl3)δ 6.77(d,J=8.8Hz,1H),6.47(d,J=2.4Hz,1H),6.44(dd,J=2.8Hz,8.8Hz,1H),4.25-4.21(m,4H),3.63-3. 58(m,2H),3.32-3.17(m,2H),1.97-1.92(m,2H),1.47(s,9H),1.29-1.23(m,2H),1.00(d,J=7.2Hz,3H).

[0296] 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidine (Intermediate AT1): To a solution of tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidine-1-carboxylate (102 mg, 0.29 mmol) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol). The mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated to give 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidine as the 2,2,2-trifluoroacetic acid salt (98 mg). [ka]

[0297] 2,2,3,3-Tetradeuterio-6-tetrahydropyran-2-yloxy-1,4-benzodioxine (Intermediate AU): To a solution of 2,2,3,3-tetradeuterio-1,4-benzodioxin-6-ol (2.0 g) and pyridinium tosylate (48 mg) in DCM (32 mL) was added 3,4-dihydro-2H-pyran (1.8 mL). The reaction was stirred at room temperature for 3 h. The reaction was diluted with DCM and washed with 5% NaOH solution. The organic layer was dried (MgSO), filtered, and concentrated. The crude oil was purified by flash chromatography on silica gel (0-30% EtOAc / hexanes) to give the title compound (2.61 g). 1 H NMR(400MHz,CDCl3)δ 6.75(d,J=8.9Hz,1H),6.62(d,J=2.8Hz,1H),6.54(dd,J=8.8,2.8,1H),5.26(t,J=3.4,1H),3.95-3 .89(m,1H),3.60-3.55(m,1H),2.01-1.91(m,1H),1.84-1.80(m,2H),1.67-1.57(m,3H);ES-MS[M+1] + :241. [ka]

[0298] 5-Bromo-2,2,3,3-tetradeuterio-6-tetrahydropyran-2-yloxy-1,4-benzodioxine (Intermediate AV): To a solution of 2,2,3,3-tetradeuterio-6-tetrahydropyran-2-yloxy-1,4-benzodioxine (1500 mg) in THF (62 mL) at -50 °C, n-butyllithium (7.49 mL, 2.5 M solution in hexanes) was added dropwise and stirred at -50 °C for 2 h, followed by the slow addition of 1,2-dibromotetrafluoroethane (3.72 mL). The mixture was stirred for 1 h, and then the cooling bath was removed. At room temperature, the reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic layers were dried (MgSO), filtered, and concentrated. The crude oil was purified by flash chromatography on silica gel (0-15% EtOAc / hexanes) to afford the title compound (1.63 g). 1 H NMR(400MHz,CDCl3)δ 6.77(d,J=9.1Hz,1H),6.69(d,J=9.1Hz,1H),5.37(t,J=2.9Hz,1H),3.98-3.92(m,1H),3.62-3.57 (m,1H),2.13-1.97(m,1H),1.95-1.86(m,1H),1.85-1.82(m,1H),1.71-1.59(m,3H);ES-MS[M+Na] + :341. [ka]

[0299] 5-Bromo-2,2,3,3-tetradeuterio-1,4-benzodioxin-6-ol (intermediate AW): In a vial, 5-bromo-2,2,3,3-tetradeuterio-6-tetrahydropyran-2-yloxy-1,4-benzodioxine (1632 mg), THF (50 mL), and 1N hydrochloric acid (30 mL) were combined. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (2x), and the combined organic layers were washed with brine, dried (MgSO), filtered, and concentrated. The crude oil was purified by flash chromatography on silica gel (0-20% EtOAc / hexanes) to provide the title compound (1.10 g). 1 H NMR(400MHz,CDCl3)δ 6.77(d,J=8.9Hz,1H),6.55(d,J=8.9Hz,1H),5.19(s,1H);ES-MS[M+1] + :235. [ka]

[0300] tert-Butyl 4-[(5-bromo-2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (Intermediate AX): In a round-bottom flask, tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (2.6 g), 5-bromo-2,2,3,3-tetradeuterio-1,4-benzodioxin-6-ol (1.1 g), potassium carbonate (1.97 g), and tetrabutylammonium chloride (0.26 g) were combined in water (17 mL) and DMF (0.9 mL). The reaction was heated to 100 °C. After 18 h, the reaction was allowed to cool, diluted with EtOAc, washed with water (3x), brine (2x), and the organic layer was dried (MgSO), filtered, and concentrated. The crude oil was purified by flash chromatography on silica gel (0-40% EtOAc / hexanes) to give the title compound (1.18 g). 1H NMR(400MHz,CDCl3)δ 6.76(d,J=9.1Hz,1H),6.47(d,J=8.9Hz,1H),4.40-4.39(m,1H),3.68-3.62(m,2H),3.41-3.38(m,2H),1.82-1.81(m,4H),1.45(s,9H). [ka]

[0301] tert-Butyl 4-[(2,2,3,3-tetradeuterio-5-methyl-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (Intermediate AY): In a vial, tert-butyl 4-[(5-bromo-2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (100 mg), cesium carbonate (233 mg), [1,1'-bis(diphenyl)phosphino)ferrocene]dichloropalladium(II) (26 mg), and 2,4,6-trimethylboroxine (0.2 mL; 50% w / w solution in THF) were combined, and after degassing the solid (3x), 1,4-dioxane (2.3 mL) was added. The reaction was heated to 80 °C. After 2 h, the reaction was filtered through a pad of Celite and rinsed thoroughly with EtOAc / DCM. The filtrate was concentrated and purified by flash chromatography on silica gel (0-40% EtOAc / hexanes) to give the title compound (46 mg). ES-MS [M+1] + :354. [ka]

[0302] 4-[(2,2,3,3-tetradeuterio-5-methyl-1,4-benzodioxin-6-yl)oxy]piperidine (Intermediate AZ): In a vial, tert-butyl 4-[(2,2,3,3-tetradeuterio-5-methyl-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (46 mg), trifluoroacetic acid (0.2 mL), and DCM (2 mL) were combined. The reaction was stirred at rt for 1 h and then concentrated. The crude residue was loaded onto an SCX cartridge (strong cation exchanger; Agilent part #14256027) in MeOH, washed with MeOH, and then eluted with 7N NH3 / MeOH solution. The solvent was removed in vacuo to give the title compound (28 mg). 1 H NMR(400MHz,CDCl3)δ 6.62(d,J=8.9Hz,1H),6.41(d,J=8.9Hz,1H),4.21-4.15(m,1H),3.15-3.09(m,2H) ,2.73-2.66(m,2H),2.09(s,3H),1.99-1.94(m,2H),1.71-1.62(m,2H);ES-MS[M+1] + :254. [ka]

[0303] 6-Bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine (Intermediate BA): To a solution of 5-fluoro-2,3-dihydro-1,4-benzodioxine (900 mg) and sodium acetate (727 mg) in chloroform (9.7 mL) at 0 °C was added bromine (0.3 mL). The ice bath was removed, and after 2 h at rt, the reaction was treated with saturated aqueous NaSO, extracted with DCM (3x), and concentrated by passing through a phase separator. The crude oil was purified by flash chromatography on silica gel (0-35% EtOAc / hexanes) to give the title compound (1.16 g) as a 3:1 mixture of regioisomers. Major regioisomer (Intermediate BA): 1 H NMR(400MHz,CDCl3)δ,6.95(dd,J=8.9,6.9Hz,1H),,6.58(dd,J=8.9,2.0Hz,1H),4.32-4.30(m,2H),4.28-4.26(m,2H). [ka]

[0304] 2-(5-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate BB): To a vial was added 6-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine (715 mg), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (126 mg), potassium acetate (903 mg), and bis(pinacolato)diboron (935 mg) in DMF (21 mL). After degassing the reaction (3x), the reaction was heated to 90 °C for 18 h. The reaction was cooled, diluted with EtOAc, filtered through Celite, and the filtrate was washed with water (3x), brine (2x), dried (MgSO), filtered, and concentrated. The crude oil was purified by flash chromatography on silica gel (0-40% EtOAc / hexanes) to give the title compound (575 mg). ES-MS [M+1] + :281. [ka]

[0305] 5-Fluoro-2,3-dihydro-1,4-benzodioxin-6-ol (Intermediate BC): To a solution of 2-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (575 mg) in a mixture of 1N sodium hydroxide solution (6.1 mL) and THF (7.9 mL) at 0 °C, hydrogen peroxide (0.19 mL, 30% w / w) was added. The reaction was stirred at room temperature for 1 h. The pH was adjusted to 3 with 1 M HCl solution. The aqueous layer was extracted with EtOAc (3x), and the organic layer was washed with water, brine, dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (0-40% EtOAc / hexanes) to give the title compound (124 mg). ES-MS [M+1] +:171. [ka]

[0306] tert-Butyl 4-[(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (Intermediate BD): To a vial was added tert-butyl 4-methylsulfonyloxy-piperidine-1-carboxylate (407 mg), 5-fluoro-2,3-dihydro-1,4-benzodioxin-6-ol (124 mg), potassium carbonate (306 mg), and tetrabutylammonium chloride (41 mg) in water (2.3 mL) and DMF (0.1 mL). The vial was sealed and heated to 100 °C for 18 h. The reaction was cooled, diluted with EtOAc, and washed with water, saturated NaHCO (2x), and brine (2x), before the organic layer was dried (MgSO), filtered, and concentrated. The crude oil was purified by flash chromatography on silica gel (0-40% EtOAc / hexanes) to give the title compound (176 mg). 1 H NMR(400MHz,CDCl3)δ 6.56(dd,J=9.1,1.9Hz,1H),6.49(dd,J=9.1,7.8Hz,1H),4.31-4.29(m,2H),4.26-4.23(m,2H),3. 77-3.71(m,2H),3.29-3.23(m,2H),1.91-1.85(m,2H),1.77-1.69(m,2H),1.46(s,9H);ES-MS[M+1] + :354. [ka]

[0307] 4-((5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-ium 2,2,2-trifluoroacetic acid (Intermediate BE): To the vial was added tert-butyl 4-[(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (176 mg), trifluoroacetic acid (0.5 mL), and DCM (2.5 mL). After 1 h at rt, the reaction was concentrated in vacuo and co-evaporated with DCM (2×) to give the title compound (202 mg). 1 H NMR(400MHz,MeOD)δ 6.63(dd,J=9.1,7.8Hz,1H),6.58(dd,J=9.2,1.6Hz,1H),4.48-4.44(m,1H),4.28-4.26(m,2H),4.23- 4.21(m,2H),3.44-3.37(m,2H),3.22-3.17(m,2H),2.14-2.05(m,2H),2.04-1.97(m,2H);ES-MS[M+1] + :254. [ka]

[0308] 2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxin (intermediate BF): To a solution of 3-fluorocatechol (2.0 g) in acetone (52 mL) was added potassium carbonate (6.6 g), followed by 1,2-dibromoethane-D4 (1.43 mL). The reaction was heated at 60 °C for 18 h. The reaction was filtered over Celite, and the filtrate was concentrated. The crude residue was purified by flash chromatography on silica gel (0 to 40% EtOAc / hexanes) to give the title compound (1.54 g). 1 H NMR(400MHz,CDCl3)δ 6.76-6.70(m,1H),6.69-6.64(m,2H). [ka]

[0309] 6-Bromo-2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxin (Intermediate BG): To a solution of 2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxine (500 mg) and sodium acetate (394 mg) in chloroform (5.3 mL) at 0 °C, bromine (162 μL) was added dropwise. The ice bath was removed, and the reaction was stirred at rt for 2 h. The reaction was treated with saturated NaSO, extracted with DCM (3×), passed through a phase separator, and concentrated. The crude residue was purified by flash chromatography on silica gel (0–20% EtOAc / hexanes) to afford the title compound (660 mg; a 3:1 mixture of regioisomers). Major regioisomer (Intermediate BG): 1 H NMR(400MHz,CDCl3)δ 6.96(dd,J=9.0,7.0Hz,1H),6.59(dd,J=9.0,2.0,1H). [ka]

[0310] 4,4,5,5-tetramethyl-2-(2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxin-6-yl)-1,3,2-dioxaborolane (Intermediate BH): To a vial was added bis(pinacolato)diboron (848 mg), 6-bromo-2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxine (660 mg), dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (114 mg), and potassium acetate (820 mg) in DMF (9.3 mL). After degassing the reaction, the reaction was heated to 90 °C for 18 h. The reaction was allowed to cool to room temperature, diluted with EtOAc, filtered through Celite, and the filtrate was washed with water (3x) and Bryan (2x), then dried (MgSO), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (0–40% EtOAc / hexanes) to afford the title compound (494 mg). 1 H NMR(400MHz,CDCl3)δ 7.16(dd,J=8.4,6.1Hz,1H),6.64(dd,J=8.3,1.4Hz,1H),1.33(s,12H);ES-MS[M+1] +:285. [ka]

[0311] 2,2,3,3-Tetradeuterio-5-fluoro-1,4-benzodioxin-6-ol (Intermediate BI): To a solution of 4,4,5,5-tetramethyl-2-(2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxin-6-yl)-1,3,2-dioxaborolane (494 mg) in a mixture of sodium hydroxide solution (5.2 mL, 1 M) and THF (6.7 mL) at 0 °C was added hydrogen peroxide (160 μL, 30% w / w). The reaction was stirred at room temperature for 1 h, after which the pH was adjusted to 3 with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with water, brine, dried (MgSO), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (0–40% EtOAc / hexanes) to afford the title compound (116 mg). 1 H NMR(400MHz,CDCl3)δ 6.55(dd,J=9.1,2.1Hz,1H),6.47(t,J=8.8Hz,1H),4.27(s,1H);ES-MS[M+1] + :175. [ka]

[0312] tert-Butyl 4-[(2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (Intermediate BJ): To a vial was added tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (369 mg), 2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxin-6-ol (115 mg), potassium carbonate (278 mg), and tetrabutylammonium chloride (37 mg) in water (2.0 mL) and DMF (0.1 mL). The vial was sealed and heated at 100 °C for 18 h. The reaction was cooled, diluted with EtOAc, and washed with water, saturated NaHCO solution, and Bryan (2x), before the organic layer was dried (MgSO), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (0-40% EtOAc / hexanes) to afford the title compound (124 mg). 1 H NMR(400MHz,CDCl3)δ 6.56(dd,J=9.1,1.9Hz,1H),6.50(dd,J=9.1,7.9Hz,1H),4.26(m,1H),3.77-3.71(m,2 H),3.29-3.23(m,2H),1.91-1.85(m,2H),1.78-1.70(m,2H),1.47(s,9H);ES-MS[M+1] + :358. [ka]

[0313] 4-[(2,2,3,3-tetradeuterio-5-fluoro-1,4-benzodioxin-6-yl)oxy]piperidine; 2,2,2-trifluoroacetic acid (Intermediate BK): To the vial was added tert-butyl 4-[(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)oxy]piperidine-1-carboxylate (124 mg), trifluoroacetic acid (0.3 mL), and DCM (1.7 mL). After 1 h at rt, the reaction was concentrated in vacuo and co-evaporated with DCM (2×) to give the title compound (158 mg). 1H NMR(400MHz,CD3OD)δ 6.63(dd,J=9.1,7.8Hz,1H),6.58(dd,J=9.2,1.6Hz,1H),4.49-4.44(m,1H),3.43-3.37(m,2H),3.22-3.17(m,2H),2.13-1.98(m,4H);ES-MS[M+1] + :258. [ka]

[0314] tert-Butyl 4-deuterio-4-hydroxypiperidine-1-carboxylate (Intermediate BL): To a solution of 1-tert-butyl-4-piperidone (10 g, 50 mmol) in methanol (250 mL) at 0 °C was added sodium borodeuteride (3.2 mL, 100 mmol). The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated NH4Cl(aq) and then extracted with EtOAc (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford 10 g (99%) of the title compound. 1 H NMR(400MHz,CDCl3)δ 3.85(d,J=12.4Hz,2H),3.06-3.00(m,2H),1.87-1.82(m,2H),1.48-1.42(m,2H),1.46(s,9H). [ka]

[0315] tert-Butyl 4-deuterio-4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (Intermediate BM): To a suspension of tert-butyl-4-deuterio-4-hydroxy-piperidine-1-carboxylate (10 g) and 4-dimethyl-aminopyridine (0.6 g) in pyridine (45 mL) was added tosyl chloride (11.8 g). The mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (2x). The combined organic layers were washed with water (2x), brine (2x), dried (MgSO4), filtered, and concentrated. The crude oil was purified by normal phase column chromatography (0-20% EtOAc / hexanes). After removal of the solvent, 14.3 g (81%) of the desired compound was obtained. 1 H NMR(400MHz,CDCl3)δ 7.79(d,J=8.4Hz,2H),7.34(d,J=8.0Hz,2H),3.61-3.55(m,2H),3.28-3.22(m,2 H),2.45(s,3H),1.79-1.73(m,2H),1.70-1.64(m,2H),1.43(s,9H).ES-MS[M+Na] + :379. [ka]

[0316] 4-deuterio-4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (intermediate BN): To a round-bottom flask was added 2,2,3,3-tetradeuterio-1,4-benzodioxin-6-ol (1.0 g, 6.7 mmol), tert-butyl 4-deuterio-4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (2.0 g, 5.6 mmol), potassium carbonate (2.4 g, 16.8 mmol), and tetrabutylammonium chloride (0.31 g, 1.1 mmol) in water (25 mL) and DMF (1.3 mL). The reaction was heated under reflux for 18 h. The reaction was diluted with 3:1 CHCl3 / IPA, and the layers were separated. The aqueous layer was extracted with 3:1 CHCl3 / IPA (2x), and the combined organic layers were washed with water, Brilliant Green, then dried (MgSO4), filtered, and concentrated. The crude oil was purified by normal-phase column chromatography (0–20% EtOAc / hexanes). After removing the solvent, the oil was dissolved in DCM (9 mL) and then trifluoroacetic acid (2.1 mL, 28 mmol) was added. After 1 hour, the solvent was removed under vacuum. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was rinsed with MeOH and 7N NH3 / MeOH solution. The solvent was removed to give 725 mg (53%) of the title compound. 1 H NMR(400MHz,CDCl3)δ 6.75(d,J=8.7,1H),6.45(d,J=2.8,1H),6.41(dd,J=8.8,2.9Hz,1H),3.21-3.1 5(m,2H),2.87-2.81(m,2H),2.07-2.00(m,2H),1.78-1.72(m,2H).ES-MS[M+1] + :241. [ka]

[0317] tert-Butyl (2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-1-carboxylate (intermediate BO): To a mixture of 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol (5 g, 32.02 mmol), (2R,4R)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate (6.89 g), and PPh3 (10.93 g) in THF (100 mL) was added DIAD (8.1 mL) slowly at 20 °C, and the reaction was stirred at 20 °C for 16 h. The reaction was concentrated, and the residue was purified by Combi Flash (silica gel, 0–30%, ethyl acetate in petroleum ether) to give tert-butyl (2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-1-carboxylate (3.7 g). 1 H NMR(400MHz,CDCl3)δ 6.77(d,J=8.8Hz,1H),6.46(s,1H),6.42(dd,J=8.8Hz,1.6Hz,1H),4.61-4.46(m,1H),4.41-4.31(m,1H),4.13-4.06(m,1H) ),2.96-2.89(m,1H),2.14-2.04(m,1H),2.01-1.90(m,1H),1.74-1.64(m,1H),1.52-1.42(s,10H),1.19(d,J=7.2Hz,3H). [ka]

[0318] (2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine (intermediate BP): To a solution of tert-butyl (2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-1-carboxylate (3.7 g) in DCM (20 mL) was added TFA (4 mL), and the reaction was stirred at 20 °C for 3 h. The reaction was quenched with saturated aqueous Na2CO3 at 0 °C to pH 8-9 and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give (2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine (2.6 g, crude). ES-MS [M+1] + :254.2. [ka]

[0319] 9-Bromo-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Intermediate BQ): To a solution of 9-bromo-7-chloro-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (2.27 g) in DMF (30 mL) was added 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine (1.98 g) and KCO (1.14 g). The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent: 0-100% ethyl acetate / petroleum ether gradient at 100 mL / min) to give 9-bromo-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (750 mg). 1H NMR(400MHz,CDCl3)δ 8.22(d,J=6.4Hz,1H),6.79(d,J=8.8Hz,1H),6.60(d,J=6.0Hz,1H),6.51-6.44(m,2H),4.43-4.39(m,1H),4 .28-4.20(m,4H),3.64-3.54(m,2H),3.30-3.20(m,2H),2.56(s,3H),2.20-2.09(m,2H),2.04-1.93(m,2H).

[0320] b. Exemplary compounds of the present invention Example 1. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 1) [ka] A solution of 7-chloro-8-methyl-pyrimido[1,2-b]pyridazin-4-one (15 mg) in t-butanol (1 mL) was treated with N,N-diisopropylethylamine (67 μL) and 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine (28 mg) was added. The reaction mixture was heated to 120° C. for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 10–55% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid, 15 mg. 1H NMR(400MHz,DMSO)δ 8.11(d,J=6.3Hz,1H),7.74(q,J=1.2Hz,1H),6.76(d,J=8.8Hz,1H),6.54(d,J=2.8Hz,1H),6.49(dd,J=8.8,2.9Hz,1H),6.40(d,J=6.3Hz,1H) ),4.50(hept,J=3.8Hz,1H),3.64-3.46(m,2H),3.21-3.10(m,2H),2.42(d,J=1.2Hz,3H),2.10-2.01(m,2H),1.84-1.71(m,2H).ES-MS[M+1] + :399.

[0321] Example 2.7 (4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 2) [ka] To a solution of 7-chloro-8,9-dimethylpyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (17 mg) in t-butanol (1 mL) was added N,N-diisopropylethylamine (42 μL). The mixture was heated to 120 °C for 18 h. The solvent was removed, and the crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 25–60% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (11 mg; 53% yield). 1H NMR(400MHz,CDCl3)δ 8.15(d,J=6.3Hz,1H),6.78(d,J=8.7Hz,1H),6.55(d,J=6.3Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),4.38(hept,J=3.7Hz ,1H),3.61-3.46(m,2H),3.24-3.14(m,2H),2.53(d,J=0.5Hz,3H),2.37(d,J=0.5Hz,3H),2.19-2.09(m,2H),2.02-1.90(m,2H).ES-MS[M+1] + :413.

[0322] Example 3. 7-[4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 3) [ka] To a solution of 7-chloro-2,8-dimethylpyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (26 mg) was added N,N-diisopropylethylamine (62 μL). The mixture was heated to 120 °C for 18 h, then cooled to room temperature and concentrated. The crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 15–55% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (14 mg; 47% yield). 1H NMR(400MHz,CDCl3)δ 7.44(q,J=1.0Hz,1H),6.78(d,J=8.7Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),6.42(s,1H),4.39(hept,J=3.5Hz ,1H),3.66-3.55(m,2H),3.30-3.19(m,2H),2.43(d,J=1.2Hz,3H),2.39(s,3H),2.17-2.03(m,2H),2.03-1.89(m,2H).ES-MS[M+1] + :413.

[0323] Example 4. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 4) [ka] To a solution of 7-chloro-2,3,8-trimethylpyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (16 mg) in t-butanol (1 mL) was added N,N-diisopropylethylamine (40 μL). The mixture was heated to 120 °C for 18 h, then cooled to room temperature and concentrated. The crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 20–60% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (11 mg; 56% yield). 1H NMR(400MHz,CDCl3)δ 7.40(q,J=1.2Hz,1H),6.78(d,J=8.7Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.7,2.8Hz,1H),4.38(hept,J=3.6Hz,1H),3.65-3 .55(m,2H),3.29-3.18(m,2H),2.42(s,3H),2.40(d,J=1.2Hz,3H),2.23(s,3H),2.18-2.07(m,2H),2.01-1.88(m,2H).ES-MS[M+1] + :427.

[0324] Example 5. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 5) [ka] To a solution of 7-chloro-2,8,9-trimethyl-pyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (16 mg) in t-butanol (1 mL) was added N,N-diisopropylethylamine (40 μL). The mixture was heated to 120 °C for 18 h. Additional N,N-diisopropylethylamine (40 μL) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (16 mg) were added, and the reaction was stirred at 120 °C for an additional 18 h. The solvent was removed, and the crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 30–70% ACN / 0.05% aqueous NH OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (12 mg; 61% yield). 1H NMR(400MHz,CDCl3)δ 6.78(d,J=8.7Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),6.42(s,1H),4.37(hept,J=3.7Hz,1H),3.59-3 .47(m,2H),3.22-3.12(m,2H),2.53(s,3H),2.42(s,3H),2.35(s,3H),2.18-2.08(m,2H),2.01-1.88(m,2H).ES-MS[M+1] + :427.

[0325] Example 6. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 6) [ka] To a solution of 7-chloro-8-methyl-2-(trifluoromethyl)pyrimido[1,2-b]pyridazin-4-one (13 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (18 mg) in t-butanol (1 mL) was added N,N-diisopropylethylamine (43 μL). The mixture was heated to 120 °C for 18 h and then concentrated. The crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 25–65% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (12 mg; 54% yield). 1H NMR(400MHz,CDCl3)δ 7.62(q,J=1.1Hz,1H),6.88(s,1H),6.78(d,J=8.7Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),4.42(hept,J ES-MS[M+1] + :467.

[0326] Example 7. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 7) [ka] To a solution of 7-chloro-8,9-dimethyl-2-(trifluoromethyl)pyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (13 mg) in t-butanol (1 mL) was added N,N-diisopropylethylamine (32 μL). The mixture was heated to 120 °C for 18 h. The solvent was removed, and the crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC column (30 × 100 mm column, 25–65% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (15.5 mg; 90% yield). 1H NMR(400MHz,CDCl3)δ 6.92(s,1H),6.79(d,J=8.7Hz,1H),6.50(d,J=2.8Hz,1H),6.46(dd,J=8.8,2.9Hz,1H),4.39(hept,J=3.6Hz,1H),3.51-3.3 7(m,2H),3.14-3.03(m,2H),2.48(d,J=0.6Hz,3H),2.34(d,J=0.6Hz,3H),2.15-2.03(m,2H),2.01-1.88(m,2H).ES-MS[M+1] + :481.

[0327] Example 8. 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 8) [ka] To a solution of 7-chloro-2-(difluoromethyl)-8-methyl-pyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (15 mg) in t-butanol (1 mL) was added N,N-diisopropylethylamine (36 μL). The mixture was heated to 120 °C for 18 h. The solvent was removed, and the crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 20–60% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (13 mg; 70% yield). 1H NMR(400MHz,CDCl3)δ 7.56(q,J=1.2Hz,1H),6.80(d,J=8.8Hz,1H),6.78(d,J=8.7Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.8,2.8Hz,1H),6.44(t,J=55.0Hz,1 H),4.41(hept,J=3.5Hz,1H),3.69-3.58(m,2H),3.35-3.24(m,2H),2.47(d,J=1.2Hz,3H),2.18-2.07(m,2H),2.04-1.91(m,2H).ES-MS[M+1] + :449.

[0328] Example 9. 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 9) [ka] To a solution of 7-chloro-2-(difluoromethyl)-8,9-dimethylpyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (14 mg) in t-butanol (1 mL) was added N,N-diisopropylethylamine (34 μL). The mixture was heated to 120 °C for 18 h. The solvent was removed, and the crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 30–70% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (14 mg; 76% yield). 1H NMR(400MHz,CDCl3)δ 6.82(s,1H),6.78(d,J=8.7Hz,1H),6.53(t,J=55.0Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),4.39(hept,J= 3.5Hz,1H),3.62-3.52(m,2H),3.32-3.13(m,2H),2.54(s,3H),2.38(s,3H),2.21-2.08(m,2H),2.05-1.90(m,2H).ES-MS[M+1] + :463.

[0329] Example 10. 2-Cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 10) [ka] To a solution of 7-chloro-2-cyclopropyl-8-methylpyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (15 mg) in t-butanol (1 mL) was added N,N-diisopropylethylamine (37 μL). The mixture was heated to 120 °C for 18 h. The solvent was removed, and the crude product was dissolved in DMSO (2 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 25–65% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (8.4 mg; 45% yield). 1H NMR(400MHz,CDCl3)δ 7.39(q,J=1.2Hz,1H),6.78(d,J=8.7Hz,1H),6.49(d,J=2.8Hz,1H),6.45(d d,J=8.7,2.9Hz,1H),6.41(s,1H),4.37(hept,J=3.7Hz,1H),3.64-3.53(m,2 H),3.27-3.17(m,2H),2.40(d,J=1.2Hz,3H),2.17-2.05(m,2H),2.03-1.91( m,2H),1.90-1.82(m,1H),1.13-1.04(m,2H),1.03-0.95(m,2H).ES-MS[M+1] + :439.

[0330] Example 11. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 11) [ka] To a solution of 7-chloro-2-ethyl-8,9-dimethylpyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)piperidine (28 mg) in t-butanol (0.5 mL) was added N,N-diisopropylethylamine (55 μL). The mixture was heated to 120 °C for 18 h. The solvent was removed, and the crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 30–75% ACN / 0.1% aqueous TFA, 8 min run). The product-containing fractions were basified with saturated NaHCO3 and then extracted with 4:1 chloroform / IPA. The organic extract was passed through a phase separator and concentrated to give the title compound as a solid (11 mg; 41% yield). 1H NMR(400MHz,CDCl3)δ 6.77(d,J=8.7Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,1H),6.44(s,1H),4 .36(hept,J=3.7Hz,1H),4.27-4.23(m,2H),4.23-4.19(m,2H),3.59-3.48 (m,2H),3.22-3.11(m,2H),2.67(q,J=7.5Hz,2H),2.52(s,3H),2.35(s,3H) ),2.21-2.08(m,2H),2.05-1.87(m,2H),1.29(t,J=7.6Hz,3H).ES-MS[M+1] + :437.

[0331] Example 12. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 12) [ka] To a solution of 7-chloro-2-isopropyl-8,9-dimethyl-pyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)piperidine (28 mg) in t-butanol (0.5 mL) was added N,N-diisopropylethylamine (52 μL). The mixture was heated to 120 °C for 18 h. The solvent was removed, and the crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 20–65% ACN / 0.1% aqueous TFA, 8 min run). The product-containing fractions were basified with saturated NaHCO3 and then extracted with 4:1 chloroform / IPA. The organic extract was passed through a phase separator and concentrated to give the title compound as a solid (21 mg; 79% yield). 1H NMR(400MHz,CDCl3)δ 6.79(d,J=8.7Hz,1H),6.50(d,J=2.8Hz,1H),6.46(dd,1H),6.45(s,1H),4.3 9(tt,J=7.1,3.6Hz,1H),4.28-4.24(m,2H),4.23-4.20(m,2H),3.66(hept,J =6.9Hz,1H),3.43-3.32(m,2H),3.10-2.97(m,2H),2.49(s,3H),2.32(s,3H) ,2.24-2.06(m,2H),2.04-1.90(m,2H),1.31(s,3H),1.29(s,3H).ES-MS[M+1] + :451.

[0332] Example 13. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 13) [ka] To a solution of 7-chloro-2-(methoxymethyl)-8,9-dimethylpyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)piperidine (28 mg) in t-butanol (0.5 mL) was added N,N-diisopropylethylamine (52 μL). The mixture was heated to 120 °C for 18 h. The solvent was removed, and the crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 25–65% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (20 mg; 75% yield). 1H NMR(400MHz,CDCl3)δ 6.78(d,J=8.7Hz,1H),6.69(s,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),4.43(s,2H),4.37(hept,J=3.8Hz,1H),4.29-4.23(m,2H), 4.23-4.19(m,2H),3.62-3.51(m,2H),3.50(s,3H),3.23-3.12(m,2H),2. 50(s,3H),2.35(s,3H),2.24-2.07(m,2H),2.02-1.89(m,2H).ES-MS[M+1] + :453.

[0333] Example 14. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 14) [ka] To a solution of 7-chloro-2-(methoxymethyl)-8-methylpyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (30 mg) in NMP (1 mL) was added N,N-diisopropylethylamine (55 μL). The mixture was heated to 180 °C for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 20–65% ACN / 0.1% aqueous TFA, 10 min run). The product-containing fractions were made basic with saturated NaHCO3 and extracted with 3:1 chloroform / IPA. The organic extract was passed through a phase separator and concentrated to give the title compound as a solid (18 mg; 66% yield). 1H NMR(400MHz,CDCl3)δ 7.48(q,J=1.2Hz,1H),6.78(d,J=8.7Hz,1H),6.66(t,J=0.9Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),4.40(d,J=0.9Hz,2H),4.3 9(hept,J=3.7Hz,1H),3.66-3.56(m,2H),3.49(s,3H),3.31-3.20(m,2H) ,2.43(d,J=1.2Hz,3H),2.18-2.05(m,2H),2.02-1.89(m,2H).ES-MS[M+1] + :443.

[0334] Example 15. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 15) [ka] To a solution of 7-chloro-3-fluoro-2,8-dimethylpyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (16 mg) in t-butanol (0.5 mL) was added N,N-diisopropylethylamine (38 μL). The mixture was heated to 120 °C for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography using a Gilson HPLC (30 × 100 mm column, 25–60% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (10 mg; 54% yield). 1H NMR(400MHz,CDCl3)δ 7.38(q,J=1.2Hz,1H),6.72(d,J=8.7Hz,1H),6.43(d,J=2.8Hz,1H),6.39(dd,J=8.7,2.9Hz,1H),4.34(hept,J=3.6Hz,1H),3.56(ddd,J=12. 0,7.6,3.5Hz,2H),3.21(ddd,J=12.5,7.8,3.4Hz,2H),2.40(d,J=3.5Hz,3H),2.36(s,3H),2.11-2.02(m,2H),1.97-1.78(m,2H).ES-MS[M+1] + :431.

[0335] Example 16. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-fluoro-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 16) [ka] To a solution of 7-chloro-3-fluoro-2,8,9-trimethylpyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (15 mg) in t-butanol (0.5 mL) was added N,N-diisopropylethylamine (36 μL). The mixture was heated to 120 °C for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography using a Gilson HPLC (30 × 100 mm column, 20–70% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (12 mg; 65% yield). 1H NMR(400MHz,MeOD)δ 6.73(d,J=8.8Hz,1H),6.51(d,J=2.7Hz,1H),6.48(dd,J=8.7,2.8Hz,1H),4.45(dt,J=7.6,3.9Hz,1H),3.56(ddd,J=11.7,7.2,3.5Hz,2H),3. 21(ddd,J=12.5,8.2,3.3Hz,2H),2.56(d,J=0.6Hz,3H),2.50(d,J=3.5Hz,3H),2.41(s,3H),2.25-2.08(m,2H),1.99-1.82(m,2H).ES-MS[M+1] + :445.

[0336] Example 17. 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 17) [ka] To a solution of 3,7-dichloro-2,8-dimethylpyrimido[1,2-b]pyridazin-4-one (10 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (15 mg) in tert-butanol (0.5 mL) was added N,N-diisopropylethylamine (36 μL). The mixture was heated to 120 °C for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 25–65% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (12.9 mg; 71% yield). 1H NMR(400MHz,CDCl3)δ 7.47(d,J=0.6Hz,1H),6.78(d,J=8.7Hz,1H),6.49(d,J=2.8Hz,1H),6.45(dd,J=8.8,2.9Hz,1H),4.40(hept,J=3.6Hz,1H), 3.74-3.57(m,2H),3.33-3.22(m,2H),2.56(s,3H),2.44(d,J=1.2Hz,3H),2.18-2.07(m,2H),2.02-1.89(m,2H).ES-MS[M+1] + :447.

[0337] Example 18. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-(methoxymethyl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 18) [ka] To a solution of 7-chloro-8-(methoxymethyl)-9-methylpyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (30 mg) in tert-butanol (1 mL) was added N,N-diisopropylethylamine (55 μL). The mixture was heated to 120 °C for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 20–65% ACN / 0.1% aqueous TFA, 8 min run). The product-containing fractions were made basic with saturated NaHCO3 and extracted with 4:1 chloroform / IPA. The organic extract was passed through a phase separator and concentrated to give the title compound as a solid (11.4 mg; 41% yield). 1H NMR(400MHz,CDCl3)δ 8.15(d,J=6.3Hz,1H),6.78(d,J=8.7Hz,1H),6.58(d,J=6.3Hz,1H),6.49(d,J=2.8Hz ,1H),6.45(dd,J=8.7,2.9Hz,1H),4.42(s,2H),4.37(hept,J=3.7Hz,1H),3.67(ddd, J=11.3,6.9,3.6Hz,2H),3.48(s,3H),3.25(ddd,J=12.6,8.5,3.2Hz,2H),2.60(s,3H) ),2.16(ddt,J=13.4,6.9,3.5Hz,2H),1.95(dtd,J=12.4,8.0,3.5Hz,2H).ES-MS[M+1] + :443.

[0338] Example 19. 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 19) [ka] To a solution of 7-chloro-9-(methoxymethyl)-8-methylpyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (30 mg) in tert-butanol (1 mL) was added N,N-diisopropylethylamine (55 μL). The mixture was heated to 120 °C for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 15–55% ACN / 0.1% aqueous TFA, 8 min run). The product-containing fractions were made basic with saturated NaHCO3 and extracted with 4:1 chloroform / IPA. The organic extract was passed through a phase separator and concentrated to give the title compound as a solid (6 mg; 22% yield). 1H NMR (400 MHz, CDCl3) δ 8.14(d,J=6.3Hz,1H),6.78(d,J=8.7Hz,1H),6.54(d,J=6.3Hz,1H),6.49(d,J=2 .8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),4.91(s,2H),4.38(hept,J=3.7Hz,1H),3. 58(ddd,J=11.8,7.4,3.5Hz,2H),3.48(s,3H),3.22(ddd,J=12.4,8.0,3.3Hz,2H) ,2.48(s,3H),2.18-2.08(m,2H),1.96(dtd,J=11.2,7.6,3.4Hz,2H).ES-MS[M+1] + :443.

[0339] Example 20. 9-Cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 20) [ka] To a solution of 7-chloro-9-cyclopropyl-8-methylpyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)piperidine (43 mg) in tert-butanol (0.5 mL) was added N,N-diisopropylethylamine (55 μL). The mixture was heated to 120 °C for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 20–60% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (16 mg; 57% yield). 1H NMR (400 MHz, CDCl3) δ 8.14(d,J=6.3Hz,1H),6.78(d,J=8.7Hz,1H),6.52(d,J=6.3Hz,1H),6.49(d,J=2 .8Hz,1H),6.45(dd,J=8.7,2.9Hz,1H),4.37(tt,J=3.8Hz,1H),4.27-4.24(m,2H ),4.24-4.18(m,2H),3.63-3.51(m,2H),3.29-3.10(m,2H),2.50(s,3H),2.18-2 .07(m,2H),2.01-1.87(m,3H),1.34-1.18(m,2H),1.14-1.07(m,2H).ES-MS[M+1] + :435.

[0340] Example 21. 8-Cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 21) [ka] To a solution of 7-chloro-8-cyclopropyl-9-methylpyrimido[1,2-b]pyridazin-4-one (15 mg) and 4-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)oxy]piperidine (30 mg) in tert-butanol (0.5 mL) was added N,N-diisopropylethylamine (55 μL). The mixture was heated to 120 °C for 18 h. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase chromatography on a Gilson HPLC (30 × 100 mm column, 25–65% ACN / 0.05% aqueous NH4OH, 8 min run). The product-containing fractions were concentrated to give the title compound as a solid (1.8 mg; 7% yield). 1H NMR(400MHz,CDCl3)δ 8.13(d,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),6.53(d,J=8.0Hz,1H),6.49( d,J=4.0Hz,1H),6.45(dd,J=8.0,4.0Hz,1H),4.38-4.35(m,1H),3.85-3.7 9(m,2H),3.40-3.31(m,2H),2.66(s,3H),2.20-2.12(m,2H),2.01-1.93(m ,2H),1.88-1.84(m,1H),1.30-1.17(m,2H),0.81-0.73(m,2H).ES-MS[M+1] + :435.

[0341] Example 22. 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 108) [ka] in NMP (1 mL) 2R, 4S To a solution of 7-chloro-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (43 mg) and DIEA (156 mg) were added. The mixture was subjected to microwave irradiation at 180° C. for 2 hours. The reaction mixture was diluted with EtOAc (10 mL) and extracted with H2O (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by basic preparative HPLC to give 7-(( 2R, 4S )-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (16 mg) was obtained. 1H NMR(400MHz,CDCl3)δ 8.11(d,J=6.4Hz,1H),7.51(s,1H),6.78(d,J=8.8Hz,1H),6.54(d,J=6.4Hz ,1H),6.51-6.42(m,2H),4.62-4.47(m,1H),4.29-4.20(m,4H),4.19-4.11( m,1H),3.62-3.56(m,1H),3.40-3.33(m,1H),2.45(s,3H),2.18-2.15(m,1H ),2.07-1.99(m,2H),1.95-1.82(m,1H),1.27(d,J=6.4Hz,3H);ES-MS[M+1] + :409.1.

[0342] Example 23. 7-[4-[(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-9-methoxy-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 126) [ka] To a solution of 9-bromo-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (300 mg) in MeOH (5 mL) was added NaOMe (137 mg) and the resulting mixture was stirred at 60 °C for 6 h. To the reaction was added HO (5 mL) and extracted with EtOAc (5 mL × 5). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude compound was purified by preparative thin-layer chromatography (SiO, ethyl acetate:petroleum ether=1:0) to give 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-9-methoxy-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (55 mg). 1H NMR(400MHz,CDCl3)δ 8.15(d,J=6.4Hz,1H),6.79(d,J=8.4Hz,1H),6.57(d,J=6.4Hz,1H),6.50 (d,J=2.4Hz,1H),6.46(dd,J=2.8,8.8Hz,1H),4.41-3.36(m,1H),4.28-4 .25(m,2H),4.24-4.21(m,2H),4.18(s,3H),3.64-3.55(m,2H),3.27-3.1 8(m,2H),2.33(s,3H),2.18-2.09(m,2H),2.01-1.91(m,2H).ES-MS[M+1] + :425.2.

[0343] Example 24. 9-(Azetidin-1-yl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 127) [ka] A mixture of 9-bromo-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (200 mg), azetidine hydrochloride (198 mg), CsCO (1.1 g), BrettPhos Pd G3 (77 mg), and BRETTPHOS (45 mg) in toluene (5 mL) was degassed and purged with N three times, then stirred at 100 °C under N for 16 h. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, eluting with a 0–100% ethyl acetate / petroleum ether gradient at 30 mL / min) to give the crude product. The crude product was purified by recrystallization from EtOAc (3 mL) at 80° C. Further recrystallization with DCM (5 mL) and EtOAc (15 mL) gave 9-(azetidin-1-yl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (50 mg). 1 H NMR(400MHz,CDCl3)δ 7.98(d,J=6.0Hz,1H),6.78(d,J=8.8Hz,1H),6.50-6.44(m,3H),4.68(t,J=8.0Hz,4H),4.39-4.29(m,1H),4.28-4.24(m,2H),4.24-4 .18(m,2H),3.62-3.52(m,2H),3.21-3.12(m,2H),2.40-2.32(m,2H),2.20(s,3H),2.15-2.06(m,2H),1.96-1.85(m,2H).ES-MS[M+1] + :450.0.

[0344] Example 25. 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (Compound 129) [ka] A solution of 7-chloro-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (2 g), (2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine (2.59 g), and CsF (1.86 g) in DMSO (20 mL) was stirred at 80 °C for 2 h. The mixture was diluted with HO (20 mL) and extracted with EtOAc (40 mL × 5). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated. The residue was purified by Combi Flash (silica gel, 0-100% ethyl acetate in petroleum ether) followed by preparative HPLC (instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; column: Xtimate C18 Column temperature: 30°C; wavelength: 220 nm, 254 nm) to give 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (1.4 g). 1 H NMR(400MHz,CDCl3)δ 8.10(d,J=6.4Hz,1H),7.50(d,J=1.2Hz,1H),6.77(d,J=8.8Hz,1H),6.53(d,J=6. 4Hz,1H),6.48(d,J=2.8Hz,1H),6.44(d,J=8.8Hz,2.8Hz,1H),4.56-4.48(m,1H), 4.18-4.11(m,1H),3.61-3.55(m,1H),3.39-3.32(m,1H),2.44(s,3H),2.21-2.12 (m,1H),2.07-1.97(m,2H),1.93-1.84(m,1H),1.27(d,J=6.8Hz,3H).ES-MS[M+1] + :413.0.SFC:tR =3.62 min, ee=99.8%, [α] 20 D =+104.0 (c=1.2 g / 100 mL, DCM). SFC Method: Instrument: Waters UPCC with PAD detector; Column: Chiralcel OJ-3 100 x 4.6 mm ID, 3 μm; Mobile Phase: A: CO2 B: Ethanol (0.05% DEA); Gradient: 5% to 40% B in 4 min, then hold at 40% for 2.5 min, then hold at 5% B for 1.5 min; Flow Rate: 2.8 mL / min; Column Temperature: 35 °C; ABPR: 1500 psi; Run Time: 8 min; Wavelength: 220 nm.

[0345] In a similar manner, using the appropriate starting materials, the compounds shown in Table 1 were prepared.

[0346] [Table 1-1]

[0347] [Table 1-2]

[0348] [Table 1-3]

[0349] [Table 1-4]

[0350] [Table 1-5]

[0351] [Table 1-6]

[0352] [Table 1-7]

[0353] Table 1-8

[0354] Table 1-9

[0355] Table 1-10

[0356] Table 1-11

[0357] Table 1-12

[0358] Table 1-13

[0359] Table 1-14

[0360] Table 1-15

[0361] Table 1-16

[0362] Table 1-17

[0363] Table 1-18

[0364] Table 1-19

[0365] Table 1-20

[0366] Table 1-21

[0367] Table 1-22

[0368] Table 1-23

[0369] Table 1-24

[0370] Table 1-25

[0371] Table 1-26

[0372] Table 1-27

[0373] [Table 1-28]

[0374] [Table 1-29]

[0375] [Table 1-30]

[0376] [Table 1-31]

[0377] [Table 1-32]

[0378] c. Biological activity A. Cell lines expressing muscarinic acetylcholine receptors Human and rat M4 cDNAs were cloned into the chimeric G protein G qi5 Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection were transfected with hM4-G using Lipofectamine 2000. qi5 Cells were grown in Ham's F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, 50 μg / mL G418 sulfate, and 500 μg / mL hygromycin B. rM4-G qi5 Cells were grown in DMEM containing 10% heat-inactivated FBS, 20 mM HEPES, 400 μg / mL G418 sulfate, and 500 μg / mL hygromycin B.

[0379] B. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor Activity For high-throughput measurements of agonist-induced increases in intracellular calcium, CHO-K1 cells stably expressing muscarinic receptors were plated at 15,000 cells / 20 μL / well in Greiner 384-well black-walled tissue culture (TC)-treated clear-bottom plates (VWR) in growth medium lacking G418 and hygromycin. Cells were incubated overnight at 37°C and 5% CO2. The following day, cells were washed with assay buffer using an ELX405 (BioTek) and then the final volume was aspirated to 20 μL. Next, 20 μL of a 2.3 μM stock of Fluo-4 / acetoxymethyl ester (Invitrogen, Carlsbad, CA), prepared as a 2.3 mM stock in DMSO, mixed 1:1 with 10% (w / v) Pluronic F-127, and diluted in assay buffer, was added to the wells, and the cell plates were incubated at 37°C and 5% CO2 for 50 minutes. The dye was removed by washing with ELX405, and the final volume was aspirated to 20 μL. A compound master plate was formatted in 11-point concentration-response curve (CRC) format (1:3 dilution) in 100% DMSO with a starting concentration of 10 mM using a BRAVO liquid handler (Agilent). Test compound CRCs were then transferred to a daughter plate (240 nL) using an Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA) and then diluted into assay buffer (40 μL) to a 2× stock using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA).

[0380] Calcium influx was measured as an increase in static fluorescence ratio using a Functional Drug Screening System (FDSS) 6000 or 7000 (Hamamatsu Corporation, Tokyo, Japan). Compounds were applied to cells (20 μL, 2×) for 2–4 seconds of the protocol using the FDSS automated system, and data were collected at 1 Hz. The EC50 of 10 μL was measured at 144 seconds. 20 The muscarinic receptor agonist acetylcholine was added at a concentration of 5×, followed by 12 μL of EC50 at 230 s. 80 A concentration of acetylcholine was added (5x). Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Positive allosteric modulator activity was assessed by EC 20 Antagonist activity was analyzed as a concentration-dependent increase in the acetylcholine response. 80 A concentration-dependent decrease in the acetylcholine response was analyzed. Concentration-response curves were generated using a four-parameter logistic equation in XLFit curve-fitting software (IDBS, Bridgewater, NJ) for Excel (Microsoft, Redmond, WA) or Prism (GraphPad Software, Inc., San Diego, CA).

[0381] The above assay was also operated in a second mode in which, after establishing a fluorescence baseline, an appropriate fixed concentration of a compound of the present invention was added to the cells for approximately 3 seconds, and the response in the cells was measured. After 140 seconds, an appropriate concentration of agonist was added, and the calcium response (maximum-minimal response) was measured. The EC of the agonist in the presence of the test compound was 50 Values ​​were determined by non-linear curve fitting. EC 50 A decrease in the EC value (a shift to the left of the agonist concentration-response curve) is indicative of the degree of muscarinic positive allosteric modulation at a given concentration of the compound of the invention. 50An increase in value (a shift to the right of the agonist concentration-response curve) is indicative of the degree of muscarinic antagonism at a given concentration of a compound of the invention. The second mode also indicates whether a compound of the invention affects the maximum response of a muscarinic receptor to an agonist.

[0382] d. Activity of compounds in the mAChR M4 cell-based assay The compounds were synthesized as previously described. 50 and E max ) was determined in the mAChR M4 cell-based functional assay as described above, and the data are shown in Table 2. Compound numbers correspond to the compound numbers used in Examples 1-11 and Table 1.

[0383] [Table 2-1]

[0384] [Table 2-2]

[0385] [Table 2-3]

[0386] [Table 2-4]

[0387] It will be understood that the foregoing detailed description and accompanying examples are merely illustrative and should not be construed as limiting the scope of the invention, which is defined solely by the appended claims and equivalents thereof.

[0388] 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, with respect to the chemical structure, substituents, derivatives, intermediates, compounds, compositions, formulations, or methods of use of the invention, can be made without departing from the spirit and scope thereof. The present invention may include the following aspects. [1] Formula (I) [ka] (In the formula, X is CR 5a Or N; R 1 is hydrogen, C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, C 1 ~C 4 -hydroxyalkyl, C 3 ~C 6 -cycloalkyl, -L 1 -C 3 ~C 6 -cycloalkyl, halo, -L 1 OR a and OR a Selected from; R 2 is hydrogen, C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, C 3 ~C 6 -cycloalkyl, halo, -L 2 OR b , OR b , NHR b , and N(R b ) 2 Selected from; R 3 is C1 ~C 4 -Alkyl, hydrogen, C 1 ~C 4 -haloalkyl, C 3 ~C 6 -cycloalkyl, halo, -L 3 OR c , and OR c Selected from; Each R 4 is C 1 ~C 4 -Alkyl, OR d 、-L 4 OR d and halo; m is 2, 0, or 1; The Two R's 5 together with the carbon atom to which they are attached form a 5-8 membered fused monocyclic heterocycle containing two or one heteroatom independently selected from O, N, and S, and the fused monocyclic heterocycle is 6 or Each R 5 is C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, OR e 、-L 5 OR e , 5- or 6-membered heteroaryl, phenyl, C 3 ~C 6 -independently selected from cycloalkyl, and halo; R 5a is hydrogen, C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, C 3 ~C 6 -cycloalkyl, OR e 、-L 5 OR e and halo; Each R 5b is C 1 ~C 2 -Alkyl, C 1 ~C 2 -fluoroalkyl, C 3 ~C 4 -cycloalkyl, -OC 1 ~C2 -Alkyl, -OC 1 ~C 2 -independently selected from fluoroalkyl, cyano, and halo; Each R 6 is oxo, C 1 ~C 4 -Alkyl, OR f 、-L 6 OR f and halo; R 7 is hydrogen, C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, C 3 ~C 6 -cycloalkyl, halo, -L 2 OR b , OR b , NHR b , and N(R b ) 2 Selected from; o is 0, 1 or 2; n is 0, 1 or 2; L 1 、L 2 、L 3 、L 4 、L 5 , and L 6 are each independently generated by C 1 ~C 3 - alkylene; R a 、R b 、R c 、R d 、R e , and R f are each independently generated by C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, and C 3 ~C 6 -cycloalkyl, wherein two R b together with the nitrogen atom to which they are attached, optionally form a 4- to 7-membered monocyclic heterocyclyl, said heterocyclyl being selected from the group consisting of halo, C 1 ~C 4 -alkyl, and C 1 ~C 4 -haloalkyl) or a pharmaceutically acceptable salt thereof. [2] Formula (IA)

change

change

change

change

change

change

change

[10] 10. The compound according to any one of claims 1 to 9, wherein n is 0, or a pharmaceutically acceptable salt thereof.

[11] Each R 5 or R 5c But hydrogen, C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, OR e 、-L 5 OR e , 5- or 6-membered heteroaryl, phenyl, C 3 ~C 6 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: - is independently selected from: -cycloalkyl, and -halo.

[12] Each R 5 or R 5c But hydrogen, C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, OR e 、-L 5 OR e 12. The compound of claim 1, 2, or 11, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from:

[13] Formula (IB)

change

change

[14] G 1 but,

change

[15] G 1 but,

change

[16] R 3 But C 1 ~C 4 -Alkyl, hydrogen, C 3 ~C 6 -cycloalkyl, or -L 3 OR c 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein:

[17] R 3 But C 1 ~C 4 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein:

[18] R 3 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[19] R 1 But hydrogen, C 1 ~C 4 -Alkyl, C 1 ~C 4 -haloalkyl, C 3 ~C 6 -cycloalkyl, -L 1 -C 3 ~C 6 -cycloalkyl, or -L 1 OR a 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:

[20] R 1 But C 1 ~C 4 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein:

[21] R 1 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[22] R 1 But C 1 ~C 4 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein:

[23] R 1 23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl.

[24] R 1 23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein is difluoromethyl.

[25] R 2 But hydrogen, C 1 ~C 4 -Alkyl, C 3 ~C 6 -cycloalkyl, -L 2 OR b , OR b , NHR b , and N(R b ) 2 25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, selected from:

[26] R 2 But C 1 ~C 4 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein:

[27] R 2 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[28] R 2 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[29] R 4 But C 1 ~C 4 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein - is alkyl or halo.

[30] 30. The compound according to any one of claims 1 to 29, wherein o is 0, or a pharmaceutically acceptable salt thereof.

[31] 30. The compound according to any one of claims 1 to 29, wherein o is 1, or a pharmaceutically acceptable salt thereof.

[32] R7 But hydrogen, C 1 ~C 4 -Alkyl, C 3 ~C 6 -cycloalkyl, halo, and N(R b ) 2 32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, selected from:

[33] R 7 33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, methyl, cyclopropyl, fluoro, chloro, and azetidin-1-yl.

[34] R 7 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[35] 35. The compound according to claim 1, wherein X is N, or a pharmaceutically acceptable salt thereof.

[36] X is CR 5a 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein:

[37] R 5a 37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[38] below: 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-fluorophenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-8-methyl-7-(4-((8-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-((8-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-fluoro-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-(azetidin-1-yl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-(benzo[d][1,3]dioxol-5-yloxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-3-fluoro-4-(isochroman-6-yloxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzofuran-5-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-(chroman-7-yloxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-2-(difluoromethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-methoxy-5-methylpyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-(methoxymethyl)pyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-(p-tolyloxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-chlorophenoxy)piperidin-1-yl)-2-(difluoromethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-8,9-dimethyl-7-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-fluorophenoxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-7-(4-(4-fluorophenoxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(Difluoromethyl)-8,9-dimethyl-7-(4-(p-tolyloxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(3-fluoro-4-methylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-ethylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-isopropylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-(4-propylphenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-(p-tolyloxy)piperidin-1-yl-4-d)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-(methoxymethyl)-5-methylpyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(cyclopentylmethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-(methoxymethyl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-(methoxymethyl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-9-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-9-(methylamino)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-9-methoxy-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-(azetidin-1-yl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-2,2,6,6-d4)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one 2. The compound of claim 1, selected from the group consisting of:

[39] 39. A pharmaceutical composition comprising the compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[40] 40. A method for treating a neurological and / or psychiatric disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[41] 41. The method of claim 40, wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, borderline personality disorder, Tourette's syndrome, bipolar disorder, tardive dyskinesia, Huntington's disease, a pain disorder, and a cognitive disorder.

[42] 41. The method of claim 40, wherein the disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, autistic disorder, movement disorder, Tourette's syndrome, akinetic rigidity syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[43] 43. The method according to any one of claims 40 to 42, wherein the disorder is associated with muscarinic acetylcholine receptor M4 dysfunction.

[44] 39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in therapy.

[45] 40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in the treatment of a disorder selected from Alzheimer's disease, schizophrenia, a sleep disorder, borderline personality disorder, Tourette's syndrome, bipolar disorder, tardive dyskinesia, Huntington's disease, a pain disorder, and a cognitive disorder.

[46] 40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a disorder selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, autistic disorder, movement disorder, Tourette's syndrome, akinetic rigidity syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[47] Use of the compound or pharmaceutical composition according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder selected from Alzheimer's disease, schizophrenia, borderline personality disorder, Tourette's syndrome, bipolar disorder, tardive dyskinesia, Huntington's disease, a sleep disorder, a pain disorder, and a cognitive disorder.

[48] 40. Use of the compound or pharmaceutical composition according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, autistic disorder, movement disorders, Tourette's syndrome, akinetic rigidity syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, X is CR ５ａ or N; R １ is hydrogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, C ３ ~C ６ -cycloalkyl, -L １ -C ３ ~C ６ -cycloalkyl, and -L １ OR ａ Selected from: R ２ is hydrogen, C １ ~C ４ -Alkyl, C ３ ~C ６ -cycloalkyl, -L ２ OR ｂ , OR ｂ , N.H.R. ｂ , and N(R ｂ ) ２ Selected from: R ３ is C １ ~C ４ - alkyl, hydrogen, C ３ ~C ６ -cycloalkyl, and -L ３ OR ｃ Selected from: Each R ４ is C １ ~C ４ - independently selected from alkyl, and halo; m is 2 or 1; Two R's ５ together with the carbon atoms to which they are attached form a 5-8 membered fused monocyclic heterocycle containing two or one heteroatom independently selected from O and N, said fused monocyclic heterocycle being bound to one or more of 1 to 4 R ６ or Each R ５ is C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, OR ｅ , -L ５ OR ｅ and halo; R ５ａ is hydrogen, C １ ~C ４ - selected from alkyl, and halo; Each R ５ｂ is C １ ~C ２ -Alkyl, C １ ~C ２ -fluoroalkyl, -OC １ ~C ２ - independently selected from alkyl, and halo; Each R ６ is oxo and C １ ~C ４ - independently selected from alkyl; R ７ is hydrogen, C １ ~C ４ -Alkyl, C ３ ~C ６ -cycloalkyl, halo, and N(R ｂ ) ２ Selected from: o is 0 or 1; n is 0, 1 or 2; L １ , L ２ , L ３ , and L ５ is, for each occurrence, independently of each other, C １ ~C ３ - alkylene; R ａ , R ｂ , R ｃ , and R ｅ is, for each occurrence, independently of each other, C １ ~C ４ -alkyl, where two R ｂ together with the nitrogen atom to which they are attached optionally form a 4- to 7-membered monocyclic heterocyclyl, said heterocyclyl being selected from the group consisting of halo, C １ ~C ４ - alkyl, and C １ ~C ４ -haloalkyl) or a pharmaceutically acceptable salt thereof.

2. Formula (IA) 【Chemistry 2】 (In the formula, Two R's ５ｃ together with the carbon atoms to which they are attached form a 5-8 membered fused monocyclic heterocycle containing two or one heteroatom independently selected from O and N, said fused monocyclic heterocycle being bound to one or more of 1 to 4 R ６ or Each R ５ｃ is hydrogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, OR ｅ , -L ５ OR ｅ and halo) 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. Two R's ５ or R ５ｃ and R 1 and R 2 together with the carbon atoms to which they are attached form a fused 5- to 8-membered monocyclic heterocycle, or a pharmaceutically acceptable salt thereof.

4. R ５ or R ５ｃ and the 5- to 8-membered fused monocyclic heterocycle formed together contains two or one heteroatom independently selected from O and N, and one to two R ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, optionally substituted by:

5. Formula (IB) 【Transformation 3】 (In the formula, G １ teeth, 【Chemistry 4】 and each q is independently 0, 1, 2, 3, or 4 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. G １ but, 【Transformation 5】 and R ５ａ But hydrogen, C １ ~C ４ - alkyl, or halo, or a pharmaceutically acceptable salt thereof.

7. G １ but, 【Transformation 6】 7. The compound of claim 6, wherein:

8. Formula (Ia) 【Transformation 7】 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

9. Formula (Ib) 【Transformation 8】 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1 to 9, wherein n is 0, or a pharmaceutically acceptable salt thereof.

11. Each R ５ or R ５ｃ But hydrogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, OR ｅ , -L ５ OR ｅ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

12. Formula (IB) 【Chemistry 9】 (In the formula, G １ teeth, 【Chemistry 10】 is) 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof.

13. G １ but, 【Chemistry 11】 13. The compound of claim 12, wherein:

14. G １ but, 【Chemistry 12】 14. The compound of claim 13, wherein:

15. R ３ But C １ ~C ４ - alkyl, or a pharmaceutically acceptable salt thereof.

16. R ３ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein is methyl.

17. R １ But hydrogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, C ３ ~C ６ -cycloalkyl, -L １ -C ３ ~C ６ -cycloalkyl, or -L １ OR ａ 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein:

18. R １ But C １ ~C ４ - alkyl, or a pharmaceutically acceptable salt thereof.

19. R １ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

20. R １ But C １ ~C ４ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein: -fluoroalkyl.

21. R １ 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl.

22. R １ 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein is difluoromethyl.

23. R ２ But C １ ~C ４ - alkyl, or a pharmaceutically acceptable salt thereof.

24. R ２ The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

25. R ２ The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein is methyl.

26. 26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein o is 0.

27. 26. The compound according to any one of claims 1 to 25, wherein o is 1, or a pharmaceutically acceptable salt thereof.

28. R ７ 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, methyl, cyclopropyl, fluoro, chloro, and azetidin-1-yl.

29. R ７ 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

30. 30. The compound according to any one of claims 1 to 5 or 8 to 29, wherein X is N, or a pharmaceutically acceptable salt thereof.

31. X is CR ５ａ 30. The compound according to any one of claims 1 to 29, wherein:

32. R ５ａ 32. The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein: is hydrogen.

33. below: 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-fluorophenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-8-methyl-7-(4-((8-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-((8-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-fluoro-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-(azetidin-1-yl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-3-fluoro-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-(benzo[d][1,3]dioxol-5-yloxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-3-fluoro-4-(isochroman-6-yloxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzofuran-5-yl)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-(chroman-7-yloxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-2,3,8-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-2-(difluoromethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-7-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-methoxy-5-methylpyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-(methoxymethyl)pyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-(p-tolyloxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-chlorophenoxy)piperidin-1-yl)-2-(difluoromethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-8,9-dimethyl-7-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 2,8-dimethyl-7-(4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-fluorophenoxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-7-(4-(4-fluorophenoxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(difluoromethyl)-8,9-dimethyl-7-(4-(p-tolyloxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8,9-dimethyl-7-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(3-fluoro-4-methylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-ethylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-(4-isopropylphenoxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-(4-propylphenoxy)piperidin-1-yl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-7-(4-(p-tolyloxy)piperidin-1-yl-4-d)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((6-(methoxymethyl)-5-methylpyridin-3-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2,8,9-trimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-isopropyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-ethyl-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 2-(cyclopentylmethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-8-(methoxymethyl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-(methoxymethyl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-9-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 8-cyclopropyl-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-9-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-4-d)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-3-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3S,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-9-(methylamino)-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-9-methoxy-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 9-(azetidin-1-yl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-3-fluoropiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-2-methylpiperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one; 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl-2,2,6,6-d4)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one 10. The compound of claim 1, selected from the group consisting of:

34. The compound is 2-(difluoromethyl)-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d ４ 34. The compound of claim 33, which is )oxy)piperidin-1-yl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one, or a pharmaceutically acceptable salt thereof.

35. The compound is 3-chloro-7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d ４ 34. The compound of claim 33, which is )oxy)piperidin-1-yl)-2,8-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one, or a pharmaceutically acceptable salt thereof.

36. The compound is 7-((3R,4R)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d ４ 34. The compound of claim 33, which is 4H-pyrimido[1,2-b]pyridazin-4-one, or a pharmaceutically acceptable salt thereof.

37. 34. The compound of claim 33, wherein the compound is 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl-4-d)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one, or a pharmaceutically acceptable salt thereof.

38. The compound is 7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d ４ 34. The compound of claim 33, which is 4-(d)-2-(methoxymethyl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one, or a pharmaceutically acceptable salt thereof.

39. The compound is 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d ４ 34. The compound of claim 33, which is 4H-pyrimido[1,2-b]pyridazin-4-one, or a pharmaceutically acceptable salt thereof.

40. The compound is 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d ４ 34. The compound of claim 33, which is 4H-pyrimido[1,2-b]pyridazin-4-one, or a pharmaceutically acceptable salt thereof.

41. 41. A pharmaceutical composition comprising the compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof for the treatment of neurological and / or psychiatric disorders.

43. 43. The pharmaceutical composition of claim 42, wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, borderline personality disorder, Tourette's syndrome, bipolar disorder, tardive dyskinesia, Huntington's disease, a pain disorder, and a cognitive disorder.

44. 43. The pharmaceutical composition of claim 42, wherein the disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, autistic disorder, movement disorders, Tourette's syndrome, akinetic rigidity syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, cognitive disorders, dementia, and memory disorders.

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