Antagonists of the muscarinic acetylcholine receptor m4

Abstract

Disclosed are (pyrrolidin-3-yl)methyl)pyridazin-3-amine and (pyrrolidin-3-yl)methyl)pyridin-3-amine compounds substituted on the pyrrolidine nitrogen and the 6-position of the pyridazine or pyridine. The compounds are useful as antagonists of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.

Description

ANTAGONISTS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 736,289, filed December 19, 2024, which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to compounds, compositions, and methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction.BACKGROUND

[0003] Parkinson’s disease (PD) is the second most common neurodegenerative disease with an increasing prevalence as a function of age. Moreover, early-onset PD is also increasing. A hallmark of PD is the progressive degeneration and loss of dopaminergic neurons in the substantia nigra (SN) and basal ganglia (BG), leading to pronounced motor symptoms including bradykinesia, tremor, rigidity, gait dysfunction and postural instability. At present, levodopa (L-DOPA) is the standard of care for treating the motor symptoms, but it is not curative, and prolonged use can engender L-DOPA induced dyskinesia (LID).

[0004] Prior to L-DOPA, compounds with anticholinergic activity represented the preferred mode of PD treatment. Cholinergic neurons provide important neuromodulatory control of the BG motor circuit. While the actions of cholinergic pathways on basal ganglia pathways are complex, activation of muscarinic acetylcholine receptors (mAChRs) generally have actions that oppose dopamine (DA) signaling. For instance, mAChR agonists inhibit DA release, and inhibit multiple behavioral effects of drugs that increase DA levels and signaling. Interestingly, muscarinic acetylcholine receptor (mAChR) antagonists were the first available treatments for PD and are still widely used for treatment of this disorder. While many studies of the actions of mAChR antagonists were carried out before randomized controlled trials were introduced, recent well controlled double-blind cross-over design studies demonstrate significant improvement in multiple aspects of motor function in patients receiving mAChR antagonists. Unfortunately, mAChR antagonists have a number of dose-limiting adverse effects that severely limit their clinical utility, including multiple peripheral adverse effects, as well as confusion and severe cognitive disturbances.

[0005] Because adverse effects associated with mAChR antagonists limit the doses that can be tolerated, previous clinical studies may underestimate the efficacy that could be achieved if doses of mAChR antagonists could be increased to achieve more complete blockade of specific mAChR subtypes responsible for the antiparkinsonian effects of these agents. The mAChRs include five subtypes, termed Mi - Ms. Available mAChR antagonists, such as scopolamine, are nonselective across these subtypes, and many of their adverse effects are likely mediated by mAChR subtypes that are not involved in the antiparkinsonian activity. Thus, compounds possessing a more selective profile for individual mAChRs may offer an advantage in PD, as well as related disorders such as dystonia. For example, some studies indicate that the M4 mAChR subtype may play a dominant role in mAChR regulation of basal ganglia motor function.SUMMARY

[0006] One aspect of the invention provides compound s of formula (I),(I)or a pharmaceutically acceptable salt thereof, wherein:X is N or CH;R1is G1or halogen;G1is a 6- to 12-membered and or a 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein G1is optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-4fluoroalkyl, -OR10, -N(R10)2, -NR10C(O)R10, -CON(R10)2, -NR10SO2Rn, -Ci- 3alkylene-OR10, Cs-ecycloalkyl, and --Ci-3alkylene--C3-6cycloalkyl, and optionally furthersubstituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-4fluoroalkyl, and -OCi-4alkyl;R10, at each occurrence, is independently hydrogen, Ci-4alkyl, Ci-4fluoroalkyl, C3-4cycloalkyl, or Ci-3alkylene-C3-4cycloalkyl, wherein alternatively two R10, together with a nitrogen to which the two R10attach form a 4- to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Ci-4alkyl; R11, at each occurrence, is independently Ci-4alkyl, Ci-4haloalkyl, C3-4cycloalkyl, or-Ci- 3 al ky 1 ene-C3-4cy cl oalky 1;Ris hydrogen, Ci-4alkyl, C3-4cycloalkyl, or ~-Ci-3alkylene~C3-4cycloalkyl;m is 0, 1, or 2;R2, at each occurrence, is independently halogen, cyano, Ci-4alkyl, Ci-4tluoroalkyl, or C3- ecycloalkyl;R3is G2, L1G2, ---C2-6alkylene--R3a, Cb-valkyl, or Cs-rhaloalkyl;L1is Ci-3alkylene;G2is a 4- to 12-membered heterocyclyl, a Cs- carbocyclyl optionally fused to a 6-membered arene, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, the heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein G2is optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, Ci-4alkyl, Ci-4fluoroalkyl, -OR13, -N(R13)2, -Ci- 3alkylene-OR13, and -Ci-3alkylene--N(R13)2, and optionally further substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-4fluoroalkyl, and -OCi-4alkyl;R3ais -OR14or -N(RI4)2;R13and R14, at each occurrence, are independently hydrogen, Ci-4alkyl, Ci-4fluoroalkyl, C3- 4cycloalkyl, or Ci-3alkylene-C3-4cycloalkyl, wherein alternatively two R1Jor two R14, together with a nitrogen to which the two R13or two R14attach form a 4- to 6-membered heterocyclic ring optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Ci-4alkyl;R4, at each occurrence, is independently hydrogen, Cj-4alkyl, Ci-4fluoroalkyl, or C3-4cycloalkyl; n is 0, 1, 2, 3, or 4; andR5, at each occurrence, is independently halogen or C i-aalkyl.

[0007] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] In another aspect, the invention provides a method of treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M4, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0009] In another aspect, the invention provides a method for antagonizing mAChR M4 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0010] In another aspect, the invention provides a method for the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0011] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

[0012] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in antagonizing mAChR Wk in a subject.

[0013] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

[0014] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for antagonizing mAChR M4 in a subject.

[0015] In another aspect, the invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.DETAILED DESCRIPTION1. Definitions

[0016] 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 document, 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 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 not intended to be limiting.

[0017] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0018] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1 ” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0019] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties andreactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0020] The term “alkoxy,” as used herein, refers to a group -O-alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0021] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “Ci-ealkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “Ci-4alkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, -propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, w-hexyl, 3 -methyl hexyl, 2, 2-dimethyl pentyl, 2,3-dimethylpentyl, n-heptyl, w-octyl, w-nonyl, and w-decyl.

[0022] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond.

[0023] 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.

[0024] 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.

[0025] The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH2-, -CD₂-, -CH2CH2-, -C(CH3)(H)-, -C(CH3)(D)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0026] The term “alkylamino,” as used herein, means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein.

[0027] The term “amide,” as used herein, means -C(O)NR- or -NRC(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0028] The term “aminoalkyl,” as used herein, means at least one amino group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0029] The term “amino,” as used herein, means -NRxRy, wherein Rxand Rymay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where amino appends together two other moieties, amino may be NRXwherein Rxmay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0030] The term “aryl,” as used herein, refers to a phenyl or a phenyl appended to the parent molecular moiety and fused to a cycloalkane group (e.g., the aryl may be indan-4-yl), fused to a 6-membered arene group (i.e., the aryl is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl may be benzo[d][l,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6-membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

[0031] The term “cyanoalkyl,” as used herein, means at least one -CN group, is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0032] The term “cyanofluoroalkyl,” as used herein, means at least one -CN group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[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” or “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthal enyl), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl).Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicycl o[ 1.1.1 ]pentanyl.

[0035] The term “cycloalkenyl” or “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic ring system containing all carbon atoms as ring members and at leastone carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0036] The term “carbocyclyl” means a “cycloalkyl” or a “cycloalkenyl.” The term “carbocycle” means a “cycloalkane” or a “cycloalkene.” The term “carbocyclyl” refers to a “carbocycle” when present as a substituent.

[0037] The term “1,1-carbocyclylene” means a geminal divalent group derived from acycloalkyl. A representative example is l,l-C3-6cycloalkylene (i.e.,°’3). A furtherexample is 1,1 -cyclopropylene (i.e.,

[0038] 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 are 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 -tri fluor opropy 1.

[0039] The term “difluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which two hydrogen atoms are replaced by fluorine. Representative examples of difluoroalkyl include difluorom ethyl and difluoroethyl.

[0040] The term “fluoroalkylene,” as used herein, means an alkylene group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkylene include, but are not limited to -CF2-, -CH2CF2 -, 1,2-difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3, 3, 3 -tetrafluoropropylene, 1,1,2,3,3-pentafluoropropylene, and perfluoropropylene such as 1,1,2,2,3,3-hexafluoropropylene.

[0041] The term “fluoroalkoxy,” as used herein, means at least one fluoroalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoro ethoxy and 2, 2, 2 -tri fluoroethoxy.

[0042] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

[0043] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.

[0044] The term “haloalkoxy,” as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.

[0045] The term “halocycloalkyl,” as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halogen.

[0046] The term “heteroalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been 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.

[0047] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatomcontaining ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term “heteroaryl” is used herein to refer to a heteroarene when present as a substituent. The monocyclic heteroaryl are five or six membered rings 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 O, S, and N). The five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl is an 8- to 12-membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., 10% electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-l-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4-yl), A bicyclic heteroaryl / heteroarene group includes a 9-membered fused bicyclic heteroaromatic ring system having four double bonds and at least one heteroatom contributing a lone electron pair to a fully aromatic 10% electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes afused bicyclic ring system composed of one heteroaromatic ring and one non-aromatic ring such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-l-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyri din-3 -yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3 -tri azolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benz.imidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[l,2-a]pyridinyl (e.g., imidazo[l,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-d]pyridin-2-yl, and thiazolo[5,4- ]pyrimidin-2-yl,

[0048] The term “heterocycle” or “heterocyclic,” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term “heterocyclyl” is used herein to refer to a heterocycle when present as a substituent. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-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. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consi sting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl,pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane (e.g., 7- to 12-membered fused bicyclic heterocyclyl ring system such as hexahydro-2H-cyclopenta[b]furanyl, octahydro-3 aH-cyclohepta[b]furanyl, or 3-oxabicyclo[3.1.0]hexanyl), or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group (e.g., a 7- to 12-membered spiro heterocyclyl ring system such as 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octanyl, or 5-oxaspiro[2.4]heptanyl), or a bridged heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., a 6- to 10-membered bridged bicyclic heterocyclyl ring system such as 7-oxabicyclo[2.2,l]heptanyl or 2-oxabicyclo[2.1.1]hexanyl), or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-l-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-2-yl, l,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3 -dihydro- 17 -indol- 1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2. l]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-l-yl, and 3-oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, 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 two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2, 5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[Z’]furan,hexahydro- lH-l,4-methanocy cl openta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom.

[0049] The term “hydroxyl” or “hydroxy,” as used herein, means an -OH group.

[0050] The term “hydroxyalkyl,” as used herein, means at least one -OH group, is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0051] The term “hydroxyfluoroalkyl,” as used herein, means at least one -OH group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0052] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance ( e.g., " Ci-4alkyl," " C3-6cycloalkyl," " Ci-4alkylene"). These designations are used as generally- understood by those skilled in the art. For example, the representation " C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, " Csalkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in " Ci-4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A " Ci-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0053] The terms "parent molecule" or "parent molecular moiety" refer to the entire portion of a molecule to which a substituent is attached, i.e., the remainder of the molecule.

[0054] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups 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.

[0055] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections andsubstitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0056] The term “mAChR M4 receptor antagonist” as used herein refers to any exogenously administered compound or agent that directly or indirectly antagonizes mAChR M4, for example in an animal, in particular a mammal (e.g., a human).

[0057] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.2. Compounds

[0058] In one aspect, the invention provides compounds of formula (I), wherein X, R, R1, R2, R3, ’, R5, m, and n are as defined herein.

[0059] Unsubstituted or substituted rings (i.e., optionally substituted) such as aryl, heteroaryl, etc. are composed of both a ring system and the ring system's optional substituents. Accordingly, the ring system may be defined independently of its substituents, such that redefining only the ring system leaves any previous optional substituents present. For example, a 5- to 12-membered heteroaryl with optional substituents may be further defined by specifying the ring system of the 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., 5- to 6-membered heteroaryl ring system), in which case the optional substituents of the 5- to 12-membered heteroaryl are still present on the 5- to 6-membered heteroaryl, unless otherwise expressly indicated.

[0060] Where heterocyclic and heteroaromatic ring systems are defined to "contain" or as "containing" specified heteroatoms (e.g., 1-3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atoms of the heterocyclic and heteroaromatic ring systems that are not one of the specified heteroatoms are carbon atoms.

[0061] In the following, numbered embodiments of the invention are disclosed. The first embodiment is denoted El, and subsequent embodiments are denoted El.l, El.2, E2, E2.1, E2.2, E3, etc.

[0062] El. A compound of formula (I):(I)or a pharmaceutically acceptable salt thereof, wherein:X is N or CH;R1is G1or halogen;G1is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein G1is optionally- substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-4fluoroalkyl, -OR10, -N(R10)2, -NR10C(O)R10, -CON(R10)2, -NR10SO2Rn, -Ci- salkylene-OR10, Cs-ecycloalkyl, and -Ci-3alkylene-C3-6cycloalkyl, and optionally further substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, Ci-ialkyl, cyano, Ci-4fluoroalkyl, and -OCwalkyl;R10, at each occurrence, is independently hydrogen, Ci-4alkyl, Ci-4fluoroalkyl, C'3-4cycloalkyl, or Ci-3alkylene-C3-4cycloalkyl, wherein alternatively two R10, together with a nitrogen to which the two R10attach form a 4- to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Ci-4alkyl; R11, at each occurrence, is independently Ci-4alkyl, Ci-4haloalkyl, C3-4cycloalkyl, or -Ci- 3alkylene-C3-4cycloalkyl;Ris hydrogen, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;m is 0, 1, or 2;R2, at each occurrence, is independently halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, or C3- ecycloalkyl;R3is G2, -L / -G2, -C2-6alkylene-Rja, C3-7alkyl, or C3-?haloalkyl;L1is Cnsalkylene;G2is a a 4- to 12-membered heterocyclyl, a C3-i2carbocyclyl optionally fused to a 6-membered arene, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, the heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein G2is optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, Ci-4alkyl, Cj -4fluoroalkyl, -OR1J, -N(R13)2, -Ci- 3alkylene-OR13, and -Ci-3alkylene--N(R13)2, and optionally further substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, Ci-4alkyl, cyano, Cwifluoroalkyl, and -OCwialkyl;R3ais -OR14or -N(R14)2;R13and R14, at each occurrence, are independently hydrogen, Ci-4alkyl, Ci-4tluoroalkyl, C3- 4cycloalkyl, or Ci-3alkylene-C3-4cycloalkyl, wherein alternatively two R13or two R14, together with a nitrogen to which the two R13or two R14attach form a 4- to 6-membered heterocyclic ring optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Cwialkyl;R4, at each occurrence, is indepedently hydrogen, Ci-4alkyl, Ci-4fluoroalkyl, or C3-4cycloalkyl; n is 0, 1, 2, 3, or 4; andR5, at each occurrence, is independently halogen or Ci-4alkyl.

[0063] El l. The compound of El, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II):

[0064] El. 2. The compound of El, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III):(R5)n

[0065] E2. The compound of any of El-El.2, or a pharmaceutically acceptable salt thereof, wherein R1is G1

[0066] E2.1. The compound of any of El -El.2, or a pharmaceutically acceptable salt thereof, wherein R1is halogen.

[0067] E2.2. The compound of any of El -E l.2 or E2.1, or a pharmaceutically acceptable salt thereof, wherein the halogen of R1is chloro.

[0068] E3. The compound of any of E1-E2 or E2.2, or a pharmaceutically acceptable salt thereof, wherein G1is the optionally substituted 6- to 12-membered aryl.

[0069] E4. The compound of any of El -E2 or E2.2-E3, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at G1is a phenyl.

[0070] E4.1. The compound of E4, or a pharmaceutically acceptable salt thereof, wherein

[0071] E4.2. The compound of E4.1, or a pharmaceutically acceptable salt thereof,

[0072] E5. The compound of any of E1-E2 or E2.2-E3, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at G1is a phenyl bonded to the parent molecule and fused to a 5- to 6-membered heterocycle containing 1-2 ring heteroatonis independently selected from nitrogen and oxygen.

[0073] E5.1. The compound of E5, or a pharmaceutically acceptable salt thereof, whereinthe ring system of the 6- to 12-membered aryl at G1isO w /

[0074] E5.2. The compound of E5.1, or a pharmaceutically acceptable salt thereof,wherein G1is

[0075] E5.3. The compound of E5.2, or a pharmaceutically acceptable salt thereof,wherein Gis O

[0076] E6. The compound of any of E1-E2 or E2.2, or a pharmaceutically acceptable salt thereof, wherein G1is the optionally substituted 5- to 12-membered heteroaryl.

[0077] E7. The compound of any of El -E2, E2.2, or E6, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 12-menibered heteroaryl at G1is a 5-to 6-membered monocyclic heteroaryl ring system containing 1-3 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

[0078] E7.1. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 12-membered heteroaryl at G1is pyridinyl or pyrazolyl.

[0079] E7.2. The compound of E7.1, or a pharmaceutically acceptable salt thereof,

[0080] E7.3. The compound of E7.2, or a pharmaceutically acceptable salt thereof,

[0081] E8. The compound of any of E1-E2, E2.2, or E6, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 12-membered heteroaryl at G1is a 9- to 10-membered fused bicyclic heteroaryl ring system containing 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] E8.1. The compound of E8, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 12-membered heteroaryl at G1is indazolyl or benzothiazolyl.

[0083] E8.2. The compound of E8.1, or a pharmaceutically acceptable salt thereof,SC-i^alkyl— Nwherein G1is or N

[0084] E8.3. The compound of E8.2, or a pharmaceutically acceptable salt thereof,wherein G1is

[0085] E9. The compound of any of E1-E2, E2.2-E4, E5-E5.1, E6-E7.1, or E8-E8.1, or a pharmaceutically acceptable salt thereof, wherein G1is optionally substituted with a firstsubstituent selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-2fluoroalkyl, -OR10, “CON(R10)2, -Ci-salkylene-OR10, and C3-4cycloalkyl and G1is optionally further substituted with 1-2 substituents independently selected from the group consisting of halogen and Ci-4alkyl.

[0086] E9.1. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein G1is optionally substituted with a first substituent selected from the group consisting of fluoro, chloro, methyl, cyano, trifluoromethyl, -OCEb, ~CON(H)cyclopropyl, -Ci-salkylene-OH, and cyclopropyl and G1is optionally further substituted with 1-2 substituents independently selected from the group consisting of fluoro, chloro, and methyl.

[0087] E9.2. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein G1is optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-2fluoroalkyl, -OR10, and C3-4cycloalkyl and G1is optionally further substituted with 1-2 substituents independently selected from the group consisting of halogen and Ci-4alkyl.

[0088] E9.3. The compound of E9.2, or a phar aceutically acceptable salt thereof, wherein G1is optionally substituted with a first substituent selected from the group consisting of fluoro, chloro, methyl, cyano, trifluoromethyl, -OGIE, and cyclopropyl and G1is optionally further substituted with 1-2 substituents independently selected from the group consisting of fluoro, chloro, and methyl.

[0089] E10. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein

[0090] El 0.1. The compound of any of El -El 0, or a pharmaceutically acceptable salt thereof, wherein R10is hydrogen.

[0091] E10.2. The compound of any of El -El 0, or a pharmaceutically acceptable salt thereof, wherein R10is Ci-4alkyl.

[0092] El 0.3. The compound of any of El -El 0, or a pharmaceutically acceptable salt thereof, wherein Ri0is C3-4cycloalkyl.

[0093] El 1. The compound of any of E1-E10.3, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted 4- to 12-membered heterocyclyl.

[0094] E12. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 4- to 12-membered heterocyclyl at G2is a 4- to 8-membered heterocyclyl ring system, wherein the heterocyclyl ring system contains 1 or 2 oxygen ring atoms.

[0095] E12.1. The compound of E12, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 4- to 12-membered heterocyclyl at G2is a 1,4-dioxanyl, 7- oxabicyclo[2.2.1]heptanyl, tetrahydropyranyl, or tetrahydrofuranyl.

[0096] E12.2. The compound of any of El 1-E12.1, or a pharmaceutically acceptable salt thereof, wherein G2is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl.

[0097] E12.3. The compound of E12.2, or a pharmaceutically acceptable salt thereof, wherein G2is unsubstituted or substituted with 1-4 methyl.

[0098] E12.4. The compound of E12.3, or a pharmaceutically acceptable salt thereof,

[0099] E13. The compound of any of E1-E10.3, or a phar aceutically acceptable salt thereof, wherein G2is the optionally substituted 6- to 12-membered aryl.

[0100] E14. The compound of any of E1-E10.3, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted 5- to 12-membered heteroaryl.

[0101] E15. The compound of any of E1-E10.3, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted Cs-ncarbocyclyl.

[0102] E16. The compound of any of E1-E10.3 or E15, or a pharmaceutically acceptable salt thereof, wherein the ring system of the C3-12carboc.yc.lyl is a C3-6cycloalkyl ring system.

[0103] E 16.1. The compound of E15 or E16, or a pharmaceutically acceptable salt thereof, wherein G2is unsubstituted or substituted with hydroxy.

[0104] E16.2. The compound of E16.1, or a pharmaceutically acceptable salt thereof,wherei

[0105] E17. The compound of any of E1-E12.4 or E15-16.2, or a pharmaceuticallyacceptable salt thereof, wherein

[0106] E18. The compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, wherein L1is CH2 or CH2CH2.

[0107] E18.1. The compound of E18, or a pharmaceutically acceptable salt thereof, wherein L1is CH2CH2.

[0108] E18.2. The compound of E18, or a pharmaceutically acceptable salt thereof, wherein L1is CH2.

[0109] E19. The compound of any of E1-E18.2, or a pharmaceutically acceptable salt thereof, wherein R3is -L1-G2.

[0110] E20, The compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, wherein R3is G2.

[0111] E21. The compound of any of E1-E10.3, or a pharmaceutically acceptable salt thereof, wherein R3is C3-?alkyl.

[0112] E21.1. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R3is 3, 3 -dimethylbutyl.

[0113] E22. The compound of any of E1-E21.1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

[0114] E23. The compound of any of E1-E22, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0115] E23.1. The compound of E23, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-a):

[0116] E24. The compound of any of E1-E22, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0117] E24.1. The compound of E24, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-b):(R5)n

[0118] E25. The compound of any of E1-E22 or E24-E24. I, or a pharmaceutically acceptable salt thereof, wherein R2is Ci-2fluoroalkyl.

[0119] E25.1. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R2is trifluoromethyl.

[0120] E26. The compound of any of E1-E25.1, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0121] E27. The compound of any of E1-E25.1, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0122] E28. The compound of any of E1-E27, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

[0123] E29. The compound of any of E1-E28, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0124] E29.1. The compound of E29, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-c):

[0125] E29.2. The compound of E29.1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-c):(II-c).

[0126] E29.3. The compound of E29.1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III-c):R(III-c).

[0127] E29.4. The compound of E29.1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-ac):R3R1(I-ac).

[0128] E29.5. The compound of E29.2 or E29.4, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Il-ac):R3R1(Il-ac).

[0129] E29.6. The compound of E29.3 or E29.4, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ill-ac):RNR1(Ill-ac).

[0130] E29.7. The compound of E29.1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-bc):R3(I-bc).

[0131] E29.8. The compound of E29.2 or E29.7, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Il-bc):R3R1(Il-bc).

[0132] E29.9. The compound of E29.3 or E29.7, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IILbc):(IILbc).

[0133] E30. The compound of any of E1-E28, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0134] E30.1. The compound of E30, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-d):R3(I-d).

[0135] E30.2. The compound of E30.1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Lad):R1(Lad).

[0136] E31. The compound of any of E1-E28, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0137] E31.1. The compound of E31, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-e):(I-e).

[0138] E32. The compound of any of E1-E28 or E30-E31.1, or a pharmaceutically acceptable salt thereof, wherein R5, at each occurrence is independently fluoro or C1-4alkyl.

[0139] E32.1. The compound of E32, or a pharmaceutically acceptable salt thereof, wherein R5, at each occurrence is independently C1-4alkyl,

[0140] E32.2. The compound of E32.1, or a pharmaceutically acceptable salt thereof, wherein R5, at each occurrence, is independently methyl.

[0141] E32.3. The compound of E32, or a pharmaceutically acceptable salt thereof, wherein R5, at each occurrence, is independently fluoro.

[0142] E33. The compound of El selected from the group consisting of:(R)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine;(R)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2,3,5- trifluorophenyl)pyridazin-3-amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(2-methyl-2H-indazol-5-yl)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(S)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyri din-3 -yl)pyridazin-3 -amine;(S)-N-((l -((tetr ahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2, 3,5- trifluorophenyl)pyridazin-3-amine;(S)-6-(2-chloro-5-fluorophenyl)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;6-(2-chloro-5-fluorophenyl)-N-(((3R)-l-((2,2-dimethyltetrahydro-2H-pyran-4- yl)methy 1 )py rroli di n-3 -yl)methyl)pyri dazin-3 -ami ne;(R)-l-((3-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)methyl)pyrrolidin-l- y 1 )m ethyl)cy cl oheptan - 1 -ol;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(3,3-dimethylbutyr)pyrrolidin-3-yl)methyl)pyri dazin-3- amine;(R)-6-chloro-N-((l-(2-(tetrahydro-2H-pyi’an-4-yl)ethyl)pyi olidin-3-yl)methyl)pyridazin-3- amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyri din-3 -yl)pyridazin-3 -amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2,3,5- trifluorophenyl)pyridazin-3 -amine;(R)-6-(5-fluoro-2-methylphenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(2-methyl-2H-indazol-5-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl )pyridazin-3-amine;(R)-6-(2-methylpyri din-3 -yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(5-fluoro-2-methoxyphenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(4- (trifluoromethyl)pyridin-3 -yl)pyridazin-3 -amine;(R)-6-(l,3-dimethyl-lH-pyrazol-4-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-y1)ethyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine;(R)-6-(benzo[d]thiazol-6-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-2'-(trifluoromethyl)-[2,3'- bipyridin]-5-amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyri din-3 -amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethy1)pyrrolidin-3-yl)methyl)-6-(2,3,5- trifluorophenyl)pyri din-3 -amine;(R)-6-(5-fluoro-2-methylphenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridin-3-amine;(R)-6-(2,6-dimethylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl )pyridazin-3-amine;(R)-6-(2-isopropoxypyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(2-cyclopropylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yi)ethyl)pyrrolidin-3-yl)methyl)-4-(trifluoromethyl)-6- (2,3,5-trifluorophenyl)pyridazin-3-amine;(R)-6-(5 -fluoro-2-methylphenyl)-N-(( 1 -(2-(tetrahy dro-2 H-pyran-4-y 1 )ethyl)pyrroli din-3 - yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-4-(trifluoromethyl)-6-(2- (trifluoromethyl)pyri din-3 -yl)pyridazin-3 -amine;(R)-6-(2-methylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yi)ethyl)pyrrolidin-3- yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-6-(2-cyclopropylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-6-(2-methyl-2H-indazol-5-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-6-(benzo[d]thiazol-6-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)- 4-(trifluoromethyl)pyridazin-3-amine;(R)-6-(lH-pyrazol-l-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl )pyridazin-3-amine;(R)-6-(3, 5 -dimethyl- IH-pyrazol- 1 -yl)-N-(( 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3 - yl)methyl)pyridazin-3-amine;(R)-2-(3-(6-(((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)amino)pyridazin-3- yl)phenyl)propan-2-ol;(R)-6-( 1,3 -dimethyl- lH-pyrazol-4-yl)-N-(( 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3 - yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;N-((3-fluoro-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluorom ethyl)pyri din-3 -yl)pyridazin-3 -amine;6-(2-chloro-5-fluorophenyl)-N-((3-fluoro-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;N-(((3R)-l-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyri din-3 -yl)pyridazin-3 -amine;N-(((3R)-l-((6,6-dimethyltetrahydro-2H-pyran-3-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyridin-3-yl)pyridazin-3 -amine;(R)-N-((l-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluorom ethyl)pyri din-3 -yl)pyri dazin-3 -ami ne;(R)-6-(5-fluoro-2-methylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-2-methyl-3 -(6-((( 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3 - yl)methyl)amino)pyridazin-3-yl)benzonitrile;6-(2-chloro-5-fluorophenyl)-N-((3-methyl-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;N-((3 -methyl- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3 -yl)methyl)-6-(2- (trifluoromethyl)pyridin-3 -yl)pyridazin-3 -amine;2-methyl-3-(6-(((3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)amino)pyridazin-3-yl)benzonitrile;6-( 1,3 -di m ethyl- 1 H-pyrazol -4-y l)-N-((3 -m ethyl- 1 -(2-(tetrahy dro-2 H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine;N-((3 -methyl- l-(2-(tetrahy dro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2- methylpyridin-3-yl)pyridazin-3-amine;N-((3-methyl-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyiTolidin-3-yl)methyl)-6-(2-methyl-2H- indazol-5-yl)pyridazin-3-amine;6-(2-cyclopropylpyridin-3-yl)-N-((3-methyl-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;N-cy cl opropyl-4-(6-(((3-methyl-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrroli din-3- yl)methyl)amino)pyridazin-3-yl)benzamide;or a pharmaceutically acceptable salt thereof.

[0143] E34. The compound of any of El -E33, or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled.

[0144] E35. A pharmaceutical composition comprising the compound of any of E1-E34, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0145] E36, A method for antagonizing m AChR M4 in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any of El-E34, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of E35.

[0146] E37. A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M4, comprising administering to the subject a therapeutically effective amount of the compound of any of E1-E34, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of E35.

[0147] E38. The method of E37, wherein the disorder is a neurodegenerative disorder, a movement disorder, or a brain disorder.

[0148] E39, The method of E38, wherein the disorder is a movement disorder.

[0149] E40. The method of E38, wherein the disorder is selected from Parkinson’s disease, drug-induced Parkinsonism, dystonia, Tourette’s syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington’s disease, chorea, cerebral palsy, and progressive supranuclear palsy.

[0150] E41. A method for treating motor symptoms in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound ofany of E1-E34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition ofE35.

[0151] E42. The method of E41, wherein the subject has a disorder selected from Parkinson’s disease, drug-induced Parkinsonism, dystonia, Tourette’s syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington’s disease, chorea, cerebral palsy, and progressive supranuclear palsy.

[0152] E43. A compound of any of E1-E34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E35 for use in the treatment of aneurodegenerative disorder, a movement disorder, or a brain disorder.

[0153] E44. The use of a compound of any of El -E34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E35, for the preparation of a medicament for the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

[0154] Throughout the embodiments and description of the compounds of the invention, all instances of haloalkyl may be fluoroalkyl (e.g., any Ci-ihaloalkyl may be Ci-4fluoroalkyl).

[0155] Compound names and / or structures can be assigned / determined by using the Struct=Name naming algorithm as part of CHEMDRAW® UETRA.

[0156] The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “7?” or “5” depending on the configuration of substituents around the chiral carbon atom. The terms “A” and “5”’ used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution 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 OrganicChemistiy,” 5th edition (1989), Longman Scientific & Technical, Essex CM202JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.

[0157] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure.

[0158] In the compounds of formula (I), and any subformulas, any "hydrogen" or " H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes1H (protium) and2H (deuterium).

[0159] The present disclosure also includes isotopically-labeled compounds (e.g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,l3C,14C,l5N,1SO,i70,31P,32P,35S,18F, and36C1, respectively. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positronemitting isotopes that can be incorporated in compounds of formula (I) arenC,l3N,15O, and18F.

[0160] Isotopically-enriched form s of compounds of formula (I), or any subformulas, 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 using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent of isotopic enrichment can be characterized as a percent incorporation of a particular isotope at an isotopically-labeled atom (e.g., % deuterium incorporation at a deuterium label).a. Pharmaceutically Acceptable Salts

[0161] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanoland water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a 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 -phenyl propionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0162] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a 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 an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethyl amine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, A, -dimethylaniline, N-methylpiperidine, A-methylmorpholine, di cyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1 -ephenamine and N, N ’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.b. General Synthesis

[0163] Compounds of formula (I) or any of its subformulas may be prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

[0164] Abbreviations: AcOH is acetic acid; BMS is borane dimethyl sulfide complex; Boc is tert-butyloxycarbonyl; 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 (CAS Number 1470372-59-8); t-BuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; DAST is diethylaminosulfur trifluoride; DCE is 1,2-di chloroethane; DCM is di chloromethane; DIAD is di ispropyl azodi carboxylate; DIBAL is diisobutylaluminum hydride; DIEA and DIPEAboth refer to A’, A-diisopropylethylamine; DMF is A t-dim ethylformamide; EtOH is ethanol; EtsSiCl is chlorotriethylsilane; HATU is 2-(7-aza-177-benzotriazole-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate; LiAlH(0tBu)3 is lithium tri-tert-butoxyaluminum hydride; m-CPBA is meta-chloroperoxybenzoic acid; MeOH is methanol; MsCl is methanesulfonyl chloride; NaBH(0Ac)3 and STAB both refer to sodium triacetoxyborohydride; rt or r.t. is room temperature; NMP is N-methyl-2-pyrrolidone; Pd(dppf)C12 is [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); PPhs is triphenylphosphine; RuPhos-Pd-G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(Il) methanesulfonate (CAS Number 1445085-77-7); Selectfluor™ is 1-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); t-BuOH is tert¬ butyl alcohol; t-BuOK is potassium tert-butoxide; TBAI is tetrabutylammonium iodide; THF is tetrahydrofuran; and TosMIC is toluenesulfonylmethyl isocyanide.

[0165] Compounds of formula (I) or any of its subformulas may be synthesized as shown in the following schemes.Scheme 1K2CO3 BrettPhos-Pd-G3C 1,4-dioxane / H2OHCI1,4-dioxane r.t.reductive amination HNaldehyde / ketone

[0166] As shown in Scheme 1, compound A may be reacted with a 3,6-dichloropyridazine B to generate compound C. Coupling of C with a suitable boronic acid or ester may provide compound D, which may be deprotected (e.g., with hydrochloric acid) to generate compound E. Compound E may be reacted with suitable aldehydes or ketones corresponding to R3by reductive amination to provide F, wherein R3is G2, -iJ-G2, -C2-6alkylene-R3a, or C3-?alkyl and G2is the carbocyclyl or heterocyclyl of G2.Scheme 2

[0167] Scheme 2 illustrates an alternate synthesis route to compounds of formula F, wherein the reductive amination and boronic acid coupling steps are reversed. Deprotection of compound C under acid conditions may provide compound G, which may be reacted with suitable aldehydes or ketones corresponding to R3by reductive amination to provide compounds H, wherein R3is G2, -L’-G2, -C2-6alkylene--R3a, or C3-?alkyl. In turn, reaction of compounds H with suitable boronic acids or esters may provide compounds F. Intermediate H may also be prepared using the alkylation process of Scheme 4.EtMgBr, Ti(OiPr)4THF, -78 °C to reflux

[0168] As shown in Scheme 3, reaction of compound G with a carboxylic acid R20CO2H under standard amide bond forming conditions may provide amides I. Suitable reaction conditions include reacting G (1 equiv.) with the carboxylic acid (1.2 equiv.) in the presence of DIPEA (3 equiv.) and HATU (1.5 equiv.) in DME at room temperature. Amides I may react with a titanacyclopropane generated in situ from an ethyl Grignard and Ti(OiPr)4 (Kulinkovich- de Meijere reaction) to provide cyclopropyl compounds of formula J. Suitable reaction conditions include reacting a solution of ethylmagnesium bromide (5 equiv., 1.0 M solution) in THF with titanium(IV) isopropoxide (2.1 equiv.) at -78 °C for 30 min under an inert atmosphere, and adding compound 1 (1 equiv. in THF), followed by warming to r.t. and then stirring at reflux for 1 h. Compounds J may be processed according to the Suzuki coupling method outlined in Scheme 2 to provide additional compounds of the invention. In Scheme 3, R20is an alkyl group (e.g., Ci-4alkyl), -Ci-salkylene-OR13, or -Ci-3alkylene-N(R13)2, wherein R13is as defined herein.Scheme 4LGx C3.7haloalkylorLG.,orLG\3-R3abase

[0169] As shown in Scheme 4, compounds of formula G may be alkylated using standard secondary amine alkylation conditions to provide tertiary amines F, wherein R3is -L'-G2, -C2-6alkylene-R3a, or C3-7haloalkyl; L3is a C2-6alkyiene group; LG is a leaving group (e.g., Cl, Br, L mesylate, tosylate, triflate); and R3a, Ll, and G2are as defined herein. An exemplary' set of conditions for alkylation is to heat the reactants to about 70 °C in a solvent such as DMF or DMSO in the presence of a base such as CS2CO3 Another exemplary set of alkylation conditions is to heat the reactants to about >100 °C in a sealed vessel in a microwave reactor using a solvent such as acetonitrile, DMF or DMSO in the presence of a tertiary amine base such as DIPEA.Scheme 5DIPEA, EtOH,70 °C

[0170] As shown in Scheme 5, secondary amine compounds E may be reacted with epoxides under basic conditions to provide hydroxy compounds K, wherein R30are alkyl groups, together having 2-4 carbons, or two R30, together with the carbon to which they attach form the carbocyclyl or heterocyclyl of G2(e.g., tetrahydropyranyl, cyclohexyl).Scheme 6amide coupling

[0171] As shown in Scheme 6, compounds E may be reacted with an appropriate carboxylic acid to form amide compound L, which may be reduced to generate compound M, wherein R4Ais G2, -Ci-2alkylene-G2, -Cj-salkylene-R3a, or C2-ealkyl, wherein G2and R3aare as defined herein. / Xmide coupling conditions are well known in the art and include treating the reactants with a coupling agent such as HATU, in the presence of a base (e.g., DIPEA) in a solvent such as DMF or DCM Amide reduction conditions are well known in the art and include treating the amide substrate with a reducing agent like DIBAL in DCM or LiAlEL in THF. The reaction may be conducted anywhere from -78 °C to room temperature. Compound L may also be reacted with LiAlD4 to introduce deuterium atoms in place of the carbonyl.

[0172] The amide coupling process of Scheme 6 may be used for compound G The chlorosubstituted intermediate may also be subjected to a Suzuki reaction prior to carbonyl reduction. Suitable Suzuki reaction conditions include those generally outlined in Schemes 1 and 2 and as described in the Examples herein.Scheme 7Cui, Cs2CO3, 2-lsobutyrylcyclohexanone DMF, r.t.K2CO3>BrettPhos-Pd-G3, 1,4-dioxane, H2O, 100°C

[0173] As shown in Scheme 7, compound A may be coupled with 2-chloro-5-iodopyridine to provide compound N, which in turn may be subjected to Suzuki coupling with a boronic acid G1B(OH)2 (or corresponding ester) to provide compounds O, wherein G1is as defined herein. Compounds O may be processed according to the methods described in Schemes 1 or 3-6 to append the R3group and provide compounds of general formula Q.Scheme 8Minisci reaction(NH4)2S2O8, AgNO3,H2O, H2SO472°C

[0174] Various substituted dichloropyridazine intermediates may be prepared using the Minisci reaction outlined in Scheme 8, to introduce a substituent R2b, wherein R2bis Ci-4alkyl, Ci-4fluoroalkyl, or Cb-ecycloalkyl and R2ais hydrogen, halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, or C3-6cycloalkyl. Synthetic procedures are disclosed in WO2021 / 119254 and WO2022 / 140499, which are incorporated herein by reference.(R2)mci—

[0175] Pyridazine reagentsthat may be used to prepare compounds of the invention include 3,6-dichloropyridazine, 3,6-dichloro-4-methylpyridazine, 3,6-dichloro-4-cyclopropylpyridazine, 3,6-dichloro-4-(trifluoromethyl)pyridazine, 3,6-dichloro-4-cyclopropyl-5-(trifluoromethyl)pyridazine, 4-(tert-butyl)-3,6-dichloropyridazine, 3,6-dichloro-4-(l,l-difluoroethyl)pyridazine, 3,6-dichloro-4-(2,2-difluorocyclopropyl)pyridazine, 3,6-dichloro-4-(difluoromethyl)pyridazine, 3,6-dichloro-4-cyclobutylpyridazine, 3,6-dichloro-4-methyl-5-(trifhioromethyl)pyridazine, and 3,6-dichloro-5-methylpyridazine-4-carbonitrile. The substituted pyridazine reagents are commercially available, known in the literature, or may be prepared using the synthetic processes described in WO2021 / 119254 and WO2022 / 140499.

[0176] Reductive amination conditions suitable for use in the processes of Schemes 1-2 are well known in the art. Representative reaction conditions for aldehyde reductive amination include treating the reactants with NaBH(OAc)3 in solvents such as DCM, THF, and MeOH, andmixtures thereof, optionally in the presence of a base (e.g., DIPEA). Aldehyde reductive amination may also be effected by treatment with NaBH₃CN in EtOH with heating (e.g., to about 80 °C). Ketone reductive amination may be facilitated by addition of an acid like acetic acid to the solvent mixture (e.g., DCM-THF) and heating to 40 °C for about an hour. A representative solvent ratio of DCM: THF: AcOH is (3:3:0.5). Ketone reductive amination may also be effected by treatment with Ti(OiPr)4 and NaBH₃CN or NaBH₄ in EtOH from room temperature to about 80 °C. NaBD₃CN may be used instead of NaBH₃CN to incorporate deuterium and provide compounds enriched in deuterium over protium.

[0177] Boronic acid or ester starting materials to prepare compounds of the invention may be purchased from commercial sources or prepared using procedures in the literature that are well known to those skilled in the art.

[0178] The compounds and intermediates may 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 can 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 temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), by Fumiss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England.

[0179] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.

[0180] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specificprocedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[0181] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0182] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0183] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0184] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.c. Muscarinic Acetylcholine Receptor M4 Activity

[0185] M4 is the most highly expressed mAChR subtype in the striatum and its expression is similar in rodents and primates. Due to a lack of selective M4 antagonists, mechanistic understanding of the role of M4 has been guided by biochemical and genetic studies, as well as the use of highly selective M4 positive allosteric modulators (PAMs). Highly selective M4PAMS induce robust decreases in behavioral responses to psychomotor stimulants that act by increasing striatal DA levels. Furthermore, genetic deletion of M4 increases exploratory locomotor activity, potentiates locomotor responses to amphetamine and other stimulants, and eliminates effects of M4PAMS on locomotor activity and these effects are also observed with selective deletion of M4 from striatal spiny projection neurons that express the DI subtype of DA receptor (Dl-SPNs). In vivo microdialysis studies reveal that administration of A PAMs reduces amphetamine-induced DA release in the dorsal and ventral striatum and fMRI studies show that M4PAMS reverse amphetamine-induced increases in cerebral blood flow (CBV) in striatum and other basal ganglia nuclei. More recently, fast-scanning cyclic voltammetry (FSCV) and genetic studies, demonstrated that M4 PAMs act, at least in part, by inhibition of DA release from presynaptic DA terminals in the striatum through release of an endocannabinoid from striatal spiny projection neurons (SPNs) and activation of CB2 cannabinoid receptors on DA terminals.

[0186] M4 is heavily expressed in a subset of SPNs that also express the Di subtype of DA receptor (DiDR), which form the direct pathway (Dl-SPNs) sending inhibitory projections to the substantia nigra pars reticulata (SNr). Interestingly, DiDRs activate a unique GTP -binding protein in Dl-SPNs, termed Gaoif that couples DiRs to activation of adenylyl cyclase, formation of cAMP, and activation of protein kinase A (PKA), This signaling pathway is critical for many of the behavioral actions of DA-mediated activation of motor activity Interestingly, M4 couples to Gcti / o G proteins, which inhibit adenyl yl cyclase and have the potential to directly counteract inhibit Di receptor signaling and effects on motor function. These studies raise the possibility that, in addition to inhibition of DA release, M4 PAMs may directly inhibit D lR-mediated signaling in Di-SPNs by direct inhibition of cAMP formation and this could also contribute to the powerful inhibitory effect of selective M4 activation of DA signaling in the basal ganglia. Consistent with this, M4PA S inhibit locomotor-stimulating effects of a direct acting Di agonist.Furthermore, a series of pharmacological, genetic, and molecular / cellular studies reveal that this response is mediated by inhibition of DiDR signaling in Dl-SPNs. Thus, the primary' action of M4 PAMs on DiDR signaling is not in the striatum, but on GABAergic terminals of Di-SPNs in the SNr, where activation of DiDRs induces a robust increase in GABA release. This challenges the widespread view that cholinergic regulation of striatal function is almost exclusively- mediated through ACh released from tonically active, striatal cholinergic interneurons (Chis) and raises the possibility that cholinergic innervation of the SNr from cholinergic projections from the pedunculopontine nucleus may also play a critical role in regulating motor activity and other functions of the basal ganglia direct pathway. Together, these data suggest that in addition to inhibiting DA release, M4 activation also acts postsynaptically in Di-expressing SPNs to inhibit motor function.

[0187] Consistent with a prominent role of M4 as the primary mAChR subtype involved in regulating motor function, multiple reports indicate that the locomotor-activating effects of the mAChR antagonist scopolamine are dramatically reduced in M4 knockout mice, but not the other four mAChR subtypes (Mi-3,5). Furthermore, haloperidol -induced catalepsy, a model of parkinsonian motor disability, is reduced in M4 knockout mice as compared to wild-type controls. Evaluation of the anti-parkinsonian effects of scopolamine, by assessing effects of this compound on catalepsy induced by the DA receptor antagonist haloperidol, display robust catalepsy that was completely reversed by scopolamine in WT mice. The reversal by scopolamine was uncommonly robust and more pronounced than we observe with agents targeting a number of other targets being evaluated for potential antiparkinsonian effects, including metabotropic glutamate (mGlu) receptors mGlu4 or mGlus, A2A adenosine receptors, and NMD A receptors. Importantly, scopolamine was ineffective in reducing catalepsy in M4KO mice, suggesting that the anti -cataleptic effect of scopolamine requires actions on mAChR M4. Taken together with the extensive studies of M4 modulation of basal ganglia and motor function, these studies provide compelling evidence that Miis the dominant m AChR subtype involved in the antiparkinsonian effects of non-selective mAChR antagonists and provide support for discovery and development of selective M4 antagonists for treatment of neurodegenerative disease such as PD, dystonia, tardive dyskinesia and other movement disorders.

[0188] Despite advances in mAChR research, there is still a scarcity of compounds that are potent, efficacious and selective antagonists of the M4 mAChR. Highly selective M4 antagonistsrepresent a new therapeutic approach for the treatment of neurodegenerative diseases including PD, dystonia, tardive dyskinesia and other movement disorders and may offer the clinical benefit of scopolamine, without the adverse effects mediated by a / z-mAChR inhibition.

[0189] In some embodiments, the disclosed compounds are antagonists of mAChR M4. Such activity can be demonstrated by methodology known in the art. For example, antagonism of mAChR M4 activity can be determined by measurement of calcium flux in response to agonist, e.g. acetylcholine, in cells loaded with a Ca2+-sensitive fluorescent dye (e.g., Fluo-4) and coexpression of a chimeric or promiscuous G protein. In some embodiments, the calcium flux can be measured as an increase in fluorescent static ratio. In some embodiments, antagonist activity can be analyzed as a concentration-dependent increase in the ECso acetylcholine response (i.e. the response of mAChR M4 at a concentration of acetylcholine that yields 80% of the maximal response).

[0190] In some embodiments, the disclosed compounds antagonize mAChR ME as a decrease in calcium fluorescence in mAChR M4-transfected CHO-K1 cells in the presence of the compound, compared to the response of equivalent CHO-K1 cells in the absence of the compound. In some embodiments, a disclosed compound antagonizes the mAChR M4 response with an IC50 of less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, of less than about 100 nM, or less than about 50 nM. In some embodiments, the mAChR M4-transfected CHO-K1 cells are transfected with human mAChR M4. In some embodiments, the m AChR M4-transfected CIIO-K 1 cells are transfected with rat mAChR M4. In some embodiments, the mAChR M4-transfected CHO-K1 cells are transfected with mAChR M4 from dog or cynomolgus monkey.

[0191] The disclosed compounds may antagonize mAChR M4 response in mAChR M4 - transfected CHO-K1 cells with an ICso less than the ICso for one or more of mAChR Mi, M2, M3 or Ms-transfected CIIO-K1 cells. That is, a disclosed compound can have selectivity for the mAChR M4 receptor vis-a-vis one or more of the mAChR Mi, M2, M3 or Ms receptors. For example, in some embodiments, a disclosed compound can antagonize mAChR M4 response with an ICso of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR Mi. In some embodiments, a disclosed compound can antagonize mAChR M4 response with an IC50 of about 5-fold less, about 10-foldless, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M2. In some embodiments, a disclosed compound can antagonize mAChR M4 response with an ICso of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400- fold less, or greater than about 500-fold less than that for mAChR M3. In some embodiments, a disclosed compound can antagonize mAChR M4 response with an ICso of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR Ms. In some embodiments, a disclosed compound can antagonize m AChR M4 response with an ICso of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M2-M5 receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for the mAChR Mi, M2, M3, or Ms receptors.

[0192] The disclosed compounds may antagonize m AChR Mil response in M4-transfected CHO-K1 ceils with an ICso of less than about 10 pM and exhibit a selectivity for the M4 receptor vis-a-vis one or more of the mAChR Mi, M2, M3, or Ms receptors. For example, in some embodiments, the compound can have an ICso of less than about 10 pM, of less than about 5 M, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with an ICso of about 5-fold less, 10-fold less, 20-fold less, 30-fold less, 50-fold less, 100-fold less, 200-fold less, 300- fold less, 400-fold less, or greater than about 500-fold less than that for m AChR Mi. In some embodiments, the compound can have an ICso of less than about 10 pM, of less than about 5 pM, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with an ICso of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M2. In some embodiments, the compound can have an ICso of less than about 10 pM, of less than about 5 pM, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can alsoantagonize mAChR M4 response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M3. In some embodiments, the compound can have an ICso of less than about 10 pM, of less than about 5 pM, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with an ICso of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR Ms. In some embodiments, the compound can have an ICso of less than about 10 pM, of less than about 5 pM, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with ICso of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M2-M5 receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, M2, M3, or Ms receptors, or greater than about 500-fold less than that for the mAChR Mi, M2, M3, or Ms receptors.

[0193] In vivo efficacy for disclosed compounds in models that predict antiparkinsonian activity can be measured in a number of preclinical rat models. For example, disclosed compounds may reverse deficits in motor function induced by the dopamine receptor antagonist in mice or rats. Also, these compounds may reverse deficits in motor function that are observed with other manipulations that reduce dopaminergic signaling, such as selective lesions of dopamine neurons. In addition, it is possible that these compounds will have efficacy in animal models of dystonia and may increase attention, cognitive function, and measures of motivation in animal models.3. Pharmaceutical Compositions and Formulations

[0194] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.

[0195] The pharmaceutical compositions and formulations may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, toachieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of formula (I) or any of its subformulas) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

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

[0197] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term ‘"pharmaceutically acceptable carrier,” as used herein, means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary' of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, 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.

[0198] Thus, the compounds and their physiologically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa ). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0199] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery’ systems, or iontophoresis).

[0200] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

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

[0202] Suitable lubricants include silica, talc, stearic acid and its magnesium salts 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 oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0203] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose,microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0204] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[0205] Suitable colorants include a colorant such as an FD& C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0206] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0207] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.

[0208] Suitable antioxidants include butylated hydroxy anisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.

[0209] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0210] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0211] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

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

[0213] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C. T. F. A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume1, Emulsifiers & Detergents, 1994, North American Edition, pp, 236-239, The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%.

[0214] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I) or any of its subformulas) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0215] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[0216] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the 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, fruit flavors, or a combination thereof.

[0217] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e g., a compound of formula (I) or any of its subformulas), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0218] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability,, which are not critical for the purposes of this invention.

[0219] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0220] Compositions for oral administration can have liquid forms. 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, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0221] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

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

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

[0224] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients 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, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0225] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0226] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane- 1, 3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethyl siloxane. The amount of emollient s) in a skin-based topical composition is typically about 5% to about 95%.

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

[0228] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinationsthereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0229] 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(s) in a topical composition is typically 0% to 95%.

[0230] The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[0231] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0232] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.

[0233] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0234] The pharmaceutical composition or formulation may antagonize mAChR M1 with an IC50 of less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, or less than about 100 nM. The pharmaceutical composition or formulation may antagonize mAChR M4 with an IC50 of between about 10 pM and about 1 nM, about 1 pM and about 1 nM, about 100 nM and about 1 nM, or between about 10 nM and about 1 nM.a. Spray-Dried Dispersion Formulations

[0235] The disclosed compounds may be formulated as a spray-dried dispersion (SDD). An SDD is a single-phase, amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution with the compound molecularly “dissolved” in a solid matrix. SDDs are obtained by dissolving drug and a polymer in an organic solvent and then spray-drying the solution. The use of spray drying for pharmaceutical applications can result in amorphous dispersions with increased solubility of Biopharmaceutics Classification System (BCS) class II (high permeability, low solubility) and class IV (low permeability, low solubility) drugs. Formulationand process conditions are selected so that the solvent quickly evaporates from the droplets, thus allowing insufficient time for phase separation or crystallization. SDDs have demonstrated long¬ term stability and manufacturability. For example, shelf lives of more than 2 years have been demonstrated with SDDs. Advantages of SDDs include, but are not limited to, enhanced oral bioavailability of poorly water-soluble compounds, delivery using traditional solid dosage forms (e.g., tablets and capsules), a reproducible, controllable and scalable manufacturing process and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.

[0236] Thus, in one embodiment, the disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I) or any of its subformulas.4. Methods of Use

[0237] The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treatment of disorders, such as neurological and / or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions may also be used in methods for decreasing muscarinic acetylcholine receptor activity in a mammal. The methods further include cotherapeutic methods for improving treatment outcomes. In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions.a. Treating disorders

[0238] The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treating, preventing, ameliorating, controlling, reducing, or reducing the risk of a variety of disorders, or symptoms of the disorders, in which a patient would benefit from antagonism of mAChR M4. In some embodiments, the disorder may be a neurodegenerative disorder, a movement disorder, or a brain disorder. The methods may comprise administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof.

[0239] Disorders in which a patient would benefit from antagonism of mAChR M4 may include neurodegenerative disorders and movement disorders. For example, exemplary disordersmay include Parkinson’s disease, drug-induced Parkinsonism, dystonia, Tourette’s syndrome, dyskinesias (e.g., tardive dyskinesia or levodopa-induced dyskinesia), schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness (e.g., narcolepsy), attention deficit hyperactivity disorder (ADHD), Huntington’s disease, chorea (e.g., chorea associated with Huntington’s disease), cerebral palsy, and progressive supranuclear palsy.

[0240] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject having Parkinson’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof. In some embodiments, the motor symptoms are selected from bradykinesia, tremor, rigidity, gait dysfunction, and postural instability. The method may treat the motor symptoms, control the motor symptoms, and / or reduce the motor symptoms in the subject.

[0241] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject having dystonia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof. The method may treat the motor symptoms, control the motor symptoms, and / or reduce the motor symptoms in the subject. For example, treatment may reduce muscle contractions or spasms in a subject having dystonia.

[0242] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject having tardive dyskinesia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof. The method may treat the motor symptoms, control the motor symptoms, and / or reduce the motor symptoms in the subject. For example, treatment may reduce involuntary movements in a subject having tardive dyskinesia.

[0243] In some embodiments, the disclosure provides a method of preventing or delaying tardive dyskinesia in a subject at risk of developing tardive dyskinesia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof. For example, the subject may be a subject being treated with a neuroleptic medication (e.g., a typical antipsychotic or an atypical antipsychotic), a dopamine antagonist, or an antiemetic.

[0244] In some embodiments, the disclosure provides a method of treating catalepsy in a subject suffering from schizophrenia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof. For example, the subject suffering from schizophrenia may have catalepsy induced by a neuroleptic agent (e.g., a typical antipsychotic or an atypical antipsychotic).

[0245] In some embodiments, the disclosure provides a method of treating a brain disorder characterized by altered dopamine and cholinergic signaling that could benefit from antagonism of mAChR M4, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof. For example, the treatment may increase motivation or goal-directed behavior in patients suffering from disorders characterized by reduced motivation for goal-directed behavior, such as schizophrenia and other brain disorders.

[0246] In some embodiments, the disclosure provides a method for increasing wakefulness and / or reducing excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a subject suffering from narcolepsy.

[0247] In some embodiments, the disclosure provides a method of increasing attention in a subject (e.g., a subject suffering from an attention deficit disorder such as ADHD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject having a drug-induced movement disorder, comprising administering the subject a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof. In some embodiments, the drug-induced movement disorder is selected from drug-induced parkinsonism, tardive dyskinesia, tardive dystonia, akathisia, myoclonus, and tremor. The method may treat the motor symptoms, control the motor symptoms, and / or reduce the motor symptoms in the subject.

[0249] The compounds and compositions may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The compounds and compositions may be further 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.

[0250] In the treatment of conditions such as those that would benefit from antagonism of mAChR M4, an appropriate dosage level may be about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. The dosage level may be about 0.1 to about 250 mg / kg per day, or about 0.5 to about 100 mg / kg per day. A suitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twiceper day. This dosage regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the 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 undergoing therapy.

[0251] Thus, in some embodiments, the disclosure relates to a method for antagonizing the mAChR M4 receptor in at least one cell, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one product of a disclosed method in an amount effective to antagonize mAChR M4 in the at least one cell. In some embodiments, the cell is mammalian, for example, human. In some embodiments, the cell has been isolated from a subject prior to the contacting step. In some embodiments, contacting is via administration to a subject.

[0252] In some embodiments, the invention relates to a method for antagonizing the mAChR M4 receptor in a subject, comprising the step of administering to the subject at least one disclosed compound or at least one product of a disclosed method in a dosage and amount effective to antagonize the mAChR M4 receptor in the subject. In some embodiments, the subject is mammalian, for example, human. In some embodiments, the mammal has been diagnosed with a need for mAChR M4 antagonism prior to the administering step. In some embodiments, the mammal has been diagnosed with a need for mAChR M4 antagonism prior to the administering step. In some embodiments, the method further comprises the step of identifying a subject in need of mAChR M4 antagonism.b. Antagonism of the Muscarinic Acetylcholine Receptor

[0253] In some embodiments, the disclosure relates to a method for antagonizing mAChR M4 in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof.

[0254] In some embodiments, antagonism of the muscarinic acetylcholine receptor decreases muscarinic acetylcholine receptor activity.

[0255] In some embodiments, the compound administered antagonizes mAChR M4 with an IC50 of less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, or less than about 100 nM. In some embodiments, the compound administered antagonizes mAChR M4 with an IC50 of between about 10 pM and about 1 nM, about 1 pM and about 1 nM, about 100 nM and about 1 nM, or about 10 nM and about 1 nM.

[0256] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for reduction of muscarinic acetylcholine receptor activity prior to the administering step. In some embodiments, the method further comprises the step of identifying a mammal in need of reducing muscarinic acetylcholine receptor activity. In some embodiments, the antagonism of the muscarinic acetylcholine receptor treats a disorder associated with muscarinic acetylcholine receptor activity in the mammal. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.

[0257] In some embodiments, antagonism of the muscarinic acetylcholine receptor in a mammal is associated with the treatment of a disorder associated with a muscarinic receptor dysfunction, such as a disorder disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4.

[0258] In some embodiments, the disclosure provides a method for antagonizing the muscarinic acetylcholine receptor in a cell, comprising the step of contacting the cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is mammalian (e.g., human). In some embodiments, the cell has been isolated from a mammal prior to the contacting step. In some embodiments, contacting is via administration to a mammal.c. Cotherapeutic methods

[0259] The present disclosure is further directed to administration of a mAChR M4 antagonist, such as a selective mAChR M4 antagonist, for improving treatment outcomes. That is, in some embodiments, the disclosure relates to a cotherapeutic method comprising a step of administering to a mammal an effective amount and dosage of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, administration improves treatment outcomes in the context of cognitive or behavioral therapy. Administration in connection with cognitive or behavioral therapy can be continuous or intermittent. Administration need not be simultaneous with therapyand can be before, during, and / or after therapy. For example, cognitive or behavioral therapy can be provided within 1, 2, 3, 4, 5, 6, 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 a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.

[0261] In some embodiments, administration may improve treatment outcomes in the context of physical or occupational therapy. Administration in connection with physical or occupational therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and / or after therapy. For example, physical or occupational therapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or after administration of the compound. As a further example, physical or occupational therapy can be provided within 1, 2, 3, or 4 weeks before or after administration of the compound. As a still further example, physical or occupational therapy can be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.

[0262] It is understood that the disclosed cotherapeutic methods can be used in connection with the disclosed compounds, compositions, kits, and uses.d. Combination Therapies

[0263] In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administrati on of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. / Xccordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula (I) or any of its subformulas. The abovecombinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

[0264] The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound may be used. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.

[0265] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.

[0266] The above combinations include combinations of a disclosed compound not only with one other active compound, but also with two or more other active compounds. Likewise, disclosed compounds can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which disclosed compounds are useful. Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred. Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

[0267] The weight ratio of a disclosed compound to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose ofeach will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of a disclosed compound to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0268] In such combinations a disclosed compound and other active agents can be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).

[0269] Accordingly, the disclosed compounds can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compound and the other agent can be coadministered, either in concomitant therapy or in a fixed combination.

[0270] In some embodiments, the compound can be employed in combination with any other agent that is used to treat a disorder described herein, such as a standard of care therapy for a disorder that would benefit from mAChR M4 antagonism, such as a disorder described herein. For example, in some embodiments, the compound can be employed in combination with a Parkinsonian drug (e.g., L-DOPA, or carbidopa / levodopa) an mGlui positive allosteric modulator, an mGlus negative allosteric modulator, an A2A inhibitor, a T-type calcium channel antagonist, a VMAT2 inhibitor, a muscle relaxant (e.g., baclofen), an anticholinergic agent, an antiemetic, a typical or atypical neuroleptic agent (e.g., risperidone, ziprasidone, haloperidol, pimozide, fluphenazine), an antihypertensive agent (e.g., clonidine or guanfacine), a tricyclic antidepressant (e.g., amitriptyline, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, iprindole, lofepramine, nortriptyline, protriptyline, or trimipramine) an agent that increases extracellular dopamine levels (e.g., amphetamine, methylphenidate, or lisdexamfetamine), an agent for treating excessive daytime sleepiness (e.g., sodium oxybate or a wakefulness-promoting agent such as armodafmil or modafinil), and a norepinephrine reuptake inhibitor (including selective NRIs, e.g., atomoxetine, and non-selective NRIs, e.g., bupropion).e. Modes of Administration

[0271] Methods of treatment may include any number of modes of administering a disclosedcomposition. 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 admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non¬ aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire™) In the pharmaceutical composition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.

[0272] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.

[0273] The term “parenterally,” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.5. Kits

[0274] In one aspect, the disclosure provides a kit comprising 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 and one or more of:(a) at least one agent known to increase mAChR M4 activity;(b) at least one agent known to decrease mAChR M4 activity;(c) at least one agent known to treat a disorder associated with mAChR M4, such as a disorder described herein; and(d) instructions for administering the compound.

[0275] In some embodiments, the at least one disclosed compound and the at least one agent are co-formuiated. In some embodiments, the at least one disclosed compound and the at least one agent are co-packaged. The kits can also comprise compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0276] That the disclosed kits can be employed in connection with disclosed methods of use.

[0277] The kits may further comprise information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may include the compound, a composition, or both; and information, instructions, or both, regarding methods of application of compound, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans).

[0278] The compounds and processes of the invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.6. Examples

[0279] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR. spectrometer.lH chemical shifts are reported in 6 values in ppm downfield with the deuterated solvent as the 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, integration. Reversed-phase LCMS analysis was performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, C18 column, diode-array detector (DAD) and an Agilent 6150 MSD with the following parameters. The gradient conditions were 5% to 95% acetonitrile with the aqueous phase 0.1% TFA in water over 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 pm, 1.0 x 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, and the signals used were 220 nm and 254 nm (both with a band width of 4nm). TheMS detector was configured with an electrospray ionization source, and the low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles / second, and peak width of 0.008 minutes. The drying gas flow was set to 13 liters per minute at 300 °C and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software.

[0280] Abbreviations:AcOH is acetic acid;aq is aqueousBINAP is 2,2'-Bis(diphenylphosphino)-l, 1 '-binaphthyl;Boc is tert-butyloxy carbonyl;BrettPhos-Pd-G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1, 1 biphenyl)-2-(2'-amino-l,r-biphenyl)]palladium(II) methanesulfonate (CAS Number 1470372-59-8);tBuOH is tert-butyl alcohol;Celite® is diatomaceous earth;DCE is 1,2-dichloroethane;DCM is dichloromethane;DIAD is diisopropyl azodicarboxylate;DIPEA is AGV-diisopropylethylamine;DMAP is 4-dimethylaminopyridineDMF is ACV-dimethylformamide;DMSO is dimethylsulfoxide;eq, eq., or equiv is equivalent(s);Et O is di ethyl ether;EtOAc is ethyl acetate;EtOH is ethanol;EtsN is triethylamine;HATU is 2-(7-aza-17 / -benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate; h or h. is hour(s);hex is hexane;IP A is isopropyl alcohol;LCMS is liquid chromatography mass spectrometry;LiAlD4 is lithium aluminum deuteride;LiAlH(0tBu)3 is lithium tri-tert-butoxyaluminum hydride;m-CPBA is meta-chloroperoxybenzoic acid;MeCN is acetonitrile;MeMgBr is methyl magnesium bromide;MeOH is methanol;MeOD is deuterated methanol;min or min. is minute(s);M TBE is methyl tert-butyl ether;NMP is N-methyl-2-pyrrolidone;Pd(OAc)2 is palladium! II) acetate;Pd(dppf)Ch is [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II);PPI13 is triphenylphosphine;RP-HPLC is reverse phase high-performance liquid chromatography;RuPhos-Pd-G3 is (2-dicyclohexylphosphino-2,,6,-diisopropoxy-l,r-biphenyl)[2-(2'-amino-l,r- biphenyl)]palladium(II) methanesulfonate (CAS Number 1445085-77-7);rt, RT, or r.t, is room temperature;sat. is saturated;SFC is supercritical fluid chromatography;soln, is solution;TESC1 is chlorotriethylsilane;TFA is tri fluoroacetic acid;THF is tetrahydrofuran;tosyl is toluenesulfonyl.Intermediate Example 1. (Tetrahydro-2 / 7-pyran-4-yI)methyI-< / 24-methyIbenzenesulfonate.

[0281] Lithium aluminum deuteride (2.0 g, 53 mmol, 2.5 eq) was added to THF (60 mL) at 0 °C. The resulting solution was placed under an inert atmosphere, followed by the dropwise addition of methyl tetrahydro-2H-pyran-4-carboxylate (3.0 g, 21 mmol, 1 eq). The resulting solution stirred while warming to r.t. for 2 h, after which time the reaction was chilled to 0 °C and quenched with the slow' repeated addition of 0.05 mL water and 0.15 mL of IN NaOH solution until 2 mL of water and 5 mL of NaOH solution had been added. The mixture then stirred at r.t. for 1 h, after which time the aluminum precipitate was filtered off and washed several times with THF and DCM. The organic layer was dried over MgSOi and solvents were removed under reduced pressure (2.46 g, 100%). The resulting alcohol was suspended in DCM (30 mL), followed by the addition of triethylamine (6.4 mL, 2.2 eq) and tosyl chloride (5.1 g, 27 mmol, 1.3 eq), and heated to 40 °C overnight. Solvents were concentrated and the crude residue was purified by column chromatography (3-70% EtOAc in hexanes). Fractions containing product were concentrated to yield the title compound as a white crystalline solid (3.55 g, 63% over 2 steps).lH NMR (400 MHz, CDCh) 87.77 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 3.92 (dd, J 11.6, 3.9 Hz, 2H), 3.32 (td, J ------ 11.8, 2.1 Hz, 2H), 2.44 (s, 3H), 1.91 (tt, J== 11.7, 3.9 Hz, 1H), 1.59-1.52 (m, 2H), 1.31-1.19 (m, 2H). ES-MS [M+H]+= 273.2.Intermediate Example 2. 4-(BromomethyI-d2)tetrahydro-2H-pyran

[0282] (Tetrahydro-2H-pyran-4-yl)methan-d2-ol. To a solution of lithium aluminum deuteride (1.45 g, 38.1 mmol, 1.1 eq) in THF (30 mL) was added a solution of methyl tetrahydro-2H-pyran-4-carboxylate (5.00 g, 34.7 mmol, 1 eq) in THF (70 mL) dropwise at 0 °C under an inert atmosphere. The resulting reaction mixture was warmed to r.t. and stirred for 1.5 h, after which time the reaction was cooled back to 0 °C, and H2O (1 mL), IM NaOH (1 mL) and H2O (3 mL) were added sequentially. The reaction mixture was warmed to r.t. and stirred for 5 min, after which time MgSO4 was added with additional stirring. The reaction mixture was filtered through a pad of Celite® with EtOAc. The filtrate was concentrated to afford the title compound as a slightly yellow oil which was used directly without further purification (4.10 g,100%). ’ll NMR (400 MHz, CDCI3) 54.02-3.92 (m, 2H), 3.39 (td, J ------ 11.8, 2.2 Hz, 2H), 1.78- 1.72 (m, 1H), 1.64 (ddd, J= 13.3, 4.1, 2.1 Hz, 2H), 1.39-1.20 (m, 2H).

[0283] 4-(Bromomethyl-d2)tetrahydro-2H-pyran. (Tetrahydro-2H-pyran-4-yl)methan-d -ol (4.10 g, 34.7 mmol, 1 eq) and triphenylphosphine (11.8 g, 45.1 mmol, 1.3 eq) were dissolved in DCM (100 mL) and cooled to 0 °C. Carbon tetrabromide (15.0 g, 45.1 mmol, 1.3 eq) was then added. The resulting solution was warmed to r.t. and stirred overnight under an inert atmosphere, after which time H2O was added. The aqueous layer was extracted with DCM, and combined organic extracts were washed with brine, dried over MgSO4, and solvents were filtered and removed. Crude residue was purified by column chromatography (3-20% EtOAc in hexanes) to afford the title compound as a colorless liquid (4.61 g, 73%). 'HNMR (400 MHz, CDCI3) 64.01-3.96 (m, 2H), 3.37 (td, J= 11.9, 2.1 Hz, 2H), 1.91-1.84 (m, 1H), 1.76 (ddd, J = 13.1, 4.0, 2.0 Hz, 2H), 1.40-1.30 (m, 2H).Intermediate Example 3. Tetrahydro-2 / / -pyran-4-carboxylic-2,2,6,6-< / 4 acid

[0284] (E)-Diethyl 3-styryIpentanedioate. A mixture of cinnamaldehyde (60 g, 456 mmol, 57.4 mL, 1 eq), 3 -ethoxy-3 -oxopropanoic acid (301.4 g, 2281 mmol, 5 eq), and DMAP (11.2 g, 91.3 mmol, 0.2 eq), in pyridine (210 mL) was degassed and purged withN2, and the mixture was stirred at 60 °C for 20 h under an inert atmosphere. The mixture was then stirred at 140 °C for 48 h. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was then diluted with H2O and extracted with MTBE. The combined organic layers were washed with HC1 (15%) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh,petroleum ether / ethyl acetate::::1 / 0 to 10 / 1) to afford the title compound as a yellow solid (27 g, 61%). ‘HNMR (400 MHz, CDCh) 57.27-7.37 (m, 4H) 7.17-7.25 (m, 1H) 6.48 (d, J= 15.9 Hz, 1H) 6.12 (dd, J = 15.8, 8.4 Hz, 1 H) 4.13 (q, J= 7.1 Hz, 4 H) 3.23 (dq, J= 14.6, 7.2 Hz, 1 H) 2.52 (qd,. / = 15.4, 7.1 Hz, 4 H) 1.23 (t, J= 7.1 Hz, 6H).

[0285] 1,1, 5, 5-Tetradeuter io-3-[(E)-styryI] pentane- 1,5-diol. To a solution of lithium aluminum deuteride (7,60 g, 180,8 mmol, 1.5 eq) in THF (80 mL) was added (E)-diethyl 3-styrylpentanedioate (35 g, 120.5 mmol, 1 eq) in THF (350 mL) dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 1 h. To the reaction mixture was added H? O (76 mL), 15% NaOH aq solution (76 mL) and H2O (227 mL) sequentially, with stirring. MgSCh was added with stirring, and the reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound as a white solid (20.4 g, 80%). ’HNMR (400 MHz, CDCh) 57.27-7.37 (m, 4H) 7.17-7.23 (m, 1H) 6.43 (d, J= 15.8 Hz, 1 H) 5.96 (dd, J === 15.9, 9.1 Hz, 1H) 2.54 (qt, J ------ 92, 4.8 Hz, 1H) 1.72 (dd,. / 13.8, 4.9 Hz, 2H) 1.52-1.64 (m, 2H).

[0286] 2, 2, 6, 6-Tetradeuterio-4-[(E)-styryI] tetrahydropyran. A mixture of 1,1, 5,5-tetradeuterio-3-[(E)-styryl]pentane-l,5-diol (14 g, 66.6 mmol, 1 eq), and TsOH (2.29 g, 13.3 mmol, 0.2 eq) in toluene (140 mL) was heated to reflux with a Dean-Stark trap at 140 °C for 12 h. The resulting residue was poured into sat. NaHCCh solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried with anhydrous NazSCh, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate:::20 / 1 to 5 / 1) to affordthe title compound as a colorless oil (7.23 g, 56%).1H NMR (400 MHz, CDCh) 37.28-7.41 (m, 4H) 7.20-7.26 (m, 1H) 6.41 (d, J= 16.0 Hz, 1H) 6.18 (dd, J= 16.0, 6.8 Hz, 1 H) 2.34-2.46 (m, 1H) 1.68-1.75 (m, 2H) 1.52-1.63 (m, 2H).DD D

[0287] 2,2,6,6-Tetradeuteriotetrahydropyran-4-carbaIdehydc. Ozone was bubbled into a solution of 2,2,6, 6-tetradeuterio-4-[(E)-styryl]tetrahydropyran (6.0 g, 31.2 mmol, 1 eq) in DCM (90 mL) and MeOH (18 mL) at -78 °C for 30 min. After excess O3 was purged by N2, Me₂S (22 L) was added at 20 °C for 2 h. The reaction mixture was concentrated to afford the crude product. The crude residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate= 10 / 1 to 1 / 1) to afford the title compound as a colorless oil (3.05 g, 83%).1H NMR (400 MHz, CDCh) 89.64 (s, 1H) 2.43-2.55 (m, 1H) 1.83 (dd, J= 13.8, 4.1 Hz, 2 H) 1.63- 1.71 (m, 2H).O ADHO'^ y^y-DL,0D D

[0288] 2,2,6,6-Tetradeuteriotetrahydropyran-4-carboxylic acid. To a solution of 2,2,6,6-tetradeuteriotetrahydropyran-4-carbaldehyde (3.0 g, 25.4 mmol, 1 eq) in t-BuOH (30 mL), H2O (10 mL) and THF (15 mL) was added NaCICh (6.89 g, 76.2 mmol, 3 eq), NaH₂PO₄ (9.14 g, 76.2 mmol, 3 eq) and 2-methylbut-2-ene (14.2 g, 203 mmol, 21.5 mL, 8 eq). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was then quenched by addition H2O at 20 °C and was then adjusted to pH 2 with IM HC1 and extracted. The combined organic layers were washed with brine and dried over Na2SO4. Solvents were filtered and concentrated under reduced pressure to afford the title compound as a white solid (2.1 g, 62%).1H NMR (400 MHz, CDCh) 89.76-12.28 (m, 1H) 2.58 (tt, J - 10.8, 4.3 Hz, 1 H) 1.83-1.91 (m, 2H) 1.73-1.83 (m, 2H).Example 1. (R)-6-(2-Chloro-5-fluorophenyl)-N-((1-(3,3-dimethylbutyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine

[0289] tert-Butyl (!?)-3-(((6-chIoropyridazin-3-yI)amino)methyl)pyrrolidine-l-carboxylate. tert-Butyl ( / ?)-3 -(ami nomethyl)pyrrolidine-l -carboxylate (274 mg, 1.37 mmol, 1 eq), 3,6-dichloropyridazine (611 mg, 4.10 mmol, 3 eq) and DIPEA (0.71 mL, 4.10 mmol, 3 eq) were combined in t-BuOH (3 mL), and the resulting reaction mixture was stirred under microwave irradiation at 150 °C for 2 h, after which time solvents were concentrated under reduced pressure, and the crude residue was purified by column chromatography (3-100% EtOAc in hexanes) to give the title compound as an orange oil (168 mg, 39%).lH NMR (400 MHz, CDCh) 87.17 (d, J= 9.8 Hz, 1H), 6.67 (d, J= 9.3 Hz, 1H), 5.11 - 5.00 (m, 1H), 3.61 -3.27 (m, 5H), 3.11 (dt, J= 32.7, 9.2 Hz, 1H), 2.66 - 2.54 (m, 1H), 2.09 - 2.01 (m, 1H), 1.74 - 1.63 (m, 1H), 1.45 (s, 9H); ES-MS [M+l]+= 313.2.

[0290] tert-Butyl ( / ?)-3-(((6-(2-chloro-5-fluorophenyI)pyridazin-3-yl)amino)methyl)pyrrolidine-l-carboxylate. tert-Butyl (R)-3-(((6-chloropyridazin-3-yl)amino)methyl)pyrrolidine-l-carboxylate (165 mg, 0.53 mmol, 1 eq), potassium carbonate (222 mg, 1.58 mmol, 3 eq), 2-chloro-5-fluorophenylboronic acid (138 mg, 0.79 mmol, 1.5 eq) and RuPhos-Pd-G3 (44 mg, 0.053 mmol, 0.1 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. 10:1 l,4-Dioxane / H2O solution (5 mL total, degassed under vacuum) was then added via syringe. The resulting reaction mixture w'as stirred at 100 °C for 3 h, after which time the reaction mixture was cooled to r.t. and diluted with DCM and H2O. The aqueous layer was extracted with DCM, and the combined organic extracts were dried overMgSOi. Solvents were filtered and concentrated, and the crude residue was purified by column chromatography (3-80% EtOAc in hexanes) to give the title compound as an orange oil (114 mg, 53%). 'HNMR (400 MHz, CDCh) 67.64 (d, J = 9.3 Hz, 1H), 7.48 (dd, J= 9.1, 3.1 Hz, 1H), 7.42 (dd,.7 = 8.8, 5.1 Hz, 1H), 7.06 (ddd,.7= 8.8, 7.6, 3.1 Hz, 1H), 6.72 (d,.7= 9.2 Hz, 1H), 5.19 - 5.11 (m, 1H), 3.69 - 3.29 (m, 5H), 3.15 (dt, J= 32.2, 9.1 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.13 -2.05 (m, 1H), 1.79 - 1.65 (m, 1H), 1.46 (s, 9H); ES-MS [M+l] = 407.3.H NF-

[0291] (R)-6-(2-Chloro-5-fluorophenyl)-N-((1-(3,3-dimethylbutyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine. tert-Butyl (7?)-3-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)methyl)pyrrolidine-l -carboxylate (107 mg, 0.26 mmol, 1 eq) was dissolved in 1,4-dioxane (2 mL) and 4M HC1 in dioxane solution (2 mL) was added. The resulting reaction mixture was stirred at r.t. for 1 h, after which time solvents were concentrated, and the resulting HC1 salt was dried under vacuum and used directly without additional purification (90 mg, 100%). To a suspension of the HC1 salt (18 mg, 0.052 mmol, 1 eq) and 3, 3 -dimethylbutanal (16 mg, 0.16 mmol, 3 eq) in DCM (1 mL) was added sodium triacetoxyborohydride (33 mg, 0.16 mmol, 3 eq). The resulting reaction mixture was stirred at r.t. for 1 h, after which time the reaction mixture was quenched with the addition of sat. NaHCCh solution, and stirred for 10 min. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC (5-35% MeCN in 0.1 % aqueous TFA solution over 5 min). Fractions containing product were basified with sat. NaHCCh solution and extracted with DCM. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (10.2 mg, 50%).1H NMR (400 MHz, MeOD) 87.58 (d, J= 9.3 Hz, 1H), 7.54 (dd, J= 8.9, 5.0 Hz, 1H), 7.34 (dd, 9.0, 3.1 Hz, 1H), 7.20 (ddd, J= 8.8, 7.9, 3.1 Hz, 1H), 6.95 (d, 7 = 9.3 Hz, 1H), 3.51 - 3.42 (m, 2H), 2.90 (dd, J= 9.8, 7.9 Hz, 1H), 2.76 - 2.69 (m, 1H), 2.67 - 2.60 (m,2H), 2.58 - 2.48 (m, 211), 2.39 (dd,. / 9.8, 6.7 Hz, IH), 2.13 - 2.04 (m, IH), 1.67 - 1.58 (m, 1H), 1.50 - 1.46 (m, 2H), 0.94 (s, 9H); ES-MS [M+l]+= 391.4.

[0292] (R)-6-(2-Chloro-5-fluorophenyl)-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine. The title compound was prepared in analogous fashion using 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde. ES-MS [M+l]+= 419.3.Example 2. (R)-1-((3-(((6-(2-Chloro-5-fluorophenyl)pyridazin-3-yl)amino)methyl)pyrrolidin-1-yl)methyl)cycloheptan-1-ol

[0293] To a solution of (R)-6-(2-chloro-5-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)pyridazin-3-amine hydrochloride (18 mg, 0.053 mmol, 1 eq) and DIPEA (0.046 mL, 0.26 mmol, 5 eq) in EtOH (1 mL) was added l-oxaspiro[2.6]nonane (33 mg, 0.26 mmol, 5 eq). The resulting reaction mixture was stirred at 70 °C overnight, after which time the reaction mixture was cooled to r.t. and solvents were concentrated. The crude residue was purified by RP-HPLC (5-35% MeCN in 0.1 % aqueous TFA solution over 5 min). Fractions containing product were basified with sat. NaHCCh solution and extracted with DCM. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (8.6 mg, 38%). 'H NMR (400 MHz, MeOD) 67.57 (d, J= 9.3 Hz, IH), 7.54 (dd, J = 8.9, 5.0 Hz, IH), 7.35 (dd, J= 9.0, 3.1 Hz, IH), 7.20 (ddd, J= 8.9, 7.9, 3.1 Hz, IH), 6.95 (d, J = 9.3 Hz, IH), 3.45 (d,. / = 6.7 Hz, 2H), 2.90 - 2.79 (m, 2H), 2.74 -- 2.68 (m, IH), 2.62 - 2.46(m, 4H), 2.08 - 1.99 (m, 1H), 1.71 - 1.49 (m, 11H), 1.46 - 1.37 (m, 2H); ES-MS [M+1]+= 433.4.Example 3. (R)-6-(5-Fluoro-2-methylphenyl)-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine

[0294] (R)-6-Chloro-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine. tert-Butyl (7?)-3-(((6-chloropyridazin-3-yl)amino)methyl)pyrrolidine-l -carboxylate (1.32 g, 4.22 mmol, 1 eq) was dissolved in 1,4-dioxane (20 mL) and MeOH (5 mL), and 4M HC1 in dioxane solution (25 mL) was added. The resulting reaction mixture was stirred at r.t. for 2 h, after which time solvents were concentrated, and the resulting HCl salt was dried under vacuum and used directly without additional purification (1.05 g, 100%). To a suspension of the HC1 amine (1.05 g, 4.22 mmol, 1 eq) and 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (1.62 g, 12.66 mmol, 3 eq) in DCM (25 mL) was added sodium triacetoxyborohydride (2.68 g, 12.66 mmol, 3 eq). The resulting reaction mixture was stirred at r.t. overnight, after which time the reaction mixture was quenched with the addition of sat. NaHCCh solution, and stirred for 20 min. The aqueous layer was extracted with DCM, and the combined organic extracts were dried over MgSCh. Solvents were filtered and concentrated to give the title compound as an orange oil, which was dried under vacuum and used without further purification (1.17 g, 85% yield). ’H NMR (400 MHz, MeOD) 67.30 (d, J = 9.4 Hz, 1H), 6.90 (d,. / 9.4 Hz, 1 H), 3.93 - 3.89 (m, 2H), 3.43 - 3.37 (m, 4H), 2.88 (dd, J = 9.8, 7.9 Hz, 1H), 2.73 (ddd, J = 9.6, 7.7, 6.2 Hz, 1H), 2.67 - 2.51 (m, 4H), 2.38 (dd, J= 9.8, 6.7 Hz, 1H), 2.11 - 2.02 (m, 1H), 1.66 - 1.47 (m, 6H), 1.33 - 1.23 (m, 2H); ES-MS [M+l]+= 325.3.

[0295] (R)-6-(5-Fluoro-2-methylphenyl)-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine. (R)-6-Chloro-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine (23 mg, 0.072 mmol), potassium carbonate (30 mg, 0.22 mmol, 3 eq), 5-fluoro-2-methylphenylboronic acid (17 mg, 0.11 mmol, 1.5 eq) and BrettPhos-Pd-G3 (6.0 mg, 0.007 mmol, 0.1 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. 10:1 l,4-Dioxane / H2O solution (1 mL total, degassed under vacuum) was then added via syringe. The resulting reaction mixture was stirred at 100 °C for 2 h, after which time the reaction mixture was cooled to r.t. and diluted with DCM and H2O. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC (2-32% MeCN in 0.1% aqueous TFA solution over 5 min). Fractions containing product were basified with sat. NaHCCh solution and extracted with DCM. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (6.6 mg, 23%). 'HNMR (400 MHz, MeOD) 07.40 (d, 9.3 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.11 - 7.03 (m, 2H), 6.96 (d,. / 9.3 Hz, 1 H), 3.93 - 3.89 (m, 2H), 3.46 - 3.37 (m, 4H), 2.89 (dd, J= 9.7, 7.9 Hz, 1H), 2.72 (ddd, J= 9.6, 7.8, 6.2 Hz, 1H), 2.67 - 2.60 (m, 2H), 2.60 - 2.50 (m, 2H), 2.39 (dd, 9.7, 6.6 Hz, 1H), 2.29 (s, 3H), 2.13 -2.04 (m, 1H), 1.67 - 1.48 (m, 6H), 1.33 - 1.23 (m, 2H); ES-MS [M+l]+= 399.5.

[0296] (R)-6-(2-Chloro-5-fluorophenyl)-N-((1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine. The title compound was prepared in analogous fashion using tetrahydro-2H-pyran-4-carbaldehyde. ES-MS [M+1]+= 405.2.

[0297] (S)-6-(2-Chloro-5-fluorophenyl)-N-((1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine. The title compound was prepared in analogous fashion using tert-butyl (5)-3-(aminomethyl)pyrrolidine-l -carboxylate and tetrahydro-2H-pyran-4-carbaldehyde. ES-MS [M+1]+= 405.2.F

[0298] (R)-N-((1-((Tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-amine. The title compound was prepared in analogous fashion using 2,3,5-trifluorophenylboronic acid and tetrahydro-2H-pyran-4-carbaldehyde. ESMS [M+l]+===: 407.3.

[0299] (R)-N-((1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-amine The title compound was prepared in analogous fashion using (2-(trifluoromethyl)pyridin-3-yl)boronic acid. ES-MS [M+l]+= 436.4.Example 4. (R)-6-(5-Fluoro-2-methylphenyl)-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridin-3-amine

[0300] tert-Butyl (R)-3-(((6-chloropyridin-3-yl)amino)methyl)pyrrolidine-1-carboxylate. tert-Butyl ( / ?)-3 -(ami nomethyl)pyrrolidine-l -carboxylate (544 mg, 2.71 mmol, 1.3 eq), 2-chloro-5-iodopyridine (500 nig, 2.09 mmol, 1 eq), cesium carbonate (1.37 g, 4.18 mmol, 2 eq), and Cui (20 mg, 0.10 mmol, 0,05 eq) were combined in DMF (2 mL) and 2-isobutyrylcyclohexanone (0.070 mL, 0.42 mmol, 0.2 eq) was added. The resulting reaction mixture was stirred under an inert atmosphere for 4 days, after which time solids were removed by filtration, and the filtrate was further diluted with EtOAc and H2O. The organic layer was washed with H2O, and dried over MgSCU. Solvents were filtered and concentrated, and the crude residue was purified by column chromatography (3-100% EtOAc in hexanes) to give the title compound as a colorless oil (413 mg, 63%). 'HNMR (400 MHz, CDCI3) 57.78 (d, J= 3.1 Hz, 1H), 7.10 (d, J= 8.6 Hz, 1H), 6.88 (dd, J = 8.6, 3.0 Hz, 1H), 3.61 - 3.40 (m, 2H), 3.40 - 3.28 (m, 1H), 3.17 - 3.03 (m, 3H), 2.53 - 2.42 (m, 1H), 2.10 - 2.02 (m, 1H), 1.75 - 1.62 (m, 1H), 1.46 (s, 9H); ES-MS [MH]+= 256.1 (-Boc).

[0301] (R)-6-Chloro-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridin-3-amine. tert-Butyl (R)-3-(((6-chloropyridin-3-yl)amino)methyl)pyrrolidine-1-carboxylate (410 mg, 1.32 mmol, 1 eq) was dissolved in 1,4-di oxane (5 mL) and MeOH (1 mL), and 4M HC1 in 1,4-dioxane solution (5 mL) was added. The resulting reaction mixture was stirred at r.t. for 1 h, after which time solvents were concentrated, and the resulting HC1 salt was dried under vacuum and used without further purification (326 mg, 100%). To a suspension of the HC1 amine (326 mg, 1.32 mmol, 1 eq) and 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (506mg, 3.95 mmol, 3 eq) in DCM (7 mL) was added sodium triacetoxyborohydride (836 mg, 3.95 mmol, 3 eq). The resulting reaction mixture was stirred at r.t. for 1 h, after which time the reaction mixture was quenched with the slow addition of sat. NaHCCh solution, and stirred for 20 min. The aqueous layer was extracted with DCM, and the combined organic extracts were dried over MgSO₄. Solvents were filtered and concentrated, and the crude residue was purified by RP-HPLC (5-40% MeCN in 0.05% aqueous NH4OH over 20 min). Fractions containing product were concentrated to give the title compound as a colorless oil (93 mg, 22%). ’H NMR (400 MHz, MeOD) δ7.69 (dd, J= 3.0, 0.6 Hz, 1H), 7.14 (dd, 8.7, 0.6 Hz, 1H), 7.04 (dd, J = 8.7, 3.1 Hz, 1H), 3.94 - 3.88 (m, 2H), 3.43 - 3.37 (m, 2H), 3.07 (d, J= 7.3 Hz, 2H), 2.83 (dd, J = 9.7, 7.8 Hz, 1H), 2.69 - 2.59 (m, 2H), 2.57 - 2.47 (m, 3H), 2.36 (dd, J = 9.7, 6.4 Hz, 1H), 2.11 - 2.02 (m, 1H), 1.68 - 1.46 (m, 6H), 1.36 - 1.23 (m, 2H); ES-MS [M+1]+= 324.3.HN

[0302] (R)-6-(5-Fluoro-2-methylphenyl)-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridin-3-amine. (R)-6-Chloro-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)pyridin-3-amine (22 mg, 0.069 mmol, 1 eq), potassium carbonate (29 mg, 0.21 mmol, 3 eq), 5-fluoro-2-methylphenylboronic acid (16 mg, 0.10 mmol, 1.5 eq) and BrettPhos-Pd-G3 (5.8 mg, 0.007 mmol, 0.1 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. 10:1 l,4-Dioxane / H2O solution (1 mL total, degassed under vacuum) was then added via syringe. The resulting reaction mixture was stirred at 100 °C for 2 h, after which time the reaction mixture was cooled to r.t. and diluted with DCM and H2O. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC (2-32% MeCN in 0.1% aqueous TFA solution over 5 min). Fractions containing product were basified with sat. NaHCO₃ solution and extracted with DCM. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (11.6 mg, 42%).lH NMR (400 MHz, MeOD) 67.99 (dd, J= 2.9, 0.7 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.11 (dd, 8.6, 2.9 Hz, 1H), 7.03 - 6.96 (m, 2H), 3.94 - 3.89 (m, 2H), 3.44 - 3.37 (m,2H), 3.16 (d, J = 7.3 Hz, 2H), 2.90 (dd, J = 9.8, 7.9 Hz, 1H), 2.76 - 2.67 (m, 2H) 2.63 - 2.52 (m, 3H), 2.44 (dd, J= 9.8, 6.5 Hz, 1H), 2.25 (s, 3H), 2.15 - 2.06 (m, 1H), 1.67 - 1.49 (m, 6H), 1.34 - 1.24 (m, 2H); ES-MS [M+1]+= 398.5.HN

[0303] (R)-N-((1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-2'-(trifluoromethyl)-[2,3'-bipyridin]-5-amine. The title compound was prepared in analogous fashion using (2-(trifluoromethyl)pyridin-3-yl)boronic acid. ES-MS [M+1]+= 435.3.

[0304] The compounds shown in Table 1 may be prepared similarly to the compounds described above, with appropriate starting materials. Additional starting materials that may be used to prepare compounds of the invention include tert-butyl 3 -(aminomethyl )-3-fluoropyrrolidine- 1 -carboxylate, tert-butyl 3 -(aminomethyl)-3 -methylpyrrolidine- 1 -carboxylate, tetrahydro-2H-pyran-4-carbaldehyde, (S)-(l,4-dioxan-2-yl)methanol), (R)-(l,4-dioxan-2-yl)methanol), (S)-l,4-dioxane-2-carboxylic acid, (R)-l,4-dioxane-2-carboxylic acid, (S)-tetrahydro-2H-pyran-2-carboxylic acid, (R)-tetrahydro-2H-pyran-2-carboxylic acid, (S)~ tetrahydro-2H-pyran-3-carboxylic acid, (R)-tetrahydro-2H-pyran-3 -carboxylic acid, 4-fluorotetrahydro-2H-pyran-4-carboxylic acid, 4-methoxytetrahydro-2H-pyran-4-carboxylic acid, 3-methyltetrahydro-2H-pyran-3-carboxylic acid, 2-methyltetrahydro-2H-pyran-2-carboxylic acid, 4-ethyltetrahydro-2H-pyran-4-carboxylic acid, 2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid, 3,3-dimethyltetrahydro-2H-pyran-4-carboxylic acid, 2, 2,6,6-tetramethyltetrahydro-2H-pyran-4-carboxylic acid, (S)-tetrahydrofuran-3-carboxylic acid, (R)-tetrahydrofuran-3 -carboxylic acid, (R)-(tetrahydrofuran-3 -yl)methanol, 2-(tetrahy dro-2H-pyran- 4-yl)acetaldehyde, 4-methyltetrahydro-2H-pyran-4-carbaldehyde, 4-methyltetrahydro-2H-pyran-4-carboxylic acid, rac-(lR,2S,4S)-2-(bromomethyl)-7-oxabicyclo[2.2. l]heptane, rac-(lR,2R,4S)-2-(bromomethyl)-7-oxabicyclo[2.2.1]heptane, rac-(3aR,6aS)-hexahydro-2H-cyclopenta[b]furan-3a-carboxylic acid, octahydro-3 aH-cy cl ohepta[b]furan-3a-carboxylic acid, 2, 2,6,6-tetramethyltetrahydro-4H-pyran-4-one, 2-oxaspiro[3.3]heptan-6-one, l,6-dioxaspiro[2.5]octane,cyclohexanecarbaldehyde, cycloheptanecarbaldehyde, cyclohexanone, picolinaldehyde, 6-methylpicolinaldehyde, 6-methoxypicolinaldehyde, 4-chloropicolinaldehyde, 6-chloropicolinaldehyde, 5-fluoropicolinaldehyde, 6-fluoropicolinaldehyde, 3-methylpicolinaldehyde, l-(pyridin-2-yl)ethan-l-one, 6,7-dihydro-4H-pyrazolo[5,l-c] [ 1,4]oxazine-2-carbaldehyde, 2,2-difluorobenzo[d] [ 1,3]dioxole-5-carbaldehyde, pyridazine-4-carbaldehyde, 1-fluorocyclohexane-l-carboxylic acid, 2 -fluorobenzaldehyde, 2,3-difluorobenzaldehyde, 2,4-difluorobenzaldehyde, 2,6-difluorobenzoic acid and 3,3-di fl uorote trahy dro- 2 H-py r an-4-carb oxy 1 i c aci d.Table 1Cpd. ES-MS Name StructureNo. [M+l]+(R)-N -(( 1 -((tetrahydro-2H-pyran-4- 1 yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- 422.3 (trifluoromethyl)pyridin-3-yl)pyridazin-3- araine(R)-N-(( 1 -((tetrahydro-2H-pyran-4- 2 yl)methyl)pyrrolidin-3-yl)methyl)-6- 407.3 (2,3,5 -trifluorophenyl)pyridazin-3 -amine(R)-6-(2-chIoro-5-fluorophenyl)-N-((l- H N— ~ ' 3 ((tetrahydro-2H-pyran-4- 405.2 yl)methyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amineCpd. ES-MS Name StructureNo, [M+l]+z~O(R)-6-(2 -methyl -2H-indazol-5-yl)-N-(( 1 - H P N— - >4 ((tetrahydro-2H-pyran-4- 407.3 yl)methyl)pyrrolidin-3- yl)methyl )pyridazin-3 -amine ~CTTN"Nr~ 0(S)-N-(( 1 -((tetrahydro-2H-pyran-4- H I |\| —5 yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- 422.3 (trifluoromethyl)py ridin-3 -yl)pyridazin -3 - amine N NwQ' / ' / " Z\—.(S)-N-(( 1 -((tetrahydro-2H-pyran-4- 6 yl)methyl)pyrrolidin-3-yl)methyl)-6- 407.3 / (2,3, 5 -trifluorophenyl)pyridazin- 3 -amines(S)-6-(2-chloro-5-fluorophenyl)-N-((l- 7 ((tetrahydro-2H-pyran-4- 405.2 yl)m ethyl)pyrroli din-3- yl)methyl)pyridazin-3 -amine(R)-6-(2-chloro-5-fluorophenyl)-N-((l- 8 (tetrahydro-2H-pyran-4-yl)pyrrolidin-3- 391.3Nyl)methyl )pyrid azin-3 -amine(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(2- 9 (tetrahydro-2H-pyran-4- 419.3 yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin- 3 -amineCpd. ES-MS Name StructureNo, [M+l]+6-(2-chloro-5-fluorophenyl)-N-(((3R)-l- ((2,2-dimethyltetrahydro-2H-pyran-4- s10 433.4 yl)methyl)pyrrolidin-3- Z V- yl)methyl)pyridazin-3 -amineQ \= / LL(R)-l-((3-(((6-(2-chloro-5- 11 fluorophenyl)pyridazin-3 - T1 T1 T| 433.4 yl)amino)methyl)pyrrolidin- 1 - yl)methyl)cycloheptan- 1 -ol 4 ~n m — —y o Q / =\=\ z az n / / cZI(R)-6-(2-chloro-5-fluorophenyl)-N-(( 1 - 12 (3,3 -dim ethylbutyl)pyrrolidin-3 - 391.4 yl)methyl)pyridazin-3 -amineb5(R)-6-chloro-N-((l-(2-(tetrahydro-2H- H \ \ O p' / 13 pyran-4-yl)ethyl)pyrrolidin-3- 325.2 yl)methyl)pyridazin-3 -amine CI'X|sfN(R)-N-(( 1 -(2-(tetrahydro-2H-pyran-4- 14 y1)ethyl)pyrroIidin-3-yI)methyl)-6-(2- 436.4 (trifluoromethyl )pyri din-3 -yl)pyridazin-3 - amineu(R)-N-(( 1 -(2-(tetrahydro-2H-pyran-4- 15 yl)ethyl)pyrrolidin-3 -yl)methyl)-6-(2,3,5 - 421.4 trifluorophenyl)pyridazin-3-amineCpd. ES-MS Name StructureNo, [M+l]+2(R)-6-(5-fluoro-2-methylphenyl)-N-((l-(2- X 2 2216 ( tetrah ydro-2H-pyran-4- 399.5 yl)ethyi)pyrrolidin-3-yi)methyl)pyridazin- 3 -amine s3 / / A - (R)-6-(2-methyl-2H-indazol-5-yl)-N-((l- f \ \ / / 17 (2-(tetrahydro-2H-pyran-4- o 421.4 yl)ethyI)pyrrolidin-3-yI)methyl)pyridazin- ) 3, \ oz. ~3 -amineT(R)-6-(2-methylpyridin-3-yl)-N-((l-(2- H j \ P 18 (tetrahydro-2H-pyran-4- 382.3 yl)ethyI)pyrrolidin-3-yI)methyl)pyridazin- 3 -anime6^(R)-6-(5-fluoro-2-methoxyphenyl)-N-((l- 19 (2-(tetrahydro-2H-pyran-4- 415.5 yl)ethyI)pyrrolidin-3-yI)methy1)pyridazin- 3 -amine(R)-N-(( 1 -(2-(tetrahydro-2H-pyran-4- 20 yl)ethyl)pyrrolidin-3-yl)methyl)-6-(4- 436.4 (trifluoromethyl)pyridin-3-yl)pyridazin-3- aniine(R)-6-( 1,3 -dimethyl- IH-py razol-4-y 1)-N - 21 ((1 -(2-(tetrahy dro-2H-pyran-4- 385.4 yl)ethyI)pyrrolidin-3-yl)methyl)pyridazin- 3 -anime(R)-6-(2,2-difluorobenzo [d] 11,3 ]dioxol-5 - 22 yl)-N-(( 1 -(2-(tetrahydro-2H-pyran-4- 447.4 yl)ethyI)pyrrolidin-3-yI)methyl)pyridazin- 3 -anime(R)-6-(benzo[d]thiazol-6-yl)-N-((l-(2- H r \ p 23 (tetrahydro-2H-pyran-4- 424.4 yl)etliyl)pyrrolidin-3-yl)methyl)pyridazin- 3 -amine M JCpd. ES-MS Name StructureNo, [M+l]+H R KI— / 2- ( - 2 ( e X 2 \ P(R)-N ( 1 ( - t trahydro-2H-pyran-4- 24 yl)ethyl)pyrrolidin-3-yl)methyl)-2'- 435.3 (trifluoromethy 1) - [2, 3 ' -bipyridin] -5 -amineT. Z. y' / / (R)-6-(2-chloro-5-fluorophenyl)-N-((l-(2- Q \= / 25 (tetrahydro-2H-pyran-4- 418.4 yl )ethyl)pyrrolidin-3 -yl)methyl)pyridin-3 - amine U- LUH N— / C_ / °(R)-N-(( 1 -(2-(tetrahydro-2H-pyran-4- 26 yl)ethyl)pyrrolidin-3 -yl)methyl)-6-(2,3,5 - 420.4 trifluorophenyl)pyridin-3-amineF(R)-6-(5-fluoro-2-methylphenyl)-N-((l-(2- 27 ( tetrah ydro-2H-pyran-4- 398.5 yl)ethyl)pyrrolidin-3-yl)methyl)pyridin-3- araine(R)-6-(2,6-dimethylpyridin-3-yl)-N-((l-(2- 28 ( tetrah ydro-2H-pyran-4- 396.5 yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin- 3 -amine(R)-6-(2-isopropoxypyridin-3-yl)-N-((l- JL N CZ / ° 29 (2-(tetrahydro-2H-pyran-4- 426.5 yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin- 3 -anime(R)-6-(2-cyciopropylpyridin-3-yI)-N-((l- 30 (2-(tetrahydro-2H-pyran-4- JUu 408.6 yl)ethyl)pyiTolidin-3-yl)methyl)pyridazin- N 'V N3 -amine |l JCpd. ES-MS Name StructureNo, [M+l]+(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(2- 9231 (tetrahydro-2H-pyran-4- 487.2 yl)ethyl)pyrrolidin-3 -yl)m ethyl)-4- (trifluoromethyl)pyridazin-3-amine A(R)-N-(( 1 -(2-(tetrahydro-2H-pyran-4- 32 yl)ethyi)pyrrolidin-3 -yl)m ethyl)-4- U489.2 (tri fluoromethyl )-6-(2,3, 5 - trifluorophenyl)pyridazin-3-amine(R)-6-(5-fluoro-2-methylphenyl)-N-((l-(2- T O vXT}O33 ( tetrah ydro-2H-pyran-4- yl) y J o==\L 467.2 ethyI)pyrrolidin-3 -yl)methy1 )-4- (trifluoromethyi)pyridazin-3-amine C X(R)-N-((l-(2-(tetrahydro-2H-pyran-4- yl)ethyi)pyrrolidin-3-yl)methyl)-4- 34 (trifluoromethyl)-6-(2- 504.2 (trifluoromethyl)py ridin-3 -yl)pyridazin-3 - aminel \ \ J(R)-6-(2-methylpyridin-3-yl)-N-((l-(2- 35 ( tetrah ydro-2H-pyran-4- 450.3 yl)ethyI)pyrrolidin-3 -yl)methy1 )-4- AV(trifluoromethyi)pyridazin-3-amine(R)-6-(2-cyclopropylpyridin-3-yl)-N-((l- 36 (2-(tetrahydro-2H-pyran-4- 476.3 yl)ethyI)pyrrolidin-3 -yl)methy1 )-4- V(trifluoromethyi)pyridazin-3-amine(R)-6-(2 -methyl -2H-indazol-5-yl)-N-(( 1 - 37 (2-(tetrahydro-2H-pyran-4- 489.3 yi)ethyl)pyrrolidin-3-yl)methyl)-4- (trifluoromethyl)pyridazin-3 -amineCpd. ES-MS Name StructureNo, [M+l]+(R)-6-(benzo[d]thiazol-6-yl)-N-((l-(2-?F3 HX38 (tetrahydro-2H-pyran-4- zyl)ethyl)pyr. J-l -> N 492.2 rolidin-3-yl)methyl)-4- 4IL“ - (trifluoromethyl)pyridazin-3-amineNTZ\ z — / / ''(R)-6-(lH-pyrazol-l-yl)-N-((l-(2- \o \= / z39 (tetrahydro-2H-pyran-4- 357.3 yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin- 3 -amine(R)-6-(3,5-dimethyl- IH-pyrazol- 1 -yl)-N- 40 (( 1 -(2-(tetrahydro-2H-pyran-4- 385.3 yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin- 3 -amine / =\ZT(R)-2-(3-(6-((( 1 -(2-(tetrahydro-2H-pyran- 41 4-yl)ethy l)pyrrolidin-3 - 425.3 yl)methyl)amino)pyridazin-3- (yl)pheny] )propan -2-ol'" OH1 1o(R)-6-( 1, 3 -dimethyl- lH-pyrazol-4-yl)-N - 42 ((1 -(2-(tetrahy dro-2H-pyran-4- 453.2 yi)ethyI)pyrrolidin-3-yl)methyl)-4-N(trifluoromethyl)pyridazin -3 -amine N’XN -((3 -fluoro- 1 -(2-(tetrahydro-2H-pyran-4- CF3p- / 43 yl)ethyl)pyrroiidin-3-yi)methyl)-6-(2- 454.2 (trifluoromethyl)pyridin-3-yl)pyridazin-3- amine H 16-(2-chloro-5-fluorophenyl)-N-((3-fluoro- 44 1 -(2-(tetrahy dro-2H-pyran-4- 436.93 yl)ethyI)pyrrolidin-3-yi)methyl)pyridazin- 3 -animeCpd. ES-MS Name StructureNo, [M+l]+0N-(((3R)-l-((2,2-dimethyltetrahydro-2H- 45 pyran-4-yl)methyi)pyrrolidin-3- H N— ' ~~~ / 450.3 yl)methyi)-6-(2-(trifluoromethyl)pyridin- CF,3 -yl)pyridazin-3 -amineX VN-(((3R)- 1 -((6,6-dimethyltetrahydro-2H- \ / °H N— z46 pyran-3 -yl)methyl)pyrrolidin-3 - CF3450.3 yl)methyl)-6-(2-(trifluorometliyl)pyridin- X / / T|3 -yl)pyridazin-3 -amineN LA N < N(R)-N-(( 1 -((2,2,6,6-tetramethyltetraliydro- 47 2H-pyran-4-yl)methyl)pyrrolidin-3- ^3478.3 yl)methyl)-6-(2-(trifluoromethyl)pyridin- 3 -yl)py ridazin-3 -amine(R)-6-(5-fluoro-2-methylpyridin-3-yl)-N- 48 ((1 -(2-(tetrahydro-2H-pyran -4- N WXX N'yl)ethyl)pyiTolidin-3-yl)methyl)pyridazin- 400.3 n J3 -amineF(R)-2-methy 1-3 -(6-((( 1 -(2-(tetrahy dro-2H- H;o49 pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)amino)py ridazin-3 - 406.3 yl)benzonitrile6-(2-chloro-5-fluorophenyl)-N-((3-methyl- H r^N_y \ p50 l-(2-(tetrahydro-2H-pyran-4- 433.3 yl)ethyl)pyrrolidin-3-yl)metliyl)pyridazin- ji x N3 -amine yy-C|Cpd. ES-MS Name StructureNo, [M+l]+N-((3 -methyl- 1 -(2-(tetrahydro-2H-pyran- H51 4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2- 450.3 (trifluoromethyl )pyri din-3 -yl)pyridazin-3 - N Namine2-methyI-3-(6-(((3-methyl-l-(2- H XN-Z X / ° (tetrahydro-2H-pyran-4- 52 yl)ethyl)pyrro1 idin-3- 420.4 yl)methyl)amino)pyridazin-3 - yl)benzonitrile6-( 1,3-dimethyl- lH-pyrazol-4-yl)-N-((3- 53 m ethyl- 1 -(2-(tetrahydro-2H-pyran -4- 399.4 yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin- 3 -aminewOM N'-- / / \ \ _ / ON-((3 -methyl- 1 -(2-(tetrahydro-2H-pyran- 54 4-yl)ethyi)pyrrolidin-3-yi)methyl)-6-(2- 396.5 methylpyridin-3 -yl)pyridazin-3 -amineQ H M _ / \ PN-((3-metliyl-l-(2-(tetrahydro-2H-pyran- 55 4-yl)ethyI)pyrrolidin-3-yI)methyl)-6-(2- V 435.4 methyl-2H-indazol -5 -yl)pyridazin-3 -amine6-(2-cyclopropyipyridin-3-yl)-N-((3- x—, Hr\ Nl— z / \ V / 0 56 methyl- 1 -(2-(tetrahy dro-2H-pyran-4- n 1 422.4 yl)ethyl)pyrrolidin-3-yl)methyl)pyridazin- 3 -amine |l JN -cyclopropyl-4-(6-(((3 -methyl- 1 -(2- (tetrahydro-2H-pyran-4- 57 yl)ethyl)pyrrolidin-3 - 464.4 yl)methyl)amino)pyridazin-3- yl)benzamideBiological ActivityA. Ceil Lines Expressing Muscarinic Acetylcholine Receptors

[0305] Human or rat M4 cDNA, along with the chimeric G protein Gqis, were transfected intoChinese hamster ovary (CH0-K1) cells purchased from the American Type Culture Collection using Lipofectamine2000. M Gqis / CHO cells were grown in Ham’s F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20mM HEPES, 500 pg / mL G418 sulfate, and 200 pg / mL Hygromycin B.B. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor Activity

[0306] For high throughput measurement of agonist-evoked increases in intracellular calcium, CHO-K1 cells stably expressing muscarinic receptors were plated in growth medium lacking G418 and hygromycin at 15,000 cells / 20 pL / well in Greiner 384-well black-walled, tissue culture (TC)-treated, clear-bottom plates (VWR). Cells were incubated overnight at 37 °C and 5% CO2. The next day, cells were washed using an ELX 405 (BioTek) with assay buffer; the final volume was then aspirated to 20 pL. Next, 20 pL of a 2.3 pM stock of Fluo-4 / acetoxymethyl ester (Invitrogen, Carlsbad, CA), prepared as a 2.3 mM stock in DMSO and mixed in a 1:1 ratio with 10% (w / v) Pluronic F-127 and diluted in assay buffer, was added to the wells and the cell plates were incubated for 50 min at 37 °C and 5% CO2 Dye was removed by washing with the ELX 405 and the final volume was aspirated to 20 pL. Compound master plates were formatted in a 10 point concentration-response curve (CRC) format (1:3 dilutions) in 100% DMSO with a starting concentration of 10 or 1 mM using a BRAVO liquid handler (Agilent). Test compound CRCs were then transferred to daughter plates (240 nL) using the Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA) and then diluted into assay buffer (40 pL) to a 2* stock using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA).

[0307] Calcium flux was measured using the Functional Drug Screening System (FDSS) 6000 or 7000 (Hamamatsu Corporation, Tokyo, Japan) as an increase in the fluorescent static ratio. Compounds were applied to cells (20 pL, 2X) using the automated system of the FDSS at 2 seconds into the protocol and the data were collected at 1 Hz. At 143 s, 10 L of an EC20 concentration of the muscarinic receptor agonist acetylcholine was added (5X), followed by the addition of 12 pL of an ECso concentration of acetylcholine at the 268 s time point (5X). Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Positive allosteric modulator activity was analyzed as a concentration¬ dependent increase in the EC20 acetylcholine response. Antagonist activity' was analyzed as a concentration-dependent decrease in the ECso acetylcholine response; for the purposes of the tables herein, an IC50 (inhibitory' concentration 50) was calculated as a concentration-dependentdecrease of the response elicited by an ECso concentration of acetylcholine. Concentration-response curves were generated using a four-parameter logistical equation in XLFit curve fitting software (IDBS, Bridgewater, NJ) for Excel (Microsoft, Redmond, WA) or Prism (GraphPad Software, Inc., San Diego, CA) or the Dotmatics software platform (Dotmatics, Bishop’s S tortford, UK).

[0308] The above described assay was also operated in a second mode where an appropriate fixed concentration of the present compounds were added to the cells after establishment of a fluorescence baseline for about 3 seconds, and the response in cells was measured. 140 s later, a full concentration-response range consisting of increasing concentrations of agonist was added and the calcium response (maximum-local minima response) was measured. The ECso values for the agonist in the presence or absence of test compound were determined by nonlinear curve fitting. A decrease in the ECso value of the agonist with increasing concentrations of the present compounds (a leftward shift of the agonist concentration-response curve) is an indication of the degree of muscarinic positive allosteric modulation at a given concentration of the present compound. An increase in the ECso value of the agonist with increasing concentrations of the present compounds (a rightward shift of the agonist concentration response curve) is an indication of the degree of muscarinic antagonism at a given concentration of the present compound. The second mode also indicates whether the present compounds also affect the maximum response of the muscarinic receptor to agonists.C. Activity of Compounds in a mAChR M4 Cell-Based Assay

[0309] Compounds were synthesized as described above. Activity (ICso and Emm) was determined in the mAChR M4 cell-based functional assay as described above and the data are shown in Table 2.Table 2.Human M4Cpd.EminNo. IC50(μM)(%)*1 >102 6.69 173 0.67 64 >105 >106 >107 >10Human M4 Cpd.Emin No. IC50 (μM)(%)* 8 >109 0.00028 7 10 0.028 6 11 0.17 4 12 0.0077 4 13 >1014 0.0075 5 15 0.0011 4 16 0.00087 3 17 0.012 5 18 0.00061 3 19 0.0016 4 20 0.75 6 21 0.0043 4 22 0.274 4 23 0.0016 3 24 0.87 9 25 0.018 3 26 0.65 3 27 0.020 3 28 0.00076 2 29 0.79 10 30 0.00023 4 31 0.58 5 32 3.8 5 33 0.46 4 34 5.0 12 35 2.2 5 36 0.21 4 37 >1038 0.23 5 39 >1040 0.013 5 41 0.32 7 42 2.2 11 43 0.028 4 44 0.00017 4 45 >1046 0.73 9 47 >1048 0.00028 4Human M4Cpd.EminNo. IC50 (pM)(%)*49 0.00064 450 0.000049 251 0.00020 452 0.000083 253 >1054 0.00012 455 0.0010 856 0.00054 357 0.0010 10* %ACh maximum at 30 pM.

[0310] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0311] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

CLAIMSWhat is claimed is:

1. A compound of formula (I):(I)or a pharmaceutically acceptable salt thereof, wherein:X is N or CH;R1is G1or halogen;G1is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein G1is optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-4fluoroalkyl, -OR10, -N(R10)2, -NR10C(O)R10, -CON(R10)2, -NR10SO2R11, -Ci- 3alkylene-OR10, Cs-ecycloalkyl, and -Ci-3alkylene-C3-6cycloalkyl, and optionally further substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-4fluoroalkyl, and -OCi-4aikyl;R10, at each occurrence, is independently hydrogen, Ci-4alkyl, Ci-4fluoroalkyl, C3-4cycloalkyl, or Ci-3alkylene-C3-4cycloalkyl, wherein alternatively two R10, together with a nitrogen to which the two R10attach form a 4- to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Ci-4alkyl; R11, at each occurrence, is independently Ci-4alkyl, Ci-4haloalkyl, C3-4cycloalkyl, or-Ci- 3 al ky 1 ene-C3-4cy cl oalkyl;Ris hydrogen, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;m is 0, 1, or 2;R2, at each occurrence, is independently halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, or C3- 6cycloalkyl;R3is G2, -L1-G2, -C2-6alkylene-R3a, C3-?alkyl, or C3-?haloalkyl;L1is Ci-3alkylene;G2is a 4- to 12-membered heterocyclyl, a Cs-ncarbocyclyl optionally fused to a 6-membered arene, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, the heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein G2is optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, Ci-4alkyl, Ci-4fluoroalkyl, -OR13, -N(R13)2, -Ci- 3alkylene-OR13, and -Ci-3alkylene-N(R13)2, and optionally further substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-4fluoroalkyl, and -OCi-4alkyl;R3ais -OR14or -N(R14)2;R13and R14, at each occurrence, are independently hydrogen, Ci-4alkyl, Ci-4fluoroalkyl, C3- 4cycloalkyl, or Ci-3alkylene-C3-4cycloalkyl, wherein alternatively two R13or two R14, together with a nitrogen to which the two R13or two R14attach form a 4- to 6-membered heterocyclic ring optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Ci-4alkyl;R4, at each occurrence, is independently hydrogen, Ci-4alkyl, Ci-4fluoroalkyl, or C3-4cycloalkyl; n is 0, 1, 2, 3, or 4; andR5, at each occurrence, is independently halogen or Ci-4alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is G1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G1is the optionally substituted 6- to 12-membered aryl.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at G1is a phenyl.

5. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at G1is a phenyl bonded to the parent molecule and fused to a 5- to 6-membered heterocycle containing 1-2 ring heteroatoms independently selected from nitrogen and oxygen.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G1is the optionally substituted 5- to 12-membered heteroaryl.

7. The compound of any of claims 1-2 or 6, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 12-membered heteroaryl at G1is a 5- to 6-membered monocyclic heteroaryl ring system containing 1-3 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

8. The compound of any of claims 1-2 or 6, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 12-membered heteroaryl at G1is a 9- to 10-membered fused bicyclic heteroaryl ring system containing 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein G1is optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, cyano, Ci-4fluoroalkyl, -OR10, -CON(R10)2, -Ci-3alkylene-OR10, and C3-4cycloalkyl and G1is optionally further substituted with 1-2 substituents independently selected from the group consisting of halogen and Cwialkyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein G1is11. The compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted 4- to 12-membered heterocyclyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 4- to 12-membered heterocyclyl at G2is a 4- to 8-membered heterocyclyl ring system, wherein the heterocyclyl ring system contains 1 or 2 oxygen ring atoms.

13. The compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted 6- to 12-membered aryl.

14. The compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted 5- to 12-membered heteroaryl.

15. The compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted C3-12carbocyclyl.

16. The compound of any of claims 1-10 or 15, or a pharmaceutically acceptable salt thereof, wherein the ring system of the C3-12carbocyclyl is a C3-6cycloalkyl ring system.

17. The compound of any of claims 1-12 or 15-16, or a pharmaceutically acceptable saltthereof, wherein, or ‘ OH18. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein L1is CH2or CH2CH2.

19. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R3is -L1-G2.

20. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R3is G2.

21. The compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R3is C3-7alkyl22. The compound of any of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

23. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein m is 0.

24. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein m is 1.

25. The compound of any of claims 1-22 or 24, or a pharmaceutically acceptable salt thereof, wherein R2is Ci-2fluoroalkyl.

26. The compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof,wherein X is N,27. The compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein X is CH.

28. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

29. The compound of any of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein n is 0,30. The compound of any of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein n is 1.

31. The compound of any of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein n is 2.

32. The compound of any of claims 1-28 or 30-31, or a pharmaceutically acceptable salt thereof, wherein R3, at each occurrence is independently fluoro or Ci-4alkyl.

33. The compound of claim 1, wherein the compound is selected from the group consisting of:(R)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine;(R)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2,3,5- trif1uorophenyl)pyridazm-3-amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3- yl)methyl)pyrid azin-3 -amine;(R)-6-(2-methyl-2H-indazol-5-yr)-N-((T-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(S)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-amine;(S)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2,3,5- trifluorophenyl)pyridazin-3-amine;(S)-6-(2-chloro-5-fluorophenyl)-N-((l-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;6-(2-chloro-5-fluorophenyl)-N-(((3R)-l-((2,2-dimethyltetrahydro-2H-pyran-4- yl)methyl)pyrrolidin-3-yl)methyl)pyridazin-3-amine;(R)-l-((3-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)methyl)pyrrolidin-l- yl)methyl)cycloheptan-l -ol;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(3,3-dimethylbutyl)pyrrolidin-3-yl)methyl)pyridazin-3- amine;(R)-6-chloro-N-(( 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3 -yl)methyl)pyridazin-3 - amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2,3,5- trifluorophenyl)pyridazin-3-amine;(R)-6-(5 -fluoro-2-methylphenyl)-N-(( 1 -(2-(tetrahy dro-2 H-pyran-4-y 1 )ethyl)pyrroli din-3 - yl)methyl)pyridazin-3-amine;(R)-6-(2-mefliyl-2H-indazol-5-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-6-(2-methylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yi)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-6-(5-fluoro-2-methoxyphenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-N-(( 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3 -yl)methyl)-6-(4- (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine;(R)-6-(l,3-dimethyl-lH-pyrazol-4-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrroli din-3- yl)methyl)pyridazin-3 -amine;(R)-6-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-((l-(2-(tetrahydro-2H-pyran-4- yl)ethyl)pyrrolidin-3-yl)methyl)pyrida in-3-amine;(R)-6-(benzo[d]thiazol-6-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-2'-(trifluoromethyl)-[2,3'- bipyridin]-5-amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- y 1 )m ethyl)pyri din-3 -amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2,3,5- trifluorophenyl)pyridin-3 -amine;( R)-6-(5 -fluoro-2-methylphenyl)-N-(( 1 -(2-(tetrahy dro-2 H-pyran-4-y 1 )ethyl)pyrroli din-3 - yl)methyl)pyridin-3 -amine;(R)-6-(2,6-dimethylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-6-(2-isopropoxypyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-6-(2-cyclopropylpyridin-3-yl)-N-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;(R)-6-(2-chloro-5-fluorophenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)-4-(trifiuoromethyl)pyridazin-3-amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-4-(trifluoromethyl)-6- (2, 3, 5 -trifluorophenyl)pyri dazin-3 -ami ne;(R)-6-(5-fluoro-2-methylphenyl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)metliyl)-4-(trifluoromethyl)-6-(2- (trifluoromethyl)pyridin-3 -yl)pyrid azin-3 -amine;(R)-6-(2-methylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-6-(2-cyclopropylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-6-(2-metliyl-2H-indazol-5-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;(R)-6-(benzo[d]thiazol-6-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)- 4-(trifluoromethyl)pyridazin-3-amine;(R)-6-(lH-pyrazol-l-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-2-(3-(6-(((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)amino)pyridazin-3- y 1 )phenyl)propan-2-ol;(R)-6-(l,3-dimethyl-lH-pyrazol-4-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)-4-(trifluoromethyl)pyridazin-3-amine;N-((3-fluoro-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine;6-(2-chloro-5-fluorophenyl)-N-((3-fluoro-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;N-(((3R)-l-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine;N-( ((3 R)- 1 -( (6, 6-di methyltetrahy dro-2H-pyran-3 -y 1 )methyl)pyrrol idin-3 -y I )methyl)-6-(2- (trifluorom ethyl)pyri din-3 -yl)pyridazin-3 -amine;(R)-N-((l-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)methyl)-6-(2- (trifluoromethyl)pyridin-3 -yl)pyridazin-3 -amine;(R)-6-(5-fluoro-2-methylpyridin-3-yl)-N-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3 -amine;(R)-2-methyl-3-(6-(((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)amino)pyridazin-3-yl)benzonitrile;6-(2-chloro-5-fluorophenyl)-N-((3-methyl-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;N-((3 -methyl- 1 -(2-(tetrahy dro-2H-pyran-4-yl)ethyl)pyrrolidin-3 -yl)methyl)-6-(2- (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine;2-methyl-3-(6-(((3-methyl-l -(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)amino)pyridazin-3-yl)benzonitrile;6-( 1,3 -dimethyl- lH-pyrazol-4-yl)-N-((3 -methyl- 1 -(2-(tetrahydro-2H-pyran-4- yl)ethyl)pyrrolidin-3-yl)methyl)pyrid zin-3-amine;N-((3 -methyl- l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(2- methylpyri din-3 -yljpyri dazin-3 -ami ne;N-((3 -methyl- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3 -yl)methyl)-6-(2-methyl-2H- indazol-5-yl)pyridazin-3-amine;6-(2-cy cl opropylpyri din-3 -yl)-N-((3 -methyl- l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)pyridazin-3-amine;N-cyclopropyl-4-(6-(((3-methyl-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-3- yl)methyl)amino)pyridazin-3-yl)benzamide;or a pharmaceutically acceptable salt thereof.

34. The compound of any of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled.

35. A pharmaceutical composition comprising the compound of any of claims 1-34, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

36. A method for antagonizing mAChR M4 in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 35.

37. A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of m AChR M4, comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 35.

38. The method of claim 37, wherein the disorder is a neurodegenerative disorder, a movement disorder, or a brain disorder.

39. The method of claim 38, wherein the disorder is a movement disorder.

40. The method of claim 38, wherein the disorder is selected from Parkinson’s disease, drug-induced Parkinsonism, dystonia, Tourette’s syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington’s disease, chorea, cerebral palsy, and progressive supranuclear palsy.

41. A method for treating motor symptoms in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any of claims 1-34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 35.

42. The method of claim 41, wherein the subject has a disorder selected from Parkinson’s disease, drug-induced Parkinsonism, dystonia, Tourette’s syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington’s disease, chorea, cerebral palsy, and progressive supranuclear palsy.

43. A compound of any of claims 1 -34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 35 for use in the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

44. The use of a compound of any of claims 1-34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 35, for the preparation of a medicament for the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

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