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WO2024086569A1 - Positive allosteric modulators of the muscarinic acetylcholine receptor m1 - Google Patents

Positive allosteric modulators of the muscarinic acetylcholine receptor m1 Download PDF

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Publication number
WO2024086569A1
WO2024086569A1 PCT/US2023/077078 US2023077078W WO2024086569A1 WO 2024086569 A1 WO2024086569 A1 WO 2024086569A1 US 2023077078 W US2023077078 W US 2023077078W WO 2024086569 A1 WO2024086569 A1 WO 2024086569A1
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Prior art keywords
compound
indazol
pharmaceutically acceptable
pyridin
methyl
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PCT/US2023/077078
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French (fr)
Inventor
Craig W. Lindsley
Darren W. Engers
Julie L. Engers
Cayden J. Dodd
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Vanderbilt University
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Publication of WO2024086569A1 publication Critical patent/WO2024086569A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M1 RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/416,839, filed October 17, 2022, which is hereby incorporated by reference in its entirety.
  • TECHNICAL FIELD [0002] The present disclosure relates to compounds, compositions, and methods for treating muscarinic acetylcholine receptor M1 related diseases and/or disorders, such as neurological and psychiatric disorders.
  • Positive allosteric modulators are compounds that bind to a site distinct from that of the orthosteric agonist binding site of a target protein.
  • modulators enhance the affinity or efficacy of an orthosteric agonist.
  • a selective muscarinic M 1 positive allosteric modulator would result in an increased affinity at the orthosteric binding site for acetylcholine (ACh), the endogenous agonist for the muscarinic M1 receptor, or an increase in the efficacy induced by ACh.
  • the compound may also have an intrinsic activity to activate the receptor in the absence of orthosteric ligand. Positive allosteric modulation (potentiation), therefore, can be an attractive mechanism for enhancing appropriate physiological receptor activation.
  • nAChRs nicotinic acetylcholine receptors
  • mAChRs muscarinic acetylcholine receptors
  • AD Alzheimer’s disease
  • M 1 , M 3 and M 5 mainly couple to Gq and activate phospholipase C, whereas M2 and M4 mainly couple to Gi/o and associated effector systems.
  • M1-M5 mAChRs have varying roles in cognitive, sensory, motor and autonomic functions. Activation of various muscarinic receptors, particularly the M 1 subtype, has been proposed as a mechanism to enhance cognition in disorders such as AD and schizophrenia (as well as negative symptoms).
  • allosteric modulation may be an advantageous pathway because allosteric sites on mAChRs are less highly conserved.
  • muscarinic receptor mAChR
  • mAChR muscarinic receptor
  • a 1 is selected from the group , ;
  • Z 2 is N or CR z2 ;
  • Z 3 is N or CR z3 ;
  • Z 4 is N or CR z4 ; wherein 0, 1, or 2 of Z 1 , Z 2 , Z 3 , and Z 4 is N;
  • R z1 , R z2 , R z3 , and R z4 are independently selected from the group consisting of H, D, halogen, C 1- 2alkyl, C1-2deuterioalkyl, C1-2fluoroalkyl, cyano, –OC1-2alkyl, –OC1-2deuterioalkyl, –OC1- 2fluoroalkyl, and C 3-4 cycloalkyl;
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, D, C 1-4 alkyl, C 1- 4deu
  • the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a disorder associated with muscarinic acetylcholine receptor activity.
  • 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 disorder associated with muscarinic acetylcholine recepter activity.
  • the invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, with minimal to substantially no M 1 agonist activity compared to acetylcholine. The relative absence of M1 agonist activity is expected to avoid or reduce cholinergic adverse effect liability at therapeutic concentrations and/or doses.
  • mAChR M 1 muscarinic acetylcholine receptor M 1
  • the modulators can have the structure of formula (I).
  • Compounds of formula (I) exhibit high affinity for mAChR M1, and can also exhibit selectivity over other muscarinic acetylcholine receptors.
  • Compounds of formula (I) can be used to treat or prevent diseases and disorders associated with mAChR M 1 by modulating mAChR M 1 activity.
  • mAChR M1 has been implicated in a number of different diseases and disorders including, but not limited to, neurological and psychiatric disorders.
  • 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.
  • “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.
  • 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, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein.
  • alkyl means a straight or branched, saturated hydrocarbon chain.
  • lower alkyl or “C 1-6 alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • C1-4alkyl means a straight or branched chain saturated hydrocarbon containing from 1 to 4 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkenyl means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond.
  • alkylene refers to a divalent group derived from a straight or branched saturated chain hydrocarbon, for example, of 1 to 6 carbon atoms.
  • alkylene examples include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -C(CH3)2CH2CH2-, - CH2C(CH3)2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.
  • alkenylene refers to a divalent group derived from a straight or branched chain hydrocarbon having at least one carbon-carbon double bond.
  • aryl 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][1,3]dioxol-5-yl).
  • 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).
  • cycloalkane refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds.
  • 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., decahydronaphthalenyl), 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), or spirocyclic.
  • a monocyclic cycloalkyl e.g., cyclopropyl
  • a fused bicyclic cycloalkyl e.g., decahydronaphthalenyl
  • 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
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.
  • cycloalkene means a non-aromatic monocyclic or multicyclic all-carbon ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • 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.
  • deuterioalkyl means an alkyl group, as defined herein, in which one or more hydrogen atoms in the alkyl are the isotope deuterium, i.e., 2 H. Representative examples of deuterioalkyl include CD 3 , CH 2 CD 3 , and CD 2 CD 3 .
  • 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 a fluoro group.
  • fluoroalkyl examples include CH2F, CHF2, CF3, and CH2CF3.
  • fluorodeuterioalkyl means a fluoroalkyl group, as defined herein, in which one or more hydrogen atoms in the fluoroalkyl are the isotope deuterium, i.e., 2 H.
  • fluorodeuterioalkyl examples include CD2F, CDF2, and CD2CF3.
  • halogen or “halo,” as used herein, means Cl, Br, I, or F.
  • haloalkyl 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.
  • halodeuterioalkyl means a haloalkyl, as defined herein, in which one or more hydrogen atoms in the haloalkyl are the isotope deuterium, i.e., 2 H.
  • Representative examples of halodeuterioalkyl include CD 2 F, CDF 2 , CD 2 CF 3, CD 2 Cl, CDCl 2 , and CD2CCl3, .
  • heteroaryl refers to an aromatic monocyclic heteroatom- containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaryl (bicyclic heteroaryl).
  • heteroaryl is used herein to refer to a heteroarene when present as a substituent, the term “heteroarene” being used in cases of ring fusion.
  • 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 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., "fully aromatic" 10 ⁇ electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1- yl), a monocyclic heteroaryl ring fused to a monocyclic 5- to 6-membered heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic 5- to 6-membered heteroarene (e.g., quinolin-5-yl, indol-4-yl).
  • a fused bicyclic heteroaromatic ring system i.e., "fully aromatic" 10
  • 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 a fused 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.
  • heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (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 (
  • heterocycle or “heterocyclic,” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle.
  • 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 consisting of O, N, and S.
  • monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group, or a bridged monocyclic 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, or an alkenylene bridge of two, three, or four carbon atoms.
  • bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl).
  • bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3- dihydrobenzothien-2-yl, 1,2,3,4-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-1H-indol-1-yl, isoindolin-2-yl, oc
  • 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.
  • tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1- azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane).
  • the monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom.
  • hydroxyl or “hydroxy,” as used herein, means an -OH group.
  • 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., “C 1-4 alkyl,” “C 3-6 cycloalkyl,” “C 1-4 alkylene”). 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.
  • C m to C n refers to the number of carbon atoms in the relevant group. That is, the group can contain from “m” to “n”, inclusive, carbon atoms.
  • a “C1 to C6 alkyl” group refers to all alkyl groups having from 1 to 6 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )-, CH 3 CH(CH) 3 CH 2 - , CH 3 CH(CH) 3 CH 2 - and (CH 3 ) 3 C-.
  • “C3alkyl” is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl).
  • a “C1-4alkyl,” for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched). If no “m” and “n” are designated with regard to a group, the broadest range described in these definitions is to be assumed.
  • substituted refers to a group that may be further substituted with one or more non-hydrogen substituent groups.
  • an "optional substituent” is a substituent that may or may not be present on another molecular group, such as a ring (e.g., phenyl) or chain (e.g., alkyl).
  • a group that is "optionally substituted” with a substituent means the group is either unsubstituted or substituted with the substituent.
  • groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3, or 4, solvent or water molecules.
  • a "prodrug” refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration.
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have better solubility than the active parent drug in pharmaceutical compositions.
  • polymorphs and “polymorphic forms” refer to crystalline forms of the same molecule, and different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and/or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice.
  • Polymorphs of a molecule can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation.
  • DSC differential scanning calorimetry
  • XRPD X-ray powder diffractometry
  • XRPD single crystal X- ray diffractometry
  • vibrational spectroscopy e.g., IR and Raman spectroscopy
  • solid state NMR hot stage optical microscopy
  • SEM scanning electron microscopy
  • PSA particle size analysis
  • surface area analysis solubility studies and dissolution studies.
  • haloalkyl may be fluoroalkyl (e.g., any C1-4haloalkyl may be C1-4fluoroalkyl).
  • Unsubstituted or substituted rings such as aryl, heteroaryl, etc. are composed of both a ring system and the ring system's optional substituents.
  • the ring system may be defined independently of its substituents, such that redefining only the ring system leaves any previous optional substituents present.
  • 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.
  • 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.
  • any ring atoms of the heterocyclic and heteroaromatic ring systems that are not one of the specified heteroatoms are carbon atoms.
  • numbered embodiments of the invention are disclosed (e.g., E1, E2, E2.1, etc.).
  • the reference to a range of preceding embodiments in multiple dependent format e.g., "the compound of any of E1-E2.6" is a reference, in the alternative, to each embodiment sequentially listed herein in the recited range.
  • any of E1-E2.6 means "any of E1, E2, E2.1, E2.2, E2.3, E2.4a, E2.4b, E2.5a, E2.5b, or E2.6.”
  • E1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein
  • a 1 is selected from the group consisting of , , , , , and ; Z 1 is N or CR z1 ; Z 2 is N or CR z2 ; Z 3 is N or CR z3 ; Z 4 is N or CR z4 ; wherein 0, 1, or 2 of Z 1 , Z 2 , Z 3 , and Z 4 is N; R z1 , R z2 , R z3 , and R z4 are independently selected from the group consisting of H, D, halogen, C 1- 2 alkyl, C 1-2 deuterioalkyl, C 1-2 fluoroalkyl, cyano, –OC 1-2 alkyl, –OC 1-2 deuterioalkyl, –OC 1- 2fluoroalkyl, and C3-4cycloalkyl; R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, D, C 1-4 alkyl, C 1- 4 deuterioalkyl, C
  • E2 The compound of E1, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4 deuterioalkyl, C 1-4 fluoroalkyl, halogen, cyano, C 3-6 cycloalkyl, –OR a , –O–C 2-3 alkylene–OR b , and –N(R c )(R d ), wherein the C3-6cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C 1-4 fluoroalkyl, OH, –OC 1-4 alkyl, –OC 1-4 deuterioalkyl, and –OC 1-4 fluoroalkyl.
  • E2.1 The compound of E2, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4 fluoroalkyl, halogen, C 3-6 cycloalkyl, –OR a , –O–C 2-3 alkylene–OR b , and –N(R c )(R d ).
  • R 1 and R 2 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4 fluoroalkyl, halogen, C 3-6 cycloalkyl, –OR a , –O–C 2-3 alkylene–OR b , and –N(R c )(R d ).
  • R 1 and R 2 are independently selected from the group consisting of H, CH3, CH(CH3)2, CD3, CF3, fluoro, chloro, cyano, cyclopropyl, cyclopentyl, –OCH3, –OCH2CH(CH3)2, –O–(CH 2 ) 2 –OCH 3 , –N(CH 3 ) 2 , and azetidin-1-yl.
  • R 1 and R 2 are independently selected from the group consisting of H, CH3, CH(CH3)2, CD3, CF3, fluoro, chloro, cyano, cyclopropyl, cyclopentyl, –OCH3, –OCH2CH(CH3)2, –O–(CH 2 ) 2 –OCH 3 , –N(CH 3 ) 2 , and azetidin-1-yl.
  • R 1 and R 2 are independently selected from the group consisting of H, CH3, CH(CH3)2, CF 3 , fluoro, chloro, cyclopropyl, cyclopentyl, –OCH 3 , –OCH 2 CH(CH 3 ) 2 , –O–(CH 2 ) 2 –OCH 3 , –N(CH 3 ) 2 , and azetidin-1-yl.
  • R 1 and R 2 are independently selected from the group consisting of H, CH3, CH(CH3)2, CF 3 , fluoro, chloro, cyclopropyl, cyclopentyl, –OCH 3 , –OCH 2 CH(CH 3 ) 2 , –O–(CH 2 ) 2 –OCH 3 , –N(CH 3 ) 2 , and azetidin-1-yl.
  • E1-E2.1 The compound of any of E1-E2.1, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of H, C 1-4 alkyl, halogen, C 3-6 cycloalkyl, –OR a , and –N(R c )(R d ).
  • E2.4b The compound of any of E1-E2.1 or E2.4a, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of C 1-4 alkyl, halogen, and C 3-6 cycloalkyl.
  • E2.5a The compound of any of E1-E2.1, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of C 1-4 alkyl, halogen, and C 3-6 cycloalkyl.
  • E2.5b The compound of any of E1-E2.5a, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of H, CH3, fluoro, chloro, cyclopropyl, –OCH 3 , and –N(CH 3 ) 2 .
  • E2.5b The compound of any of E1-E2.5a, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of CH3, fluoro, chloro, and cyclopropyl.
  • E2.6 The compound of any of E1-E2.4a or E2.5a, or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
  • E2.7 The compound of any of E1-E2.4a or E2.5a, or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
  • E3.1 The compound of any of E1-E2.9, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from the group consisting of H, D, C1- 4 alkyl, C 1-4 deuterioalkyl, C 1-2 fluoroalkyl, halogen, cyano, –OC 1-4 alkyl, –OC 1-4 deuterioalkyl, and –OC 1-2 fluoroalkyl.
  • E3.1 The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R 3 is C1-4alkyl or halogen.
  • E3.2 The compound of E3.1, or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen.
  • E3.3 E3.3.
  • E3.4 The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
  • E3.5 The compound of any of E1-E3.4, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 alkyl or halogen.
  • E3.6 The compound of E3.5, or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen.
  • E3.7 The compound of E3.6, or a pharmaceutically acceptable salt thereof, wherein R 4 is fluoro.
  • E3.8 The compound of any of E1-E3.4, or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
  • E4 The compound of any of E1-E3.8, or a pharmaceutically acceptable salt . a pharmaceutically acceptable salt thereof, wherein A 1 is selected from the group , wherein A 1 is selected from the group consisting of , , , , , , , and .
  • E6 The compound of E5, or a pharmaceutically acceptable salt thereof, , , thereof, wherein A 1 is selected from the group , , , , , , , and .
  • E7 The compound of E6 or E6.1, or a pharmaceutically acceptable salt thereof, wherein:
  • E8 The compound of any of E1-E3.8, or a pharmaceutically acceptable salt thereof, wherein A 1 is selected from the group , . acceptable salt thereof, . E8, or a pharmaceutically acceptable salt thereof, wherein A 1 is . [0081] E8.3. The compound of E8, or a pharmaceutically acceptable salt thereof, wherein . [0082] of E8, or a pharmaceutically acceptable salt thereof, wherein . [0083] of E8, or a pharmaceutically acceptable salt thereof, wherein . [0084] of any of E1-E8.5, or a pharmaceutically acceptable salt thereof, wherein R 5 is the substituted 5- to 12-membered heteroaryl. [0085] E10.
  • the compound of E11, or a pharmaceutically acceptable salt thereof, wherein the 9- to 10-membered heteroaryl ring system is selected from the group consisting of 2H-indazol-4-yl, 2H-indazol-3-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, 2H-indazol-7-yl, 1H- indazol-3-yl, 1H-indazol-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-8-yl, 1H-indol-3-yl, 1H- benzo[d][1,2,3]triazol-7-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, and [1,2,4]triazolo[1,5-a]pyridin-8-yl.
  • E12a The compound of E12, or a pharmaceutically acceptable salt thereof, wherein the 9- to 10-membered heteroaryl ring system is selected from the group consisting of 2H-indazol-4-yl, 2H-indazol-5-yl, quinolin-5-yl, quinolin-6-yl, and quinolin-8-yl.
  • E12.1. The compound of any of E11-E12a, or a pharmaceutically acceptable salt thereof, wherein R 5 is substituted with 2 R 7 substituents.
  • E12.2. The compound of any of E11-E12a, or a pharmaceutically acceptable salt thereof, wherein R 5 is substituted with 1 R 7 substituent.
  • E13 The compound of any of E12, E12.2, or E12.3, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of , , , , , , , , , , and ; and R 7a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C 1-4 alkyl.
  • E13.1 The compound of any of E12, E12a, E12.2, E12.3, or E13, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of 6cycloalkyl, and –C 1-3 alkylene–C 3-6 cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl.
  • R 5 is selected from the group consisting of 6cycloalkyl, and –C 1-3 alkylene–C 3-6 cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl.
  • R 7a is selected from the group consisting of C 1-4 alkyl, C 1-4 deuterioalkyl, C 1-4 haloalkyl, C 3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C 1-4 alkyl; and R 7b , R 7c , and R 7d are independently selected from the group consisting of hydrogen, halogen, cyano, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, –OC 1-4 haloalkyl, C 3-6 cycloalkyl, and –C 1-3 alkylene–C 3-6 cycloalkyl, wherein each
  • E14.1 The compound of E14, or a pharmaceutically acceptable salt thereof, wherein R 7b , R 7c , and R 7d are independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, CH3, CD3, CF3, OH, OCH3, OCD3, OCHF2, OCF3, and cyclopropyl.
  • E15 The compound of any of E13-E14.1, or a pharmaceutically acceptable salt .
  • E16.1. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R 7a is CH 3 or CD 3 .
  • E17 The compound of any of E1-E8.5, or a pharmaceutically acceptable salt thereof, wherein R 5 is the substituted 6- to 12-membered aryl.
  • E17.1. The compound of any of E1-E8.5 or E17, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at R 5 is phenyl.
  • E17.2. The compound of any of E1-E8.5 or E17, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at R 5 is naphthalenyl.
  • R 5 is selected from the group consisting of , , , , , , , , and ; and R 7a , R 7b , R 7c , and R 7d are independently selected from the group consisting of halogen, cyano, C1- 4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, –OC1- 4haloalkyl, C 3-6 cycloalkyl, and –C 1-3 alkylene–C 3-6 cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl.
  • E18a The compound of E18, or a pharmaceutically acceptable salt thereof, . acceptable salt thereof, wherein R 7a , R 7b , R 7c , and R 7d are independently halogen or C 1-4 alkyl.
  • E18.2. The compound of E18.1, or a pharmaceutically acceptable salt thereof, wherein R 7a , R 7b , R 7c , and R 7d are independently selected from the group consisting of fluoro, chloro, and CH 3 .
  • E18.3. The compound of E18 or E18.1, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group , , , , and .
  • E19 The compound of any of E1-E18.4, or a pharmaceutically acceptable salt thereof, wherein R 6a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, and C1- 4haloalkyl.
  • R 6a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, and C1- 4haloalkyl.
  • E19.1. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R 6a is C 1-4 alkyl.
  • E19.2. The compound of E19.1, or a pharmaceutically acceptable salt thereof, wherein R 6a is CH 3 .
  • E19.3. The compound of E19 or E19.1, or a pharmaceutically acceptable salt thereof, wherein R 6a is C1-4deuterioalkyl.
  • E19.4. The compound of any of E19-E19.3, or a pharmaceutically acceptable salt thereof, wherein R 6a is CD 3 .
  • E19.5. The The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R 6a is C1-4haloalkyl.
  • E19.6. The compound of E19.5, or a pharmaceutically acceptable salt thereof, wherein R 6a is C 1-4 fluoroalkyl.
  • E19.7. The compound of E19.6, or a pharmaceutically acceptable salt thereof, wherein R 6a is C 1-2 fluoroalkyl.
  • E20 The compound of any of E1-E18.4, or a pharmaceutically acceptable salt thereof, wherein R 6a is D.
  • E21 The compound of any of E1-E20, or a pharmaceutically acceptable salt thereof, wherein R 6b is H.
  • E22 The compound of any of E1-E21, or a pharmaceutically acceptable salt thereof, wherein R 6b is D.
  • E23 The compound of any of E1-E22, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group , . salt thereof, wherein R 6 is selected from the group , .
  • E27.2. The compound of E26.2, salt thereof, wherein the compound is a compound of .
  • E27.3. The compound of E26.3, thereof, wherein the compound is a compound of .
  • E27.4. The compound of E26.4, thereof, wherein the compound is a compound of .
  • E27.5 The compound of E26.5, wherein the compound is a compound of .
  • E27.6 The compound of E26.5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of . [00149] E27.7.
  • E28 The compound of any of or a pharmaceutically acceptable salt thereof, wherein A 1 is selected from the group consisting of . salt thereof, wherein R 8a and R 8b are H.
  • a 1 is selected from the group consisting of . salt thereof, wherein R 8a and R 8b are H.
  • E30.1 The compound of any of E1-E28, or a pharmaceutically acceptable salt thereof, wherein R 8a is H; and R 8b is CH3.
  • E30.2. The compound of any of E1-E28, or a pharmaceutically acceptable salt thereof, wherein R 8a is CH 3 ; and R 8b is H. [00154] E31.
  • E33.1 The compound of any of E1-E30.2, or a pharmaceutically acceptable salt thereof, wherein R 9a and R 9b are H.
  • E32 The compound of any of E1-E31, or a pharmaceutically acceptable salt thereof, wherein R 9a and R 9b are D.
  • E33 The compound of E1, selected from a compound of Table 12, or a pharmaceutically acceptable salt thereof.
  • E33 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.2 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.3 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrol
  • E33.4 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)-6- methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.4 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-cyclopropyl-6-fluoro-4-(7-(hydroxymethyl-d 2 )-2-methyl-2H- indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.5 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)-6- methoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00162] E33.6.
  • E33.9 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,3-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.10 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,5-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00167] E33.11.
  • E33 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-chloro-6-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.12 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.13 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyri
  • the compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-((5-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)pyrimidin-2- yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.21 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(6-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.22 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-5- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00179] E33.23.
  • E33 or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d 2 )-2-(methyl-d 3 )-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.27 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(7-(hydroxymethyl-d 2 )-2-(methyl-d 3 )-2H-indazol-4-yl)-2- methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.28 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(5-(hydroxymethyl-d 2 )quinolin-8-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.29 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(8-(hydroxymethyl-d2)quinolin-6-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.30 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(8-(hydroxymethyl-d2)quinolin-6-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one
  • E33 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(8-(hydroxymethyl-d2)quinolin-5-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.31 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)benzo[d][1,3]dioxol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.32 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)benzo[d][1,3]dioxol-4- yl)benzyl)-6,
  • E33 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol- 4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d 2 .
  • E33.41 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-4-fluoroisoindolin-1-one.
  • E33.42 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00199] E33.43.
  • E33 or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.44 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(hydroxymethyl-d 2 )-2-methyl-2H-indazol-4- yl)benzyl)-7-fluoroisoindolin-1-one.
  • E33.45 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(hydroxymethyl-d 2 )-2-methyl-2H-indazol-4- yl)benzyl)-7-fluoroisoindolin
  • E33.46 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)- 2,6-difluorobenzyl)-7-fluoroisoindolin-1-one.
  • E33.47 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)- 2,6-difluorobenzyl)-7-fluoroisoindolin-1-one.
  • E33 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4- yl)benzyl)-7-fluoroisoindolin-1-one.
  • E33.48 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.
  • E33.49 The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4- yl)benzyl)-7-fluoroisoind
  • E34 A compound of any of E1-E33.49, or a pharmaceutically acceptable salt thereof, that has at least 50% deuterium incorporation at each deuterium label.
  • E34.1 The compound of E34, or pharmaceutically acceptable salt thereof, that has at least 75% deuterium incorporation at each deuterium-label.
  • E34.2 The compound of E34, or pharmaceutically acceptable salt thereof, that has at least 75% deuterium incorporation at each deuterium-label.
  • E34 or E34.1 or pharmaceutically acceptable salt thereof, that has at least 90% deuterium incorporation at each deuterium-label.
  • E34.3 The compound of any of E34-E34.2, or pharmaceutically acceptable salt thereof, that has at least 99% deuterium incorporation at each deuterium-label.
  • E34.4 The compound of any of E34-E34.3, or pharmaceutically acceptable salt thereof, that has at least 99.5% deuterium incorporation at each deuterium-label.
  • E35 A hydrate, solvate, polymorph, or prodrug of the compound of any of E1- E34.4, or a pharmaceutically acceptable salt thereof.
  • E36 A hydrate, solvate, polymorph, or prodrug of the compound of any of E1- E34.4, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E35, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • E37 A method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E36.
  • E38 The method of E37, wherein the mammal is human.
  • E39 E39.
  • E37 or E38 wherein the muscarinic acetylcholine receptor is mAChR M1.
  • E40 The method of any of E37-E39, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.
  • E41 The method of any of E37-E40, further comprising the step of identifying a mammal in need of treatment of the disorder.
  • E42 The method of any of E37-E41, wherein the disorder is a neurological disorder or psychiatric disorder, or a combination thereof.
  • E43 E43.
  • the disorder is psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson’s disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, or memory disorders, or a combination thereof.
  • the disorder is psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome,
  • E45 The method of any of E37-E42, wherein the disorder is Alzheimer’s disease, schizophrenia, a sleep disorder, a pain disorder, or a cognitive disorder, or a combination thereof.
  • the pain disorder is neuropathic pain, central pain syndrome, postsurgical pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesis, primary allodynia, secondary allodynia, or a combination thereof.
  • E46 E46.
  • E47. Use of the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E35, or a pharmaceutically acceptable salt thereof, or the composition of E36, for the preparation of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.
  • Compounds may exist as a stereoisomer wherein asymmetric or chiral centers are present.
  • the stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • the terms “R” and “S” 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.
  • the compounds of formula (I) when no specific configuration is indicated at a stereogenic center (e.g., carbon), the compounds include all possible stereoisomers.
  • 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.
  • any "hydrogen” or "H,” whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes 1 H (protium) and 2 H (deuterium).
  • the present disclosure also includes an isotopically-labeled compound (e.g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom.
  • 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 to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Isotopically-enriched forms 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).
  • the disclosed compounds may exist as pharmaceutically acceptable salts.
  • 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.
  • a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid.
  • a suitable solvent such as but not limited to methanol and 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.
  • 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-phenylpropionate, 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.
  • 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, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. 3.
  • 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.
  • 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, to achieve 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)) 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.
  • a therapeutically effective amount of a compound of formula (I) may be about 1 mg/kg to about 1000 mg/kg, about 5 mg/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
  • compositions and formulations may include pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non- toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • 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;
  • the compounds and their physiologically acceptable salts and solvates 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.
  • the route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used.
  • compositions 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).
  • 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.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • Suitable antioxidants include butylated hydroxyanisole (“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%.
  • Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate.
  • Suitable glidants include silicon dioxide.
  • the amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.
  • 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%.
  • 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%.
  • 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 Volume 1, 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%.
  • 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.
  • Compositions for oral administration can have various dosage forms.
  • 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%.
  • 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.
  • Capsules typically include an active compound (e.g., a compound of formula (I)), 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.
  • 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.
  • 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.
  • Compositions for oral administration can have liquid forms.
  • 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.
  • 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.
  • 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)), 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.
  • 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.
  • a carrier may include a single ingredient or a combination of two or more ingredients.
  • 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.
  • 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.
  • 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,
  • emollients for skin include stearyl alcohol and polydimethylsiloxane.
  • the amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.
  • 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%.
  • 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 combinations thereof.
  • Specific solvents include ethyl alcohol and homotopic alcohols.
  • the amount of solvent(s) in a topical composition is typically about 0% to about 95%.
  • 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%.
  • the amount of thickener(s) in a topical composition is typically about 0% to about 95%.
  • 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%.
  • the amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.
  • Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.
  • a. Spray-Dried Dispersion Formulations [00273] The disclosed compounds may be formulated as a spray-dried dispersion (SDD).
  • 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 disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I). 4. Therapeutic Uses and Methods [00275]
  • the disclosed compounds are positive allosteric modulators of mAChR M 1 . Thus, by positive allosteric modulation, the compounds indirectly activate the muscarinic receptor subtype M1.
  • the disclosed compounds potentiate the agonist response (e.g., acetylcholine) of mAChR M 1 .
  • the disclosed compounds increase mAChR M 1 response to non-maximal concentrations of agonist in the presence of compound compared to the response to agonist in the absence of compound.
  • the potentiation of mAChR M1 activity can be demonstrated by methodology known in the art. For example, activation of mAChR M 1 activity can be determined by measurement of calcium flux in response to agonist, e.g. acetylcholine, in cells loaded with a Ca 2+ -sensitive fluorescent dye (e.g., Fluo-4).
  • the calcium flux was measured as an increase in fluorescent static ratio.
  • positive allosteric modulator activity was analyzed as a concentration-dependent increase in the EC 20 acetylcholine response (i.e. the response of mAChR M1 at a concentration of acetylcholine that yields 20% of the maximal response).
  • the disclosed compounds may activate mAChR M 1 response as an increase in calcium fluorescence in mAChR M 1 -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.
  • a disclosed compound may have an EC50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM.
  • the mAChR M1-transfected CHO-K1 cells are transfected with human mAChR M 1 .
  • the mAChR M 1 -transfected CHO-K1 cells are transfected with rat mAChR M 1 .
  • the disclosed compounds exhibit weak or substantially no agonist activation of mAChR M 1 response (i.e., lack of activation in the absence of a known agonist such as acetylcholine).
  • Lack of agonist activity may be measured as weak or no increase in calcium fluorescence in mAChR M1-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.
  • Lack of mAChR M 1 agonist activity may be determined as a percent response relative to acetylcholine.
  • a disclosed compound may have less than or equal to 30%, 25%, 20%, 15%, 10%, 5%, or 1% mAChR M1 agonist activity relative to acetylcholine.
  • a disclosed compound may have substantially no mAChR M 1 agonist activity.
  • the disclosed compounds exhibit positive allosteric modulation of mAChR M 1 response to acetylcholine, as described herein, at concentrations that have weak or substantially no agonist activity, as described herein. The absence of mAChR M 1 agonist activity may contribute to the avoidance of cholinergic adverse effect liability.
  • the disclosed compounds exhibit potentiation of mAChR M1 response to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with a mammalian mAChR M 1 in the presence of the compound, compared to the response to acetylcholine in the absence of the compound.
  • CHO-K1 cells can be transfected with human mAChR M1.
  • CHO-K1 cells can be transfected with rat mAChR M 1 .
  • a compound can exhibit positive allosteric modulation of mAChR M1 with an EC50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, or less than or equal to 100 nM.
  • the disclosed compounds exhibit potentiation of mAChR M 1 response to acetylcholine as an increase in response to non- maximal concentrations of acetylcholine in CHO-K1 cells transfected with human mAChR M1 in the presence of the compound, compared to the response to acetylcholine in the absence of the compound.
  • a compound can exhibit positive allosteric modulation of mAChR M1 with an EC 50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM.
  • the disclosed compounds exhibit positive allosteric modulation of mAChR M 1 response to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with a mAChR M1 in the presence of the compound, compared to the response to acetylcholine in the absence of the compound.
  • the disclosed compounds may exhibit positive allosteric modulation of the mAChR M 1 response to acetylcholine with an EC50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, or less than or equal to 100 nM.
  • the EC 50 for positive allosteric modulation is determined in CHO-K1 cells are transfected with a mAChR M1.
  • the CHO-K1 cells are transfected with a human mAChR M1.
  • the CHO-K1 cells are transfected with a rat mAChR M 1 .
  • Positive allosteric modulation of the mAChR M 1 response to acetylcholine with EC 50 of less than or equal to 0.5 ⁇ M, less than or equal to 0.25 ⁇ M, or less than or equal to 0.1 ⁇ M are all considered potent postive allosteric modulating activity.
  • the compounds activate mAChR M 1 response in mAChR M 1 - transfected CHO-K1 cells with an EC50 less than the EC50 for one or more of mAChR M2, mAChR M 3 , mAChR M 4 , or mAChR M 5 response in mAChR M 2 , M 3 , M 4 or M 5 -transfected CHO-K1 cells. That is, the disclosed compounds can have selectivity for the mAChR M 1 receptor vis-à-vis one or more of the mAChR M2, M3, M4 or M5 receptors.
  • the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M 2 , at least 10-fold less than that for mAChR M 2 , at least 20-fold less than that for mAChR M2, at least 30-fold less than that for mAChR M2, at least 50-fold less than that for mAChR M2, or at least 100-fold less than that for mAChR M2.
  • the disclosed compounds can activate mAChR M 1 response with an EC 50 of at least 5-fold less than that for mAChR M 3 , at least 10-fold less than that for mAChR M 3 , at least 20-fold less than that for M3, at least 30-fold less than that for mAChR M3, at least 50-fold less than that for mAChR M3, or at least 100-fold less than that for mAChR M3.
  • the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M 4 , at least 10-fold less than that for mAChR M 4 , at least 20-fold less than that for M 4 , at least 30-fold less than that for mAChR M4, at least 50-fold less than that for mAChR M4, or at least 100-fold less than that for mAChR M4.
  • the disclosed compounds can activate mAChR M 1 response with an EC 50 of at least 5-fold less than that for mAChR M 5 , at least 10-fold less than that for mAChR M 5 , at least 20-fold less than that for mAChR M 5 , at least 30-fold less than that for mAChR M5, at least 50-fold less than that for mAChR M5, or at least 100-fold less than that for mAChR M 5 .
  • the disclosed compounds can activate mAChR M 1 response with an EC 50 of at least 5-fold less than that for the mAChR M 2 , M3, M4 or M5 receptors, at least 10-fold less than that for the mAChR M2 , M3, M4 or M5 receptors, at least 20-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 30- fold less than that for the mAChR M 2 , M 3 , M 4 or M 5 receptors, at least 50-fold less than that for the mAChR M2, M3, M4 or M5 receptors, or at least 100-fold less than that for the mAChR M2, M3, M4 or M5 receptors.
  • the compound activates mAChR M1 response in mAChR M 1 -transfected CHO-K1 cells and is inactive for one or more of mAChR M 1 , mAChR M 3 , mAChR M 4 , or mAChR M 5 response in mAChR M 2 , M 3 , M 4 or M 5 -transfected CHO-K1 cells.
  • the compounds activate mAChR M 1 response in M 1 -transfected CHO-K1 cells with an EC 50 of less than or equal to 10 ⁇ M and exhibits a selectivity for the M 1 receptor vis-à-vis one or more of the mAChR M2, M3, M4 or M5 receptors.
  • the compounds can have an EC 50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M 2 , at least 10-fold less than that for mAChR M 2 , at least 20-fold less than that for mAChR M2, at least 30-fold less than that for mAChR M2, or at least 50-fold less than that for mAChR M2.
  • the compounds can have an EC50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M3, at least 10-fold less than that for mAChR M3, at least 20-fold less than that for mAChR M3, at least 30-fold less than that for mAChR M3, or at least 50-fold less than that for mAChR M 3 .
  • the compounds can have an EC 50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M 1 response with an EC 50 of at least 5-fold less than that for mAChR M 4 , of at least 10-fold less than that for mAChR M4, of at least 20-fold less than that for mAChR M4, of at least 30-fold less than that for mAChR M 4 , or at least 50-fold less than that for mAChR M 4 .
  • the compound can have an EC 50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M 1 response with an EC 50 of at least 5-fold less than that for mAChR M5, of at least 10-fold less than that for mAChR M5, of at least 20-fold less than that for mAChR M5, of at least 30-fold less than that for mAChR M5, or at least 50-fold less than that for mAChR M 5 .
  • the compounds can have an EC 50 of less than or equal to 10 ⁇ M, less than or equal to 5 ⁇ M, less than or equal to 2.5 ⁇ M, less than or equal to 1 ⁇ M, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M 1 response with an EC 50 of at least 5-fold less than that for the mAChR M 2 , M 3 , M 4 or M 5 receptors, at least 10-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 20-fold less than that for the mAChR M 2 , M 3 , M 4 or M 5 receptors, at least 30-fold less than that for the mAChR M 2 , M 3 , M 4 or M 5 receptors, or at least 50-fold less than that for the mAChR M 2 , M 3 ,
  • the disclosed compounds may be used in methods for treatment of mAChR M1 related medical disorders and/or diseases.
  • the methods of treatment may comprise administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of the compound of formula (I).
  • the compounds can be administered to a subject in need thereof to modulate mAChR M 1 , for a variety of diverse biological processes.
  • the present disclosure is directed to methods for administering the composition to potentiate mAChR M 1 , a GPCR whose dysfunction is associated with neurological and psychiatric disorders, for example.
  • the compounds may be useful for treating and preventing certain diseases and disorders in humans and animals related to mAChR M1 dysfunction.
  • Treatment or prevention of such diseases and disorders can be effected by modulating mAChR M 1 in a subject, by administering a compound or composition of the disclosure, either alone or in combination with another active agent as part of a therapeutic regimen to a subject in need thereof.
  • the other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound.
  • a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred.
  • 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.
  • the compounds can be coadministered with anti-Alzheimer’s agents, beta-secretase inhibitors, gamma-secretase inhibitors, orthosteric muscarinic agonists, muscarinic potentiators, cholinesterase inhibitors, HMG-CoA reductase inhibitors, NSAIDs and anti-amyloid antibodies.
  • the compounds can be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyT1 inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and combinations thereof.
  • sedatives hypnotics, anxiolytics, antipsychotics (typical and atypical), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyT1 inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam
  • the compounds may be useful for treating a disease or disorder associated with dysfunction of mAChR M 1 , wherein the disease or disorder is selected from at least one of Alzheimer’s disease, a sleep disorder, a pain disorder, a cognitive disorder, psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson’s disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders.
  • Alzheimer’s disease a sleep disorder, a pain disorder, a cognitive disorder, psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with
  • the compounds may be useful for treating a pain disorder, wherein the pain disorder is neuropathic pain, central pain syndrome, postsurgical pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesis, primary allodynia, secondary allodynia, or a combination thereof.
  • the compounds disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders wherein the patient or subject would benefit from selective positive allosteric modulation of the M 1 receptor.
  • a treatment can include selective M 1 receptor modulation to an extent effective to affect cholinergic activity.
  • a disorder can be associated with cholinergic activity, for example cholinergic hypofunction.
  • a method of treating or preventing a disorder in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject.
  • a method for the treatment of one or more disorders, for which muscarinic receptor activation is predicted to be beneficial, in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject.
  • the disclosure is directed to the use of described chemical compositions to treat diseases or disorders in patients (preferably human) wherein muscarinic receptor activation would be predicted to have a therapeutic effect, such as Alzheimer’s disease (both palliative cognitive and disease-modifying), cognitive impairment, schizophrenia, pain disorders (including acute pain, neuropathic pain and inflammatory pain), and sleep disorders, by administering one or more disclosed compounds or products.
  • a method for the treatment of a disorder in a mammal comprising the step of administering to the mammal at least one disclosed compound, composition, or medicament.
  • the disclosed compounds have utility in treating a variety of neurological and psychiatric disorders, including one or more of the following conditions or diseases: schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis psychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, “schizophrenia-spectrum” disorders such as schizoid or sch
  • the present disclosure provides a method for treating cognitive disorders, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure.
  • Particular cognitive disorders are dementia, delirium, amnestic disorders and age-related cognitive decline.
  • the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • the term “cognitive disorders” includes treatment of those mental disorders as described in DSM-IV-TR.
  • the present disclosure provides a method for treating anxiety disorders, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure.
  • anxiety disorders are generalized anxiety disorder, obsessive-compulsive disorder and panic attack.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • AD Alzheimer’s disease
  • Hallmarks of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain and other regions of the brain important for memory and cognition.
  • Other hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau and accumulation of amyloid ⁇ peptide (A ⁇ ).
  • a ⁇ is a 39-43 amino acid peptide produced in the brain by proteolytic processing of ⁇ -amyloid precursor protein (APP) by the ⁇ -amyloid cleaving enzyme (BACE) and gamma secretase which leads to accumulation of A ⁇ in the brain, where A ⁇ 1-40 and 1-42 are the principal aggregate-forming species of A ⁇ .
  • APP ⁇ -amyloid precursor protein
  • BACE ⁇ -amyloid cleaving enzyme
  • gamma secretase which leads to accumulation of A ⁇ in the brain, where A ⁇ 1-40 and 1-42 are the principal aggregate-forming species of A ⁇ .
  • Schizophrenia is a debilitating psychiatric disorder characterized by a combination of negative (blunted affect, withdrawal, anhedonia) and positive (paranoia, hallucinations, delusions) symptoms as well as marked cognitive deficits. While schizophrenia remains an idiopathic disorder, it appears to be produced by a complex interaction of biological, environmental, and genetic factors. Over 40 years ago it was found that phencyclidine (PCP) induces a psychotic state in humans that is very similar to that observed in schizophrenic patients.
  • PCP phencyclidine
  • the finding that the main mode of action of PCP is that of a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptor stimulated a series of studies that have led to the development of the NMDA receptor hypofunction model of schizophrenia.
  • the present disclosure provides a method for treating schizophrenia or psychosis comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure.
  • Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
  • NMDA receptor function can be modulated by activation of G Protein-Coupled Receptors (GPCRs) that are known to physically and/or functionally interact with the NMDA receptor.
  • GPCRs G Protein-Coupled Receptors
  • any agent that can potentiate NMDA receptor currents either directly by action on modulatory sites on the NMDA receptor (e.g., the glycine co-agonist binding site) or indirectly by activation of GPCRs known to potentiate NMDA receptor function (e.g. the mAChR M1), has the potential to ameliorate the symptoms of schizophrenia.
  • NMDA receptor e.g., the glycine co-agonist binding site
  • GPCRs known to potentiate NMDA receptor function e.g. the mAChR M1
  • M1 activation is a reasonable approach to the treatment of schizophrenia.
  • the selective M 1 allosteric agonist TBPB demonstrated efficacy in multiple preclinical models of schizophrenia.
  • schizophrenia or psychosis includes treatment of those mental disorders as described in DSM-W-TR.
  • DSM-W-TR the term “schizophrenia or psychosis” includes treatment of those mental disorders as described in DSM-W-TR.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress.
  • the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources. 5.
  • Substance-Related Disorders and Addictive Behaviors [00304] The present disclosure provides a method for treating substance-related disorders and addictive behaviors, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure.
  • Particular substance-related disorders and addictive behaviors are persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse; and tolerance of, dependence on or withdrawal from substances of abuse.
  • the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse; and tolerance of, dependence on or withdrawal from substances of abuse.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • the term “substance- related disorders and addictive behaviors” includes treatment of those mental disorders as described in DSM-IV- TR.
  • the present disclosure provides a method for treating pain, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure.
  • a compound of the present disclosure is bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain.
  • the present disclosure provides a method for treating obesity or eating disorders associated with excessive food intake and complications associated therewith, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure.
  • Obesity is included in the tenth edition of the International Classification of Diseases and Related Health Problems (ICD-10) (1992 World Health Organization) as a general medical condition.
  • the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes obesity in the presence of psychological factors affecting medical condition.
  • the term “obesity or eating disorders associated with excessive food intake” includes treatment of those medical conditions and disorders described in ICD-10 and DSM-W-TR.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for general medical conditions, and that these systems evolve with medical and scientific progress.
  • the term “obesity or eating disorders associated with excessive food intake” is intended to include like conditions and disorders that are described in other diagnostic sources.
  • the compounds are 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 are 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.
  • the present disclosure is further directed to administration of a selective M1 receptor modulator for improving treatment outcomes in the context of cognitive or behavioral therapy. That is, in one aspect, the disclosure relates to a cotherapeutic method comprising the step of administering to a mammal an effective amount and dosage of at least one compound of the disclosure in connection with cognitive or behavioral therapy. [00309] In another aspect, 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 therapy and can be before, during, and/or after therapy.
  • cognitive or behavioral therapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or after administration of the compound.
  • cognitive or behavioral therapy can be provided within 1, 2, 3, or 4 weeks before or after administration of the compound.
  • 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.
  • Methods of treatment may include any number of modes of administering a disclosed composition.
  • 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.
  • 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.
  • 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, aque
  • the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.
  • 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.
  • a physiologically acceptable diluent such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used.
  • 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.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • the disclosed compounds can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which disclosed compounds or the other drugs can have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure.
  • a pharmaceutical composition in unit dosage form containing such other drugs and a disclosed compound is preferred.
  • the combination therapy can also include therapies in which a disclosed compound and one or more other drugs are administered on different overlapping schedules.
  • the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.
  • the pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.
  • 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.
  • 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 disclosure.
  • a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred.
  • the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure.
  • 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 of each will be used. Thus, for example, when a compound of the present disclosure 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 disclosure 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. [00317] In such combinations disclosed compounds 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).
  • 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.
  • the disclosed compounds can be employed in combination with anti- Alzheimer’s agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID’s including ibuprofen, vitamin E, and anti-amyloid antibodies.
  • the subject compound can be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, buspirone, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlor
  • the disclosed compounds can be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.
  • levodopa with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide
  • anticholinergics such as biperi
  • the dopamine agonist can be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.
  • the disclosed compounds can be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the neuroleptic agents when used in combination with the subject compound can be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • a pharmaceutically acceptable salt for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixen
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • the subject compound can be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, ris
  • the disclosed compounds can be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, ⁇ - adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • norepinephrine reuptake inhibitors including tertiary amine tricyclics and secondary amine tricyclics
  • Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts.
  • kits 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 M 1 activity; (b) at least one agent known to decrease mAChR M1 activity; (c) at least one agent known to treat a disorder associated with cholinergic activity; (d) instructions for treating a disorder associated with cholinergic activity; (e) instructions for treating a disorder associated with M 1 receptor activity; or (f) instructions for administering the compound in connection with cognitive or behavioral therapy.
  • the at least one disclosed compound and the at least one agent are co-formulated.
  • kits can also comprise compounds and/or products co-packaged, co-formulated, and/or co-delivered with other components.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • Chemical Synthesis [00328] Compounds of formula (I) 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.
  • Compounds of formula (I) may be synthesized as shown in the Schemes and Examples set forth below.
  • S2 may be prepared via nucleophilic displacement of a leaving group LG 1 (e.g., halogen, triflate, mesylate, tosylate) using a benzyl amine A, followed by cyclization, in the presence of a base (e.g., DIEA) with heating in an appropriate solvent (e.g., MeCN, DMF), wherein A 2 and X are as defined in General Scheme I.
  • LG 1 e.g., halogen, triflate, mesylate, tosylate
  • a base e.g., DIEA
  • an appropriate solvent e.g., MeCN, DMF
  • General Scheme IV or triflate may be art.
  • General Scheme VI [00335] As shown in General Scheme VI, S2, wherein X is halogen or triflate, may be transformed to S6 using a Suzuki reaction under conditions well known in the art.
  • General Scheme VII
  • compounds S2 may be enriched in deuterium in the lactam ring by reaction with NaOD in an appropriate solvent such as THF/D2O, wherein A 2 and X are as defined in General Scheme I.
  • a methylating agent e.g., MeI
  • methyl benzoates of formula A-2 may be subjected to reduction conditions, wherein A-2 is reacted with an appropriate reducing agent (e.g., DIBAL-H) to form intermediate benzyl alcohol of formula A-3.
  • benzyl alcohols of formula A-3 may be subjected to oxidation conditions, wherein A-3 is reacted with an appropriate oxidizing agent (e.g, Dess-Martin Periodinane) to form intermediate benzaldehyde of formula A-4.
  • benzaldehydes of formula A-4 may be reacted with a suitable hydroxylamine (e.g., NH2OH-HCl) to form intermediate oxime of formula A-5.
  • oximes of formula A-5 may be subjected to reduction conditions, wherein A-5 is reacted with an appropriate reducing agent (e.g., Zn dust/acetic acid) to form benzyl amine intermediates of formula A-1.
  • an appropriate reducing agent e.g., Zn dust/acetic acid
  • 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 Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England. [00339] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt.
  • 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.
  • 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.
  • Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures 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.
  • 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 (4 th ed.), 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.
  • an optically active form of a disclosed compound 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).
  • an optically active starting material prepared, for example, by asymmetric induction of a suitable reaction step
  • resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
  • a standard procedure such as chromatographic separation, recrystallization or enzymatic resolution
  • Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 ⁇ m, 1.0 x 50 mm) at 0.5 mL/min, with column and solvent temperatures maintained at 55 oC.
  • 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).
  • the MS 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 oC 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. [00346] The following abbreviations may be used herein: AcOH acetic acid Ac 2 O acetic anhydride aq aqueous atm atmosphere(s) CDCl3 chloroform-d CD 3 OD or MeOD methanol-d 4 CD3COOD acetic acid-d4 Celite® diatomaceous earth conc.
  • Step -4-bromo-2- chloro-6- g was added zinc powder (4.85 g, 74.3 mmol). The resulting suspension was sonicated at rt for 3 h then filtered through a pad of Celite®, which was washed thoroughly with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure, azeotroped with toluene (3x), and then dried under vacuum to provide the title compound. The product was carried forward without further purification.
  • Step 1 4- To an oven-dried 250 mL flask was added 4-bromo-2,6-difluoro-benzoic acid (5.0 g, 21.1 mmol) and THF (100 mL) under N2. The reaction was cooled to 0 °C and cyclopropylmagnesium bromide (75.35 mL, 52.74 mmol) was added slowly. The ice bath was removed.
  • Step 2 Methyl 4-bromo-2-cyclopropyl-6-fluorobenzoate.
  • 4- bromo-2-cyclopropyl-6-fluoro-benzoic acid 5.46 g, 21.08 mmol
  • DMF 42 mL
  • potassium carbonate 8.87 g, 63.23 mmol
  • MeI 2.62 mL, 42.15 mmol
  • Step 3 (4- To a solution of methyl 4-bromo-2-cyclopropyl-6-fluoro-benzoate (4.51 g, 16.51 mmol) in DCM (80 mL) was added diisobutylaluminum hydride solution (1.0 M in THF, 49.54 mL, 49.54 mmol) dropwise at 0 °C. The ice bath was removed.
  • Step 4 4- a of (4-bromo- 2-cyclopropyl-6-fluoro-phenyl)methanol (1.74 g, 7.10 mmol) in DCM (40 mL) was added Dess- Martin periodinane (6.02 g, 14.20 mmol) at rt. After 2 h, the reaction was quenched by addition of sat. aq. NaHCO3. The reaction mixture was extracted with DCM (3x). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the crude material. The crude material was purified using silica gel chromatography (0-20% EtOAc/hexanes) to give the title compound (1.66 g, 96% yield).
  • Step 1 4- suspension of 6-fluoro- 4-bromosalicylaldehyde (500 mg, 2.28 mmol) in MeCN (22.8 mL) was added K 2 CO 3 (640 mg, 4.57 mmol) followed by 1-iodo-2-methylpropane (0.53 mL, 4.57 mmol). The mixture was stirred at 50 °C for 72 h, and recharged with 1-iodo-2-methylpropane (0.53 mL, 4.57 mmol) every 24 h. After 72 h, water was added to the reaction mixture, and the resulting solution was extracted with EtOAc (3x).
  • Step 3 (4- The title compound was prepared in a similar manner as (4-bromo-2-chloro-6-fluorophenyl)methanamine.
  • Step 3 2-(Aminomethyl)-5-bromo-3-fluoro-N,N-dimethylaniline.
  • the title compound was prepared in a similar manner as (4-bromo-2-chloro-6-fluorophenyl)methanamine.
  • Step 2 6- - [3,4-d]pyrimidin- 5-one.
  • the title compound was prepared in a similar manner as 6-(4-bromo-2,6-difluorobenzyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one.
  • Step 1 6-[(5-Bromopyrimidin-2-yl)methyl]-7H-pyrrolo[3,4-b]pyridin-5- one
  • Step 1 (1.0 g, 6.62 mmol) and trichlorocyanuric acid (2.31 g, 9.92 mmol) were dissolved in DCM (20 mL) and stirred at rt. After 20 h, the suspension was quenched with sat. soln. NaHCO 3 and extracted with DCM (3x). The combined extracts were washed with H 2 O and brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to provide the title compound which was used without further purification (1.23 g).
  • Methyl 2-(chloromethyl)pyridine-3-carboxylate 250 mg, 1.35 mmol
  • (5-bromopyrimidin-2- yl)methanamine hydrochloride (454 mg, 2.02 mmol)
  • DIEA 0.7 mL, 4.04 mmol
  • DMF 7.5 mL
  • the solution was quenched with sat. soln. NaHCO3 and extracted with DCM (3x).
  • the combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 2 Methyl 8-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate.
  • methyl (E/Z)-5-bromo-6-(N'-hydroxyacetimidamido)picolinate (374 mg, 1.30 mmol) in THF (3.0 mL) at 0 °C was added trifluoacetic anhydride (0.54 mL, 3.9 mmol). After 16 h at rt, the reaction mixture was quenched with sat. soln.
  • reaction mixture was evacuated and purged with N2 (3x) and allowed to stir at 100 ⁇ C. After 2 h, the mixture was diluted with EtOAc and DCM, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to provide the title compound (8.9 mg).
  • Example 2 (S)-6-(1-(2,6-Difluoro-4-(7-(hydroxymethyl-d 2 )-2-methyl-2H-indazol-4- yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 15) [00399] ethyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (29.7 mg, 0.07 mmol), (4-bromo-2-methyl-2H- indazol-7-yl)methan-d2-ol (13.9 mg, 0.06 mmol), Pd(dppf)Cl2 (8.4 mg, 0.01 mmol), and Cs2CO3 (56.1 mg, 0.17 mmol) were combined into a reaction vial.
  • Example 3 6-(2,6-Difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d 2 (Compound 19) [00400] 2- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d 2 (30.3 mg, 0.078 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1-d-1- ol (15.4 mg, 0.06 mmol), Pd(dppf)Cl2 (8.8 mg, 0.01 mmol), Cs2CO3 (59.0 mg, 0.18 mmol) and D 2 O (0.2 mL).
  • Example 4 6-(2,6-Difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d 4 )-2-methyl-2H-indazol-4- yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 36) [00401] 2- yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (24.1 mg, 0.062 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1,2,2,2-d 4 -1-ol (11.3 mg, 0.045 mmol), Pd(dppf)Cl2 (6.5 mg, 0.01 mmol), Cs2CO3 (43.8 mg, 0.13 mmol) and H 2 O (0.2 mL).
  • the resulting mixture was evacuated and purged with nitrogen. After 2 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite® and concentrated under reduced pressure.
  • the crude material was purified using reverse phase HPLC to afford a racemic mixture which was further resolved using SFC chiral preparative separation (Phenomenex Lux-Cellulose 4, 21 x 250 mm column, particle size 5-micron, primary solvent: liquid CO2, co-solvent: 2- propanol, 40% isocratic, flow rate: 80, temperature: 40 °C). After an additional purification using reverse phase HPLC, two separated stereoisomers were obtained.
  • reaction mixture was evacuated and purged with N2 (3x) and allowed to stir at 100 ⁇ C. After 16 h, the mixture was diluted with EtOAc and DCM, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to provide the title compound (5.5 mg).
  • CHO-K1 cells stably expressing rat (r)M 1 were purchased from the American Type Culture Collection and cultured according to their indicated protocol.
  • CHO cells stably expressing human (h)M2, hM3, and hM5 were described previously (Levey, et al., 1991); hM1 and hM4 cDNAs were purchased from Missouri S&T cDNA Resource; rM4 cDNA was provided by T. I. Bonner (National Institutes of Health, Bethesda, MD).
  • rM 2 and rM 3 were cloned from a rat brain cDNA library and sequence verified.
  • hM1, rM2, rM3, hM4, and rM4 cDNAs were used to stably transfect CHO-K1 cells purchased from the American Type Culture Collection using Lipofectamine2000.
  • rM 2 , hM 2 , rM3, hM 4, and rM 4 cell lines were stably transfected with a chimeric G- protein (Gqi5) (provided by B.R. Conklin, University of California, San Francisco) using Lipofectamine 2000.
  • Gqi5 chimeric G- protein
  • rM 1, hM 1 , rM 3 , hM 3 , rM 5 , and hM 5 cells were grown in Ham’s F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, and 50 ⁇ g/mL G418 sulfate.
  • FBS heat-inactivated fetal bovine serum
  • rM2-Gqi5, hM2–Gqi5, and hM4–Gqi5 cells were grown in the same medium also containing 500 ⁇ g/mL Hygromycin B.
  • Stable rM4–Gqi5 cells were grown in DMEM containing 10% heat-inactivated FBS, 20 mM HEPES, 400 ⁇ g/mL G418 sulfate, and 500 ⁇ g/mL Hygromycin B.
  • b. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor Activity 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 ⁇ L/well in Greiner 384-well black-walled, tissue culture (TC)-treated, clear-bottom plates (VWR).
  • Dye was removed by washing with the ELX 405 (four 80 ⁇ L washes of assay buffer) then aspirated to 20 ⁇ L.
  • Compound master plates were formatted in an 11 point CRC format (1:3 dilutions) in 100% DMSO with a starting concentration of 10 mM using the 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 ⁇ L) to a 2 ⁇ stock using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA).
  • FDSS Functional Drug Screening System
  • Compounds were applied to cells (20 ⁇ L, 2X) using the automated system of the FDSS 6000 at 4 s into the 300 s protocol and the data were collected at 1 Hz.
  • 10 ⁇ L of an EC20 concentration of the muscarinic receptor agonist acetylcholine was added (5X), followed by the addition of 12 ⁇ L of an EC 80 concentration of acetylcholine at the 230 s time point (5X).
  • Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition.
  • Emax values for agonist activity are expressed relative to the maximum for acetylcholine.
  • Positive allosteric modulator activity was analyzed as a concentration-dependent increase in the EC 20 acetylcholine response.
  • Antagonist activity was analyzed as a concentration-dependent decrease in the EC80 acetylcholine response.
  • 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).
  • 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 the appropriate concentration of agonist was added and readings taken for an additional 106 s. Data were reduced as described above and the EC 50 values for the agonist in the presence of test compound were determined by nonlinear curve fitting. A decrease in the EC 50 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.

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Abstract

N-Biarylmethylene substituted pyrrolopyridinone, pyrrolopyrazinone, pyrrolopyrimidinone, and isoindolin-1-one compounds having a primary or secondary alcohol-containing group substituted on the biarylmethylene are positive allosteric modulators of the muscarinic acetylcholine receptor M1 (mAChR M1). The compounds and pharmaceutical compositions may be used in treating neurological disorders, psychiatric disorders, or a combination thereof.

Description

POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M1 RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/416,839, filed October 17, 2022, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD [0002] The present disclosure relates to compounds, compositions, and methods for treating muscarinic acetylcholine receptor M1 related diseases and/or disorders, such as neurological and psychiatric disorders. BACKGROUND [0003] Positive allosteric modulators are compounds that bind to a site distinct from that of the orthosteric agonist binding site of a target protein. These modulators enhance the affinity or efficacy of an orthosteric agonist. For example, a selective muscarinic M1 positive allosteric modulator would result in an increased affinity at the orthosteric binding site for acetylcholine (ACh), the endogenous agonist for the muscarinic M1 receptor, or an increase in the efficacy induced by ACh. In some systems, the compound may also have an intrinsic activity to activate the receptor in the absence of orthosteric ligand. Positive allosteric modulation (potentiation), therefore, can be an attractive mechanism for enhancing appropriate physiological receptor activation. [0004] Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or the muscarinic acetylcholine receptors (mAChRs) by the binding of the endogenous orthosteric agonist ACh. Acetylcholinesterase (AChE) inhibitors, which inhibit the hydrolysis of ACh, have been approved in the United States for use in the palliative, but not disease-modifying, treatment of the cognitive deficits in Alzheimer’s disease (AD) patients. [0005] mAChRs are members of the family A GPCRs, and include five subtypes, designated M1, M2, M3, M4, and M5. M1, M3 and M5 mainly couple to Gq and activate phospholipase C, whereas M2 and M4 mainly couple to Gi/o and associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system where they are prevalent and differentially expressed. M1-M5 mAChRs have varying roles in cognitive, sensory, motor and autonomic functions. Activation of various muscarinic receptors, particularly the M1 subtype, has been proposed as a mechanism to enhance cognition in disorders such as AD and schizophrenia (as well as negative symptoms). Thus, selective positive allosteric modulators of mAChR subtypes that regulate processes involved in cognitive function could prove superior to AChE inhibitors for treatment of AD and related disorders as these compounds may exhibit improved selectivity for specific mAChRs. [0006] Efforts to create selective M1 agonists have been largely unsuccessful, in part due to the high conservation of the orthosteric ACh binding site. As a result, mAChR agonists in clinical studies induce the same adverse effects of AChE inhibitors by activation of peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes and to further explore the therapeutic utility of mACh receptors in AD, schizophrenia and other disorders, there exists a need to develop compounds that are highly selective modulators of M1 and other individual mAChR subtypes. Accordingly, allosteric modulation may be an advantageous pathway because allosteric sites on mAChRs are less highly conserved. [0007] Despite advances in muscarinic receptor (mAChR) research, there remains a scarcity of compounds that are potent, efficacious and selective positive allosteric modulators of the M1 mAChR that are also effective in the treatment of neurological and psychiatric disorders associated with cholinergic activity, or other neurologic diseases in which the muscarinic M1 receptor may be involved. SUMMARY [0008] In one aspect, disclosed are compounds of formula (I), or pharmaceutically acceptable salts thereof, (I) wherein A1 is selected from the group ,
Figure imgf000004_0001
;
Figure imgf000004_0002
Z2 is N or CRz2; Z3 is N or CRz3; Z4 is N or CRz4; wherein 0, 1, or 2 of Z1, Z2, Z3, and Z4 is N; Rz1, Rz2, Rz3, and Rz4 are independently selected from the group consisting of H, D, halogen, C1- 2alkyl, C1-2deuterioalkyl, C1-2fluoroalkyl, cyano, –OC1-2alkyl, –OC1-2deuterioalkyl, –OC1- 2fluoroalkyl, and C3-4cycloalkyl; R1, R2, R3 and R4 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4deuterioalkyl, C1-4fluoroalkyl, halogen, cyano, G1, –ORa, –O–C2-3alkylene–ORb, and –N(Rc)(Rd); Ra, Rb, Rc, and Rd are independently selected from the group consisting of H, C1-4alkyl, C1- 4deuterioalkyl, C1-4fluoroalkyl, G1, and –C1-3alkylene–G1, wherein alternatively, Rc and Rd, together with the nitrogen to which the Rc and Rd attach, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of O, N, and S, wherein the 4- to 7-membered heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C1-4fluoroalkyl, OH, –OC1-4alkyl, –OC1- 4deuterioalkyl, and –OC1-4fluoroalkyl; G1 is C3-6cycloalkyl or a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C1-4fluoroalkyl, OH, –OC1- 4alkyl, –OC1-4deuterioalkyl, and –OC1-4fluoroalkyl; R5 is a 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or R5 is a 6- to 12 membered aryl, the heteroaryl and aryl being substituted by R6 and optionally further substituted with 1-4 substituents R7; R6 is –C(R6a)(R6b)OH; R6a is selected from the group consisting of D, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, –C1-3alkylene–C3-6cycloalkyl, and –C1-5alkylene–X1, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R6b is H or D; X1 is selected from the group consisting of –SR6c, –SOR6c, –SO2R6c, and –S(O)(NR6d)R6c; R6c is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R6d is selected from the group consisting of H, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R7, at each occurrence, is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, –OC1- 4haloalkyl, C3-6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R8a and R8b are independently selected from the group consisting of H, D, CH3, and CD3; and R9a and R9b are independently H or D. [0009] 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. [0010] In another aspect, the invention provides a method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an 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 disorder associated with muscarinic acetylcholine receptor activity. [0012] 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 disorder associated with muscarinic acetylcholine recepter activity. [0013] 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. [0014] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, with minimal to substantially no M1 agonist activity compared to acetylcholine. The relative absence of M1 agonist activity is expected to avoid or reduce cholinergic adverse effect liability at therapeutic concentrations and/or doses. DETAILED DESCRIPTION [0015] Disclosed herein are positive allosteric modulators of the M1 muscarinic acetylcholine receptor M1 (mAChR M1). The modulators can have the structure of formula (I). Compounds of formula (I) exhibit high affinity for mAChR M1, and can also exhibit selectivity over other muscarinic acetylcholine receptors. Compounds of formula (I) can be used to treat or prevent diseases and disorders associated with mAChR M1 by modulating mAChR M1 activity. mAChR M1 has been implicated in a number of different diseases and disorders including, but not limited to, neurological and psychiatric disorders. [0016] Since the orthosteric binding sites of the mAChR isoforms are highly conserved, selective modulators of the mAChRs that bind at the orthosteric site remain elusive. One strategy to selectively bind and modulate the mAChRs includes identifying allosteric sites which may be amenable to modulation by a small molecule. In particular, positive allosteric modulation of mAChR M1 can result in potentiation of the mAChR M1 receptor and provide therapeutic benefits for disorders associated with mAChR M1 dysfunction. 1. Definitions [0017] 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. [0018] 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. [0019] 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. [0020] 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, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. [0021] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “C1-6alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1-4alkyl” means a straight or branched chain saturated hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-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 “alkylene,” as used herein, refers to a divalent group derived from a straight or branched saturated chain hydrocarbon, for example, of 1 to 6 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -C(CH3)2CH2CH2-, - CH2C(CH3)2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-. [0024] The term “alkenylene,” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon having at least one carbon-carbon double bond. [0025] 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][1,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6- membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system). [0026] The term “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., decahydronaphthalenyl), 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), or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl. [0027] The term “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic all-carbon ring system containing at least one 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. [0028] The term “deuterioalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more hydrogen atoms in the alkyl are the isotope deuterium, i.e., 2H. Representative examples of deuterioalkyl include CD3, CH2CD3, and CD2CD3. [0029] 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 a fluoro group. Representative examples of fluoroalkyl include CH2F, CHF2, CF3, and CH2CF3. [0030] The term “fluorodeuterioalkyl,” as used herein, means a fluoroalkyl group, as defined herein, in which one or more hydrogen atoms in the fluoroalkyl are the isotope deuterium, i.e., 2H. Representative examples of fluorodeuterioalkyl include CD2F, CDF2, and CD2CF3. [0031] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F. [0032] 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. [0033] The term "halodeuterioalkyl," as used herein, means a haloalkyl, as defined herein, in which one or more hydrogen atoms in the haloalkyl are the isotope deuterium, i.e., 2H. Representative examples of halodeuterioalkyl include CD2F, CDF2, CD2CF3, CD2Cl, CDCl2, and CD2CCl3, . [0034] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatom- containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaryl (bicyclic heteroaryl). The term “heteroaryl”is used herein to refer to a heteroarene when present as a substituent, the term "heteroarene" being used in cases of ring fusion. 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 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., "fully aromatic" 10 ^ electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1- yl), a monocyclic heteroaryl ring fused to a monocyclic 5- to 6-membered heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic 5- to 6-membered 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 a fused 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. Representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (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., benzimidazol-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[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2-yl. [0035] 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 consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2- thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 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, 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, or a bridged monocyclic 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, 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-1-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, 1,2,3,4-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-1H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2- oxaspiro[3.3]heptanyl, and 3-oxaspiro[5.5]undecanyl. 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[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1- azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom. [0036] The term “hydroxyl” or “hydroxy,” as used herein, means an -OH group. [0037] 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., "C1-4alkyl," "C3-6cycloalkyl," "C1-4alkylene"). 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. As used herein, “Cm to Cn,” “Cm-Cn” or “Cm-n” in which “m” and “n” are integers refers to the number of carbon atoms in the relevant group. That is, the group can contain from “m” to “n”, inclusive, carbon atoms. Thus, for example, a “C1 to C6 alkyl” group refers to all alkyl groups having from 1 to 6 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, CH3CH(CH)3CH2- , CH3CH(CH)3CH2- and (CH3)3C-. Thus, "C3alkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "C1-4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "C1-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched). If no “m” and “n” are designated with regard to a group, the broadest range described in these definitions is to be assumed. [0038] A dashed bond, , represents an optional unsaturation between the atoms forming the bond. This bond may be unsaturated (e.g. C=C, C=N, C=O) or saturated (e.g. C-C, C-N, C-O). When a dashed bond is present in a ring system it may form part of an aromatic ring system. [0039] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups may include, for example, 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. [0040] As used herein, an "optional substituent" is a substituent that may or may not be present on another molecular group, such as a ring (e.g., phenyl) or chain (e.g., alkyl). A group that is "optionally substituted" with a substituent means the group is either unsubstituted or substituted with the substituent. [0041] 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 and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. [0042] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3, or 4, solvent or water molecules. [0043] As used herein, a "prodrug" refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have better solubility than the active parent drug in pharmaceutical compositions. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g. Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392). [0044] The terms, “polymorphs” and “polymorphic forms” refer to crystalline forms of the same molecule, and different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and/or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice. Polymorphs of a molecule can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation. Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X- ray diffractometry, vibrational spectroscopy, e.g., IR and Raman spectroscopy, solid state NMR, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies. [0045] 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 [0046] Throughout the embodiments and description of the compounds of the invention, all instances of haloalkyl may be fluoroalkyl (e.g., any C1-4haloalkyl may be C1-4fluoroalkyl). [0047] Unsubstituted or substituted rings 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. [0048] 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. [0049] In the following, numbered embodiments of the invention are disclosed (e.g., E1, E2, E2.1, etc.). In the numbered embodiments, the reference to a range of preceding embodiments in multiple dependent format (e.g., "the compound of any of E1-E2.6") is a reference, in the alternative, to each embodiment sequentially listed herein in the recited range. For example, the range "any of E1-E2.6" means "any of E1, E2, E2.1, E2.2, E2.3, E2.4a, E2.4b, E2.5a, E2.5b, or E2.6." [0050] E1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000015_0001
A1 is selected from the group consisting of , , , , , and ; Z1 is N or CRz1; Z2 is N or CRz2; Z3 is N or CRz3; Z4 is N or CRz4; wherein 0, 1, or 2 of Z1, Z2, Z3, and Z4 is N; Rz1, Rz2, Rz3, and Rz4 are independently selected from the group consisting of H, D, halogen, C1- 2alkyl, C1-2deuterioalkyl, C1-2fluoroalkyl, cyano, –OC1-2alkyl, –OC1-2deuterioalkyl, –OC1- 2fluoroalkyl, and C3-4cycloalkyl; R1, R2, R3 and R4 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4deuterioalkyl, C1-4fluoroalkyl, halogen, cyano, G1, –ORa, –O–C2-3alkylene–ORb, and –N(Rc)(Rd); Ra, Rb, Rc, and Rd are independently selected from the group consisting of H, C1-4alkyl, C1- 4deuterioalkyl, C1-4fluoroalkyl, G1, and –C1-3alkylene–G1, wherein alternatively, Rc and Rd, together with the nitrogen to which the Rc and Rd attach, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of O, N, and S, wherein the 4- to 7-membered heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C1-4fluoroalkyl, OH, –OC1-4alkyl, –OC1- 4deuterioalkyl, and –OC1-4fluoroalkyl; G1 is C3-6cycloalkyl or a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C1-4fluoroalkyl, OH, –OC1- 4alkyl, –OC1-4deuterioalkyl, and –OC1-4fluoroalkyl; R5 is a 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or R5 is a 6- to 12 membered aryl, the heteroaryl and aryl being substituted by R6 and optionally further substituted with 1-4 substituents R7; R6 is –C(R6a)(R6b)OH; R6a is selected from the group consisting of D, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, –C1-3alkylene–C3-6cycloalkyl, and –C1-5alkylene–X1, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R6b is H or D; X1 is selected from the group consisting of –SR6c, –SOR6c, –SO2R6c, and –S(O)(NR6d)R6c; R6c is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R6d is selected from the group consisting of H, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R7, at each occurrence, is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, –OC1- 4haloalkyl, C3-6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R8a and R8b are independently selected from the group consisting of H, D, CH3, and CD3; and R9a and R9b are independently H or D. [0051] E2. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4deuterioalkyl, C1-4fluoroalkyl, halogen, cyano, C3-6cycloalkyl, –ORa, –O–C2-3alkylene–ORb, and –N(Rc)(Rd), wherein the C3-6cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C1-4fluoroalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, and –OC1-4fluoroalkyl. [0052] E2.1. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4fluoroalkyl, halogen, C3-6cycloalkyl, –ORa, –O–C2-3alkylene–ORb, and –N(Rc)(Rd). [0053] E2.2. The compound of E2.1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from the group consisting of H, CH3, CH(CH3)2, CD3, CF3, fluoro, chloro, cyano, cyclopropyl, cyclopentyl, –OCH3, –OCH2CH(CH3)2, –O–(CH2)2–OCH3, –N(CH3)2, and azetidin-1-yl. [0054] E2.3. The compound of E2.2, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from the group consisting of H, CH3, CH(CH3)2, CF3, fluoro, chloro, cyclopropyl, cyclopentyl, –OCH3, –OCH2CH(CH3)2, –O–(CH2)2–OCH3, –N(CH3)2, and azetidin-1-yl. [0055] E2.4a. The compound of any of E1-E2.1, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of H, C1-4alkyl, halogen, C3-6cycloalkyl, –ORa, and –N(Rc)(Rd). [0056] E2.4b. The compound of any of E1-E2.1 or E2.4a, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of C1-4alkyl, halogen, and C3-6cycloalkyl. [0057] E2.5a. The compound of any of E1-E2.4a, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of H, CH3, fluoro, chloro, cyclopropyl, –OCH3, and –N(CH3)2. [0058] E2.5b. The compound of any of E1-E2.5a, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of CH3, fluoro, chloro, and cyclopropyl. [0059] E2.6. The compound of any of E1-E2.4a or E2.5a, or a pharmaceutically acceptable salt thereof, wherein R2 is H. [0060] E2.7. The compound of any of E1-E2.6, or a pharmaceutically acceptable salt thereof, wherein R1 is H. [0061] E2.8. The compound of any of E1-E2.6, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-4alkyl or halogen. [0062] E2.9. The compound of E2.8, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of CH3, fluoro, and chloro. [0063] E3. The compound of any of E1-E2.9, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently selected from the group consisting of H, D, C1- 4alkyl, C1-4deuterioalkyl, C1-2fluoroalkyl, halogen, cyano, –OC1-4alkyl, –OC1-4deuterioalkyl, and –OC1-2fluoroalkyl. [0064] E3.1. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R3 is C1-4alkyl or halogen. [0065] E3.2. The compound of E3.1, or a pharmaceutically acceptable salt thereof, wherein R3 is halogen. [0066] E3.3. The compound of E3.2, or a pharmaceutically acceptable salt thereof, wherein R3 is fluoro. [0067] E3.4. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R3 is H. [0068] E3.5. The compound of any of E1-E3.4, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-4alkyl or halogen. [0069] E3.6. The compound of E3.5, or a pharmaceutically acceptable salt thereof, wherein R4 is halogen. [0070] E3.7. The compound of E3.6, or a pharmaceutically acceptable salt thereof, wherein R4 is fluoro. [0071] E3.8. The compound of any of E1-E3.4, or a pharmaceutically acceptable salt thereof, wherein R4 is H.
[0072] E4. The compound of any of E1-E3.8, or a pharmaceutically acceptable salt . a pharmaceutically acceptable salt thereof,
Figure imgf000020_0001
wherein A1 is selected from the group ,
Figure imgf000020_0002
Figure imgf000020_0003
wherein A1 is selected from the group consisting of
Figure imgf000020_0004
, , , , , , , , , and . [0075] E6. The compound of E5, or a pharmaceutically acceptable salt thereof, , ,
Figure imgf000021_0001
thereof, wherein A1 is selected from the group ,
Figure imgf000021_0002
, , , , , , , , and . [0077] E7. The compound of E6 or E6.1, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000022_0001
[0078] E8. The compound of any of E1-E3.8, or a pharmaceutically acceptable salt thereof, wherein A1 is selected from the group ,
Figure imgf000023_0001
. acceptable salt thereof,
Figure imgf000023_0002
.
Figure imgf000023_0003
E8, or a pharmaceutically acceptable salt thereof, wherein A1 is .
Figure imgf000023_0004
[0081] E8.3. The compound of E8, or a pharmaceutically acceptable salt thereof, wherein . [0082] of E8, or a pharmaceutically acceptable salt thereof,
Figure imgf000024_0001
wherein . [0083]
Figure imgf000024_0002
of E8, or a pharmaceutically acceptable salt thereof, wherein . [0084]
Figure imgf000024_0003
of any of E1-E8.5, or a pharmaceutically acceptable salt thereof, wherein R5 is the substituted 5- to 12-membered heteroaryl. [0085] E10. The compound of any of E1-E9, or a pharmaceutically acceptable salt thereof, wherein the ring system of the substituted 5- to 12-membered heteroaryl at R5 is a 5- to 6-membered heteroaryl containing 1-3 nitrogen atoms. [0086] E10.1. The compound of E10, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 6-membered heteroaryl containing 1-3 nitrogen atoms is selected from the group consisting of pyridin-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl. [0087] E10.2. The compound of E10.1, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group ,
Figure imgf000025_0001
is selected from the group consisting and –C1-3alkylene–C3-6cycloalkyl,
Figure imgf000025_0002
wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl. [0088] E10.3. The compound of E10.2, or a pharmaceutically acceptable salt thereof, wherein R7a is C1-4alkyl. [0089] E10.4. The compound of E10.3, or a pharmaceutically acceptable salt thereof, wherein R7a is CH3. [0090] E11. The compound of any of E1-E9, or a pharmaceutically acceptable salt thereof, wherein the ring system of the substituted 5- to 12-membered heteroaryl at R5 is a 9- to 10-membered heteroaryl containing 1-3 nitrogen atoms. [0091] E12. The compound of E11, or a pharmaceutically acceptable salt thereof, wherein the 9- to 10-membered heteroaryl ring system is selected from the group consisting of 2H-indazol-4-yl, 2H-indazol-3-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, 2H-indazol-7-yl, 1H- indazol-3-yl, 1H-indazol-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-8-yl, 1H-indol-3-yl, 1H- benzo[d][1,2,3]triazol-7-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, and [1,2,4]triazolo[1,5-a]pyridin-8-yl. [0092] E12a. The compound of E12, or a pharmaceutically acceptable salt thereof, wherein the 9- to 10-membered heteroaryl ring system is selected from the group consisting of 2H-indazol-4-yl, 2H-indazol-5-yl, quinolin-5-yl, quinolin-6-yl, and quinolin-8-yl. [0093] E12.1. The compound of any of E11-E12a, or a pharmaceutically acceptable salt thereof, wherein R5 is substituted with 2 R7 substituents. [0094] E12.2. The compound of any of E11-E12a, or a pharmaceutically acceptable salt thereof, wherein R5 is substituted with 1 R7 substituent. [0095] E12.3. The compound of any of E11-E12a, or a pharmaceutically acceptable salt thereof, wherein R5 is substituted with 0 R7 substituent. [0096] E13. The compound of any of E12, E12.2, or E12.3, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of , , , , , , , , , , , , , , , and ; and R7a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl. [0097] E13.1. The compound of any of E12, E12a, E12.2, E12.3, or E13, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of
Figure imgf000028_0001
6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl. [0098] E14. The compound of any of E12-E13.1, or a pharmaceutically acceptable salt thereof, wherein R5 is ; R7a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; and R7b, R7c, and R7d are independently selected from the group consisting of hydrogen, halogen, cyano, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, –OC1-4haloalkyl, C3-6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl. [0099] E14.1. The compound of E14, or a pharmaceutically acceptable salt thereof, wherein R7b, R7c, and R7d are independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, CH3, CD3, CF3, OH, OCH3, OCD3, OCHF2, OCF3, and cyclopropyl. [00100] E15. The compound of any of E13-E14.1, or a pharmaceutically acceptable salt .
Figure imgf000029_0001
E15, or a pharmaceutically acceptable salt thereof, wherein R7a is C1-2alkyl or C1-2deuterioalkyl. [00102] E16.1. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R7a is CH3 or CD3. [00103] E17. The compound of any of E1-E8.5, or a pharmaceutically acceptable salt thereof, wherein R5 is the substituted 6- to 12-membered aryl. [00104] E17.1. The compound of any of E1-E8.5 or E17, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at R5 is phenyl. [00105] E17.2. The compound of any of E1-E8.5 or E17, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at R5 is naphthalenyl. [00106] E17.3. The compound of any of E1-E8.5 or E17, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 6- to 12-membered aryl at R5 is benzo[d][1,3]dioxol-4-yl or benzo[d][1,3]dioxol-5-yl. [00107] E18. The compound of any of E17-E17.3, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of , , , , , , , , and ; and R7a, R7b, R7c, and R7d are independently selected from the group consisting of halogen, cyano, C1- 4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, –OC1- 4haloalkyl, C3-6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl. [00108] E18a. The compound of E18, or a pharmaceutically acceptable salt thereof, .
Figure imgf000031_0001
acceptable salt thereof, wherein R7a, R7b, R7c, and R7d are independently halogen or C1-4alkyl. [00110] E18.2. The compound of E18.1, or a pharmaceutically acceptable salt thereof, wherein R7a, R7b, R7c, and R7d are independently selected from the group consisting of fluoro, chloro, and CH3. [00111] E18.3. The compound of E18 or E18.1, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group ,
Figure imgf000031_0002
, , , and . [00112] E18.4. The compound of E18.2 or E18.3, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group ,
Figure imgf000032_0001
, , , , and . [00113] E19. The compound of any of E1-E18.4, or a pharmaceutically acceptable salt thereof, wherein R6a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, and C1- 4haloalkyl. [00114] E19.1. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R6a is C1-4alkyl. [00115] E19.2. The compound of E19.1, or a pharmaceutically acceptable salt thereof, wherein R6a is CH3. [00116] E19.3. The compound of E19 or E19.1, or a pharmaceutically acceptable salt thereof, wherein R6a is C1-4deuterioalkyl. [00117] E19.4. The compound of any of E19-E19.3, or a pharmaceutically acceptable salt thereof, wherein R6a is CD3. [00118] E19.5. The The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R6a is C1-4haloalkyl. [00119] E19.6. The compound of E19.5, or a pharmaceutically acceptable salt thereof, wherein R6a is C1-4fluoroalkyl. [00120] E19.7. The compound of E19.6, or a pharmaceutically acceptable salt thereof, wherein R6a is C1-2fluoroalkyl. [00121] E19.8. The compound of E19.7, or a pharmaceutically acceptable salt thereof, wherein R6a is CHF2. [00122] E20. The compound of any of E1-E18.4, or a pharmaceutically acceptable salt thereof, wherein R6a is D. [00123] E21. The compound of any of E1-E20, or a pharmaceutically acceptable salt thereof, wherein R6b is H. [00124] E22. The compound of any of E1-E21, or a pharmaceutically acceptable salt thereof, wherein R6b is D. [00125] E23. The compound of any of E1-E22, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from the group ,
Figure imgf000034_0001
.
Figure imgf000034_0002
salt thereof, wherein R6 is selected from the group ,
Figure imgf000034_0003
.
Figure imgf000034_0004
or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of a compound of formula: (I-a), (I-b), (I-c), (I-d), (I-e), and (I-f). [00128] E25.1. The compound of any of E1-E25, or a pharmaceutically acceptable salt thereof, wherein Rz1 is hydrogen. [00129] E25.2. The compound of any of E1-E25, or a pharmaceutically acceptable salt thereof, wherein Rz1 is halogen. [00130] E25.3. The compound of E25.2, or a pharmaceutically acceptable salt thereof, wherein Rz1 is fluoro. [00131] E25.4. The compound of any of E1-E25.3, or a pharmaceutically acceptable salt thereof, wherein Rz2 is hydrogen. [00132] E25.5. The compound of any of E1-E25.4, or a pharmaceutically acceptable salt thereof, wherein Rz3 is hydrogen. [00133] E25.6. The compound of any of E1-E25.5, or a pharmaceutically acceptable salt thereof, wherein Rz4 is hydrogen. [00134] E25.7. The compound of any of E1-E25.5, or a pharmaceutically acceptable salt thereof, wherein Rz4 is halogen. [00135] E25.8. The compound of E25.7, or a pharmaceutically acceptable salt thereof, wherein Rz4 is fluoro. [00136] E26. The compound of any of E25 or E25.4-E25.8, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (I-a). [00137] E26.1. The compound of any of E25-E25.4 or E25.6-E25.8, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (I-b). [00138] E26.2. The compound of any of E25-E25.5, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (I-c). [00139] E26.3. The compound of any of E25 or E25.4-E25.5, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (I-d). [00140] E26.4. The compound of any of E25, E25.4, or E25.6-E25.8, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (I-e). [00141] E26.5. The compound of any of E25-E25.8, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (I-f). [00142] E27. The compound of E26, or a pharmaceutically acceptable salt thereeof, wherein the compound is a compound of .
Figure imgf000036_0001
[00143] E27.1. The compound of E26.1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of (I-b1). [00144] E27.2. The compound of E26.2, salt thereof,
Figure imgf000037_0001
wherein the compound is a compound of . [00145] E27.3. The compound of E26.3, thereof,
Figure imgf000037_0002
wherein the compound is a compound of . [00146] E27.4. The compound of E26.4,
Figure imgf000037_0003
thereof, wherein the compound is a compound of . [00147] E27.5. The compound of E26.5,
Figure imgf000037_0004
wherein the compound is a compound of .
Figure imgf000037_0005
[00148] E27.6. The compound of E26.5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of . [00149] E27.7. The compound of E26.5, thereof,
Figure imgf000038_0001
wherein the compound is a compound of . [00150] E28. The compound of any of or a
Figure imgf000038_0002
pharmaceutically acceptable salt thereof, wherein A1 is selected from the group consisting of .
Figure imgf000038_0003
salt thereof, wherein R8a and R8b are H. [00152] E30.1. The compound of any of E1-E28, or a pharmaceutically acceptable salt thereof, wherein R8a is H; and R8b is CH3. [00153] E30.2. The compound of any of E1-E28, or a pharmaceutically acceptable salt thereof, wherein R8a is CH3; and R8b is H. [00154] E31. The compound of any of E1-E30.2, or a pharmaceutically acceptable salt thereof, wherein R9a and R9b are H. [00155] E32. The compound of any of E1-E31, or a pharmaceutically acceptable salt thereof, wherein R9a and R9b are D. [00156] E33. The compound of E1, selected from a compound of Table 12, or a pharmaceutically acceptable salt thereof. [00157] E33.1. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00158] E33.2. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00159] E33.3. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)-6- methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00160] E33.4. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-cyclopropyl-6-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H- indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00161] E33.5. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)-6- methoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00162] E33.6. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00163] E33.7. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)-6- methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00164] E33.8. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-cyclopropyl-6-fluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H- indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00165] E33.9. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,3-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00166] E33.10. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,5-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00167] E33.11. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-chloro-6-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00168] E33.12. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00169] E33.13. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-(dimethylamino)-6-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H- indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00170] E33.14. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-6-(1-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol- 4-yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00171] E33.15. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-6-(1-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol- 4-yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00172] E33.16. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one. [00173] E33.17. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4- yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one. [00174] E33.18. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2. [00175] E33.19. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2. [00176] E33.20. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-((5-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)pyrimidin-2- yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00177] E33.21. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(6-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00178] E33.22. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-5- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00179] E33.23. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00180] E33.24. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4-yl)- 6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00181] E33.25. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-cyclopropyl-6-fluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H- indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00182] E33.26. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00183] E33.27. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4-yl)-2- methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00184] E33.28. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(5-(hydroxymethyl-d2)quinolin-8-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00185] E33.29. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(8-(hydroxymethyl-d2)quinolin-6-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00186] E33.30. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(8-(hydroxymethyl-d2)quinolin-5-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00187] E33.31. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)benzo[d][1,3]dioxol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00188] E33.32. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)benzo[d][1,3]dioxol-5- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00189] E33.33. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)- 2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00190] E33.34. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)- 2,6-difluorobenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one. [00191] E33.35. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol- 4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00192] E33.36. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol- 4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one. [00193] E33.37. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(2-ethyl-7-(hydroxymethyl-d2)-2H-indazol-4-yl)-2,6- difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00194] E33.38. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2. [00195] E33.39. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)- 2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2. [00196] E33.40. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol- 4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2. [00197] E33.41. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-4-fluoroisoindolin-1-one. [00198] E33.42. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00199] E33.43. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00200] E33.44. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)benzyl)-7-fluoroisoindolin-1-one. [00201] E33.45. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol- 4-yl)benzyl)-7-fluoroisoindolin-1-one. [00202] E33.46. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)- 2,6-difluorobenzyl)-7-fluoroisoindolin-1-one. [00203] E33.47. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(2,6-difluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4- yl)benzyl)-7-fluoroisoindolin-1-one. [00204] E33.48. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2,6-difluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00205] E33.49. The compound of E33, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(2-fluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4-yl)-6- methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. [00206] E34. A compound of any of E1-E33.49, or a pharmaceutically acceptable salt thereof, that has at least 50% deuterium incorporation at each deuterium label. [00207] E34.1. The compound of E34, or pharmaceutically acceptable salt thereof, that has at least 75% deuterium incorporation at each deuterium-label. [00208] E34.2. The compound of E34 or E34.1, or pharmaceutically acceptable salt thereof, that has at least 90% deuterium incorporation at each deuterium-label. [00209] E34.3. The compound of any of E34-E34.2, or pharmaceutically acceptable salt thereof, that has at least 99% deuterium incorporation at each deuterium-label. [00210] E34.4. The compound of any of E34-E34.3, or pharmaceutically acceptable salt thereof, that has at least 99.5% deuterium incorporation at each deuterium-label. [00211] E35. A hydrate, solvate, polymorph, or prodrug of the compound of any of E1- E34.4, or a pharmaceutically acceptable salt thereof. [00212] E36. A pharmaceutical composition comprising the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E35, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00213] E37. A method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E36. [00214] E38. The method of E37, wherein the mammal is human. [00215] E39. The method of E37 or E38, wherein the muscarinic acetylcholine receptor is mAChR M1. [00216] E40. The method of any of E37-E39, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. [00217] E41. The method of any of E37-E40, further comprising the step of identifying a mammal in need of treatment of the disorder. [00218] E42. The method of any of E37-E41, wherein the disorder is a neurological disorder or psychiatric disorder, or a combination thereof. [00219] E43. The method of any of E37-E42, wherein the disorder is psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson’s disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, or memory disorders, or a combination thereof. [00220] E44. The method of any of E37-E42, wherein the disorder is Alzheimer’s disease, schizophrenia, a sleep disorder, a pain disorder, or a cognitive disorder, or a combination thereof. [00221] E45. The method of E44, wherein the pain disorder is neuropathic pain, central pain syndrome, postsurgical pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesis, primary allodynia, secondary allodynia, or a combination thereof. [00222] E46. The compound, hydrate, solvate, polymorph, or prodrug of any of E1-E35, or a pharmaceutically acceptable salt thereof, or the composition of E36, for use in the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal. [00223] E47. Use of the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E35, or a pharmaceutically acceptable salt thereof, or the composition of E36, for the preparation of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal. [00224] Compound names and/or structures can be assigned/determined by using the Struct=Name naming algorithm as part of CHEMDRAW®, versions 19.1 or 20.0. [00225] Compounds may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” 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. In the compounds of formula (I) when no specific configuration is indicated at a stereogenic center (e.g., carbon), the compounds include all possible stereoisomers. [00226] 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 Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods. [00227] 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. [00228] In the compounds of formula (I), and any subformulas, any "hydrogen" or "H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes 1H (protium) and 2H (deuterium). [00229] The present disclosure also includes an isotopically-labeled compound (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 to 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. [00230] Isotopically-enriched forms 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). [00231] 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 methanol and 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-phenylpropionate, 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. [00232] 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, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. 3. Pharmaceutical Compositions [00233] 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. [00234] 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, to achieve 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)) 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. [00235] For example, a therapeutically effective amount of a compound of formula (I), may be about 1 mg/kg to about 1000 mg/kg, about 5 mg/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. [00236] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non- toxic, 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's solution; 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. [00237] Thus, the compounds and their physiologically acceptable salts and solvates 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. [00238] 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). [00239] 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. [00240] 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%. [00241] 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%. [00242] 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%. [00243] 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%. [00244] 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%. [00245] 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%. [00246] 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%. [00247] Suitable antioxidants include butylated hydroxyanisole (“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%. [00248] 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%. [00249] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%. [00250] 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%. [00251] 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%. [00252] 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 Volume 1, 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%. [00253] 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)) 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. [00254] 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%. [00255] 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. [00256] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), 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. [00257] 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. [00258] 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. [00259] 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. [00260] 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. [00261] 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)), 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. [00262] 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 this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976). [00263] 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. [00264] 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. [00265] 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 polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%. [00266] 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%. [00267] 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 combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%. [00268] 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%. [00269] The amount of thickener(s) in a topical composition is typically about 0% to about 95%. [00270] 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%. [00271] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%. [00272] Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. a. Spray-Dried Dispersion Formulations [00273] 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. Formulation and 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. [00274] Thus, in one embodiment, the disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I). 4. Therapeutic Uses and Methods [00275] The disclosed compounds are positive allosteric modulators of mAChR M1. Thus, by positive allosteric modulation, the compounds indirectly activate the muscarinic receptor subtype M1. In one aspect, the disclosed compounds potentiate the agonist response (e.g., acetylcholine) of mAChR M1. In a further aspect, the disclosed compounds increase mAChR M1 response to non-maximal concentrations of agonist in the presence of compound compared to the response to agonist in the absence of compound. The potentiation of mAChR M1 activity can be demonstrated by methodology known in the art. For example, activation of mAChR M1 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). In a further aspect, the calcium flux was measured as an increase in fluorescent static ratio. In a yet further aspect, positive allosteric modulator activity was analyzed as a concentration-dependent increase in the EC20 acetylcholine response (i.e. the response of mAChR M1 at a concentration of acetylcholine that yields 20% of the maximal response). [00276] In an embodiment, the disclosed compounds may activate mAChR M1 response as an increase in calcium fluorescence in mAChR M1-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. For example, a disclosed compound may have an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. In an embodiment, the mAChR M1-transfected CHO-K1 cells are transfected with human mAChR M1. In another embodiment, the mAChR M1-transfected CHO-K1 cells are transfected with rat mAChR M1. [00277] In an embodiment, the disclosed compounds exhibit weak or substantially no agonist activation of mAChR M1 response (i.e., lack of activation in the absence of a known agonist such as acetylcholine). Lack of agonist activity may be measured as weak or no increase in calcium fluorescence in mAChR M1-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. Lack of mAChR M1 agonist activity may be determined as a percent response relative to acetylcholine. For example, a disclosed compound may have less than or equal to 30%, 25%, 20%, 15%, 10%, 5%, or 1% mAChR M1 agonist activity relative to acetylcholine. A disclosed compound may have substantially no mAChR M1 agonist activity. In further embodiments, the disclosed compounds exhibit positive allosteric modulation of mAChR M1 response to acetylcholine, as described herein, at concentrations that have weak or substantially no agonist activity, as described herein. The absence of mAChR M1 agonist activity may contribute to the avoidance of cholinergic adverse effect liability. [00278] In an embodiment, the disclosed compounds exhibit potentiation of mAChR M1 response to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with a mammalian mAChR M1 in the presence of the compound, compared to the response to acetylcholine in the absence of the compound. For example, CHO-K1 cells can be transfected with human mAChR M1. For example, CHO-K1 cells can be transfected with rat mAChR M1. For example, a compound can exhibit positive allosteric modulation of mAChR M1 with an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, or less than or equal to 100 nM. Alternatively, the disclosed compounds exhibit potentiation of mAChR M1 response to acetylcholine as an increase in response to non- maximal concentrations of acetylcholine in CHO-K1 cells transfected with human mAChR M1 in the presence of the compound, compared to the response to acetylcholine in the absence of the compound. For example, a compound can exhibit positive allosteric modulation of mAChR M1 with an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. [00279] In an embodiment, the disclosed compounds exhibit positive allosteric modulation of mAChR M1 response to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with a mAChR M1 in the presence of the compound, compared to the response to acetylcholine in the absence of the compound. For example, the disclosed compounds may exhibit positive allosteric modulation of the mAChR M1 response to acetylcholine with an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, or less than or equal to 100 nM. In an embodiment, the EC50 for positive allosteric modulation is determined in CHO-K1 cells are transfected with a mAChR M1. In another embodiment, the CHO-K1 cells are transfected with a human mAChR M1. In another embodiment, the CHO-K1 cells are transfected with a rat mAChR M1. [00280] Positive allosteric modulation of the mAChR M1 response to acetylcholine with EC50 of less than or equal to 0.5 µM, less than or equal to 0.25 µM, or less than or equal to 0.1 µM are all considered potent postive allosteric modulating activity. [00281] In an embodiment, the compounds activate mAChR M1 response in mAChR M1 - transfected CHO-K1 cells with an EC50 less than the EC50 for one or more of mAChR M2, mAChR M3, mAChR M4, or mAChR M5 response in mAChR M2, M3, M4 or M5-transfected CHO-K1 cells. That is, the disclosed compounds can have selectivity for the mAChR M1 receptor vis-à-vis one or more of the mAChR M2, M3, M4 or M5 receptors. For example, the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M2, at least 10-fold less than that for mAChR M2, at least 20-fold less than that for mAChR M2, at least 30-fold less than that for mAChR M2, at least 50-fold less than that for mAChR M2, or at least 100-fold less than that for mAChR M2. In another embodiment, the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M3, at least 10-fold less than that for mAChR M3, at least 20-fold less than that for M3, at least 30-fold less than that for mAChR M3, at least 50-fold less than that for mAChR M3, or at least 100-fold less than that for mAChR M3. In another embodiment, the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M4, at least 10-fold less than that for mAChR M4, at least 20-fold less than that for M4, at least 30-fold less than that for mAChR M4, at least 50-fold less than that for mAChR M4, or at least 100-fold less than that for mAChR M4. In another embodiment, the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M5, at least 10-fold less than that for mAChR M5, at least 20-fold less than that for mAChR M5, at least 30-fold less than that for mAChR M5, at least 50-fold less than that for mAChR M5, or at least 100-fold less than that for mAChR M5. In another embodiment, the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 10-fold less than that for the mAChR M2 , M3, M4 or M5 receptors, at least 20-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 30- fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 50-fold less than that for the mAChR M2, M3, M4 or M5 receptors, or at least 100-fold less than that for the mAChR M2, M3, M4 or M5 receptors. In another embodiment, the compound activates mAChR M1 response in mAChR M1-transfected CHO-K1 cells and is inactive for one or more of mAChR M1, mAChR M3, mAChR M4, or mAChR M5 response in mAChR M2, M3, M4 or M5-transfected CHO-K1 cells. [00282] In an embodiment, the compounds activate mAChR M1 response in M1-transfected CHO-K1 cells with an EC50 of less than or equal to 10 µM and exhibits a selectivity for the M1 receptor vis-à-vis one or more of the mAChR M2, M3, M4 or M5 receptors. For example, the compounds can have an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M2, at least 10-fold less than that for mAChR M2, at least 20-fold less than that for mAChR M2, at least 30-fold less than that for mAChR M2, or at least 50-fold less than that for mAChR M2. In another embodiment, the compounds can have an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M3, at least 10-fold less than that for mAChR M3, at least 20-fold less than that for mAChR M3, at least 30-fold less than that for mAChR M3, or at least 50-fold less than that for mAChR M3. In another embodiment, the compounds can have an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M4, of at least 10-fold less than that for mAChR M4, of at least 20-fold less than that for mAChR M4, of at least 30-fold less than that for mAChR M4, or at least 50-fold less than that for mAChR M4. In another embodiment, the compound can have an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of at least 5-fold less than that for mAChR M5, of at least 10-fold less than that for mAChR M5, of at least 20-fold less than that for mAChR M5, of at least 30-fold less than that for mAChR M5, or at least 50-fold less than that for mAChR M5. In another embodiment, the compounds can have an EC50 of less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 2.5 µM, less than or equal to 1 µM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM; and the compounds can also activate mAChR M1 response with an EC50 of at least 5-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 10-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 20-fold less than that for the mAChR M2, M3, M4 or M5 receptors, at least 30-fold less than that for the mAChR M2 , M3, M4 or M5 receptors, or at least 50-fold less than that for the mAChR M2, M3, M4 or M5 receptors. [00283] The disclosed compounds may be used in methods for treatment of mAChR M1 related medical disorders and/or diseases. The methods of treatment may comprise administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of the compound of formula (I). [00284] The compounds can be administered to a subject in need thereof to modulate mAChR M1, for a variety of diverse biological processes. The present disclosure is directed to methods for administering the composition to potentiate mAChR M1, a GPCR whose dysfunction is associated with neurological and psychiatric disorders, for example. [00285] The compounds may be useful for treating and preventing certain diseases and disorders in humans and animals related to mAChR M1 dysfunction. Treatment or prevention of such diseases and disorders can be effected by modulating mAChR M1 in a subject, by administering a compound or composition of the disclosure, either alone or in combination with another active agent as part of a therapeutic regimen to a subject in need thereof. [00286] In combination therapy, the other drug(s) can be administered by a route and in an amount commonly used therefore, 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 is preferred. 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. [00287] In an embodiment, the compounds can be coadministered with anti-Alzheimer’s agents, beta-secretase inhibitors, gamma-secretase inhibitors, orthosteric muscarinic agonists, muscarinic potentiators, cholinesterase inhibitors, HMG-CoA reductase inhibitors, NSAIDs and anti-amyloid antibodies. In a further aspect, the compounds can be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyT1 inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and combinations thereof. [00288] The compounds may be useful for treating a disease or disorder associated with dysfunction of mAChR M1, wherein the disease or disorder is selected from at least one of Alzheimer’s disease, a sleep disorder, a pain disorder, a cognitive disorder, psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson’s disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders. [00289] The compounds may be useful for treating a pain disorder, wherein the pain disorder is neuropathic pain, central pain syndrome, postsurgical pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesis, primary allodynia, secondary allodynia, or a combination thereof. [00290] The compounds disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders wherein the patient or subject would benefit from selective positive allosteric modulation of the M1 receptor. In one aspect, a treatment can include selective M1 receptor modulation to an extent effective to affect cholinergic activity. Thus, a disorder can be associated with cholinergic activity, for example cholinergic hypofunction. In one aspect, provided is a method of treating or preventing a disorder in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject. [00291] Also provided is a method for the treatment of one or more disorders, for which muscarinic receptor activation is predicted to be beneficial, in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject. [00292] The disclosure is directed to the use of described chemical compositions to treat diseases or disorders in patients (preferably human) wherein muscarinic receptor activation would be predicted to have a therapeutic effect, such as Alzheimer’s disease (both palliative cognitive and disease-modifying), cognitive impairment, schizophrenia, pain disorders (including acute pain, neuropathic pain and inflammatory pain), and sleep disorders, by administering one or more disclosed compounds or products. [00293] Also provided is a method for the treatment of a disorder in a mammal comprising the step of administering to the mammal at least one disclosed compound, composition, or medicament. a. Neurological and Psychiatric Disorders [00294] The disclosed compounds have utility in treating a variety of neurological and psychiatric disorders, including one or more of the following conditions or diseases: schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis psychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, “schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer’s disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer’s disease, ischemia, multi- infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson’s disease, Huntington’s disease, Pick’s disease, Creutzfeldt- Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age-related cognitive decline; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); obesity, bulimia nervosa and compulsive eating disorders; bipolar disorders, mood disorders including depressive disorders; depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders; learning disorders, pervasive developmental disorder including autistic disorder, attention disorders including attention-deficit hyperactivity disorder (ADHD) and conduct disorder; NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury; movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson’s disease, drug-induced parkinsonism, post-encephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication- induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic- induced tardive dyskinesia and medication-induced postural tremor), Gilles de La Tourette’s syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias including tremor (such as rest tremor, postural tremor and intention tremor), chorea (such as Sydenham’s chorea, Huntington’s disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics),and dystonia (including generalized dystonia such as idiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer’s cramp and hemiplegic dystonia)]; urinary incontinence; neuronal damage including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema; emesis; and sleep disorders including insomnia and narcolepsy. 1. Cognitive Disorders [00295] The present disclosure provides a method for treating cognitive disorders, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular cognitive disorders are dementia, delirium, amnestic disorders and age-related cognitive decline. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline. As used herein, the term “cognitive disorders” includes treatment of those mental disorders as described in DSM-IV-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “cognitive disorders” is intended to include like disorders that are described in other diagnostic sources. 2. Anxiety Disorders [00296] The present disclosure provides a method for treating anxiety disorders, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular anxiety disorders are generalized anxiety disorder, obsessive-compulsive disorder and panic attack. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes anxiety disorders are generalized anxiety disorder, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. As used herein, the term “anxiety disorders” includes treatment of those mental disorders as described in DSM-IV-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “anxiety disorders” is intended to include like disorders that are described in other diagnostic sources. 3. Alzheimer’s Disease [00297] Alzheimer’s disease (AD) is a neurodegenerative disease affecting the elderly, which results in progressive impairment of memory, language skills and severe behavioral deficits. Hallmarks of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain and other regions of the brain important for memory and cognition. Other hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau and accumulation of amyloid ^ peptide (A ^). A ^ is a 39-43 amino acid peptide produced in the brain by proteolytic processing of ^-amyloid precursor protein (APP) by the ^-amyloid cleaving enzyme (BACE) and gamma secretase which leads to accumulation of A ^ in the brain, where Aβ 1-40 and 1-42 are the principal aggregate-forming species of Aβ. [00298] Activation of various muscarinic receptors, particularly the M1 subtype, has been proposed as a mechanism to enhance cognition in disorders such as AD. Thus, without wishing to be bound by theory, it is believed that selective positive allosteric modulators of mAChR subtypes that regulate processes involved in cognitive function could prove superior to AChE inhibitors for treatment of AD and related disorders as it is postulated that these compounds would exhibit improved selectivity for specific mAChRs. [00299] Phase III clinical trials have shown that orthosteric mAChR activators can have efficacy in improving cognitive performance in AD patients. Moreover, data indicate that administration of M1 activators decreases behavioral disturbances, including delusions, hallucinations, outbursts, and other symptoms in patients suffering from neurodegenerative diseases such as Alzheimer’s disease. However, dose limiting adverse effects that may be due to lack of mAChR M1 selectivity led to failed launches of previous M1 agonists. In some cases, evidence suggests that mAChR activation also has the potential to be disease-modifying in that these agents may lower A ^ in AD patients. The M1–selective allosteric agonist TBPB was found to display effects on the processing of APP toward the non-amyloidogenic pathway and decrease A ^ ^ ^ ^ ^ ^ and 1-42 production in vitro. These data suggest that selective activation of M1 may provide a novel approach for both symptomatic and disease modifying the treatment of Alzheimer’s disease. 4. Schizophrenia [00300] Schizophrenia is a debilitating psychiatric disorder characterized by a combination of negative (blunted affect, withdrawal, anhedonia) and positive (paranoia, hallucinations, delusions) symptoms as well as marked cognitive deficits. While schizophrenia remains an idiopathic disorder, it appears to be produced by a complex interaction of biological, environmental, and genetic factors. Over 40 years ago it was found that phencyclidine (PCP) induces a psychotic state in humans that is very similar to that observed in schizophrenic patients. The finding that the main mode of action of PCP is that of a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptor stimulated a series of studies that have led to the development of the NMDA receptor hypofunction model of schizophrenia. [00301] The present disclosure provides a method for treating schizophrenia or psychosis comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder. [00302] NMDA receptor function can be modulated by activation of G Protein-Coupled Receptors (GPCRs) that are known to physically and/or functionally interact with the NMDA receptor. The NMDA receptor hypofunction hypothesis is a proposal to explain the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents, either directly by action on modulatory sites on the NMDA receptor (e.g., the glycine co-agonist binding site) or indirectly by activation of GPCRs known to potentiate NMDA receptor function (e.g. the mAChR M1), has the potential to ameliorate the symptoms of schizophrenia. In both preclinical and in clinical studies, xanomeline, an M1/M4 preferring orthosteric agonist has proved efficacious with regard to positive, negative and cognitive symptoms, indicating that M1 activation is a reasonable approach to the treatment of schizophrenia. More recently, the selective M1 allosteric agonist TBPB demonstrated efficacy in multiple preclinical models of schizophrenia. [00303] As used herein, the term “schizophrenia or psychosis” includes treatment of those mental disorders as described in DSM-W-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources. 5. Substance-Related Disorders and Addictive Behaviors [00304] The present disclosure provides a method for treating substance-related disorders and addictive behaviors, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular substance-related disorders and addictive behaviors are persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse; and tolerance of, dependence on or withdrawal from substances of abuse. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse; and tolerance of, dependence on or withdrawal from substances of abuse. As used herein, the term “substance- related disorders and addictive behaviors” includes treatment of those mental disorders as described in DSM-IV- TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “substance-related disorders and addictive behaviors” is intended to include like disorders that are described in other diagnostic sources. 6. Pain [00305] In another aspect, the present disclosure provides a method for treating pain, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain. 7. Obesity and Eating Disorders [00306] The present disclosure provides a method for treating obesity or eating disorders associated with excessive food intake and complications associated therewith, comprising: administering to a patient in need thereof an effective amount of a compound of the present disclosure. Obesity is included in the tenth edition of the International Classification of Diseases and Related Health Problems (ICD-10) (1992 World Health Organization) as a general medical condition. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes obesity in the presence of psychological factors affecting medical condition. As used herein, the term “obesity or eating disorders associated with excessive food intake” includes treatment of those medical conditions and disorders described in ICD-10 and DSM-W-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for general medical conditions, and that these systems evolve with medical and scientific progress. Thus, the term “obesity or eating disorders associated with excessive food intake” is intended to include like conditions and disorders that are described in other diagnostic sources. [00307] The compounds are 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 are 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. [00308] The present disclosure is further directed to administration of a selective M1 receptor modulator for improving treatment outcomes in the context of cognitive or behavioral therapy. That is, in one aspect, the disclosure relates to a cotherapeutic method comprising the step of administering to a mammal an effective amount and dosage of at least one compound of the disclosure in connection with cognitive or behavioral therapy. [00309] In another aspect, 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 therapy and 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 another 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. b. Modes of Administration [00310] Methods of treatment may include any number of modes of administering a disclosed composition. 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. GelucireTM). In the pharmaceutical composition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition. [00311] 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. [00312] The term “parenterally,” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. c. Combination Therapies [00313] In one aspect, the disclosed compounds can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which disclosed compounds or the other drugs can have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and a disclosed compound is preferred. However, the combination therapy can also include therapies in which a disclosed compound and one or more other drugs are administered on different overlapping schedules. It is also contemplated that 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. [00314] Accordingly, the pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present disclosure. [00315] 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 disclosure. When a compound of the present disclosure 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 disclosure. [00316] 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 of each will be used. Thus, for example, when a compound of the present disclosure 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 disclosure 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. [00317] In such combinations disclosed compounds 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). [00318] 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. [00319] In an embodiment, the disclosed compounds can be employed in combination with anti- Alzheimer’s agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID’s including ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compound can be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, buspirone, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, Zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound can be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation. [00320] In an embodiment, the disclosed compounds can be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist can be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form. [00321] In an embodiment, the disclosed compounds can be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound can be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the subject compound can be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone. [00322] In an embodiment, the disclosed compounds can be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α- adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts. thereof. 5. Kits [00323] In one aspect, the disclosure provides kits 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 M1 activity; (b) at least one agent known to decrease mAChR M1 activity; (c) at least one agent known to treat a disorder associated with cholinergic activity; (d) instructions for treating a disorder associated with cholinergic activity; (e) instructions for treating a disorder associated with M1 receptor activity; or (f) instructions for administering the compound in connection with cognitive or behavioral therapy. [00324] In some embodiments, the at least one disclosed compound and the at least one agent are co-formulated. 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. [00325] That the disclosed kits can be employed in connection with disclosed methods of use. [00326] 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). [00327] 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. Chemical Synthesis [00328] Compounds of formula (I) 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. [00329] Compounds of formula (I) may be synthesized as shown in the Schemes and Examples set forth below. General Scheme I
Figure imgf000074_0001
As shown in General Scheme I, S2
Figure imgf000074_0002
via reductive amination and cyclization using a benzyl amine A with appropriate reducing agents (e.g., Na(OAc)3BH) to provide S2. In General ,
Figure imgf000074_0003
, , , or , and X is R5 in formula (I) or X is a group such as halogen, triflate, or boronate ester that may serve as a precursor to R5. General Scheme II
Figure imgf000075_0001
As shown in General Scheme II, S2 may be prepared via nucleophilic displacement of a leaving group LG1 (e.g., halogen, triflate, mesylate, tosylate) using a benzyl amine A, followed by cyclization, in the presence of a base (e.g., DIEA) with heating in an appropriate solvent (e.g., MeCN, DMF), wherein A2 and X are as defined in General Scheme I. General Scheme III
Figure imgf000075_0002
As shown in General Scheme
Figure imgf000075_0003
via nucleophilic displacement of a leaving group LG2 (e.g., halogen, triflate, mesylate, tosylate) using lactam S4 and a base (e.g., NaH) in an appropriate solvent (e.g., DMF), wherein A2 and X are as defined in General Scheme I.
General Scheme IV or triflate, may be
Figure imgf000076_0001
art. General Scheme V
Figure imgf000076_0002
to S6 using a Suzuki reaction with X2-R5, wherein X2 is halogen or triflate, under conditions well known in the art. General Scheme VI
Figure imgf000076_0003
[00335] As shown in General Scheme VI, S2, wherein X is halogen or triflate, may be transformed to S6 using a Suzuki reaction under conditions well known in the art. General Scheme VII
[00336] As shown in General Scheme VII, compounds S2 may be enriched in deuterium in the lactam ring by reaction with NaOD in an appropriate solvent such as THF/D2O, wherein A2 and X are as defined in General Scheme I. General Scheme VIII
Figure imgf000077_0001
A-1 (e.g., X = halogen, R5) may be prepared from benzoic acids of formula A'. Benzoic acids of formula A’ may be subjected to methylation reaction conditions, wherein A’ is reacted with a methylating agent (e.g., MeI) in the presence of a base to form intermediate methyl benzoate of formula A-2. Subsequently, methyl benzoates of formula A-2 may be subjected to reduction conditions, wherein A-2 is reacted with an appropriate reducing agent (e.g., DIBAL-H) to form intermediate benzyl alcohol of formula A-3. Next, benzyl alcohols of formula A-3 may be subjected to oxidation conditions, wherein A-3 is reacted with an appropriate oxidizing agent (e.g, Dess-Martin Periodinane) to form intermediate benzaldehyde of formula A-4. Subsequently, benzaldehydes of formula A-4 may be reacted with a suitable hydroxylamine (e.g., NH2OH-HCl) to form intermediate oxime of formula A-5. Finally, oximes of formula A-5 may be subjected to reduction conditions, wherein A-5 is reacted with an appropriate reducing agent (e.g., Zn dust/acetic acid) to form benzyl amine intermediates of formula A-1. [00338] 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 Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England. [00339] 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. [00340] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures 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. [00341] 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 (4th ed.), 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. [00342] 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). [00343] 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. [00344] 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 the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims. [00345] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer.1H chemical shifts are reported in δ 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 µm, 1.0 x 50 mm) at 0.5 mL/min, with column and solvent temperatures maintained at 55 ºC. 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). The MS 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 ºC 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. [00346] The following abbreviations may be used herein: AcOH acetic acid Ac2O acetic anhydride aq aqueous atm atmosphere(s) CDCl3 chloroform-d CD3OD or MeOD methanol-d4 CD3COOD acetic acid-d4 Celite® diatomaceous earth conc. concentrated Cpd compound CypMgBr cyclopropylmagnesium bromide DCE dichloroethane DCl hydrochloric acid-d DCM dichloromethane d doublet dd doublet of doublets Deoxo-Fluor bis(2-methoxyethyl)amino]sulfur trifluoride DIPEA/DIEA diisopropylethylamine DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride DMF N,N-dimethylformamide DMF•DMA N,N-dimethylformamide dimethyl acetal DMSO dimethyl sulfoxide DMSO-d6 dimethylsulfoxide-d6 (deuterated dimethylsulfoxide) D2O deuterium oxide (deuterated or heavy water) dppf 1,1'-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane ES-MS electrospray mass spectrometry EtOAc ethyl acetate EtOH ethanol Et3N triethylamine eq./equiv equivalents h or hr hour(s) HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HPLC high performance liquid chromatography HRMS high resolution mass spectrometry Hz hertz iPA isopropyl alcohol KOAc potassium acetate LCMS liquid chromatography-mass spectrometry M molarity (for concentration) mCPBA 3-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MeI methyl iodide MeOH methanol MHz megahertz min minute(s) mw microwave NaHMDS sodium bis(trimethylsilyl)amide NaOAc sodium acetate NaOD sodium deuteroxide NaSMe sodium methanthiolate Pd(OAc)2 palladium(II)acetate Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 or PdCl2(dppf) (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride Ph phenyl (PhSO2)2NF N-fluorobenzenesulfonimide ppm parts per million RockPhos Palladacycle Gen-3 [(2-Di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate RP reverse phase r.t./rt/RT room temperature s singlet sat. saturated soln. solution STAB sodium triacetoxy borohydride TBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran Preparation of Intermediates Intermediate Example 1: (4-Bromo-2-chloro-6-fluorophenyl)methanamine  
Figure imgf000082_0001
[00347] Step 1: (E/Z)-4-Bromo-2-chloro-6-fluorobenzaldehyde oxime. To a suspension of 4-bromo-2-chloro-6-fluorobenzaldehyde (3.56 g, 15 mmol) in ethanol (75 mL) was added sodium acetate (2.46 g, 30 mmol) and hydroxylamine hydrochloride (2.08 g, 30 mmol). After 1 h at rt, the reaction mixture was diluted with EtOAc, then washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound, which was carried forward without further purification (3.75 g).1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.75 – 7.69 (m, 2H), OH proton exchangeable; ES-MS [M+H]+ = 251.9/253.9. [00348] Step -4-bromo-2-
Figure imgf000083_0001
chloro-6- g, was added zinc powder (4.85 g, 74.3 mmol). The resulting suspension was sonicated at rt for 3 h then filtered through a pad of Celite®, which was washed thoroughly with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure, azeotroped with toluene (3x), and then dried under vacuum to provide the title compound. The product was carried forward without further purification.1H NMR (400 MHz, DMSO-d6) δ 7.65 – 7.63 (m, 1H), 7.62 (dd, J = 9.0, 1.9 Hz, 1H), 3.87 (d, J = 1.8 Hz, 2H), NH protons exchangeable; ES-MS [M+H]+ = 237.9/240.2. [00349] The compounds shown in Table 1 may be prepared similarly to the compound described above, with appropriate starting materials. Table 1 Structure Name 1H-NMR and/or ES-MS [M+H]+ 99 .5 ns = (s, ns = J ), S-
Figure imgf000083_0002
H N (4-bromo-2- ES-MS [M+H]+ = 228.0/230.0. d, z, = Inter
Figure imgf000084_0003
  [00350] Step 1: 4-
Figure imgf000084_0001
To an oven-dried 250 mL flask was added 4-bromo-2,6-difluoro-benzoic acid (5.0 g, 21.1 mmol) and THF (100 mL) under N2. The reaction was cooled to 0 °C and cyclopropylmagnesium bromide (75.35 mL, 52.74 mmol) was added slowly. The ice bath was removed. After 16 h at rt, the reaction was cooled to 0 °C, recharged with cyclopropylmagnesium bromide (15.07 mL, 10.55 mmol, ~ 0.7 mol/L, 0.5 eq), and slowly warmed to rt; this step was repeated after another 16 h. The reaction was carefully quenched with water at 0 °C and concentrated under reduced pressure. The residue was acidified by 1M HCl (aq.). The aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and concentrated to give the product (5.46 g). The product was used in the next step directly without further purification. ES-MS [M+H]+ = 259.0/260.9.
Figure imgf000084_0002
[00351] Step 2: Methyl 4-bromo-2-cyclopropyl-6-fluorobenzoate. To a solution of 4- bromo-2-cyclopropyl-6-fluoro-benzoic acid (5.46 g, 21.08 mmol) in DMF (42 mL) was added potassium carbonate (8.87 g, 63.23 mmol) at rt. MeI (2.62 mL, 42.15 mmol) was added dropwise. After 16 h, the reaction mixture was quenched with water and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue was purified using normal phase chromatography on silica gel (0-10% EtOAc/hexanes) to give the title compound (4.51 g, 65% yield). ES-MS [M+H]+ = 272.9/274.8. [00352] Step 3: (4-
Figure imgf000085_0001
To a solution of methyl 4-bromo-2-cyclopropyl-6-fluoro-benzoate (4.51 g, 16.51 mmol) in DCM (80 mL) was added diisobutylaluminum hydride solution (1.0 M in THF, 49.54 mL, 49.54 mmol) dropwise at 0 °C. The ice bath was removed. After 16 h at rt, the reaction was cooled to 0 °C and diisobutylaluminum hydride solution (16.51 mL, 16.51 mmol, 1.0 M in THF) was added. After 5 h at 0 °C, to the reaction was added sat. aq. NH4Cl dropwise. The reaction mixture was filtered through Celite®, washed with EtOAc and concentrated in vacuo. The crude residue was dissolved in DCM (20 mL), filtered through a hydrophobic phase separator, and then concentrated to give the title compound (3.96 g).1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J = 9.1, 1.9 Hz, 1H), 6.93 (dt, J = 1.8, 0.8 Hz, 1H), 4.88 (d, J = 1.9 Hz, 2H), 2.15 (tt, J = 8.4, 5.3 Hz, 1H), 1.10 – 0.97 (m, 2H), 0.76 – 0.68 (m, 2H); ES-MS [M+H-H2O]+ = 227.0/228.9.
Figure imgf000085_0002
[00353] Step 4: 4- a of (4-bromo- 2-cyclopropyl-6-fluoro-phenyl)methanol (1.74 g, 7.10 mmol) in DCM (40 mL) was added Dess- Martin periodinane (6.02 g, 14.20 mmol) at rt. After 2 h, the reaction was quenched by addition of sat. aq. NaHCO3. The reaction mixture was extracted with DCM (3x). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the crude material. The crude material was purified using silica gel chromatography (0-20% EtOAc/hexanes) to give the title compound (1.66 g, 96% yield).1H NMR (400 MHz, CDCl3) δ 10.55 (s, 1H), 7.17 (dd, J = 10.2, 1.8 Hz, 1H), 6.97 (dd, J = 1.8, 1.0 Hz, 1H), 2.86 (tt, J = 8.5, 5.4 Hz, 1H), 1.17 – 1.05 (m, 2H), 0.78 – 0.70 (m, 2H); MS [M+H]+ = 243.0/244.9. [00354] Step 5: (E/Z)-4-Bromo-2-cyclopropyl-6-fluorobenzaldehyde oxime. The title compound was prepared in a similar manner as (E/Z)-4-bromo-2-chloro-6-fluorobenzaldehyde oxime. ES-MS [M+H]+ = 258.0/259.9. [00355] Step 6: (4-
Figure imgf000086_0001
The title compound was prepared in a similar manner as (4-bromo-2-chloro-6-fluorophenyl)methanamine. ES-MS [M+H]+ = 244.0/245.9. [00356] The compounds shown in Table 2 may be prepared similarly to the compound described above, with appropriate starting materials. Table 2 1H-NMR and/or ES-MS Structure Name 9 9.
Figure imgf000086_0002
Intermediate Example 3: (4-Bromo-2-fluoro-6-isobutoxyphenyl)methanamine   [00357] Step 1: 4-
Figure imgf000087_0001
suspension of 6-fluoro- 4-bromosalicylaldehyde (500 mg, 2.28 mmol) in MeCN (22.8 mL) was added K2CO3 (640 mg, 4.57 mmol) followed by 1-iodo-2-methylpropane (0.53 mL, 4.57 mmol). The mixture was stirred at 50 °C for 72 h, and recharged with 1-iodo-2-methylpropane (0.53 mL, 4.57 mmol) every 24 h. After 72 h, water was added to the reaction mixture, and the resulting solution was extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified using normal phase chromatography on silica gel (0-30% EtOAc/hexanes) to provide the title compound (500 mg, 80% yield). ES-MS [M+H]+ = 275.0/276.9.
Figure imgf000087_0002
[00358] Step 2: - oxime. The title compound was prepared in a similar manner as (E/Z)-4-bromo-2-chloro-6-fluorobenzaldehyde oxime. ES-MS [M+H]+ = 289.9/291.9. [00359] Step 3: (4-
Figure imgf000087_0003
The title compound was prepared in a similar manner as (4-bromo-2-chloro-6-fluorophenyl)methanamine.1H NMR (400 MHz, DMSO-d6) δ 7.10 (dd, J = 8.9, 1.8 Hz, 1H), 7.06 (t, J = 1.5 Hz, 1H), 3.83 (d, J = 6.4 Hz, 2H), 3.73 (s, 2H), 2.14 – 2.00 (m, 1H), 0.99 (d, J = 6.7 Hz, 6H); ES-MS [M+H]+ = 276.0/277.9. Intermdiate Example 4: 2-(Aminomethyl)-5-bromo-3-fluoro-N,N-dimethylaniline   [00360] Step 1: 4-
Figure imgf000088_0001
To a suspension of 4- bromo-2,6-difluorobenzaldehyde (1.33 g, 6.0 mmol) in DMSO (8 mL) was added K2CO3 (2.02 g, 14.4 mmol) followed by dimethylamine hydrochloride (587 mg, 7.2 mmol). The mixture was stirred at 50 °C for 1 h. After cooling to rt, the reaction mixture was poured into ice water and extracted with EtOAc (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified using normal phase chromatography on silica gel (0-30% EtOAc/hexanes) to provide the title compound (1.41 g, 95% yield).1H NMR (400 MHz, CDCl3) δ 10.19 (d, J = 0.6 Hz, 1H), 6.92 (t, J = 1.5 Hz, 1H), 6.76 (dd, J = 10.4, 1.7 Hz, 1H), 2.93 (s, 6H); ES-MS [M+H]+ = 246.0/247.9.
Figure imgf000088_0002
[00361] Step - - oxime. The title compound was prepared in a similar manner as (E/Z)-4-bromo-2-chloro-6-fluorobenzaldehyde oxime.1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 6.97 (d, J = 8.5 Hz, 2H), 2.81 (s, 6H), OH proton exchangable; ES-MS [M+H]+ = 261.0/262.9.
Figure imgf000088_0003
[00362] Step 3: 2-(Aminomethyl)-5-bromo-3-fluoro-N,N-dimethylaniline. The title compound was prepared in a similar manner as (4-bromo-2-chloro-6-fluorophenyl)methanamine. 1H NMR (400 MHz, CDCl3) δ 7.06 (t, J = 1.6 Hz, 1H), 7.00 (dd, J = 9.0, 1.8 Hz, 1H), 6.83 (s, 2H), 4.14 (d, J = 1.1 Hz, 2H), 2.70 (s, 6H); ES-MS [M+H]+ = 245.0/247.0. Intermediate Example 5: 6-(4-Bromo-2-chloro-6-fluorobenzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one [00363] A
Figure imgf000089_0001
(4-bromo-2- chloro-6-fluorophenyl)methanamine (49% wt, 921 mg, 1.89 mmol) in DCE (10 mL) was stirred for 10 min. Sodium triacetoxyborohydride (572 mg, 2.7 mmol) was added. After 16 h at rt, the reaction mixture was diluted with DCM and washed with a sat. soln. of NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified using normal phase chromatography on silica gel (0 – 100% EtOAc/DCM) to provide the title compound (358 mg, 56% yield).1H NMR (400 MHz, DMSO-d6) δ 8.74 (dd, J = 4.9, 1.6 Hz, 1H), 8.10 (dd, J = 7.7, 1.6 Hz, 1H), 7.72 – 7.63 (m, 2H), 7.56 – 7.48 (m, 1H), 4.88 (d, J = 1.9 Hz, 2H), 4.37 (s, 2H); ES-MS [M+H]+ = 355.0/356.9. [00364] The compounds shown in Table 3 may be prepared similarly to the compound described above, with appropriate starting materials. Table 3 Structure Name 1H-NMR and/or ES-MS
Figure imgf000089_0002
1 6-(4-bromo-2- H NMR (400 MHz, CDCl3) δ 8.71 (dd, J = 5.0, 1.6 Hz, 1H), 8.15 (dd, J = 7.7, 1.6 Hz, 1H), 7.42 (dd, J = = .6 = 9 s, ), .6 = 1 s, 5 .6 .0 .0 .3 S- .6 = 7 s, ); .6 = 2, 2 m, =
Figure imgf000090_0001
6-(4-bromo-2-fluoro-6- 1H NMR (400 MHz, DMSO-d6) δ 8.74 (dd, J = 4.9, 1.6 (trifluoromethyl)benzyl)- Hz, 1H), 8.12 (dd, J = 7.7, 1.6 Hz, 1H), 8.01 (dd, J = = S .6 ), S .6 = .7 = .6 m, z, z, = .6 m, ), S-
Figure imgf000091_0001
Intermediate Example 6: 6-(4-Bromo-2,6-difluorobenzyl)-5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one [00365] A
Figure imgf000092_0001
(4-bromo-2,6- difluorophenyl)methanamine (933 mg, 4.2 mmol) in DCE (20 mL) was stirred for 10 min. Sodium triacetoxyborohydride (1.272 g, 6.0 mmol) was added. After 16 h at rt, the reaction mixture was diluted with DCM and washed with a sat. soln. of NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified using normal phase chromatography on silica gel (0 – 10% MeOH/DCM) to provide the title compound (1097 mg, 81% yield).1H NMR (400 MHz, DMSO-d6) δ 8.70 (dd, J = 4.8, 1.5 Hz, 1H), 8.01 (dd, J = 7.8, 1.5 Hz, 1H), 7.59 – 7.49 (m, 3H), 4.81 (s, 2H), 4.40 (s, 2H); ES-MS [M+H]+ = 339.2/340.9. [00366] The compounds shown in Table 4 may be prepared similarly to the compound described above, with appropriate starting materials. Table 4 Structure Name 1H-NMR and/or ES-MS J 2 ), s, J z, J ), s, =
Figure imgf000092_0002
1H NMR (400 MHz, DMSO-d6) δ 8.70 (dd, J 6-(4-bromo-2-fluoro-6- = 4.8, 1.5 Hz, 1H), 7.98 (dd, J = 7.8, 1.5 Hz, d, z, ), = .7 4 d, 4, 7 = ), m, J 2, 3 ]+ J z, .8 ); = d, ), s, ), 9/ J z, d, ), s, J z, 2 ), 4
Figure imgf000093_0001
1H NMR (400 MHz, CDCl3) δ 8.81 – 8.76 (m, 6-(2-(azetidin-1-yl)-4- 1H), 7.77 – 7.70 (m, 1H), 7.41 (dd, J = 7.7, 4.8 bromo-6-fluorobenzyl)- Hz, 1H), 6.71 (dd, J = 9.3, 1.9 Hz, 1H), 6.36 ), p, = = d, 3 ); J z, d, z, S-
Figure imgf000094_0003
Intermediate Example 7: 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyrazin-5-one [00367] Step 1:
Figure imgf000094_0001
To a solution of methyl 3-methylpyrazine-2-carboxylate (500 mg, 3.3 mmol) in carbon tetrachloride (33.0 mL) was added benzoyl peroxide (21.0 mg, 0.07 mmol) and N-bromosuccinimide (614 mg, 3.45 mmol) at room temperature. The resulting mixture was heated to 80 °C. After 16 h, the mixture was filtered over Celite®, washed with DCM and concentrated to afford the title compound (759 mg) which was carried forward without further purification. ES-MS [M+H]+ = 230.9/232.9.
Figure imgf000094_0002
[00368] Step 2: 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5- one. A solution of methyl 3-(bromomethyl)pyrazine-2-carboxylate (750 mg, 1.68 mmol), 4- bromo-2,6-difluorobenzylamine (486 mg, 2.19 mmol), and N,N-diisopropylethylamine (1.47 mL, 8.42 mmol) in MeCN (5 mL) was stirred in a reaction vial at 45 °C for 18 h. The solvents were removed, and the crude residue was purified using normal phase chromatography on silica gel (0-100% EtOAc/DCM) to provide the title compound (549 mg, 96% yield). ES-MS [M+H]+ = 340.0/341.9. Intermediate Example 8: 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-5-one [00369] Step 1: Ethyl
Figure imgf000095_0001
The title compound was prepared in a similar manner as methyl 3-(bromomethyl)pyrazine-2-carboxylate.1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 9.26 (s, 1H), 4.93 (s, 2H), 4.47 (q, J = 7.2, 4.5 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H); ES-MS [M+H]+ = 245.0/246.9.
Figure imgf000095_0002
[00370] Step 2: 6- - [3,4-d]pyrimidin- 5-one. The title compound was prepared in a similar manner as 6-(4-bromo-2,6-difluorobenzyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one.1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.13 (s, 1H), 7.57 – 7.50 (m, 2H), 4.79 (s, 2H), 4.53 (s, 2H); ES-MS [M+H]+ = 340.0/341.9. Intermediate Example 9: 2-(4-Bromo-2,6-difluorobenzyl)-1,2-dihydro-3H- pyrrolo[3,4c]pyridin-3-one F O O Br N N F Br N F NH NaH, DMF, 0 oC F Br [00371] A solution of 6-aza-1-isoindolinone (200 mg, 1.49 mmol) in DMF (1.5 mL) was cooled to 0 °C. NaH (60% in dispersion oil, 89.5 mg, 2.24 mmol) was added and after 10 min, 4- bromo-2,6-difluorobenzyl bromide (0.25 mL, 1.64 mmol) was added dropwise. After 90 min at rt, the reaction mixture was filtered through Celite® and purified using RP HPLC to provide the title compound (100 mg).1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 1.1 Hz, 1H), 8.73 (d, J = 5.1 Hz, 1H), 7.63 (dd, J = 5.1, 1.1 Hz, 1H), 7.58 – 7.48 (m, 2H), 4.77 (d, J = 1.3 Hz, 2H), 4.46 (s, 2H); ES-MS [M+H]+ = 339.0/341.0. Intermediate Example 10: 6-[(5-Bromopyrimidin-2-yl)methyl]-7H-pyrrolo[3,4-b]pyridin-5- one [00372] Step 1:
Figure imgf000096_0001
(1.0 g, 6.62 mmol) and trichlorocyanuric acid (2.31 g, 9.92 mmol) were dissolved in DCM (20 mL) and stirred at rt. After 20 h, the suspension was quenched with sat. soln. NaHCO3 and extracted with DCM (3x). The combined extracts were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound which was used without further purification (1.23 g).1H NMR (400 MHz, CDCl3) δ 8.73 (dd, J = 1.8, 4.8 Hz, 1H), 8.28 (dd, J = 1.8, 7.9 Hz, 1H), 7.36 (dd, J = 4.8, 7.9 Hz, 1H), 5.12 (s, 2H), 3.97 (s, 3H); ES-MS [M+H]+ = 186.1.
Figure imgf000096_0002
[00373] Step 2: 6-[(5-Bromopyrimidin-2-yl)methyl]-7H-pyrrolo[3,4-b]pyridin-5-one. Methyl 2-(chloromethyl)pyridine-3-carboxylate (250 mg, 1.35 mmol), (5-bromopyrimidin-2- yl)methanamine hydrochloride (454 mg, 2.02 mmol), and DIEA (0.7 mL, 4.04 mmol) were dissolved in DMF (7.5 mL). After 16 h at 45 °C, the solution was quenched with sat. soln. NaHCO3 and extracted with DCM (3x). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by normal phase chromatography on silica gel (0-100% EtOAc/hexanes) to provide the title compound (273 mg, 80% yield). ES-MS [M+H]+ = 305.1/307.1. [00374] The compounds shown in Table 5 may be prepared similarly to the compound described above, with appropriate starting materials. Table 5 Structure Name 1H-NMR and/or ES-MS [M+H]+
Figure imgf000097_0002
Intermediate Example 11: 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one-7,7-d2
Figure imgf000097_0001
[00375] 6-(4- - 5-one (590 mg, 1.74 mmol) was dissolved in anhydrous THF (8.7 mL) and D2O (4.35 mL). A solution of sodium deuteroxide (40 wt% in D2O, 0.12 mL) was added. After 16 h at 45 °C, the mixture was diluted with DCM and layers were separated. The organic layers were passed through a hydrophobic phase separator and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-100% EtOAc/DCM) afforded the title compound (500 mg, 84% yield).1H NMR (400 MHz, CDCl3) δ 8.73 (dd, J = 5.0, 1.6 Hz, 1H), 8.14 (dd, J = 7.7, 1.6 Hz, 1H), 7.42 (dd, J = 7.7, 4.9 Hz, 1H), 7.22 – 7.12 (m, 2H), 4.92 (d, J = 1.5 Hz, 2H); ES-MS +
Figure imgf000098_0001
[M+H] = [00376] The compounds shown in Table 6 may be prepared similarly to the compound described above, with appropriate starting materials. Table 6 Structure Name 1H-NMR and/or ES-MS [M+H]+ = ), 5, .9 = .0 d, z, ), ), = 0, 46 ), J – 0, 39 ), z, ), S 0, 48 ), pt, S = ), 7, 77
Figure imgf000098_0002
1 6-(4-bromo-2,3- H NMR (400 MHz, DMSO-d6) δ 8.76 (dd, J = difluorobenzyl)-6,7- 4.9, 1.6 Hz, 1H), 8.13 (dd, J = 7.7, 1.6 Hz, 1H), 7.57 – 7.47 (m 2H) 7.17 (ddd J = 8.7 7.1 2.0 = I
Figure imgf000099_0003
[00377] To a mg, 3.85 mmol) in
Figure imgf000099_0001
MeCN (19.2 mL) was added (4-bromo-2,6-difluorophenyl)methanamine (853.8 mg, 3.85 mol) and N,N-diisopropyethylamine (1.34 mL, 7.70 mmol). The resulting mixture was stirred at 80 ^C for 16 h, diluted with EtOAc and washed with sat. soln. NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combned extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Purification using normal phase chromatography on silica gel (0-100% EtOAc/hexanes) to provide the title compound (736 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.58 – 7.49 (m, 4H), 7.47 – 7.41 (m, 1H), 4.77 (s, 2H), 4.47 (s, 2H); ES-MS [M+H]+ = 356.0/358.0. [00378] The compounds shown in Table 7a may be prepared similarly to the compound described above, with appropriate starting materials. Table 7a Structure Name 1H-NMR and/or ES-MS d, ), 9, 9 , 1
Figure imgf000099_0002
1H NMR (400 MHz, DMSO-d6) δ 7.62 (td, J 2-(4-bromo-2- = 7.9, 4.9 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), z, ), = d, .0 = ), S J .9 = ), . d, 3, 6 J z, = 4 ), 9, 3 = d, ), s, ), 9/
Figure imgf000100_0001
Intermediate Example 12b: 6-(2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [00379] In a round-bottomed flask was added 6-(4-bromo-2,6-difluorobenzyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one (678 mg, 2.0 mmol), PdCl2(dppf) (147 mg, 0.2 mmol), bis(pinocolato)diboron (761 mg, 3.0 mmol) and potassium acetate (589 mg, 6.0 mmol). Degassed 1,4-dioxane (13.3 mL) was added. The reaction mixture was evacuated and purged with N2 (3x). After 3 h at 100 ^C, the reaction mixture was filtered through a pad of Celite®, rinsed thoroughly with EtOAc/DCM and concentrated under pressure. The crude residue was purified using normal phase chromatography on silica gel (0-70% EtOAc/DCM) to provide the title compound (432 mg, 56% yield).1H NMR (400 MHz, DMSO-d6) δ 8.74 (dd, J = 5.0, 1.6 Hz, 1H), 8.10 (dd, J = 7.7, 1.6 Hz, 1H), 7.51 (dd, J = 7.7, 4.9 Hz, 1H), 7.29 – 7.23 (m, 2H), 4.86 (s, 2H), 4.41 (s, 2H), 1.28 (s, 12H); ES-MS [M+H]+ = 386.2 (boronic ester) and 307.4 (boronic acid). [00380] The compounds shown in Table 7b may be prepared similarly to the compound described above, with appropriate starting materials. Table 7b Structure Name 1H-NMR and/or ES-MS .7 m, = s, r)
Figure imgf000101_0001
-(4-(4,4,5,5-tetramethyl- 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.17 1,3,2-dioxaborolan-2- (d, J = 6.8 Hz, 1H), 7.79 (d, J = 7.4 Hz, 2H), 7.42 ), = 4 s, S- .2 = ), z, 0 ). = ), 8, z, ), 0 r) d d
Figure imgf000102_0001
6-(2-cyclopentyl-6- fluoro-4-(4,4,5,5- tetramethyl-1,3,2- + nd d = ), 5 s, ]+ ). d = ), 5, 2 S = ), 8, z, S-
Figure imgf000103_0001
(R)-6-(1-(2,6-difluoro-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- ES-MS [M+H]+ = 401.2 (boronic ester) and d d d d d d d d
Figure imgf000104_0001
7H-pyrrolo[3,4-b]pyridin- 7-one d d d d d
Figure imgf000105_0001
6-(2,6-difluoro-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- ES-MS [M+H]+ = 388.1 (boronic ester) and 0, 5 S- d d d d
Figure imgf000106_0001
-(2-isopropyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- ES-MS [M+H]+ = 395.2 (boronic ester) and d d d d d
Figure imgf000107_0001
2-(2,3-difluoro-4- (4,4,5,5-tetramethyl- + d
Figure imgf000108_0002
Intermediate Example 13: Methyl 4-bromo-2-methyl-2H-indazole-7-carboxylate [00381] To a
Figure imgf000108_0001
according to WO2021/174165, 1.02 g, 4.0 mmol) in EtOAc (40 mL) was added trimethyloxonium tetrafluoroborate (1.18 g, 8.0 mmol). After 16 h at rt, the mixture was quenched with sat. soln. NaHCO3 and extracted with EtOAc (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-50% EtOAc/hexanes) provided the title compound (935 mg, 87% yield).1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 0.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.24 (s, 3H), 3.88 (s, 3H); 2D NOESY (400 MHz, DMSO): a cross- peak occurred between N-methyl (CH3, s at 4.24 ppm) and indazole CH (s at 8.61 ppm); ES-MS [M+H]+ = 269.0/270.9. [00382] The compounds presented in Table 8 may be prepared in an analogous manner to those described in the preceding schemes and examples using appropriate starting materials. Table 8 Structure Name 1H-NMR and/or ES-MS ), z, ), z, + 0 8 s, 3 ), = Interm
Figure imgf000109_0002
ediate Example 14: Methyl 4-bromo-1-methyl-1H-indazole-7-carboxylate
Figure imgf000109_0001
[00383] To a according to WO2021/174165, 225 mg, 1.0 mmol) in DMF (5.0 mL) at 0 °C was added sodium hydride (60% in dispersion oil, 80 mg, 2.0 mmol). After 30 min, to the resulting suspension was added iodomethane and the ice bath was removed. After 16 h, the mixture was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-100% EtOAc/hexanes) provided two separated isomers. [00384] Isomer 1: Methyl 4-bromo-2-methyl-2H-indazole-7-carboxylate (128 mg, 48% yield); 1H NMR (400 MHz, DMSO) δ 8.61 (d, J = 0.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.24 (s, 3H), 3.88 (s, 3H); 2D NOESY (400 MHz, DMSO-d6): a cross-peak occurred between N-methyl (CH3, s at 4.24 ppm) and indazole CH (s at 8.61 ppm); ES-MS [M+H]+ = 269.0/270.9. Isomer 2: Methyl 4-bromo-1-methyl-1H-indazole-7-carboxylate (73 mg, 27% yield); 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 4.16 (s, 3H), 3.94 (s, 3H); 2D NOESY (400 MHz, DMSO-d6): no correlation between N-methyl (CH3, s at 4.16 ppm) and indazole CH (s at 8.19 ppm); ES-MS [M+H]+ = 269.0/270.9. [00385] The compounds presented in Table 9 may be prepared in an analogous manner to those described in the preceding schemes and examples using appropriate starting materials. Table 9 Structure Name 1H-NMR and/or ES-MS d, S ), z, S ), z, ), = = , ), S
Figure imgf000110_0001
Intermediate Example 15: Methyl 4-bromo-2-(methyl-d3)-2H-indazole-7-carboxylate [00386] To a
Figure imgf000111_0001
(462 mg, 1.36 mmol) in DMSO (6 mL) and MeOH (3 mL) was added Pd(OAc)2 (61 mg, 0.27 mmol), 1,3- bis(diphenylphosphino)propane (140 mg, 0.34 mmol), and triethylamine (1.89 mL, 13.6 mmol). The resulting mixture was stirred under CO (1 atm) at 45 °C. After 5 h, the mixture was diluted with EtOAc, and filtered through a pad of Celite®. The filtrate was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified using normal phase chromatography on silica gel to provide the title compound (286 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 4.00 (s, 3H); ES-MS [M+H]+ = 271.9/273.9. Intermediate Example 16: Methyl 8-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-5- carboxylate
Figure imgf000111_0002
[00387] - To a solution of N,N-dimethylacetamide dimethylacetal (247 µL, 1.7 mmol) and iPA (2.5 mL) was added methyl 6-amino-5-bromopicolinate (300 mg, 1.3 mmol). The resulting mixture was stirred at 85 °C for 3 h, and subsequently cooled to 50 °C. Hydroxyamine hydrochloride (117 mg, 1.7 mmol) was added in one portion. After 5 h at 50 °C, the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was carried forward without further purification (374 mg). ES-MS [M+H]+ = 288.0/290.0. [00388] Step 2: Methyl 8-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate. To a solution of methyl (E/Z)-5-bromo-6-(N'-hydroxyacetimidamido)picolinate (374 mg, 1.30 mmol) in THF (3.0 mL) at 0 °C was added trifluoacetic anhydride (0.54 mL, 3.9 mmol). After 16 h at rt, the reaction mixture was quenched with sat. soln. NaHCO3 and extracted with iPA/CHCl3 (1:3). The combined organic layers were concentrated under reduced pressure. The crude material was purified using normal phase chromatography on silica gel (0-10% MeOH/DCM with 1% NH4OH) to provide the title compound (342 mg, 97% yield).1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 4.07 (s, 3H), 2.72 (s, 3H); ES-MS [M+H]+ = 270.0/271.9. Intermediate Example 17: Preparation of (4-bromo-2-methyl-2H-indazol-7-yl)methan-d2-ol [00389] To a
Figure imgf000112_0001
mmol) in THF (2.5 mL) at 0 °C was added dropwise a solution of methyl 4-bromo-2-methyl-2H-indazole-7- carboxylate (200 mg, 0.74 mmol) in THF (2.5 mL). After 30 min at 0 °C, the reaction mixture was warmed to rt for 1 h, ice cold water was carefully added and extracted with DCM (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-100% EtOAc/DCM) provided the title compound.1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 5.21 (s, 1H), 4.18 (s, 3H); ES-MS [M+H]+ = 243.0/244.9. [00390] The compounds presented in Table 10 may be prepared in an analogous manner to those described in the preceding schemes and examples using appropriate starting materials. Table 10 Structure Name 1H-NMR and/or ES-MS s, 0 S
Figure imgf000112_0002
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 5b 2 hl2H 1H 781 d J 19 H 1H 729 d J 19 S s, 3 = s, 3 ), + J z, = 4 J z, 3 8 J z, 8 ); = s, =
Figure imgf000113_0001
Intermediate Example 18: Preparation of 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan- 1,2,2,2-d4-1-ol [00391] Under N2 2H-indazole (337
Figure imgf000114_0001
mg, 1.0 mmol) in ̶ was a isopropylmagnesium chloride (2.0 M in THF, 1.0 mL, 2.0 mmol). After stirring at ̶ 40 °C for 15 min, acetaldehyde- d4 (0.28 mL, 5.0 mmol) was added. After 30 min, the reaction was quenched with sat. NH4Cl, warmed to rt, and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel (0-100% EtOAc/hexanes) to provide the title compound (148 mg, 57% yield).1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 5.19 (s, 1H), 4.19 (s, 3H); ES-MS [M+H- H2O]+ = 241.0/243.0. Intermediate Example 19: Preparation of 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1-d- 1-ol
Figure imgf000114_0002
[00392] 1-one. Under N2 atmosphere, to a solution of 4-bromo-7-iodo-2-methyl-2H-indazole (674 mg, 2.0 mmol) in THF (5.0 mL) at –40 °C was added dropwise a solution of isopropylmagnesium chloride (2.0 M in THF, 2.0 mL, 4.0 mmol). After stirring at ̶ 40 °C for 30 min, N-methoxy-N-methylacetamide (1.06 mL, 10.0 mmol) was added. After 1 h, sat. soln. NH4Cl was added slowly and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel (0-100% EtOAc/hexanes) to provide the title compound (377 mg, 75% yield).1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 4.26 (s, 3H), 2.85 (s, 3H); ES-MS [M+H]+ = 253.1/254.9. [00393] Step 2: Synthesis of 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1-d-1-ol. To a solution of 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1-one (253 mg, 1.0 mmol) in MeOD (5.0 mL) and DCM (5.0 mL) at 0 °C was added sodium borodeuteride (113.5 mg, 3.0 mmol) portionwise. After 30 min at 0 °C, anhydrous acetone was added slowly and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel (0-100% EtOAc/hexanes) to provide the title compound (152 mg, 60% yield).1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.27 – 7.16 (m, 2H), 5.20 (s, 1H), 4.19 (s, 3H), 1.45 (s, 3H); ES- MS [M+H-H2O]+ = 238.0/240.0. Intermediate Example 20: Preparation of 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1-ol
Figure imgf000115_0001
[00394] 1- was a similar manner as Intermediate Example 19 using sodium borohydride in the second step.1H NMR (400 MHz, DMSO-d6) δ 8.39 – 8.34 (m, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 5.23 – 5.18 (m, 2H), 4.19 (s, 3H), 1.46 (d, J = 6.2 Hz, 3H); ; ES-MS [M+H-H2O]+ = 236.9/239.0. Intermediate Example 21: Preparation of 1-(4-bromo-2-methyl-2H-indazol-7-yl)-2,2- difluoroethan-1-d-1-ol
Figure imgf000115_0002
[00395] Step 1: 1-(4-Bromo-2-methyl-2H-indazol-7-yl)-2,2-difluoroethan-1-one. Under N2 atmosphere, to a solution of 4-bromo-7-iodo-2-methyl-2H-indazole (169 mg, 0.5 mmol) in THF (2.5 mL) at -40 °C was added dropwise a solution of isopropylmagnesium chloride (2.0 M in THF, 0.5 mL, 1.0 mmol). After stirring at ̶ 40 °C for 30 min, 2,2-difluoro-N-methoxy-N- methylacetamide (0.29 mL, 2.5 mmol) was added. After 1 h, the reaction was quenched with sat. soln. NH4Cl, warmed to rt, and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel (0-100% EtOAc/hexanes) to provide the title compound (77 mg, 53% yield).1H NMR (400 MHz, DMSO- d6) δ 8.75 (s, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 53.2 Hz, 1H); ES-MS [M+H]+ = 289.0/291.0. [00396] Step 2: 1-(4-Bromo-2-methyl-2H-indazol-7-yl)-2,2-difluoroethan-1-d-1-ol . To a solution of 1-(4-bromo-2-methylindazol-7-yl)-2,2-difluoroethanone (80 mg, 0.28 mmol) in methanol-OD (0.2 mL, 0.28 mmol) and DCM (1.38 mL) at 0 ℃ was added sodium borodeuteride (21 mg, 0.55 mmol). After 30 min, anhydrous acetone was added slowly and concentrated under reduced pressure. The crude material was re-dissolved in water and extracted with DCM (3x). The combined extracts were passed through a hydrophobic phase separator and concentrated to provide the title compound (78 mg) which was carried forward without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 6.32 (d, J = 55.5 Hz, 1H), 6.24 (s, 1H), 4.21 (s, 3H); ES-MS [M+H]+ = 292.0/294.0. Intermediate Example 22: (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H- indazol-7-yl)methan-d2-ol
Figure imgf000116_0001
[00397] (4- mg, mmol), PdCl2(dppf) (15 mg, 0.02 mmol), bis(pinocolato)diboron (47 mg, 0.19 mmol) and potassium acetate (36 mg, 0.37 mmol). Degassed 1,4-dioxane (0.75 mL) was added. The reaction mixture was evacuated and purged with N2 (3x). After 16 h at 90 ^C, the reaction mixture was filtered through a pad of Celite®, rinsed thoroughly with EtOAc/DCM and concentrated under pressure. The crude residue was carried forward without further purification. ES-MS [M+H]+ = 209.1 (boronic acid). Table 11. Commercial Starting Materials Name CAS# Supplier
Figure imgf000117_0001
Name CAS# Supplier
Figure imgf000118_0001
Preparation of Representative Compounds Example 1: 6-(2,6-Difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 1) [00398] To a solution of 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (23.2 mg, 0.060 mmol) in degassed 1,4- dioxane (0.75 mL) were added Pd(dppf)Cl2 ^DCM (7.3 mg, 0.01 mmol), cesium carbonate (49.2 mg, 0.15 mmol), (4-bromo-2-methyl-2H-indazol-7-yl)methan-d2-ol (12.2 mg, 0.05 mmol) and water (0.25 mL). The reaction mixture was evacuated and purged with N2 (3x) and allowed to stir at 100 ^C. After 2 h, the mixture was diluted with EtOAc and DCM, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to provide the title compound (8.9 mg).1H NMR (400 MHz, DMSO-d6) δ 8.75 (dd, J = 4.9, 1.6 Hz, 1H), 8.63 (s, 1H), 8.12 (dd, J = 7.7,
Figure imgf000119_0001
Hz, 1H), 7.53 (dd, J = 7.7, 4.9 Hz, 1H), 7.50 – 7.44 (m, J = 8.5 Hz, 2H), 7.35 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 5.20 (s, 1H), 4.91 (s, 2H), 4.49 (s, 2H), 4.18 (s, 3H); ES-MS [M+H]+ = 423.0. Example 2: (S)-6-(1-(2,6-Difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4- yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 15) [00399]
Figure imgf000119_0002
ethyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (29.7 mg, 0.07 mmol), (4-bromo-2-methyl-2H- indazol-7-yl)methan-d2-ol (13.9 mg, 0.06 mmol), Pd(dppf)Cl2 (8.4 mg, 0.01 mmol), and Cs2CO3 (56.1 mg, 0.17 mmol) were combined into a reaction vial. Anhydrous 1,4-dioxane (1.0 mL) and water (0.25 mL) were added. The mixture was evacuated and purged with nitrogen. After 2 h at 100 °C, the mixture was diluted with EtOAc and DCM and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to provide the title compound (12.7 mg).1H NMR (400 MHz, DMSO-d6) δ 8.78 (dd, J = 4.9, 1.6 Hz, 1H), 8.63 (s, 1H), 8.08 (dd, J = 7.7, 1.6 Hz, 1H), 7.53 (dd, J = 7.7, 4.9 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.34 (d, J = 7.1 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 5.86 (q, J = 7.3 Hz, 1H), 5.19 (s, 1H), 4.85 (d, J = 17.8 Hz, 1H), 4.54 (d, J = 17.8 Hz, 1H), 4.17 (s, 3H), 1.77 (d, J = 7.3 Hz, 3H); ES-MS [M+H]+ = 437.2. Example 3: 6-(2,6-Difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2 (Compound 19) [00400]
Figure imgf000120_0001
2- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2 (30.3 mg, 0.078 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1-d-1- ol (15.4 mg, 0.06 mmol), Pd(dppf)Cl2 (8.8 mg, 0.01 mmol), Cs2CO3 (59.0 mg, 0.18 mmol) and D2O (0.2 mL). The mixture was evacuated and purged with nitrogen. After 2 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to provide the title compound (7.0 mg); 1H NMR (400 MHz, DMSO-d6) δ 8.76 (dd, J = 4.9, 1.6 Hz, 1H), 8.61 (s, 1H), 8.12 (dd, J = 7.7, 1.6 Hz, 1H), 7.53 (dd, J = 7.7, 4.9 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 5.18 (s, 1H), 4.91 (s, 2H), 4.19 (s, 3H), 1.49 (s, 3H); ES- MS [M+H-H2O]+ = 438.2.
Example 4: 6-(2,6-Difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol-4- yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 36) [00401]
Figure imgf000121_0001
2- yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (24.1 mg, 0.062 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1,2,2,2-d4-1-ol (11.3 mg, 0.045 mmol), Pd(dppf)Cl2 (6.5 mg, 0.01 mmol), Cs2CO3 (43.8 mg, 0.13 mmol) and H2O (0.2 mL). The mixture was evacuated and purged with nitrogen. After 2 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to provide the title compound (11.2 mg); 1H NMR (400 MHz, DMSO-d6) δ 8.72 (dd, J = 4.8, 1.5 Hz, 1H), 8.61 (s, 1H), 8.04 (dd, J = 7.8, 1.5 Hz, 1H), 7.56 (dd, J = 7.7, 4.8 Hz, 1H), 7.53 – 7.43 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 5.18 (s, 1H), 4.92 (s, 2H), 4.47 (s, 2H), 4.19 (s, 3H); ES- MS [M+H]+ = 439.1. Example 5: (R)-6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one and (S)-6-(2,6-difluoro-4-(7-(1- hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one
[00402] To a solution of 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (135.5 mg, 0.35 mmol) in anhydrous 1,4-dioxane (2.5 mL) was added 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1-d-1-ol (75 mg, 0.30 mmol), Pd(dppf)Cl2 (32 mg, 0.04 mmol), Cs2CO3 (288 mg, 0.88 mmol) and water (0.5 mL). The resulting mixture was evacuated and purged with nitrogen. After 2 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to afford a racemic mixture which was further resolved using SFC chiral preparative separation (Phenomenex Lux-Cellulose 4, 21 x 250 mm column, particle size 5-micron, primary solvent: liquid CO2, co-solvent: 2- propanol, 40% isocratic, flow rate: 80, temperature: 40 °C). After an additional purification using reverse phase HPLC, two separated stereoisomers were obtained. Isomer 1 (first eluting) (6- (2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one): 1H NMR (400 MHz, DMSO-d6) δ 8.75 (dd, J = 4.9, 1.6 Hz, 1H), 8.61 (s, 1H), 8.12 (dd, J = 7.7, 1.6 Hz, 1H), 7.53 (dd, J = 7.7, 4.9 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 5.19 (s, 1H), 4.91 (s, 2H), 4.50 (s, 2H), 4.19 (s, 3H), 1.49 (s, 3H); ES-MS [M+H]+ = 436.2. Isomer 2 (second eluting) (6-(2,6-difluoro-4-(7-(1- hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5- one): 1H NMR (400 MHz, DMSO-d6) δ 8.75 (dd, J = 5.0, 1.6 Hz, 1H), 8.61 (s, 1H), 8.12 (dd, J = 7.7, 1.6 Hz, 1H), 7.53 (dd, J = 7.7, 4.9 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 5.19 (s, 1H), 4.91 (s, 2H), 4.50 (s, 2H), 4.18 (s, 3H), 1.49 (s, 3H).ES- MS [M+H]+ = 436.2. Example 6: 6-((5-(7-(Hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)pyrimidin-2-yl)methyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 20)
[00403] To a solution of 6-((5-bromopyrimidin-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one (11.7 mg, 0.04 mmol) in degassed 1,4-dioxane (0.5 mL) were added Pd(dppf)Cl2 ^DCM (4.2 mg, 0.01 mmol), cesium carbonate (37.7 mg, 0.12 mmol), (2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-7-yl)methan-d2-ol (11.1 mg, 0.04 mmol) and water (0.1 mL). The reaction mixture was evacuated and purged with N2 (3x) and allowed to stir at 100 ^C. After 16 h, the mixture was diluted with EtOAc and DCM, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to provide the title compound (5.5 mg).1H NMR (400 MHz, CDCl3) δ 8.95 (s, 2H), 8.76 (dd, J = 1.6, 5.0 Hz, 1H), 8.20 (dd, J = 1.6, 7.7 Hz, 1H), 8.00 (s, 1H), 7.44 (dd, J = 5.0, 7.7 Hz, 1H), 7.32 (d, J = 7.1 Hz, 1H), 7.13 (d, J = 7.1 Hz, 1H), 5.19 (s, 2H), 4.72 (s, 2H), 4.24 (s, 3H) ; ES-MS [M+H]+ = 389.3. [00404] The compounds presented in Table 12 may be prepared in an analogous manner to those described in the preceding schemes and examples using appropriate starting materials. Table 12 1 No. STRUCTURE NAME H-NMR and/or ES-MS [M+H]+ δ (s, ), - ), ), ); δ (s, ), .8 22 89 S-
Figure imgf000123_0001
1H NMR (400 MHz, DMSO-d6) δ 8.74 (dd, J = 4.9, 1.6 Hz, 1H), 8.58 (s, 6-(2-fluoro-4-(7- 1H), 8.13 (dd, J = 7.7, 1.6 Hz, 1H), d, .8 22 89 18 ]+ δ (s, ), 38 = ), ), ), 98 ); δ (s, ), d, z, ), ), S δ (s, ), - ), ), ), 1. δ (s, ), – ), ), );
Figure imgf000124_0001
1H NMR (400 MHz, DMSO-d6) δ 8.74 (dd, J = 5.0, 1.6 Hz, 1H), 8.47 (s, 1H), 8.13 (dd, J = 7.7, 1.6 Hz, 1H), – ), ), ), 98 ); δ d, .6 z, , J = (s, S- δ d, .6 z, ), 1, ), S δ (s, ), = 7, ), ), ), 3. δ (s, ), 7, 32 .1 ), S δ (s, ), d, z, ), ), 2.
Figure imgf000125_0001
1H NMR (400 MHz, DMSO-d6) δ 8.78 (dd, J = 5.0, 1.6 Hz, 1H), 8.63 (s, (R)-6-(1-(2,6-difluoro-4-(7- 1H), 8.08 (dd, J = 7.7, 1.6 Hz, 1H), – ), = = z, z, δ (s, ), – ), = = z, z, δ (s, ), - ), ), ); δ (s, ), – ), ), ), 2. δ (s, ), – ), ), S δ (s, ), - ), ), );
Figure imgf000126_0001
1H NMR (400 MHz, CDCl3) δ 8.95 6-((5-(7-(hydroxymethyl-d2)- (s, 2H), 8.76 (dd, J = 1.6, 5.0 Hz, 1H), 2 hl2Hid l4 820 dd 16 H 1H 800 (s, ), = ), .3 δ (s, ), m, (s, 16 δ (s, ), m, (s, 16 δ (s, ), - ), ), S δ (s, ), d, .8 22 89 49 δ (s, ), 38 = ), ), 24 – =
Figure imgf000127_0001
1H NMR (400 MHz, DMSO-d6) δ 6-(2-fluoro-4-(7- 8.77 (dd, J = 5.0, 1.6 Hz, 1H), 8.56 (s, 1H), 8.15 (dd, J = 7.7, 1.6 Hz, 1H), .9 22 89 ]+ δ (s, ), = z, 45 ]+ δ 76 = .6 70 6, z, ), S δ 9, z, d, .6 53 ), S δ 77 = .6 61 6, z, 54 δ 11 = z, ), );
Figure imgf000128_0001
1H NMR (400 MHz, DMSO-d6) δ 6-(2,6-difluoro-4-(7- 8.74 (dd, J = 4.9, 1.6 Hz, 1H), 8.11 hd hl dd 16 H 1H 59 48 01 20 S- δ (s, ), .3 ), ), 1. δ (s, ), – ), = (s, S- δ (s, ), – ), ), ); δ (s, ), – ), ), ); δ (s, ), – ), ), 51 =
Figure imgf000129_0001
1 6-(2,6-difluoro-4-(7- H NMR (400 MHz, DMSO-d6) δ (hydroxymethyl-d2)-2- 8.75 (dd, J = 4.9, 1.6 Hz, 1H), 8.63 (s, 1H 812 dd 16 H 1H), – ), ), 2. δ (s, ), .2 ), ); δ (s, ), – ), ), S δ 51 z, (s, 18 δ (s, ), – ), ), ), 2. δ (s, ), – ), ), ), 2. δ z, d, z, ), ), 0.
Figure imgf000130_0001
1 2-(2,6-difluoro-4-(7-(1- H NMR (400 MHz, DMSO-d6) δ hd hl1222d42 8.61 (s, 1H), 7.67 – 7.57 (m, 1H), 7.47 4, 18 19 δ z, = ), .0 84 S δ z, 34 q, (s, 50 = δ (s, ), – z, q, (s, 49 = δ (s, ), – ), d, z, 49 S
Figure imgf000131_0001
. econ eutng enantomer y c ra preparatve separaton Biological Activity a. Cell Lines Expressing Muscarinic Acetylcholine Receptors [00405] Chinese hamster ovary (CHO-K1) cells stably expressing rat (r)M1 were purchased from the American Type Culture Collection and cultured according to their indicated protocol. CHO cells stably expressing human (h)M2, hM3, and hM5 were described previously (Levey, et al., 1991); hM1 and hM4 cDNAs were purchased from Missouri S&T cDNA Resource; rM4 cDNA was provided by T. I. Bonner (National Institutes of Health, Bethesda, MD). rM2 and rM3 were cloned from a rat brain cDNA library and sequence verified. hM1, rM2, rM3, hM4, and rM4 cDNAs were used to stably transfect CHO-K1 cells purchased from the American Type Culture Collection using Lipofectamine2000. To make stable rM2, hM2, rM3, hM4, and rM4 cell lines for use in calcium mobilization assays, these cells also were stably transfected with a chimeric G- protein (Gqi5) (provided by B.R. Conklin, University of California, San Francisco) using Lipofectamine 2000. rM1, hM1, rM3, hM3, rM5, and hM5 cells were grown in Ham’s F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, and 50 µg/mL G418 sulfate. rM2-Gqi5, hM2–Gqi5, and hM4–Gqi5 cells were grown in the same medium also containing 500 µg/mL Hygromycin B. Stable rM4–Gqi5 cells were grown in DMEM containing 10% heat-inactivated FBS, 20 mM HEPES, 400 ^g/mL G418 sulfate, and 500 ^g/mL Hygromycin B. b. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor Activity [00406] 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 ^L/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 four washes (80 µL) of assay buffer then aspirated to 20 µL. Next, 20 µL of 16 µM 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 (four 80µL washes of assay buffer) then aspirated to 20 µL. Compound master plates were formatted in an 11 point CRC format (1:3 dilutions) in 100% DMSO with a starting concentration of 10 mM using the 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 µL) to a 2× stock using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA). [00407] Calcium flux was measured using the Functional Drug Screening System (FDSS) 6000 (Hamamatsu Corporation, Tokyo, Japan) as an increase in the fluorescent static ratio. Compounds were applied to cells (20 µL, 2X) using the automated system of the FDSS 6000 at 4 s into the 300 s protocol and the data were collected at 1 Hz. At 144 s into the 300s protocol, 10 µL of an EC20 concentration of the muscarinic receptor agonist acetylcholine was added (5X), followed by the addition of 12 µL of an EC80 concentration of acetylcholine at the 230 s time point (5X). Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Emax values for agonist activity are expressed relative to the maximum for acetylcholine. 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 EC80 acetylcholine response. 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). [00408] 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 the appropriate concentration of agonist was added and readings taken for an additional 106 s. Data were reduced as described above and the EC50 values for the agonist in the presence of test compound were determined by nonlinear curve fitting. A decrease in the EC50 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 EC50 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. Results and Discussion of Biological Activity Data [00409] Activity (EC50 and Emax) was determined in the mAChR M1 cell-based functional assay as described above and the data are shown in Table 13. The compound numbers correspond to the compound numbers used in Table 12. The data in Table 13 demonstrate that the disclosed compounds are positive allosteric modulators of human mAChR M1 and show high PAM activity for the human mAChR M1 receptor(s). Table 13. Biological Activity Data PAM Activity Agonist Activity
Figure imgf000134_0001
PAM Activity Agonist Activity
Figure imgf000135_0001
[00410] 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. [00411] 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

CLAIMS What is claimed is: 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, ,
Figure imgf000136_0001
Z2 is N or CRz2; Z3 is N or CRz3; Z4 is N or CRz4; wherein 0, 1, or 2 of Z1, Z2, Z3, and Z4 is N; Rz1, Rz2, Rz3, and Rz4 are independently selected from the group consisting of H, D, halogen, C1- 2alkyl, C1-2deuterioalkyl, C1-2fluoroalkyl, cyano, –OC1-2alkyl, –OC1-2deuterioalkyl, –OC1- 2fluoroalkyl, and C3-4cycloalkyl; R1, R2, R3 and R4 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4deuterioalkyl, C1-4fluoroalkyl, halogen, cyano, G1, –ORa, –O–C2-3alkylene–ORb, and –N(Rc)(Rd); Ra, Rb, Rc, and Rd are independently selected from the group consisting of H, C1-4alkyl, C1- 4deuterioalkyl, C1-4fluoroalkyl, G1, and –C1-3alkylene–G1, wherein alternatively, Rc and Rd, together with the nitrogen to which the Rc and Rd attach, form a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of O, N, and S, wherein the 4- to 7-membered heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C1-4fluoroalkyl, OH, –OC1-4alkyl, –OC1- 4deuterioalkyl, and –OC1-4fluoroalkyl; G1 is C3-6cycloalkyl or a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C1-4fluoroalkyl, OH, –OC1- 4alkyl, –OC1-4deuterioalkyl, and –OC1-4fluoroalkyl; R5 is a 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or R5 is a 6- to 12 membered aryl, the heteroaryl and aryl being substituted by R6 and optionally further substituted with 1-4 substituents R7; R6 is –C(R6a)(R6b)OH; R6a is selected from the group consisting of D, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, –C1-3alkylene–C3-6cycloalkyl, and –C1-5alkylene–X1, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R6b is H or D; X1 is selected from the group consisting of –SR6c, –SOR6c, –SO2R6c, and –S(O)(NR6d)R6c; R6c is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R6d is selected from the group consisting of H, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R7, at each occurrence, is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, –OC1- 4haloalkyl, C3-6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; R8a and R8b are independently selected from the group consisting of H, D, CH3, and CD3; and R9a and R9b are independently H or D.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from the group consisting of H, D, C1-4alkyl, C1-4deuterioalkyl, C1- 4fluoroalkyl, halogen, cyano, C3-6cycloalkyl, –ORa, –O–C2-3alkylene–ORb, and –N(Rc)(Rd), wherein the C3-6cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, C1-4deuterioalkyl, C1-4fluoroalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, and –OC1-4fluoroalkyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently selected from the group consisting of H, D, C1-4alkyl, C1- 4deuterioalkyl, C1-2fluoroalkyl, halogen, cyano, –OC1-4alkyl, –OC1-4deuterioalkyl, and –OC1- 2fluoroalkyl.
4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein .
Figure imgf000138_0001
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein A1 is selected from the group ,
Figure imgf000139_0001
.
Figure imgf000139_0002
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein A1 is selected from the group consisting of , , , , , , , , , , , , , , , , , , , and .
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000140_0001
8. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein A1 is selected from the group ,
Figure imgf000141_0001
.
Figure imgf000141_0002
9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R5 is the substituted 5- to 12-membered heteroaryl.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the ring system of the substituted 5- to 12-membered heteroaryl at R5 is a 5- to 6-membered heteroaryl containing 1-3 nitrogen atoms.
11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the ring system of the substituted 5- to 12-membered heteroaryl at R5 is a 9- to 10-membered heteroaryl containing 1-3 nitrogen atoms.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the 9- to 10-membered heteroaryl ring system is selected from the group consisting of 2H-indazol-4-yl, 2H-indazol-3-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, 2H-indazol-7-yl, 1H-indazol-3-yl, 1H- indazol-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-8-yl, 1H-indol-3-yl, 1H- benzo[d][1,2,3]triazol-7-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, and [1,2,4]triazolo[1,5-a]pyridin-8-yl.
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of , , , , , , , , , , , , , , , and ; and R7a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl.
14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein
R5 is ; R7a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, C3- 6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl; and R7b, R7c, and R7d are independently selected from the group consisting of hydrogen, halogen, cyano, C1-4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, – OC1-4haloalkyl, C3-6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl.
15. The compound of claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein .
Figure imgf000144_0001
16. The compound of any of claims 13-15, or a pharmaceutically acceptable salt thereof, wherein R7a is C1-2alkyl or C1-2deuterioalkyl.
17. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R5 is the substituted 6- to 12-membered aryl.
18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R5 is ,
Figure imgf000145_0001
C1- 4alkyl, C1-4deuterioalkyl, C1-4haloalkyl, OH, –OC1-4alkyl, –OC1-4deuterioalkyl, –OC1- 4haloalkyl, C3-6cycloalkyl, and –C1-3alkylene–C3-6cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl.
19. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R6a is selected from the group consisting of C1-4alkyl, C1-4deuterioalkyl, and C1- 4haloalkyl.
20. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R6a is D.
21. The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R6b is H.
22. The compound of any of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R6b is D.
23. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from the group ,
Figure imgf000146_0001
.
Figure imgf000146_0002
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from the group ,
Figure imgf000146_0003
.
Figure imgf000146_0004
25. The compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of a compound of formula: (I-a), (I-b), (I-c), (I-d), (I-e), and (I-f).
26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (I-a).
27. The compound of claim 26, or a pharmaceutically acceptable salt thereeof, wherein the compound is a .
Figure imgf000147_0001
28. The compound of any of claims 1-6, 9, 11-16, or 19-27, or a pharmaceutically acceptable ,
Figure imgf000148_0001
29. The compound of any of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R8a and R8b are H.
30. The compound of any of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R8a is H; and R8b is CH3; or R8a is CH3; and R8b is H.
31. The compound of any of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R9a and R9b are H.
32. The compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R9a and R9b are D.
33. The compound of claim 1 selected from the group consisting of: 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopropyl-6-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)-6-methoxybenzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopropyl-6-fluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,3-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; 6-(2,5-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; 6-(2-chloro-6-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one; 6-(2-(dimethylamino)-6-fluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; (R)-6-(1-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)phenyl)ethyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; (S)-6-(1-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)phenyl)ethyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; -(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one; -(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro- 7H-pyrrolo[3,4-b]pyridin-7-one; -(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one-7,7-d2; -(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2; -((5-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)pyrimidin-2-yl)methyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one; -(2,6-difluoro-4-(6-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; -(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; -(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; -(2-fluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4-yl)-6-methylbenzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; -(2-cyclopropyl-6-fluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; -(2-fluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one; -(4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4-yl)-2-methylbenzyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one; -(2,6-difluoro-4-(5-(hydroxymethyl-d2)quinolin-8-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one; -(2,6-difluoro-4-(8-(hydroxymethyl-d2)quinolin-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one; -(2,6-difluoro-4-(8-(hydroxymethyl-d2)quinolin-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)benzo[d][1,3]dioxol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)benzo[d][1,3]dioxol-5-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)- 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol-4-yl)benzyl)-5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(4-(2-ethyl-7-(hydroxymethyl-d2)-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2; 6-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2; 6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2; 2-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-4- fluoroisoindolin-1-one; (R)-6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; (S)-6-(2,6-difluoro-4-(7-(1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)benzyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 2-(2,6-difluoro-4-(7-(hydroxymethyl-d2)-2-methyl-2H-indazol-4-yl)benzyl)-7- fluoroisoindolin-1-one; 2-(2,6-difluoro-4-(7-(1-hydroxyethyl-1,2,2,2-d4)-2-methyl-2H-indazol-4-yl)benzyl)-7- fluoroisoindolin-1-one; 2-(4-(7-(2,2-difluoro-1-hydroxyethyl-1-d)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-7- fluoroisoindolin-1-one; 2-(2,6-difluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin- 1-one; 6-(2,6-difluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one; and 6-(2-fluoro-4-(7-(1-hydroxyethyl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
34. A compound of any of claims 1-33, or a pharmaceutically acceptable salt thereof, that has at least 50% deuterium incorporation at each deuterium label.
35. A hydrate, solvate, polymorph, or prodrug of the compound of any of claims 1-34, or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition comprising the compound, hydrate, solvate, polymorph, or prodrug of any of claims 1-35, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
37. A method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of the compound, hydrate, solvate, polymorph, or prodrug of any of claims 1-35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36.
38. The method of claim 37, wherein the mammal is human.
39. The method of claim 37 or 38, wherein the muscarinic acetylcholine receptor is mAChR M1.
40. The method of any of claims 37-39, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.
41. The method of any of claims 37-40, further comprising the step of identifying a mammal in need of treatment of the disorder.
42. The method of any of claims 37-41, wherein the disorder is a neurological disorder or psychiatric disorder, or a combination thereof.
43. The method of any of claims 37-42, wherein the disorder is psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette’s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson’s disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, or memory disorders, or a combination thereof.
44. The method of any of claims 37-42, wherein the disorder is Alzheimer’s disease, schizophrenia, a sleep disorder, a pain disorder, or a cognitive disorder, or a combination thereof.
45. The method of claim 44, wherein the pain disorder is neuropathic pain, central pain syndrome, postsurgical pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesis, primary allodynia, secondary allodynia, or a combination thereof.
46. The compound, hydrate, solvate, polymorph, or prodrug of any of claims 1-35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36, for use in the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.
47. Use of the compound, hydrate, solvate, polymorph, or prodrug of any of claims 1-35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36, for the preparation of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.
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