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WO2025231255A1 - Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1 - Google Patents

Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1

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Publication number
WO2025231255A1
WO2025231255A1 PCT/US2025/027317 US2025027317W WO2025231255A1 WO 2025231255 A1 WO2025231255 A1 WO 2025231255A1 US 2025027317 W US2025027317 W US 2025027317W WO 2025231255 A1 WO2025231255 A1 WO 2025231255A1
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Prior art keywords
methyl
oxo
tetrahydroisoquinolin
dihydroisoquinolin
compound
Prior art date
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Pending
Application number
PCT/US2025/027317
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English (en)
Inventor
Craig W. Lindsley
Darren W. Engers
Changho HAN
Julie L. Engers
Upendra RATHNAYAKE
Jeremy S. COLEMAN
Rory A. CAPSTICK
Alison R. Gregro
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Vanderbilt University
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Vanderbilt University
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Publication of WO2025231255A1 publication Critical patent/WO2025231255A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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

Definitions

  • 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 M 1 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.
  • ACh acetylcholine
  • the compound may also have an intrinsic activity to activate the receptor in the absence of orthosteric ligand.
  • 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.
  • nAChRs nicotinic acetylcholine receptors
  • mAChRs muscarinic acetylcholine receptors
  • AChE Acetylcholinesterase
  • AD Alzheimer’s disease
  • 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
  • M2 and M4 mainly couple to Gi/o and associated effector systems.
  • M 1 -M 5 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).
  • allosteric modulation may be an advantageous pathway because allosteric sites on mAChRs are less highly conserved.
  • mAChR muscarinic receptor
  • X 1 is selected from the group consisting of –OR 1a , –NR 1a R 1b , –S(O)2R 1a , and –C(O)NR 1a R 1b ;
  • R 1a and R 1b are independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, and –C 1-3 alkylene–C 3-4 cycloalkyl;
  • G 1 is selected from the group consisting of phenyl, a 5- to 12-membered heteroaryl containing 1- 3 heteroatoms, a 4- to 8-membered heterocyclyl
  • Z 6 is CH, CR 9 , or N;
  • Z 7 is CH, CR 14 , or N;
  • Z 8 is C or N;
  • ring 6-membered fully or partially unsaturated heterocyclic R 14 and/or R 15 wherein the heterocyclic ring contains from the group consisting of N, O, and S;
  • ring 6-membered fully or partially unsaturated heterocyclic R 14 and/or R 15 wherein the heterocyclic ring contains a first N heteroatom and optionally 1-2 additional heteroatoms independently selected from the group consisting of N, O, and S;
  • R 9 at each occurrence, is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, –OC1-4alkyl, and –OC1-4fluoroalkyl;
  • R 10 is selected from the group consisting of G 10 , –C(O)NR 10a R 10b , halogen, cyano, C 1-4 alkyl, C 1-
  • 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 M1 agonist activity compared to acetylcholine.
  • the relative lower M 1 agonist activity compared to the positive allosteric modulator M 1 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 M 1 (mAChR 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 M 1 has been implicated in a number of different diseases and disorders including, but not limited to, neurological and psychiatric disorders.
  • diseases and disorders including, but not limited to, neurological and psychiatric disorders.
  • 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.
  • positive allosteric modulation of mAChR M 1 can result in potentiation of the mAChR M 1 receptor and provide therapeutic benefits for disorders associated with mAChR M1 dysfunction. 1.
  • 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.
  • 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.
  • alkyl means a straight or branched, saturated hydrocarbon chain.
  • lower alkyl or “C1-6alkyl” 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 CH 2 F, CHF 2 , CF 3 , and CH 2 CF 3 .
  • 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 CD 2 F, CDF 2 , and CD 2 CF 3 .
  • 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 CD2F, CDF2, CD2CF3, CD2Cl, CDCl2, and CD 2 CCl 3 .
  • 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 ⁇ electron
  • 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., “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.
  • 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 “C 1 to C 6 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-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, CH3CH(CH)3CH2- , CH3CH(CH)3CH2- and (CH3)3C-.
  • “C3alkyl” is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl).
  • 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.
  • 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 C 1-4 haloalkyl may be C 1-4 fluoroalkyl).
  • 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.
  • X 1 is selected from the group consisting of –OR 1a , –NR 1a R 1b , –S(O)2R 1a , and –C(O)NR 1a R 1b ;
  • R 1a and R 1b are independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 fluoroalkyl, C3-4cycloalkyl, and –C1-3alkylene–C3-4cycloalkyl;
  • G 1 is selected from the group consisting of phenyl, a 5- to 12-membered heteroaryl containing 1- 3 heteroatoms, a 4- to 8-membered heterocyclyl containing 1-2 hetero
  • Z 6 is CH, CR 9 , or N;
  • Z 7 is CH, CR 14 , or N;
  • Z 8 is C or N;
  • ring 6-membered fully or partially unsaturated heterocyclic R 14 and/or R 15 wherein the heterocyclic ring contains from the group consisting of N, O, and S;
  • ring 6-membered fully or partially unsaturated heterocyclic R 14 and/or R 15 wherein the heterocyclic ring contains a first N heteroatom and optionally 1-2 additional heteroatoms independently selected from the group consisting of N, O, and S;
  • R 9 at each occurrence, is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, –OC1-4alkyl, and –OC1-4fluoroalkyl;
  • R 10 is selected from the group consisting of G 10 , –C(O)NR 10a R 10b , halogen, cyano, C 1-4 alkyl, C 1-
  • E1.1 The compound of E1, or a pharmaceutically acceptable salt thereof, wherein: R 2 , at each occurrence, is independently selected from the group consisting of C1-4alkyl and –C1- 3alkylene–OC1-4alkyl; or two R 2 , together with the atom(s) to which each is attached, form a C 3-6 cycloalkane; or wherein alternatively, R 1 and one R 2 , together with the atoms to which each is attached, form a 5- to 6-membered fused heterocycle optionally containing one additional heteroatom independently selected from the group consisting of O, N, and S, the fused heterocycle being optionally substituted with 1-4 R 3a substituents independently selected from the group consisting of C1-4alkyl and halogen; or wherein alternatively, R 1 and one R 2 substituted on a non-adjacent carbon atom, together link to form a first C 2-3 alkylene bridge, the first C 2-3 alkylene bridge being optionally substituted with 1-4 R 3
  • E1-E2 any of E1-E2, or a pharmaceutically acceptable salt thereof, wherein R 2 , at each occurrence, is independently selected from the group consisting of C 1-4 alkyl and –C 1-3 alkylene–OC 1-4 alkyl; or two R 2 , together with the atom(s) to which each is attached, form a C3-6cycloalkane or oxo.
  • R 2 at each occurrence, is independently selected from the group consisting of C 1-4 alkyl and –C 1-3 alkylene–OC 1-4 alkyl; or two R 2 , together with the atom(s) to which each is attached, form a C3-6cycloalkane.
  • E5.1 The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein the compound has a b).
  • E5.2 The compound of any salt c ). acceptable salt thereof, wherein the compound has a formula (IV-a): . of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
  • E8. The compound of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein R 1 is G 1 .
  • E9. The compound of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein R 1 is –C1-4alkylene–G 1 . [0066] E9.1.
  • E9 The of E9, or a pharmaceutically acceptable salt thereof, wherein R 1 is [0067] E9.2.
  • E10. The compound of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C1-4alkyl and –C1-6alkylene–X 1 .
  • E10.1 The compound of E10, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl.
  • E10.2 The compound of E10, or a pharmaceutically acceptable salt thereof, wherein R 1 is –C1-6alkylene–X 1 .
  • E10.3. The compound of E10.2, or a pharmaceutically acceptable salt thereof, wherein R 1 is –CH2CH2–X 1 .
  • E10.4. The compound of any of E1-E6, E10, or E10.2-E10.3, or a pharmaceutically acceptable salt thereof, wherein X 1 is –OR 1a .
  • E10.5. The compound of any of E1-E6, E10, or E10.2-E10.4, or a pharmaceutically acceptable salt thereof, wherein R 1a is C1-4alkyl.
  • E10.6. The compound of E10.5, or a pharmaceutically acceptable salt thereof, wherein R 1a is methyl.
  • E12.1 The compound of any of E1-E6, E8-E9.2, or E12, or a pharmaceutically acceptable salt thereof, wherein the 5- to 12-membered heteroaryl at G 1 is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, and optionally substituted as defined in any of E1-E1.2.
  • E12.2. The compound of any of E1-E6, E8-E9.2, or E12, or a pharmaceutically acceptable salt thereof, wherein the 5- to 12-membered heteroaryl at G 1 is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, and optionally substituted as defined in any of E1-E1.2.
  • E12.3 The compound of any of E12-E12.1, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heteroaryl at G 1 is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, and oxazolyl, and optionally substituted as defined in any of E1-E1.2.
  • E12.1 or E12.2, or a pharmaceutically acceptable salt thereof wherein the 5- to 6-membered heteroaryl at G 1 is selected from the group consisting of pyridin-2-yl, pyrimidin-2-yl, pyrazol-3-yl, and oxazol-5-yl, and optionally substituted as defined in any of E1-E1.2.
  • E12.5. The compound of any of E12.1-E12.4, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heteroaryl at G 1 is selected from the group consisting of pyridin-2-yl, pyrimidin-2-yl, and pyrazol-3-yl, and optionally substituted as defined in any of E1-E1.2.
  • E12.6 The compound of any of E12.1-E12.5, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heteroaryl at G 1 is selected from the group consisting of pyridin-2-yl and pyrimidin-2-yl, and optionally substituted as defined in any of E1-E1.2.
  • E12.7 The compound of E12.6, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heteroaryl at G 1 is pyridin-2-yl, and optionally substituted as defined in any of E1-E1.2.
  • E12.8 The compound of any of E12.1-E12.5, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heteroaryl at G 1 is selected from the group consisting of pyridin-2-yl and pyrimidin-2-yl, and optionally substituted as defined in any of E1-E1.2.
  • E12.12. The compound of any of E12-E12.9 or E12.11, or a pharmaceutically acceptable salt thereof, wherein G 1 is selected from the group , , wherein G 1 is selected from the group , . of E12.13, or a pharmaceutically acceptable salt thereof, wherein .
  • G 1 is selected from the group consisting , , ally acceptable salt thereof, wherein G 1 is selected from the group consisting , , , ble salt thereof, wherein G 1 is selected from the group consisting , . acceptable salt thereof, wherein .
  • E12.20 The compound of any of E12-E12.9 or E12.11, or a pharmaceutically acceptable salt thereof, wherein G 1 is selected from the group , , . of E12.13, or a pharmaceutically acceptable salt thereof, wherein .
  • G 1 is selected from the group consisting , , ally acceptable salt thereof, wherein G 1 is selected from the group consisting
  • E13 The compound of any of E1-E6 or E8-E9.2, or a pharmaceutically acceptable salt thereof, wherein G 1 is the 4- to 8-membered heterocyclyl, optionally substituted as defined in any of E1-E1.2.
  • E13.1 The compound of any of E1-E6, E8-E9.2, or E13, or a pharmaceutically acceptable salt thereof, wherein the 4- to 8-membered heterocyclyl at G 1 is selected from the group consisting of tetrahydrofuranyl, morpholinyl, and pyrrolidinyl, and optionally substituted as defined in any of E1-E1.2.
  • E15 The compound of E15, or a pharmaceutically acceptable salt thereof, wherein R 4 is –OCH 3 .
  • E15.7 The compound of E15 or E15.1, or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen.
  • E15.8 The compound of E15.7, or a pharmaceutically acceptable salt thereof, wherein R 4 is chloro.
  • E15.9. The compound of E15.7, or a pharmaceutically acceptable salt thereof, wherein R 4 is fluoro.
  • E16 The compound of any of E1-E15.9, or a pharmaceutically acceptable salt thereof, wherein R 5 is C 1-4 alkyl. [00125] E16.1.
  • E16 The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R 5 is CH3.
  • E16.2. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R 5 is CH 2 CH 3 .
  • E16.3. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R 5 is CH(CH3)2.
  • E16.4. The compound of E16 or E16.1, or a pharmaceutically acceptable salt thereof, wherein R 5 is CH3 and R 4 is H or CH3.
  • E17 The compound of any of E1-E15.9, or a pharmaceutically acceptable salt thereof, wherein R 5 is halogen. [00130] E17.1.
  • E17 The compound of E17, or a pharmaceutically acceptable salt thereof, wherein R 5 is chloro.
  • E18 The compound of any of E1-E15.9, or a pharmaceutically acceptable salt thereof, wherein R 5 is –OR 5a .
  • E19 The compound of any of E1-E15.9 or E18, or a pharmaceutically acceptable salt thereof, wherein R 5a is selected from the group consisting of C 1-4 alkyl, C 1- 4 fluoroalkyl, and –C 2-4 alkylene–OC 1-4 alkyl.
  • E19.1 The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R 5a is C1-4alkyl.
  • E19 The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R 5a is –C 2-4 alkylene–OC 1-4 alkyl.
  • E19.8 The compound of E19.7, or a pharmaceutically acceptable salt thereof, wherein R 5a is CH2CH2OCH3 (i.e., R 5 is –OCH2CH2OCH3).
  • E20 The compound of any of E1-E15.9, or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
  • E21 The compound of any of E1-E20, or a pharmaceutically acceptable salt thereof, wherein Z 1 is CR 6 . [00143] E21.1.
  • E21.2 The compound of any of E1-E21, or a pharmaceutically acceptable salt thereof, wherein R 6 is H (i.e., Z 1 is CH).
  • E21.2 The compound of any of E1-E21, or a pharmaceutically acceptable salt thereof, wherein R 6 is CH 3 .
  • E22 The compound of any of E1-E21.2, or a pharmaceutically acceptable salt thereof, wherein R 7a and R 7b are H.
  • E23 The compound of any of E1-E22, or a pharmaceutically acceptable salt thereof, .
  • R 8 is selected from the group , nd ceptable salt thereof, wherein p is 0.
  • E23.3 The compound of E23.1, or a pharmaceutically acceptable salt thereof, wherein p is 1.
  • E23.4 The compound of E23.1, or a pharmaceutically acceptable salt thereof, wherein p is 2.
  • E23.5 The compound of E23.1, or a pharmaceutically acceptable salt thereof, wherein p is 3.
  • E23.6 The compound of E23.1, or a pharmaceutically acceptable salt thereof, wherein p is 4.
  • E23.7 The compound of any of E23-E23.4, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from the group ,
  • E1-E23 or E24 or a pharmaceutically acceptable salt thereof, wherein Z 3 is CH.
  • E24.2 The compound of any of E1-E23 or E24, or a pharmaceutically acceptable salt thereof, wherein Z 3 is CR 9 .
  • E24.3 The compound of any of E1-E23 or E24, or a pharmaceutically acceptable salt thereof, wherein Z 3 is N.
  • E25 The compound of any of E1-E24 or E24.2, or a pharmaceutically acceptable salt thereof, wherein R 9 , at each occurrence, is independently selected from the group consisting of halogen, C 1-4 alkyl, and –OC 1-4 alkyl.
  • E25.2. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 9 , at each occurrence, is independently halogen.
  • E25.3. The compound of any of E25-E25.2, or a pharmaceutically acceptable salt thereof, wherein R 9 , at each occurrence, is fluoro.
  • E26 The compound of any of E1-E25.3, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from the group .
  • the compound of E26, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from the group consisting .
  • E28.2 The compound of E28, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from the group consisting of G 10 , –C(O)NR 10a R 10b , C1-4alkyl, –CO2R 10a , and –C 1-3 alkylene–OR 10b .
  • R 10 is selected from the group consisting of C1-4alkyl, –CO2R 10a , –C(O)G 12 , and –C1- R 10a R 10b H or salt group 3alkylene–OR 10b ; and R 10a and R 10b are independently H or C1-4alkyl.
  • E30.1 The compound of any of E1-E28 or E29, or a pharmaceutically acceptable salt thereof, wherein G 10 is the 5- to 10-membered heteroaryl, optionally substituted as defined in any of E1-E1.2.
  • E30.1 The compound of any of E1-E28 or E29-E30, or a pharmaceutically acceptable salt thereof, wherein the 5- to 10-membered heteroaryl at G 10 is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, and optionally substituted as defined in any of E1-E1.2.
  • E30.6 The compound of any of E30.3-E30.5, or a pharmaceutically acceptable salt thereof, wherein the 5- to 10-membered heteroaryl at G 10 is pyrazol-1-yl, and optionally substituted as defined in any of E1-E1.2. [00181] E30.7.
  • E30-E30.6 The compound of any of E30-E30.6, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl at G 10 is optionally substituted with 1-3 C1-4alkyl (i.e., the alkyl may be the same or different).
  • E30.8 The compound of any of E30-E30.7, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl at G 10 is optionally substituted with 1-3 CH3.
  • E30.9. The compound of any of E1-E28 or E29-E30.8, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl at G 10 is unsubstituted.
  • E31.1 The compound of any of E1-E28, E29, or E31, or a pharmaceutically acceptable salt thereof, wherein the phenyl at G 10 is optionally substituted with 1-2 halogen.
  • E31.2 The compound of E31.1, or a pharmaceutically acceptable salt thereof, wherein the phenyl at G 10 is optionally substituted with 1-2 fluoro.
  • E31.3 The compound of E31.2, or a pharmaceutically acceptable salt thereof, wherein .
  • E32.1 The compound of any of E1-E28, E29, or E32, or a pharmaceutically acceptable salt thereof, wherein the 4- to 8-membered heterocyclyl at G 10 is selected from the group consisting of 1,2-dihydropyridin-4-yl, 1,6-dihydropyridin-3-yl, and 1,2-dihydropyridin-3- yl, and optionally substituted as defined in any of E1-E1.2.
  • E32.2 The compound of any of E1-E28, E29, or E32, or a pharmaceutically acceptable salt thereof, wherein the 4- to 8-membered heterocyclyl at G 10 is selected from the group consisting of 1,2-dihydropyridin-4-yl, 1,6-dihydropyridin-3-yl, and 1,2-dihydropyridin-3- yl, and optionally substituted as defined in any of E1-E1.2.
  • R 10a is selected from the group consisting of H, C 1-4 alkyl, C 1- 4 fluoroalkyl, –C 1-4 alkylene–O–C 1-4 alkyl, G 12 , and –C 1-4 alkylene–G 12 .
  • E34.2 The compound of E34, or a pharmaceutically acceptable salt thereof, wherein R 10a is H.
  • E34.3 The compound of E34.1, or a pharmaceutically acceptable salt thereof, wherein R 10a is C 1-4 alkyl.
  • E34.4 The compound of E34.3, or a pharmaceutically acceptable salt thereof, wherein R 10a is CH 3 .
  • E34.5 The compound of E34.3 or E34.4, or a pharmaceutically acceptable salt thereof, wherein R 10a is CD3.
  • E34.6 The compound of E34.3, or a pharmaceutically acceptable salt thereof, wherein R 10a is –CH2CH3.
  • R 10 is selected from the group consisting of –C(O)NH2, –C(O)NHCH3, –C(O)NHCD3, –C(O)NHCH2CH3, –C(O)NHCH(CH3)2, , acceptable salt thereof, wherein R 10 is selected from the group consisting of –C(O)NH 2 , –C(O)NHCH 3 , –C(O)NHCD 3 , –C(O)NHCH 2 CH 3 , –C(O)NHCH(CH 3 ) 2 , nd cceptable salt thereof, wherein R 10 is selected from the group consisting of –C(O)NHCH3, –C(O)NHCH2CH2F, .
  • E36.4 The compound of any of E1-E28, E33-E34.1, E34.3-E34.4, or E36-E36.3, or a pharmaceutically acceptable salt thereof, .
  • E36.5 The compound of any of E1- E34.4, E35, or E36- E36.3, or a pharmaceutically acceptable salt thereof, .
  • E36.6 The compound of any of E1-E28, E35, or E36- E36.3, or a pharmaceutically acceptable salt thereof, .
  • E36.7 The compound of E36.2, or a salt thereof, wherein . [00233] E36.8.
  • E36.12. The compound of any of E1-E28, E33-E34.1, E34.3-E34.4, E35, E36- E36.3, E36.6, or E36.11, or a pharmaceutically acceptable salt thereof, wherein R 8 is .
  • E37.1 The compound of E37, or a pharmaceutically acceptable salt thereof, , salt thereof, wherein R 8 is selected from the group , . acceptable salt thereof, .
  • E38.3 is a 5- to 6-membered partially unsaturated heterocyclic ring optionally substituted with R 14 and/or R 15 , wherein the heterocyclic ring contains 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • E38.3. The compound of E38.2, or a pharmaceutically acceptable salt thereof, wherein .
  • E38.5 The compound of E38.4, or a pharmaceutically acceptable salt thereof, wherein .
  • E38.12. The compound of E38.11, or a pharmaceutically acceptable salt thereof, wherein .
  • E1-E1.2 selected from a compound of any of Tables 7-9, or a pharmaceutically acceptable salt thereof.
  • E39.2 The compound of E1 or E39 selected from the group consisting of 6- methyl-7-(4-(thiazol-4-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.2. The compound of E1 or E39 selected from the group consisting of 2-(6- methyl-1-oxo-7-(4-(thiazol-4-yl)benzyl)-3,4-dihydroisoquinolin-2(1H)-yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-(4-(thiazol-4-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.4 The compound of E1 or E39 selected from the group consisting of 2-(5- chloro-6-methyl-1-oxo-7-(4-(thiazol-4-yl)benzyl)-3,4-dihydroisoquinolin-2(1H)- yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.5 The compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-(4-(thiazol-4-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of 2-(7-(4- (1H-imidazol-1-yl)benzyl)-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.6 The compound of E1 or E39 selected from the group consisting of 2-(6- methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1-oxo-3,4-dihydroisoquinolin- 2(1H)-yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.7 The compound of E1 or E39 selected from the group consisting of 2-(7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.8 The compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.9 The compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-((2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.10 The compound of E1 or E39 selected from the group consisting of 2-(6- methyl-7-((2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)- yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.11 The compound of E1 or E39 selected from the group consisting of 2-(6- methyl-7-((2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)- yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.12. The compound of E1 or E39 selected from the group consisting of 2-(6- methyl-7-(4-(oxazol-4-yl)benzyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.13 The compound of E1 or E39 selected from the group consisting of 2-(6- methyl-7-(4-(oxazol-4-yl)benzyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.14 The compound of E1 or E39 selected from the group consisting of methyl 4-((2-(2-cyanophenyl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)benzoate, or a pharmaceutically acceptable salt thereof.
  • E39.15 The compound of E1 or E39 selected from the group consisting of 2-(6- methyl-7-(4-(oxazol-4-yl)benzyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)nicotinonitrile, or a pharmaceutically acceptable
  • the compound of E1 or E39 selected from the group consisting of methyl 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)benzoate, or a pharmaceutically acceptable salt thereof.
  • E39.16 The compound of E1 or E39 selected from the group consisting of 4-((2- (2-cyanophenyl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.17 The compound of E1 or E39 selected from the group consisting of methyl 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)benzoate, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 4-((2- (3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.18 The compound of E1 or E39 selected from the group consisting of 4-((2- (3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.19 The compound of E1 or E39 selected from the group consisting of 4-((2- (3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutical
  • the compound of E1 or E39 selected from the group consisting of 2-(7-(3- fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-6-methyl-1-oxo-3,4- dihydroisoquinolin-2(1H)-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. [00275] E39.20.
  • E39.22 The compound of E1 or E39 selected from the group consisting of 2-(7-(4- (2-hydroxypropan-2-yl)benzyl)-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.23 The compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-7-(4-(2-hydroxypropan-2-yl)benzyl)-6-methyl-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.24 The compound of E1 or E39 selected from the group consisting of 4-((2- (3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.25 The compound of E1 or E39 selected from the group consisting of 4-((2- (2-methoxyethyl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.26 The compound of E1 or E39 selected from the group consisting of 4-((2- (3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or
  • the compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(2-methoxyethyl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.27 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(2-methoxyethyl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of N- methyl-4-((6-methyl-1-oxo-2-((tetrahydrofuran-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.29 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-1-oxo-2-((tetrahydrofuran-2-yl)methyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.32 The compound of E1 or E39 selected from the group consisting of 6- methyl-7-(4-(pyridazin-3-yl)benzyl)-2-((tetrahydrofuran-2-yl)methyl)-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.33 The compound of E1 or E39 selected from the group consisting of 6- methyl-7-(4-(pyridazin-3-yl)benzyl)-2-((tetrahydrofuran-2-yl)methyl)-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of (R)-2- fluoro-4-((6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-((tetrahydrofuran-2- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.34 The compound of E1 or E39 selected from the group consisting of (S)-2- fluoro-4-((6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-((tetrahydrofuran-2- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.35 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-2-fluoro-4-((6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.36 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-(2-fluoroethyl)-4-((6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.37 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-2-fluoro-4-((6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.38 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-5-chloro-6-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.40 The compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-(4-(oxazol-4-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.42 The compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.42 The compound of E1 or E39 selected from the group consisting of 5- chloro-7-(3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-6-methyl-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.43 The compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin- 1(2H)-one,
  • E39.44 The compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-(4-(pyridazin-3-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00300] E39.45.
  • the compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-5-chloro-6-methyl-2-((tetrahydrofuran-2-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00301] E39.46.
  • the compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2-((tetrahydrofuran-2- yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00302] E39.47.
  • the compound of E1 or E39 selected from the group consisting of 5- chloro-6-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2-((tetrahydrofuran-2-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00303] E39.48.
  • the compound of E1 or E39 selected from the group consisting of 4-((5- chloro-6-methyl-1-oxo-2-((tetrahydrofuran-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.49 The compound of E1 or E39 selected from the group consisting of 2-(7-(4- (1H-pyrazol-1-yl)benzyl)-5-chloro-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)- yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.50 The compound of E1 or E39 selected from the group consisting of 4-((2- (3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.51 The compound of E1 or E39 selected from the group consisting of 5-((2- (2-cyanophenyl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.52 The compound of E1 or E39 selected from the group consisting of 5-((2- (2-cyanophenyl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- cyclopropylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.53 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.54 The compound of E1 or E39 selected from the group consisting of 5-((2- (2-cyanophenyl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.55 The compound of E1 or E39 selected from the group consisting of 7- ((2',3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.56 The compound of E1 or E39 selected from the group consisting of 7- ((2',3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.57 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-5,6-dimethyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00313] E39.58.
  • E39.59 The compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.60 The compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.61 The compound of E1 or E39 selected from the group consisting of 4-((5,6- dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof. [00317] E39.62.
  • E39.63 The compound of E1 or E39 selected from the group consisting of 4-((2- (3-cyanopyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro- N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.64 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-4-((5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluorobenzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 4-((2- (3-cyanopyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof. [00320] E39.65.
  • E1 or E39 selected from the group consisting of (S)-4- ((2-(3-cyanopyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluoro-N-((tetrahydrofuran-2-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.66 The compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-((6-methylpyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.67 The compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.68 The compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.69 The compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.70 The compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-((6'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.71 The compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.72 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-methoxypyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.73 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-methoxypyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-2-(3-methylpyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.74 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.75 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-2-(3-methylpyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-
  • E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro- N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.76 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-1-oxo-2-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.77 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro- N-methylbenzamide, or a pharmaceutical
  • E39.78 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(4-methoxypyrimidin-2-yl)-6-methyl-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.80 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(4-methylpyrimidin-2-yl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.81 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(4-methoxypyrimidin-2-yl)-6-methyl-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(3-methylpyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.82 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(5-methylpyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.83 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(3-methylpyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof
  • E39.84 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(6-methylpyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.84 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-5-methylpyridin-2-yl)-6-methyl-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.85 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(6-methylpyridin-2-yl)-3,4-dihydroisoquinolin-1(2
  • E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(5-fluoro-3-methylpyridin-2-yl)-6-methyl-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.86 The compound of E1 or E39 selected from the group consisting of 3-(7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)pyridazine-4- carbonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.87 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-2-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.88 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-2-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 4-((2- (4-cyano-1-methyl-1H-pyrazol-3-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.89 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(5-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.90 The compound of E1 or E39 selected from the group consisting of 7-((6- (1H-pyrazol-1-yl)pyridin-3-yl)methyl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.91 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-2-fluoro-4-((2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin- 7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.92 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3-fluoropyridin-2-yl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00348] E39.93.
  • the compound of E1 or E39 selected from the group consisting of 7-((6- (1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-(3-fluoropyridin-2-yl)-6-methyl-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.94 The compound of E1 or E39 selected from the group consisting of 4-((5,6- dimethyl-1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.95 E39.95.
  • E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(5-fluoropyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.96 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoropyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.97 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.98 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(4,5-dimethylpyrimidin-2-yl)-6-methyl-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.99 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(5-fluoro-4-methylpyrimidin-2-yl)-6-methyl-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.100 E39.100.
  • E39.101 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(5-methoxypyrimidin-2-yl)-6-methyl-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.101 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(4,6-dimethylpyrimidin-2-yl)-6-methyl-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.103 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(4-methylpyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.104 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(4-methylpyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.105 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3-methoxypyridin-2-yl)-6-methyl-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.106 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3-methoxypyridin-2-yl)-6-methyl-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.107 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(5-fluoropyridin-2-yl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.108. The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(pyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.109 The compound of E1 or E39 selected from the group consisting of 4-((2- (4-cyanopyridazin-3-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.110 The compound of E1 or E39 selected from the group consisting of 4-((2- (4-cyanopyridazin-3-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.111 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-2-(4-methylpyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.113 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-2-(5-methylpyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(4-methoxypyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.115 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin- 7-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.116 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((6-methyl-1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.117 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(5-fluoro-3-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.118 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(5-fluoro-6-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.119 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(5-fluoro-6-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoro-5-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.120 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoro-4-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.121 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoro-6-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.122 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoro-6-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(5-fluoro-4-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.123 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluorobenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.124 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.125 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-(methyl-d3)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.126 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluorobenzamide, or a pharmaceutically acceptable salt thereof. [00382] E39.127.
  • the compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro- N-(methyl-d3)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.128 The compound of E1 or E39 selected from the group consisting of 5-((2- (5-fluoro-6-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.129 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoro-4-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.130 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoro-6-methylpyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.131 The compound of E1 or E39 selected from the group consisting of N- methyl-5-((6-methyl-2-(3-methylpyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.132 The compound of E1 or E39 selected from the group consisting of N- methyl-5-((6-methyl-2-(6-methylpyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.133 The compound of E1 or E39 selected from the group consisting of N- methyl-5-((6-methyl-2-(4-methylpyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.134 The compound of E1 or E39 selected from the group consisting of 5-((2- (5-fluoropyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.135. The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.136. The compound of E1 or E39 selected from the group consisting of 5-((5,6- dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.138 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoro-6-methylpyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.140 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.141 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-(methyl- d3)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.142 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- (methyl-d3)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.142 The compound of E1 or E39 selected from the group consisting of 5-((5- chloro-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.143 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- (methyl-d3)picolinamide, or
  • E39.144 The compound of E1 or E39 selected from the group consisting of 4-((6- ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 4-((5- chloro-2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.146 The compound of E1 or E39 selected from the group consisting of 4-((5- chloro-2-(3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- 2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.147 The compound of E1 or E39 selected from the group consisting of 5-((5- chloro-2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof. [00403] E39.148.
  • the compound of E1 or E39 selected from the group consisting of 4-((6- ethyl-2-(3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.149 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-6-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.150 The compound of E1 or E39 selected from the group consisting of 5-((6- ethyl-2-(3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof. [00406] E39.151.
  • E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-6-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.152 The compound of E1 or E39 selected from the group consisting of 5-((5- fluoro-2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.153 The compound of E1 or E39 selected from the group consisting of 5-((6- methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.154 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.155 The compound of E1 or E39 selected from the group consisting of 5-((6- methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.156 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.158 The compound of E1 or E39 selected from the group consisting of 4-((2- (5-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.159 The compound of E1 or E39 selected from the group consisting of 4-((2- (5-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.160 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-5-fluoro-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.162 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-5-((2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.164 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-5-((2-(3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.165 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-5-((2-(3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.166 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.167 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.168 The compound of E1 or E39 selected from the group consisting of 4-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.170 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.172 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro- N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3,5-difluoropyridin-2-yl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.176 The compound of E1 or E39 selected from the group consisting of 6- methoxy-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.177 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3,5-difluoropyridin-2-yl)-6-methoxy-3,4-dihydroisoquinolin-1(2H
  • the compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00433] E39.178.
  • the compound of E1 or E39 selected from the group consisting of 2-(3,5- difluoropyridin-2-yl)-6-methoxy-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.179 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.180 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-(methyl- d3)picolinamide, or a pharmaceutically acceptable salt thereof. [00436] E39.181.
  • the compound of E1 or E39 selected from the group consisting of N- ethyl-5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.182. The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- isopropylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.183 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof. [00439] E39.184.
  • E1 or E39 selected from the group consisting of 5-((6- ethoxy-2-(3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.185 The compound of E1 or E39 selected from the group consisting of 4-((6- ethoxy-2-(3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.186 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-isopropoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.187 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-(methoxy-d3)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.188 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-6-(methoxy-d3)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.189 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-6-(methoxy-d3)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of 5-((6- (difluoromethoxy)-2-(3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.190 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-(2-methoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.191 The compound of E1 or E39 selected from the group consisting of N-(2,2- difluoroethyl)-5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof. [00447] E39.192.
  • the compound of E1 or E39 selected from the group consisting of N-(2,2- difluoroethyl)-5-((2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.193 The compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-((6-methylpyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.194. The compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-(4-(oxazol-4-yl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.195. The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-isopropyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.196 The compound of E1 or E39 selected from the group consisting of 5-((6- methoxy-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.197 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.198 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.199 The compound of E1 or E39 selected from the group consisting of N- methyl-5-((4,4,6-trimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.200 The compound of E1 or E39 selected from the group consisting of N- methyl-5-((4,4,6-trimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.201 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-4,4,6-trimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.201 The compound of E1 or E39 selected from the group consisting of 5-((6'- methoxy-1'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.202 The compound of E1 or E39 selected from the group consisting of 5-((2'- (3-fluoropyridin-2-yl)-6'-methoxy-1'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]- 7'-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.203 The compound of E1 or E39 selected from the group consisting of 5-((2'- (3-fluoropyridin-2-yl)-6'-methoxy-1'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]- 7'-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(2-methyloxazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.204 The compound of E1 or E39 selected from the group consisting of 3-(7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-1-methyl-1H- pyrazole-4-carbonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.205 The compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methyl-7-((6-methylpyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.206 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.207 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.208 The compound of E1 or E39 selected from the group consisting of 4-((6- ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.210 The compound of E1 or E39 selected from the group consisting of N- methyl-4-((6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.211 The compound of E1 or E39 selected from the group consisting of N- methyl-4-((6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2-(3- fluoro-2-pyridinyl)-6-methoxy-7-[(7-oxo-5,6-dihydropyrrolo[3,4-b]pyridin-3-yl)methyl]-3,4- dihydroisoquinolin-1-one, or a pharmaceutically acceptable salt thereof. [00467] E39.212.
  • the compound of E1 or E39 selected from the group consisting of 7- ([1,2,4]triazolo[4,3-a]pyridin-7-ylmethyl)-2-(3-fluoropyridin-2-yl)-6-methoxy-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.213 The compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-((2-methylimidazo[1,2-a]pyridin-6-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.214 The compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-(pyrazolo[1,5-a]pyridin-6-ylmethyl)-3,4-dihydroisoquinolin- 1(2H)-one, or a pharmaceutically acceptable salt thereof. [00470] E39.215.
  • the compound of E1 or E39 selected from the group consisting of 7- ([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-2-(3-fluoropyridin-2-yl)-6-methoxy-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00471] E39.216.
  • the compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methyl-7-((7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00472] E39.217.
  • the compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-((1-oxoisoindolin-5-yl)methyl)-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • E39.218 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-cyanopyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.220 The compound of E1 or E39 selected from the group consisting of 5-((2- (5-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoro-6-methylpyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.222 The compound of E1 or E39 selected from the group consisting of 5-((6- methoxy-1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.224 The compound of E1 or E39 selected from the group consisting of 5-((2- (4-cyano-1-methyl-1H-pyrazol-3-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.225 The compound of E1 or E39 selected from the group consisting of 5-((2- (4-cyano-1-methyl-1H-pyrazol-3-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-((6-(pyrrolidine-1-carbonyl)pyridin-3-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.226 The compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-((6-(morpholine-4-carbonyl)pyridin-3-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.227 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- (tetrahydro-2H-pyran-4-yl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.228 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- (tetrahydro-2H-pyran-4-yl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of N-(3- fluorocyclobutyl)-5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof. [00484] E39.229.
  • E1 or E39 selected from the group consisting of N- cyclobutyl-5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.230 The compound of E1 or E39 selected from the group consisting of N- cyclopropyl-5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.23 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-((3R,4S)- 3-hydroxytetrahydro-2H-pyran-4-yl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of (R)-5- ((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- (1,1,1-trifluoropropan-2-yl)picolinamide, or a pharmaceutically acceptable salt thereof. [00488] E39.233.
  • the compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-(3- methyloxetan-3-yl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.234 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoropyridin-2-yl)-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)- N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.235 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro- N-methylbenzamide, or a pharmaceutically acceptable salt thereof. [00491] E39.236.
  • the compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.237 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3-fluoropyridin-2-yl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.238 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-
  • the compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3,5-difluoropyridin-2-yl)-5-methyl-3,4-dihydroisoquinolin-1(2H)- one, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.240 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide,
  • E39.241 The compound of E1 or E39 selected from the group consisting of 4-((2- (3-fluoropyridin-2-yl)-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.241. The compound of E1 or E39 selected from the group consisting of 5-((5- ethyl-2-(3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-5-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.243 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of N- methyl-5-((5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.245. The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.246 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.247 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.248 The compound of E1 or E39 selected from the group consisting of 5-((2- (3,5-difluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide, or a pharmaceutically acceptable salt thereof
  • the compound of E1 or E39 selected from the group consisting of N- methyl-5-((1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.250 The compound of E1 or E39 selected from the group consisting of 2- fluoro-4-((2-(3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluoro-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.251 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.
  • E39.252 The compound of E1 or E39 selected from the group consisting of 2- fluoro-N-methyl-4-((1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide, or a pharmaceutically
  • the compound of E1 or E39 selected from the group consisting of 4-((2- (3-fluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.253 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.254 The compound of E1 or E39 selected from the group consisting of 4-((2- (3,5-difluoropyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide, or a pharmaceutically acceptable salt thereof.
  • E39.255 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3-fluoropyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.256 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(3-fluoropyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.257 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(pyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.258 The compound of E1 or E39 selected from the group consisting of 7-(4- (1H-pyrazol-1-yl)benzyl)-2-(pyridin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2-(6- methyl-7-((2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-1-oxo-3,4-dihydroisoquinolin- 2(1H)-yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof. [00514] E39.259.
  • E39.260 The compound of E1 or E39 selected from the group consisting of 6- methyl-7-(quinolin-6-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 5,6- dimethyl-7-(quinolin-6-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • E39.262 The compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-6-methoxy-7-((6-(3-methyl-1H-1,2,4-triazol-5-yl)pyridin-3-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2-(3- fluoropyridin-2-yl)-7-((6-(3-isopropyl-1H-1,2,4-triazol-5-yl)pyridin-3-yl)methyl)-6-methoxy- 3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00519] E39.264.
  • the compound of E1 or E39 selected from the group consisting of 7-((6- (1,3-dimethyl-1H-1,2,4-triazol-5-yl)pyridin-3-yl)methyl)-2-(3-fluoropyridin-2-yl)-6-methoxy- 3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof. [00520] E39.265.
  • the compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-(methoxy-d3)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- (methyl- d 3 )picolinamide, or a pharmaceutically acceptable salt thereof.
  • E39.266 The compound of E1 or E39 selected from the group consisting of 8-(4- (1H-pyrazol-1-yl)benzyl)-7-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one, or a pharmaceutically acceptable salt thereof.
  • E39.267 The compound of E1 or E39 selected from the group consisting of 5-((2- (3-fluoropyridin-2-yl)-6-(methoxy-d3)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- (methyl-
  • E39.268 The compound of E1 or E39 selected from the group consisting of 6,7- dimethyl-8-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-1-one, or a pharmaceutically acceptable salt thereof.
  • E39.270 The compound of E1 or E39 selected from the group consisting of 6,7- dimethyl-8-(4-(oxazol-4-yl)benzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one, or a pharmaceutically acceptable salt thereof.
  • the compound of E1 or E39 selected from the group consisting of 2-(7- ((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)- yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.272 The compound of E1 or E39 selected from the group consisting of 1-((2- (2-cyanophenyl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-4-(pyridin-2- yl)piperidine-4-carbonitrile, or a pharmaceutically acceptable salt thereof.
  • E39.273 The compound of E1 or E39 selected from the group consisting of 2-(7- ((4-cyano-4-phenylpiperidin-1-yl)methyl)-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)- yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E40 The compound of E1 or E39 selected from the group consisting of 2-(7- ((4-cyano-4-phenylpiperidin-1-yl)methyl)-6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)- yl)nicotinonitrile, or a pharmaceutically acceptable salt thereof.
  • E1 or E39-E39.269 selected from the group consisting of: 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide; 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluoro-N-methylbenzamide; N-methyl-4-((6-methyl-1-oxo-2-((tetrahydrofuran-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide; 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- cycloprop
  • E40.1 The compound of E40 selected from the group consisting of: 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylbenzamide; 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2- fluoro-N-methylbenzamide; N-methyl-4-((6-methyl-1-oxo-2-((tetrahydrofuran-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)benzamide; 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- cyclopropyl-2
  • E41 A compound of any of E1-E40.1, or a pharmaceutically acceptable salt thereof, that has at least 50% deuterium incorporation at each deuterium label.
  • E41.1 The compound of E41, or pharmaceutically acceptable salt thereof, that has at least 75% deuterium incorporation at each deuterium-label.
  • E41.2 The compound of E41 or E41.1, or pharmaceutically acceptable salt thereof, that has at least 90% deuterium incorporation at each deuterium-label.
  • E41.3 The compound of any of E41-E41.2, or pharmaceutically acceptable salt thereof, that has at least 99% deuterium incorporation at each deuterium-label.
  • E41.4 The compound of any of E41-E41.2, or pharmaceutically acceptable salt thereof, that has at least 99% deuterium incorporation at each deuterium-label.
  • E42 A hydrate, solvate, polymorph, or prodrug of the compound of any of E1- E41.4, or a pharmaceutically acceptable salt thereof.
  • E43 A pharmaceutical composition comprising the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E42, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • E44 A pharmaceutical composition comprising the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E42, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 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-E42, or a pharmaceutically acceptable salt thereof, or the composition of E43.
  • E45 The method of E44, wherein the mammal is human.
  • E46 The method of E44 or E45, wherein the muscarinic acetylcholine receptor is mAChR M1.
  • E44-E46 The method of any of E44-E46, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.
  • E48 The method of any of E44-E47, further comprising the step of identifying a mammal in need of treatment of the disorder.
  • E49 The method of any of E44-E45, wherein the disorder is a neurological disorder or psychiatric disorder, or a combination thereof.
  • E50 E50.
  • any of E44-E45 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.
  • 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,
  • E52 The method of any of E44-E49, 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.
  • E53 The method of any of E44-E49, wherein the disorder is Alzheimer’s disease, schizophrenia, a sleep disorder, a pain disorder, or a cognitive disorder, or a combination thereof.
  • E54 Use of the compound, hydrate, solvate, polymorph, or prodrug of any of E1-E42, or a pharmaceutically acceptable salt thereof, or the composition of E43, 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). Accordingly, any group comprising one or more hydrogen atoms encompasses corresponding deuterium-labeled versions of the group.
  • alkyl encompasses “deuterioalkyl”
  • fluoroalkyl encompasses “fluorodeuterioalkyl”
  • —CH2– encompasses encompasses , etc.
  • The 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).
  • 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
  • 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.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • 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.
  • the amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.
  • 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,
  • 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%.
  • 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 [00598] 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 [00600]
  • the disclosed compounds are positive allosteric modulators of mAChR M1. Thus, by positive allosteric modulation, the compounds indirectly activate the muscarinic receptor subtype M 1 .
  • the disclosed compounds potentiate the agonist response (e.g., acetylcholine) of mAChR M1.
  • 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 M 1 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 EC20 acetylcholine response (i.e. the response of mAChR M 1 at a concentration of acetylcholine that yields 20% of the maximal response).
  • 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.
  • 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 M 1 -transfected CHO-K1 cells are transfected with human mAChR M1.
  • the mAChR M1-transfected CHO-K1 cells are transfected with rat mAChR M1.
  • 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 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.
  • Lack of mAChR M1 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 M 1 agonist activity relative to acetylcholine.
  • a disclosed compound may have substantially no mAChR M1 agonist activity.
  • 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 relative lower mAChR M1 agonist activity may contribute to the avoidance or reduction of cholinergic adverse effect liability.
  • 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 a mammalian mAChR M1 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 M 1 .
  • CHO-K1 cells can be transfected with rat mAChR M1.
  • a compound can exhibit positive allosteric modulation of mAChR M 1 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, or less than or equal to 100 nM.
  • 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 M 1 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 M1 response to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with a mAChR M 1 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 M1 response to acetylcholine 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, or less than or equal to 100 nM.
  • the EC50 for positive allosteric modulation is determined in CHO-K1 cells are transfected with a mAChR M 1 .
  • the CHO-K1 cells are transfected with a human mAChR M 1 .
  • the CHO-K1 cells are transfected with a rat mAChR M1.
  • Positive allosteric modulation of the mAChR M1 response to acetylcholine with EC50 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 M1 response in mAChR M1 - transfected CHO-K1 cells with an EC 50 less than the EC 50 for one or more of mAChR M 2 , 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 M1 receptor vis-à-vis one or more of the mAChR M 2 , M 3 , M 4 or M 5 receptors.
  • the disclosed compounds can activate mAChR M 1 response with an EC 50 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 M 2 , at least 30-fold less than that for mAChR M 2 , at least 50-fold less than that for mAChR M 2 , or at least 100-fold less than that for mAChR M 2 .
  • 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 M 3 , at least 30-fold less than that for mAChR M 3 , 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 M 4 , at least 50-fold less than that for mAChR M 4 , or at least 100-fold less than that for mAChR M4.
  • 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 M 5 , at least 50-fold less than that for mAChR M 5 , or at least 100-fold less than that for mAChR M5.
  • the disclosed compounds can activate mAChR M1 response with an EC50 of at least 5-fold less than that for the mAChR M2, M 3 , M 4 or M 5 receptors, at least 10-fold less than that for the mAChR M 2 , M 3 , M 4 or M 5 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 M2, M3, M4 or M5 receptors, at least 50-fold less than that for the mAChR M 2 , M 3 , M 4 or M 5 receptors, or at least 100-fold less than that for the mAChR M 2 , M 3 , M 4 or M 5 receptors.
  • the compound activates mAChR M 1 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.
  • the compounds activate mAChR M1 response in M1-transfected CHO-K1 cells with an EC50 of less than or equal to 10 ⁇ M and exhibits a selectivity for the M1 receptor vis-à-vis one or more of the mAChR M 2 , M 3 , M 4 or M 5 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 M 1 response with an EC 50 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 M 2 , at least 30-fold less than that for mAChR M 2 , or at least 50-fold less than that for mAChR M 2 .
  • 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 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 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 M 4 , of at least 20-fold less than that for mAChR M 4 , of at least 30-fold less than that for mAChR M4, or at least 50-fold less than that for mAChR M4.
  • the compound 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 M 5 , of at least 10-fold less than that for mAChR M 5 , of at least 20-fold less than that for mAChR M 5 , of at least 30-fold less than that for mAChR M 5 , or at least 50-fold less than that for mAChR M5.
  • 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 the mAChR M2, M3, M4 or M5 receptors, at least 10-fold less than that for the mAChR M 2 , M 3 , M 4 or M 5 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 M5 receptors, or at least 50-fold less than that for the mAChR M2, M3, M4 or M
  • the disclosed compounds may be used in methods for treatment of mAChR M 1 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 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.
  • 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, dysmenorrhea, inflammatory pain, headache, migraine headache, cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, 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 M1 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.
  • NMDA N-methyl-D-aspartate
  • 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 M1 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 [00629] 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. [00634] 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.
  • 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. [00642] 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, fluphenazine 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, fluphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydro
  • 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: [00649] (a) at least one agent known to increase mAChR M1 activity; [00650] (b) at least one agent known to decrease mAChR M1 activity; [00651] (c) at least one agent known to treat a disorder associated with cholinergic activity; [00652] (d) instructions for treating a disorder associated with cholinergic activity; [00653] (e) instructions for treating a disorder associated with M 1 receptor activity; or [00654] (f) instructions for administering the compound in connection with cognitive or behavioral therapy.
  • 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.
  • 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.
  • That the disclosed kits can be employed in connection with disclosed methods of use.
  • the kits may further comprise information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans).
  • kits 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 [00659] 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.
  • a halogen may be subjected to reducing conditions by those skilled in the art (e.g. NaBH 4 , NaBH3CN, etc.) to afford intermediate iv.
  • Intermediate v (Y is chloro or bromo) may be formed by subjecting intermediate iv to halogenating conditions (e.g. SOCl2, DCM or PBr3, DCM, etc.).
  • Intermediate compounds of formula v may be subjected to Me 3 SiCN and TBAF to provide intermediate vi, followed by reduction (e.g. borane dimethylsulfide, etc.) to produce amine vii.
  • Intermediate vii may be subjected to a carbamate formation conditions, using dimethyl 2,2'- (carbonylbis(oxy))dibenzoate, base (e.g. DIEA) and solvent (e.g. THF).
  • Intermediate compounds of formula ix may be formed under acidic conditions (e.g. CF 3 SO 3 H) from viii.
  • Scheme III ( R 2 )n (R2 ) n
  • intermediate compounds of formula ix may be subjected to base (e.g. NaH, etc.), solvent (e.g. DMF) and R 1 -Y (wherein Y is a halogen, mesylate or other leaving group) to provide intermediate with formula x.
  • base e.g. NaH, etc.
  • solvent e.g. DMF
  • R 1 -Y wherein Y is a halogen, mesylate or other leaving group
  • Scheme IV [00664] As shown in Scheme IV, intermediate x may be subjected to bis(pinacolato)diboron and a palladium catalyst (e.g. Pd(dppf)Cl2, Pd(PPh3)4, etc.) in the presence of a base (e.g.
  • intermediate of formula xii (wherein X is a halogen) may be coupled with a boronic acid or ester under Suzuki coupling conditions, generally known in the art to provide intermediate xiii.
  • Coupling reactions may be conducted with a palladium catalyst, such as Pd(dppf)Cl2, and a base (e.g. K2CO3, Cs2CO3) in a solvent mixture of organic solvent, such as DMF or 1,4-dioxane, and water with heating to about 80-90 °C.
  • Intermediate xiv may be formed by subjecting intermediate xiii to chlorinating conditions (e.g., SOCl2, DCM) and heat.
  • Scheme VI acid or ester may be subjected to standard Suzuki reaction conditions with a palladium catalyst, such as Pd(dppf)Cl 2 , and a base (e.g., K2CO3, Cs2CO3) in a solvent mixture of organic solvent, such as DMF or 1,4-dioxane, and water with heating to about 80-90 °C to provide intermediate xiii.
  • Scheme VII synthesis shown in Scheme VII.
  • Intermediate xvi (wherein X is halogen) may be subjected to ammonium formate and formic acid with heating up to 100-110 °C to provide the intermediate compound of formula xvii.
  • Intermediate xvii may undergo a carbonylation reaction known to those skilled in the art with a palladium catalyst (e.g., Pd(OAc) 2 ), base (e.g., Et 3 N, DIPEA, etc.), a phosphine ligand (e.g., 1,3-bis(diphenylphosphino)propane), a CO atmosphere and a solvent mixture of alcohol (e.g., MeOH, EtOH, etc.) and DMSO with heating to about 70-80 °C to afford ester xviii.
  • a palladium catalyst e.g., Pd(OAc) 2
  • base e.g., Et 3 N, DIPEA, etc.
  • a phosphine ligand e.g., 1,3
  • Intermediate compounds of formula xviii may be transformed to intermediate xix by a 2-step synthesis.
  • Reduction e.g., LiAlH 4
  • chlorinating reagent e.g., SOCl 2
  • solvent e.g., DCM
  • Scheme VIII As shown in Scheme VIII, intermediate compounds of formula xx may be subjected to standard nucleophilic substitution conditions with a heteroaryl amine (e.g., imidazole, pyrazole), base (e.g., DIPEA), and solvent (e.g., DMSO, NMP, etc.) with heating to about 70- 160 °C to provide intermediate compounds of formula xxi.
  • a heteroaryl amine e.g., imidazole, pyrazole
  • base e.g., DIPEA
  • solvent e.g., DMSO, NMP, etc.
  • Aldehyde xxi may be reduced with standard reducing reagents (e.g., NaBH 4 or LiAlH 4 ) to provide intermediate compounds of formula xxii, which upon treatment with chlorinating conditions (e.g., SOCl2) and solvent (e.g., DCM) may provide intermediate compounds of formula xxiii.
  • chlorinating conditions e.g., SOCl2
  • solvent e.g., DCM
  • Scheme VIII may likewise be applied to synthesis of analogs bearing alternate heteroaryl amine substitution (e.g., pyrazole, triazole) and/or substituted heteroaryl amines.
  • Intermediate xxiv (wherein X is a halogen) may undergo a Suzuki reaction with a boronic acid or ester, a palladium catalyst (e.g., Pd 2 (dba) 3 ), and a base (e.g., K 2 CO 3 , Cs 2 CO 3 ) in a solvent mixture of organic solvent, such as toluene and water with heating to about 90-100 °C to obtain methyl ester xxv.
  • Intermediate xxv may be reduced (e.g., LiAlH4) to provide intermediate xiii.
  • Scheme X formula xi may be subjected to standard Suzuki reaction conditions with a palladium catalyst, such as Pd(PPh3)4, and a base (e.g., Na2CO3, K2CO3, etc.) in a solvent mixture of organic solvent, such as monoglyme or 1,4- dioxane, and water with heating to about 80-90 °C to provide compounds of formula xxvi.
  • Scheme XI to a phenyl or heteroaryl bromide Br-G 1 , a palladium catalyst (e.g., Pd(dba) 3 ), ligand (e.g.
  • intermediate xxx (wherein X is a halogen) may be subjected to bis(pinacolato)diboron and a palladium catalyst (e.g., Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , etc.) in the presence of a base (e.g., KOAc) and solvents such a 1,4-dioxane with heating up to 90-100 °C to provide intermediate compounds of formula xxxi.
  • a base e.g., KOAc
  • solvents such a 1,4-dioxane
  • Scheme XIV xxxi may be subjected to standard Suzuki reaction conditions with a palladium catalyst, such as Pd(PPh 3 ) 4 , and a base (e.g., Na2CO3, K2CO3, etc.) in a solvent mixture of organic solvent, such as monoglyme or 1,4-dioxane, and water with heating to about 80-90 °C to provide compounds of formula xxxii.
  • a palladium catalyst such as Pd(PPh 3 ) 4
  • a base e.g., Na2CO3, K2CO3, etc.
  • organic solvent such as monoglyme or 1,4-dioxane
  • intermediate compounds of formula xxxii may be subjected to N-phenylbis(trifluoromethanesulfonamide), base (e.g., Et3N, DIEA, etc.) and solvent (e.g. DCM) to afford intermediate xxxiii.
  • Intermediate xxxiii in the presence of acrylonitrile, a palladium catalyst (e.g., Pd(OAc)2), a ligand (e.g., PPh3), base (e.g., Et3N) and solvent with heating up to 90 – 100 °C may provide intermediate xxxiv.
  • Intermediate compounds of formula xxxiv may be subjected to Raney nickel, base (e.g., Et 3 N), sodium methoxide and solvent (e.g., MeOH) with heating up to 80 °C to provide compound xxxv.
  • Scheme XVI is a halogen
  • Scheme XVII may be subjected to cross coupling reaction (e.g. Suzuki reaction or Suzuki-Miyaura type reaction), generally known in the art, to provide intermediate xxxvii.
  • Intermediate compounds of formula xxxvii under halogenating conditions e.g. NBS, H2SO4
  • intermediate compounds of formula vii may be protected with Boc2O and base (e.g., DIEA), followed by exposure to bis(pinacolato)diboron and a palladium catalyst (e.g., Pd(dppf)Cl2, Pd(PPh3)4, etc.) in the presence of a base (e.g., KOAc, Cs 2 CO 3 , etc.) and solvents such a 1,4-dioxane with heating up to 90-100 °C to provide intermediate compounds of formula xl.
  • base e.g., KOAc, Cs 2 CO 3 , etc.
  • solvents such a 1,4-dioxane
  • Intermediate compounds of formula xl may be subjected to standard Suzuki reaction conditions with a palladium catalyst, such as Pd(dppf)Cl 2 , and a base (e.g., Cs 2 CO 3 , K 2 CO 3 , etc.) in a solvent mixture of organic solvent, such as monoglyme or 1,4-dioxane, and water with heating to about 80-90 °C, followed by exposure to acid (e.g. TFA) to provide intermediate of formula xli.
  • Intermediate xli may be subjected to a carbamate formation conditions, using dimethyl 2,2'- (carbonylbis(oxy))dibenzoate, base (e.g., DIEA) and solvent (e.g., THF).
  • Intermediate compounds of formula xliii may be formed under acidic conditions (e.g., CF3SO3H, AlCl3, etc.) from xlii.
  • Scheme XVIII may to standard Suzuki reaction conditions with a palladium catalyst, such as Pd(dppf)Cl2, and a base (e.g., Cs 2 CO 3 , etc.) in a solvent mixture of organic solvent, such as monoglyme or 1,4-dioxane, and water with heating to about 90-100 °C to provide compounds of formula xliv.
  • a palladium catalyst such as Pd(dppf)Cl2
  • a base e.g., Cs 2 CO 3 , etc.
  • organic solvent such as monoglyme or 1,4-dioxane
  • Compounds of formula xliv may be subjected to a phenyl or heteroaryl bromide Br-G 1 , a palladium catalyst (e.g., Pd(dba)3), ligand (e.g., Xantphos), base (e.g., Cs2CO3) and solvent (e.g., toluene) with heating up to 100-105 °C to provide compounds of formula xlv.
  • the ester intermediate xlv may be subjected to hydrolysis conditions (e.g., LiOH) in a solvent mixture of organic solvent, such as THF or 1,4-dioxane, and water to provide compounds of formula xlvi.
  • Intermediate xlvi may be subjected to standard amide formation (e.g., HATU, amine (e.g., H 2 NR 10a ), base (e.g., DIEA) and solvent (e.g., DMF)), generally known in the art, to provide compounds xlvii.
  • Scheme XIX xlviii may be subjected to dealkylating conditions (e.g., BBr3 and DCM) to provide compound of formula xlix.
  • the aforementioned intermediates may be subjected to alkylation conditions (e.g., base such as Cs 2 CO 3 ), alkyl halide and solvent (e.g., DMF)) to provide compounds of formula l.
  • 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. [00682]
  • 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.
  • Step 2 Preparation of 1-bromo-4-(bromomethyl)-2,3-dimethylbenzene.
  • phosphorus tribromide (0.55 mL, 5.86 mmol) dropwise.
  • the reaction mixture was diluted with water and extracted with DCM (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide the title compound which was carried to the next step without further purification.
  • Step 3 Preparation of 2-(4-bromo-2,3-dimethylphenyl)acetonitrile.
  • 1-bromo-4-(bromomethyl)-2,3-dimethylbenzene 463.7 mg, 1.7 mmol
  • MeCN MeCN
  • tetrabutylammonium fluoride 525.4 mg, 2.0 mmol
  • trimethylsilyl cyanide 0.25 mL, 2.0 mmol
  • Step 5 Preparation of methyl 2-(((4-bromo-2,3- dimethylphenethyl)carbamoyl)oxy)benzoate.
  • 2-(4-bromo-2,3- dimethylphenyl)ethan-1-amine (287 mg, 1.26 mmol)
  • 2-(2- methoxycarbonylphenoxy)carbonylbenzoate (457 mg, 1.38 mmol) followed by DIEA (0.24 mL, 1.38 mmol).
  • DIEA 0.24 mL, 1.38 mmol
  • Step 6 Preparation of 7-bromo-5,6-dimethyl-3,4-dihydroisoquinolin-1(2H)-one.
  • a solution of methyl 2-(((4-bromo-2,3-dimethylphenethyl)carbamoyl)oxy)benzoate (511 mg, 1.26 mmol) in DCM (20 mL) at 0 °C was added trifluoromethanesulfonic acid (1.11 mL, 12.6 mmol).
  • Step 2 Preparation of 6-ethyl-3,4-dihydroisoquinolin-1(2H)-one.
  • MeOH MeOH
  • 1,4-dioxane 7 mL
  • the resulting solution was degassed and backfilled with hydrogen three times and stirred at rt under hydrogen atmosphere (using a hydrogen balloon). After 16 h, the reaction mixture was filtered through a pad of Celite® and concentrated under vacuum.
  • Step 3 Preparation of 7-bromo-6-ethyl-3,4-dihydroisoquinolin-1(2H)-one.
  • 6-ethyl-3,4-dihydroisoquinolin-1(2H)-one 685 mg, 3.91 mmol
  • sulfuric acid 6.25 mL
  • N-bromosuccinimide 765 mg, 4.30 mmol
  • Step 1 Preparation of 2-(4-bromo-3-methoxyphenyl)ethan-1-amine.
  • 2-(4-bromo-3-methoxyphenyl)acetonitrile 904 mg, 4.0 mmol
  • borane dimethyl sulfide complex 10 M in THF, 0.6 mL, 6.0 mmol.
  • the reaction mixture was heated to 66 °C for 15 min then cooled to 0 °C and adjusted to pH 8-9 using an aq. solution of NaOH (1 N).
  • the resulting mixture was extracted with iPA/CHCl3 (1:3).
  • Step 2 Preparation of methyl 2-(((4-bromo-3- methoxyphenethyl)carbamoyl)oxy)benzoate.
  • Step 3 Preparation of 7-bromo-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one.
  • DCM dimethyl sulfoxide
  • trifluoromethanesulfonic acid 0.88 mL, 10.0 mmol.
  • the reaction mixture was stirred at rt under nitrogen atmosphere for 45 min, then quenched with ice cold water and extracted with iPA/CHCl 3 (3x). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo.
  • the solid was rinsed with MeCN and dried under vacuum with N2 flow to provide a first batch of the title compound (19.43 g).
  • the filtrate was concentrated under reduced pressure.
  • the crude material was sonicated in toluene (25 mL) and filtered using vacuum filtration with a Buchner funnel.
  • the solid was rinsed with toluene and dried under vacuum with N2 flow to afford a second batch of the title compound (5.08 g).
  • Step 2 Preparation of 7-bromo-2-(3-fluoropyridin-2-yl)-6-methoxy-3,4- dihydroisoquinolin-1(2H)-one.
  • acetic acid 300 mL
  • bromine 13.8 mL, 270 mmol
  • Step 2 Preparation of methyl 5-bromo-2-(cyanomethyl)-4-methoxybenzoate.
  • Step 4 Preparation of 7-bromo-6-methoxy-4,4-dimethyl-3,4-dihydroisoquinolin- 1(2H)-one
  • methanol 4.4 mL
  • nickel(II)chloride hexahydrate 104 mg, 0.44 mmol
  • sodium borohydride 166 mg, 4.4 mmol
  • Step 2 Preparation of 7'-bromo-6'-methoxy-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-1'-one.
  • methyl 5-bromo-2-(1- cyanocyclopropyl)-4-methoxybenzoate 232 mg, 0.75 mmol
  • nickel(II)chloride hexahydrate 89 mg, 0.37 mmol
  • sodium borohydride 141 mg, 3.7 mmol was added in small portions. The ice bath was removed.
  • Tri(dibenzylideneacetone)dipalladium (1.16 g, 1.0 mmol) and tricyclohexylphosphine (0.7 g, 2.5 mmol) were added.
  • the resulting mixture was subjected to microwave irradiation at 120 °C for 45 min, filtered through a pad of Celite® and concentrated.
  • the residue was purified using normal phase chromatography on silica gel (0-10% MeOH/DCM) to provide the title compound (3.27 g, 86% yield).
  • Step 2 Preparation of 4-(4-(chloromethyl)phenyl)thiazole.
  • the title compound was prepared in a similar manner as 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine.
  • Step 2 4-(4-(chloromethyl)-2-fluorophenyl)-1-methylpyridin-2(1H)-one.
  • thionyl chloride (0.44 mL, 6.0 mmol) dropwise. The ice bath was removed. At rt, the reaction was monitored by LCMS and upon completion, the reaction mixture was concentrated under reduced pressure to provide the title compound (253 g).
  • the thick suspension was stirred vigorously at rt for 2h and filtered through Celite®, rinsed thoroughly with EtOAc (200 mL), DCM (100 mL) and then 10% MeOH/DCM (200 mL). The filtrate was concentrated under reduced pressure and the residue was purified using normal phase chromatography on silica gel (0-10% MeOH/DCM) to provide the title compound (2.57 g, 89%).
  • Step 4 Preparation of 4-(4-(chloromethyl)phenyl)oxazole was prepared in a similar manner as 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine.
  • Step 1 A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (924 mg, 3.0 mmol), 2,4-dimethoxybenzylamine (0.5 mL, 3.3 mmol) and DIEA (0.57 mL, 3.3 mmol) in MeOH (15 mL) was stirred at 70 °C. After 16 h, the reaction mixture was concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-10% MeOH/DCM) provided 5- bromo-2-(2,4-dimethoxybenzyl)isoindolin-1-one (627 mg, 58% yield).
  • Step 2 To a mixture of 5-bromo-2-(2,4-dimethoxybenzyl)isoindolin-1-one (627 mg, 1.73 mmol), potassium vinyltrifluoroborate (348 mg, 2.6 mmol) and Pd(dppf)Cl 2 (141.7 mg, 0.17 mmol) was added iPA (8.7 mL) followed by DIEA (0.5 mL, 3.46 mmol). The resulting mixture was stirred at 90 °C for 5 h and filtered through a pad of Celite® which was rinsed thoroughly with DCM. The filtrate was concentrated under reduced pressure.
  • Step 3 To a solution of 2-(2,4-dimethoxybenzyl)-5-vinylisoindolin-1-one (460 mg, 1.49 mmol) in THF (5.0 mL) at 0 °C was added water (5.0 mL) followed by a solution of osmium tetraoxide (2.5% wt in t-BuOH, 1.86 mL, 0.15 mmol) and 4-methylmorpholine-N-oxide (209 mg, 1.79 mmol). After 1 h at rt, sodium periodate (799 mg, 3.72 mmol) was added to the reaction mixture. After an additional 1 h at rt, the mixture was diluted with DCM and 10% aq.
  • Step 4 To a suspension of 2-(2,4-dimethoxybenzyl)-1-oxoisoindoline-5-carbaldehyde (462 mg, 1.48 mmol) in methanol (8.9 mL) at 0 °C was added sodium borohydride (168 mg, 4.45 mmol). After 30 min at rt, acetone (1.0 mL) was added slowly to the mixture and concentrated under reduced pressure. Purification using normal phase on silica gel (0-100% EtOAc/DCM) afforded 2-(2,4-dimethoxybenzyl)-5-(hydroxymethyl)isoindolin-1-one (350 mg, 75% yield).
  • Intermediate Example 18 5-((5-fluoro-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylpicolinamide
  • Step 1 Preparation of (4-bromo-2-fluoro-3-methylphenyl)methanol.
  • 4-bromo-2-fluoro-3-methylbenzaldehyde (CAS# 1784897-62-6, 1085 mg, 5.0 mmol) in methanol (25 mL) at 0 °C was added sodium borohydride (284 mg, 7.5 mmol).
  • the reaction mixture was warmed to rt and stirred for 3 h.
  • a sat. soln. NH4Cl was slowly added and concentrated under reduced pressure to remove most methanol.
  • the resulting residue was re-dissolved in DCM and water. The layers were separated.
  • Step 2 Preparation of 1-bromo-4-(bromomethyl)-3-fluoro-2-methylbenzene.
  • phosphorous tribromide (1.17 mL, 12.5 mmol) dropwise.
  • the reaction mixture was allowed to warm to rt. After 16 h, the mixture was cooled to 0 °C, and adjusted to neutral pH using sat. soln. NaHCO3. After stirring for 10 min, the layers were separated. The aqueous layer was extracted with DCM (3x).
  • Step 6 Preparation of tert-butyl (2-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenethyl)carbamate.
  • tert-butyl (4-bromo-2-fluoro-3- methylphenethyl)carbamate 250 mg, 0.75 mmol
  • 1,4-dioxane 7.5 mL
  • bis(pinacolato)diboron 334 mg, 1.32 mmol
  • KOAc 222 mg, 2.26 mmol
  • Pd(dppf)Cl 2 83 mg, 0.11 mmol.
  • Step 7 Preparation of tert-butyl (2-fluoro-3-methyl-4-((6- (methylcarbamoyl)pyridin-3-yl)methyl)phenethyl)carbamate.
  • the reaction mixture was diluted with EtOAc/DCM, and filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc and concentrated under reduced pressure.
  • the material obtained was purified using normal phase chromatography on silica gel (0-100% EtOAc/hexanes then 0-10% MeOH/DCM).
  • the material was further purified using RP-HPLC (15-65% MeCN/0.1% aq. TFA) to provide the title compound (135 mg, 45% yield).
  • Step 8 Preparation of 5-(4-(2-aminoethyl)-3-fluoro-2-methylbenzyl)-N- methylpicolinamide.
  • tert-butyl (2-fluoro-3-methyl-4-((6- (methylcarbamoyl)pyridin-3-yl)methyl)phenethyl)carbamate (135 mg, 0.34 mmol) in DCM (1.68 mL) was added trifluoroacetic acid (0.26 mL, 3.36 mmol). After stirring at rt for 3 h, the solution mixture was concentrated under reduced pressure. The crude material was re-dissolved in DCM and adjusted to basic pH using sat. soln. NaHCO3.
  • Step 9 Preparation of methyl 2-(((2-fluoro-3-methyl-4-((6- (methylcarbamoyl)pyridin-3-yl)methyl)phenethyl)carbamoyl)oxy)benzoate.
  • Step 10 Preparation of 5-((5-fluoro-6-methyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide.
  • methyl 2-(((2- fluoro-3-methyl-4-((6-(methylcarbamoyl)pyridin-3- yl)methyl)phenethyl)carbamoyl)oxy)benzoate 70 mg, 0.15 mmol
  • DCM 1.5 mL
  • AlCl 3 77.9 mg, 0.58 mmol
  • Step 6 Preparation of methyl 2-(((3-chloro-4-((6-(methylcarbamoyl)pyridin-3- yl)methyl)phenethyl)carbamoyl)oxy)benzoate.
  • Step 7 Preparation of 5-((6-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-N-methylpicolinamide.
  • reaction mixture was diluted with DCM, filtered through a pad of Celite® which was rinsed thoroughly with EtOAc/DCM. The filtrate was concentrated and purified using normal phase chromatography on silica gel (0-100% EtOAc/hexanes) to provide the title compound (475 mg, 79% yield).
  • Step 2 Preparation of 5-(4-(cyanomethyl)-2-(prop-1-en-2-yl)benzyl)-N- methylpicolinamide.
  • 5-(2-chloro-4-(cyanomethyl)benzyl)-N- methylpicolinamide 145 mg, 0.48 mmol
  • water 1.1 mL
  • potassium carbonate 203 mg, 1.45 mmol
  • potassium isopropenyl trifluoroborate 143 mg, 0.97 mmol
  • RuPhos-Pd-G3 (40.5 mg, 0.05 mmol).
  • Step 4 Preparation of methyl 2-(((4-((6-(methylcarbamoyl)pyridin-3-yl)methyl)- 3-(prop-1-en-2-yl)phenethyl)carbamoyl)oxy)benzoate.
  • 5-(4-(2-aminoethyl)-2- (prop-1-en-2-yl)benzyl)-N-methylpicolinamide 150 mg, 0.48 mmol
  • dimethyl 2,2'-(carbonylbis(oxy))dibenzoate 176 mg, 0.53 mmol
  • DIEA 0.19 mL, 1.07 mmol
  • Step 3 Preparation of methyl 2-(((2-methoxy-4-((6-(methylcarbamoyl)pyridin-3- yl)methyl)phenethyl)carbamoyl)oxy)benzoate.
  • 5-(4-(2-aminoethyl)-3- methoxybenzyl)-N-methylpicolinamide 200 mg, 0.67 mmol
  • dimethyl 2,2'-(carbonylbis(oxy))dibenzoate 243 mg, 0.73 mmol
  • DIEA 0.26 mL, 1.47 mmol
  • Step 2 Preparation of methyl 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-2-fluorobenzoate.
  • Step 3 Preparation of 4-((2-(3-cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-2-fluorobenzoic acid.
  • a suspension of methyl 4-((2-(3- cyanopyridin-2-yl)-6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-2-fluorobenzoate (76 mg, 0.78 mmol) in THF (1.8 mL) at rt was added a solution of LiOH (1.0 N in H2O, 0.26 mL, 0.26 mmol).
  • Example 4 Preparation of 7-(4-(1H-pyrazol-1-yl)benzyl)-6-methyl-2-((tetrahydrofuran-2- yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 30) [00776] To a (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (30 mg, 0.05 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 1-(4-(chloromethyl)phenyl)-1H-pyrazole (12.0 mg, 0.06 mmol), Cs 2 CO 3 (50.9 mg, 0.15 mmol), Pd(dppf)Cl 2 (5.7 mg, 0.01 mmol), and H 2 O (0.2 mL).
  • reaction mixture was then purged with N2 and heated to 100 °C. After 3 h, the reaction mixture was diluted with EtOAc, filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc and concentrated under reduced pressure. Purification using normal phase chromatography (0-10% MeOH/DCM) then RP-HPLC (10-60% MeCN/0.05% aq. NH4OH) afforded the title compound (9.9 mg).
  • reaction mixture was then purged with N2 and heated to 100 °C. After 3 h, the reaction mixture was diluted with EtOAc/DCM, and filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc/DCM and concentrated under reduced pressure. The crude residue was purified using RP- HPLC (10-80% MeCN/0.05% aq. NH4OH) to give the title compound (6.2 mg).
  • Example 7 Preparation of 5-chloro-6-methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)-2-((tetrahydrofuran-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 45) [00779] To -5-chloro-6-methyl-2- ((tetrahydrofuran-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (25 mg, 0.06 mmol) in anhydrous 1,4-dioxane (1.2 mL) and H2O (0.33 mL) was added 1-(4-(chloromethyl)phenyl)-1H- pyrazole (14.7 mg, 0.07 mmol), Cs2CO3 (60 mg, 0.18 mmol), and Pd(dppf)Cl2 (6.8 mg, 0.01 mmol).
  • reaction mixture was then purged with N 2 and heated to 100 °C. After 3 h, the reaction mixture was diluted with EtOAc/DCM, and filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc/DCM and concentrated under reduced pressure. The crude residue was purified using RP-HPLC (10-80% MeCN/0.05% aq. NH 4 OH) to give the title compound (7.0 mg).
  • Example 8 Preparation of 5,6-dimethyl-7-((2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-3,4- dihydroisoquinolin-1(2H)-one (Compound 60) [00780] To a dioxaborolan-2-yl)-3,4- dihydroisoquinolin-1(2H)-one (25 mg, 0.08 mmol) in anhydrous 1,4-dioxane (1.0 mL) and H2O (0.2 mL) was added 5-(chloromethyl)-2'-methyl-2,4'-bipyridine dihydrochloride (24.2 mg, 0.08 mmol), Cs2CO3 (81.6 mg, 0.24 mmol), and Pd(dppf)Cl2 (6.1 mg, 0.01 mmol).
  • reaction mixture was then purged with N2 and heated to 100 °C. After 6 h, the reaction mixture was diluted with EtOAc/DCM, and filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc/DCM and concentrated under reduced pressure. Purification using RP-HPLC (10-90% MeCN/0.05% aq. NH4OH) provided the title compound (8.1 mg).
  • Step 2 Preparation of 2-fluoro-4-((2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo- 1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylbenzamide.
  • Step 2 Preparation of 5-((2-(3-fluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide.
  • N-methyl-5-((6-methyl-1-oxo- 1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinamide (16 mg, 0.052 mmol), Pd2(dba)3 (9.5 mg, 0.010 mmol), Cs2CO3 (50 mg, 0.16 mmol), 2-bromo-3-fluoropyridine (16 ⁇ L, 0.16 mmol), and XantPhos (6.0 mg, 0.01 mmol) were combined in a reaction vial. Anhydrous 1,4-dioxane (1.0 mL) was added. The resulting mixture was heated to 100 °C.
  • Example 11 Preparation of 5-((2-(3,5-difluoropyridin-2-yl)-6-methyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide (Compound 78) [00785] N- yl)methyl)picolinamide (16 mg, 0.052 mmol), Pd2(dba)3 (9.5 mg, 0.010 mmol), Cs2CO3 (51 mg, 0.16 mmol), 2-bromo-3,5-difluoropyridine (16.6 ⁇ L, 0.16 mmol), and XantPhos (6.0 mg, 0.01 mmol) were combined in a reaction vial.
  • Step 2 Preparation of 5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide.
  • Example 13a Aternative Preparation of 5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo- 1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide (Compound 154) xo- 1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinate.
  • Step 2 Preparation of 5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide.
  • Example 14 Preparation of 5-((6-chloro-2-(3-fluoropyridin-2-yl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide (Compound 165) [00791] To a 7-yl)methyl)-N- methylpicolinamide (25 mg, 0.08 mmol) in anhydrous toluene (1 mL) was added 2-bromo-3- fluoropyridine (0.038 mL, 0.38 mmol), Cs2CO3 (74.5 mg, 0.23 mmol), XantPhos (33 mg, 0.06 mmol), and Pd2(dba)3 (52 mg, 0.06 mmol).
  • the reaction mixture was evacuated and purged with N 2 and heated to 100 °C. After 1 h, the reaction mixture was diluted with EtOAc/DCM, and filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc and the filtrate was concentrated under reduced pressure.
  • the material obtained was purified using normal phase chromatography on silica gel (0-100% EtOAc/hexanes then 0-10% MeOH/DCM) to provide the material which was further purified using RP-HPLC (10-70% MeCN/0.05% aq. NH4OH). The desired fractions were concentrated to provide the title compound (254 mg, 39% yield).
  • Step 2 Methyl 5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)picolinate.
  • Step 3 Preparation of lithium 5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo- 1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinate.
  • a suspension of methyl 5-((2-(3- fluoropyridin-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinate 200 mg, 0.47 mmol
  • THF 2.4 mL
  • Step 4 Preparation of N-ethyl-5-((2-(3-fluoropyridin-2-yl)-6-methoxy-1-oxo- 1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)picolinamide (Compound 181).
  • Step 2 Preparation of 5-((2-(3-fluoropyridin-2-yl)-6-(methoxy-d 3 )-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide.
  • Example 17 Preparation of 5-((2-(3-fluoropyridin-2-yl)-6-isopropyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide (Compound 195) [00798] 5-( methylpicolinamide (24 mg, 0.07 mmol), Pd 2 (dba) 3 (19.5 mg, 0.02 mmol), Cs 2 CO 3 (70 mg, 0.21 mmol), 2-bromo-3-fluoropyridine (40 ⁇ L, 0.36 mmol), and XantPhos (12.4 mg, 0.02 mmol) were combined in a reaction vial.
  • Step 1 Preparation of 5-((6-methoxy-4,4-dimethyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide.
  • Step 2 Preparation of 5-((2-(3-fluoropyridin-2-yl)-6-methoxy-4,4-dimethyl-1- oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide.
  • Step 1 Preparation of 2-(4-bromo-3-methylphenyl)-2-methylpropanenitrile.
  • 2-(4-bromo-3-methylphenyl)acetonitrile 750 mg, 3.6 mmol
  • sodium hydride 60% in mineral oil, 428 mg, 10.7 mmol
  • iodomethane 667 ⁇ L, 10.7 mmol
  • the resulting mixture was stirred at 0 °C for 1 h and treated with ice cold water and extracted with EtOAc (3x). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated.
  • Step 3 Preparation of 5-(4-(2-cyanopropan-2-yl)-2-methylbenzyl)-N- methylpicolinamide.
  • Step 5 Preparation of methyl 2-(((2-methyl-2-(3-methyl-4-((6- (methylcarbamoyl)pyridin-3-yl)methyl)phenyl)propyl)carbamoyl)oxy)benzoate.
  • Step 2 Preparation of 2-(3-fluoropyridin-2-yl)-6-methoxy-7-((1-oxoisoindolin-5- yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one.
  • Example 21 Preparation 5-((2-(3-fluoropyridin-2-yl)-5-methoxy-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)-N-methylpicolinamide (Compound 242) [00809]
  • 5-((5-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-N- methylpicolinamide 27 mg, 0.08 mmol
  • Pd2(dba)3 (22.8 mg, 0.03 mmol)
  • Cs2CO3 81 mg, 0.25 mmol
  • 2-bromo-3-fluoropyridine 42 ⁇ L, 0.41 mmol
  • XantPhos (14.4 mg, 0.03 mmol) were combined.
  • Example 22 2-(3-fluoropyridin-2-yl)-6-methoxy-7-((6-(3-methyl-1H-1,2,4-triazol-5- yl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 262) 1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)methyl)picolinic acid (25 mg, 0.06 mmol) in DMF (2.0 mL) was added acetimidamide hydrochloride (15.6 mg, 0.17 mmol), DIEA (28 ⁇ L, 0.17 mmol) and HATU (31 mg, 0.08 mmol).
  • Table 7 The compounds shown in Table 7 may be prepared similarly to the compound described above, with appropriate starting materials.
  • Step 1 Preparation of 8-(4-(1H-pyrazol-1-yl)benzyl)-7-methyl-2,3,4,5-tetrahydro-1H- benzo[c]azepin-1-one (Compound A1) [00812] Step 1: Preparation of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl- 2(((trifluoromethyl)sulfonyl)oxy) benzoate.
  • Step 2 Preparation of methyl (E/Z)-5-(4-(1H-pyrazol-1-yl)benzyl)-2-(2- cyanovinyl)-4-methylbenzoate.
  • methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl- 2(((trifluoromethyl)sulfonyl)oxy) benzoate 250 mg, 0.55 mmol
  • triethylamine (0.23 mL, 1.65 mmol
  • triphenylphosphine 144 mg, 0.55 mmol
  • palladium(II) acetate 12.5 mg, 0.06 mmol
  • acrylonitrile 0.36 mL, 5.5 mmol.
  • Table 8 The compounds shown in Table 8 may be prepared similarly to the compound described above, with appropriate starting materials.
  • Table 8 1 No. H-NMR and/or ES-MS S TRUCTURE NAME ⁇ .8 1 m, 5, J ), ); 7-methyl-8-((6- ⁇ .8 – – J z, 2 ] +
  • Step 2 Preparation of 6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7- carbaldehyde.
  • 6-methyl-7-vinyl-3,4-dihydroisoquinolin-1(2H)-one 165 mg, 0.88 mmol
  • H2O 2.2 mL
  • 4-methylmorpholine N-oxide 124 mg, 1.06 mmol.
  • Step 3 Preparation of 1-((6-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-4-(pyridin-2-yl)piperidine-4-carbonitrile.
  • Step 4 Preparation of 2-(7-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-6- methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)nicotinonitrile (Compound B1).
  • Table 9 The compounds shown in Table 9 may be prepared similarly to the compound described above, with appropriate starting materials.
  • CHO cells stably expressing human (h)M 2 , hM 3 , and hM 5 were described previously (Levey, et al., 1991); hM 1 and hM 4 cDNAs were purchased from Missouri S&T cDNA Resource; rM 4 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. hM 1 , rM 2 , rM 3 , hM 4 , and rM 4 cDNAs were used to stably transfect CHO-K1 cells purchased from the American Type Culture Collection using Lipofectamine2000.
  • 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 (G qi5 ) (provided by B.R. Conklin, University of California, San Francisco) using Lipofectamine 2000.
  • G qi5 chimeric G- protein
  • 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 ⁇ g/mL G418 sulfate.
  • rM2-G qi5 , hM 2 –G qi5, and hM 4 –G qi5 cells were grown in the same medium also containing 500 ⁇ g/mL Hygromycin B.
  • Stable rM 4 –G qi5 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.
  • 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% CO 2 . The next day, cells were washed using an ELX 405 (BioTek) with four washes (80 ⁇ L) of assay buffer then aspirated to 20 ⁇ L.
  • TC tissue culture
  • VWR clear-bottom plates
  • 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.
  • 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). [00824] 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 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 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.
  • Activity (EC50 and Emax) was determined in the mAChR M1 cell-based functional assay as described above and the data are shown in Table 10. The compound numbers correspond to the compound numbers used in Tables 7, 8, and 9. The data in Table 10 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 10. Biological Activity Data PAM Activity PAM Activity C d PAM Activity C d PAM Activity C d PAM Activity C d PAM Activity C d PAM Activity C d PAM Activity C d PAM Activity C d PAM Activity C d PAM Activity C d d.

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Abstract

L'invention concerne des modulateurs allostériques positifs de 3,4-dihydroisoquinoléin -1 (2 H )-one et de 2,3,4,5-tétrahydro -1 H -benzo [ c ] azépin-1-one de récepteur muscarinique de l'acétylcholine M 1 (mAChR M 1 ), des compositions pharmaceutiques comprenant les composés, et des procédés d'utilisation des composés et des compositions pour traiter des troubles neurologiques, des troubles psychiatriques, ou une combinaison de ceux-ci.
PCT/US2025/027317 2024-05-01 2025-05-01 Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1 Pending WO2025231255A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012003147A1 (fr) * 2010-07-01 2012-01-05 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs du récepteur m1 de l'isoindolone
WO2012158475A1 (fr) * 2011-05-17 2012-11-22 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs du récepteur m1 contenant des lactames liés à n
WO2015163485A1 (fr) * 2014-04-23 2015-10-29 Takeda Pharmaceutical Company Limited Dérivés i isoindoline-1-one à activité de modulateur alloestérique positif du récepteur m1 muscarinique cholinergique pour le traitement de la maladie d'alzheimer
WO2018005249A1 (fr) * 2016-06-28 2018-01-04 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs du récepteur m1 de benzoisoquinoline

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012003147A1 (fr) * 2010-07-01 2012-01-05 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs du récepteur m1 de l'isoindolone
WO2012158475A1 (fr) * 2011-05-17 2012-11-22 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs du récepteur m1 contenant des lactames liés à n
WO2015163485A1 (fr) * 2014-04-23 2015-10-29 Takeda Pharmaceutical Company Limited Dérivés i isoindoline-1-one à activité de modulateur alloestérique positif du récepteur m1 muscarinique cholinergique pour le traitement de la maladie d'alzheimer
WO2018005249A1 (fr) * 2016-06-28 2018-01-04 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs du récepteur m1 de benzoisoquinoline

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
"C.T.F.A. Cosmetic Ingredient Handbook", 1992, MEADE PUBLISHING CO., pages: 587 - 592
"Remington's Pharmaceutical Sciences", 1975, pages: 335 - 337
ANSEL: "Introduction to Pharmaceutical Dosage Forms", 1976
BUBSER ET AL., ACS CHEM. NEUROSCI., vol. 5, 2014, pages 920 - 942
CARRUTHERS: "Some Modern Methods of Organic Synthesis", 1987, CAMBRIDGE UNIVERSITY PRESS
CONDE-CEIDE ET AL., ACS MED. CHEM. LETT., vol. 6, no. 1784897-62-6, 2015, pages 716 - 720
FELTS ET AL., J. MED. CHEM, vol. 60, 2017, pages 5072 - 5085
FURNISSHANNAFORDSMITHTATCHELL: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS, INC., article "Vogel's Textbook of Practical Organic Chemistry"
FURNISSHANNAFORDSMITHTATCHELL: "Vogel's Textbook of Practical Organic Chemistry", 1989, LONGMAN SCIENTIFIC & TECHNICAL
GARRISON ET AL., J. MED. CHEM., vol. 65, 2022, pages 6273 - 6286
JENNIFER E. DAVOREN ET AL: "Design and Synthesis of [gamma]- and [delta]-Lactam M 1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M 1 -Selective PAM with Weak Agonist Activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 15, 10 August 2017 (2017-08-10), US, pages 6649 - 6663, XP055549757, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b00597 *
JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, no. 2239309-43-2, 2013, pages 9934 - 9954
LIEBERMAN ET AL.: "Pharmaceutical Dosage Forms: Tablets", 1981
MCCUTCHEON'S: "Emulsifiers & Detergents", vol. 1, 1994, pages: 236 - 239
MORRIS ET AL., J. MED. CHEM., vol. 57, 2014, pages 10192 - 10197
NOGRADY: "Medicinal Chemistry A Biochemical Approach", 1985, OXFORD UNIVERSITY PRESS, pages: 388 - 392
PGM WUTSTW GREENE: "Greene's book titled Protective Groups in Organic Synthesis", 2006, JOHN WILEY & SONS
PURE APPL. CHEM., vol. 45, 1976, pages 13 - 30
SMITHMARCH: "March's Advanced Organic Chemistry,", 2001, JOHN WILEY & SONS, INC.
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS, SAUSALITO
YU ET AL., J. MED. CHEM., vol. 64, 2021, pages 4709 - 4729
ZHI-QIANG YANG ET AL: "Discovery of Naphthyl-Fused 5-Membered Lactams as a New Class of M 1 Positive Allosteric Modulators", ACS MEDICINAL CHEMISTRY LETTERS, vol. 5, no. 5, 8 May 2014 (2014-05-08), pages 604 - 608, XP055138935, ISSN: 1948-5875, DOI: 10.1021/ml500055h *

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