[go: up one dir, main page]

WO2025129082A1 - Modulateurs allostériques positifs du récepteur muscarinique m4 de l'acétylcholine - Google Patents

Modulateurs allostériques positifs du récepteur muscarinique m4 de l'acétylcholine Download PDF

Info

Publication number
WO2025129082A1
WO2025129082A1 PCT/US2024/060145 US2024060145W WO2025129082A1 WO 2025129082 A1 WO2025129082 A1 WO 2025129082A1 US 2024060145 W US2024060145 W US 2024060145W WO 2025129082 A1 WO2025129082 A1 WO 2025129082A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
methyl
acceptable salt
pyridin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/060145
Other languages
English (en)
Inventor
Craig W. Lindsley
Darren W. Engers
Kayla J. TEMPLE
Lake E. RABENOLD
Madeline F. Long
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vanderbilt University
Original Assignee
Vanderbilt University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vanderbilt University filed Critical Vanderbilt University
Publication of WO2025129082A1 publication Critical patent/WO2025129082A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or the muscarinic acetylcholine receptors (mAChRs) by the binding of the endogenous orthosteric agonist acetylcholine (ACh).
  • nAChRs nicotinic acetylcholine receptors
  • mAChRs muscarinic acetylcholine receptors
  • ACh endogenous orthosteric agonist acetylcholine
  • Conditions associated with cognitive impairment such as Alzheimer’s disease, are accompanied by a reduction of acetylcholine content in the brain. This is believed to be the result of degeneration of cholinergic neurons of the basal forebrain, which widely innervate multiple areas of the brain, including the association cortices and hippocampus, which are critically involved in higher processes.
  • AChE inhibitors have shown therapeutic efficacy, but have been found to have frequent cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, and diarrhea. These gastrointestinal side effects have been observed in about a third of the patients treated. In addition, some AChE inhibitors, such as tacrine, have also been found to cause significant hepatotoxicity with elevated liver transaminases observed in about 30% of patients. The adverse effects of AChE inhibitors have severely limited their clinical utility.
  • An alternative approach to pharmacologically target cholinergic hypofunction is the activation of mAChRs, which are widely expressed throughout the body.
  • the mAChRs are members of the family A G protein-coupled receptors (GPCRs) and include five subtypes, designated M1-M5.
  • the M1, M3 and M5 subtypes mainly couple to Gq and activate phospholipase C, whereas the M 2 and M 4 subtypes mainly couple to G i/o and associated effector systems.
  • GPCRs G protein-coupled receptors
  • M1-M5 subtypes mainly couple to Gq and activate phospholipase C
  • M 2 and M 4 subtypes mainly couple to G i/o and associated effector systems.
  • M 1 -M 5 have varying roles in cognitive, sensory, motor and autonomic functions.
  • mAChR subtypes that regulate processes involved in cognitive function could prove to be superior therapeutics for treatment of psychosis, schizophrenia and related disorders.
  • the muscarinic M4 receptor has been shown to have a major role in cognitive processing and is believed to have a major role in the pathophysiology of psychotic disorders, including schizophrenia.
  • AChE inhibitors and other cholinergic agents are mediated by activation of peripheral M 2 and M 3 mAChRs and include bradycardia, GI distress, excessive salivation, and sweating.
  • M 4 has been viewed as the most likely subtype for mediating the effects of muscarinic acetylcholine receptor dysfunction in psychotic disorders, including schizophrenia, cognition disorders, and neuropathic pain. Because of this, considerable effort has been focused on developing selective M4 agonists for treatment of these disorders. Unfortunately, these efforts have been largely unsuccessful because of an inability to develop compounds that are highly selective for the mAChR M 4 . Because of this, mAChR agonists that have been tested in clinical studies induce a range of adverse effects by activation of peripheral mAChRs.
  • Allosteric activators can include allosteric agonists, that act at a site removed from the orthosteric site to directly activate the receptor in the absence of ACh as well as positive allosteric modulators (PAMs), which do not activate the receptor directly but potentiate activation of the receptor by the endogenous orthosteric agonist ACh. Also, it is possible for a single molecule to have both allosteric potentiator and allosteric agonist activity.
  • muscarinic agonists including xanomeline have been shown to be active in animal models with similar profiles to known antipsychotic drugs, but without causing catalepsy (Bymaster et al., Eur. J. Pharmacol.1998, 356, 109, Bymaster et al., Life Sci. 1999, 64, 527; Shannon et al., J. Pharmacol. Exp. Ther.1999, 290, 901; Shannon et al., Schizophrenia Res.2000, 42, 249).
  • xanomeline was shown to reduce psychotic behavioral symptoms such as delusions, suspiciousness, vocal outbursts, and hallucinations in Alzheimer’s disease patients (Bodick et al., Arch. Neurol.1997, 54, 465), however treatment induced side effects, e.g., gastrointestinal effects, have severely limited the clinical utility of this compound.
  • treatment induced side effects e.g., gastrointestinal effects
  • gastrointestinal effects have severely limited the clinical utility of this compound.
  • muscarinic acetylcholine receptor research there is still a scarcity of compounds that are potent, efficacious, and selective activators of the M4 mAChR and also effective in the treatment of neurological and psychiatric disorders associated with cholinergic activity and diseases in which the muscarinic M4 receptor is involved.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect provides a method of treating a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of formula (I), or pharmaceutically acceptable salt or composition thereof.
  • Another aspect provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.
  • the compounds include naphthyridine-substituted pyridazine compounds.
  • the human muscarinic acetylcholine receptor M 4 (mAChR M 4 ) is a protein of 479 amino acids encoded by the CHRM 4 gene. The molecular weight of the unglycosylated protein is about 54 kDa and it is a transmembrane GPCR.
  • the mAChR M 4 is a member of the GPCR Class A family, or the rhodopsin-like GPCRs, which are characterized by structural features similar to rhodopsin such as seven transmembrane segments.
  • the muscarinic acetylcholine receptors have the N-terminus oriented to the extracellular face of the membrane and the C-terminus located on the cytoplasmic face.
  • the present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.
  • the modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity).
  • the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.”
  • the term “about” may refer to plus or minus 10% of the indicated number.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy.
  • alkyl as used herein, means a straight or branched, saturated hydrocarbon chain.
  • lower alkyl or “C 1-6 alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • C 1-4 alkyl 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.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyfluoroalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
  • alkylene refers to a divalent group derived from a straight or branched saturated chain hydrocarbon, for example, of 1 to 6 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • deuterioalkylene means an alkylene group, as defined herein, in which one or more hydrogen atoms in the alkylene are the isotope deuterium, i.e., 2 H.
  • deuterioalkylene include -CD2-, -CH2CD2-, and -CD2CD2-.
  • alkylamino means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein.
  • amide means -C(O)NR- or -NRC(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
  • aminoalkyl means at least one amino group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein.
  • amino means —NR x R y , wherein R x and R y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
  • R x and R y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
  • amino may be –NRx–, wherein Rx may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
  • 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).
  • cyanoalkyl means at least one -CN group, is appended to the parent molecular moiety through an alkylene group, as defined herein.
  • cyanofluoroalkyl means at least one -CN group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
  • cycloalkoxy refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • cycloalkyl or “cycloalkane,” as used herein, 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), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl).
  • 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).
  • fluoroalkyl means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine.
  • Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2- trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3-trifluoropropyl.
  • haloalkoxy means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
  • halocycloalkyl means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halogen.
  • heteroalkyl means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, O, P and N.
  • 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.
  • 1,4-phenylene refers to the following divalent group that links two portions of a molecule in a 1,4 or para relationship: .
  • 6-membered 1,4-heteroarylene refers to a divalent 6-membered heterarene that links two portions of a molecule in a 1,4 or para relationship on the heteroarene, .
  • hydroxyl or “hydroxy,” as used herein, means an -OH group.
  • hydroxyalkyl means at least one -OH group, is appended to the parent molecular moiety through an alkylene group, as defined herein.
  • hydroxyfluoroalkyl means at least one -OH group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
  • Terms such as “alkyl,” “cycloalkyl,” “alkylene,” etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., "C 1-4 alkyl,” “C 3-6 cycloalkyl,” “C 1-4 alkylene”). These designations are used as generally understood by those skilled in the art. For example, the representation "C” followed by a subscripted number indicates the number of carbon atoms present in the group that follows.
  • C3alkyl is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl).
  • C1-4 the members of the group that follows may have any number of carbon atoms falling within the recited range.
  • a “C 1-4 alkyl,” for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).
  • the terms "parent molecule” or “parent molecular moiety” refer to the entire portion of a molecule to which a substituent is attached, i.e., the remainder of the molecule.
  • sulfonamide means -S(O)2NR z - or –NR z S(O)-, wherein R z may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
  • substituted refers to a group “substituted” on a group such as an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, or heterocycle group, at any atom of that group. Any atom can be substituted.
  • substituted refers to a group that may be further substituted with one or more non-hydrogen substituent groups.
  • a group is optionally substituted. In some embodiments, a group is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, an aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, an aryl, heteroaryl, cycloalkyl, or heterocycle may be independently unsubstituted or substituted with 1, 2, or 3 substituents.
  • 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.
  • allosteric site refers to a ligand binding site that is topographically distinct from the orthosteric binding site.
  • modulator refers to a molecular entity (e.g., but not limited to, a ligand and a disclosed compound) that modulates the activity of the target receptor protein.
  • ligand refers to a natural or synthetic molecular entity that is capable of associating or binding to a receptor to form a complex and mediate, prevent or modify a biological effect.
  • ligand encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates and analogs of natural substrates.
  • natural ligand and endogenous ligand as used herein are used interchangeably, and refer to a naturally occurring ligand, found in nature, which binds to a receptor.
  • mAChR M4 receptor positive allosteric modulator refers to any exogenously administered compound or agent that directly or indirectly augments the activity of the mAChR M4 receptor in the presence or in the absence of acetylcholine, or another agonist, in an animal, in particular a mammal, for example a human.
  • a mAChR M 4 receptor positive allosteric modulator can increase the activity of the mAChR M 4 receptor in a cell in the presence of extracellular acetylcholine.
  • the cell can be Chinese hamster ovary (CHO- K1) cells transfected with human mAChR M 4 .
  • the cell can be Chinese hamster ovary (CHO-K1) cells transfected with rat mAChR M4 receptor.
  • the cell can be Chinese hamster ovary (CHO-K1) cells transfected with a mammalian mAChR M4.
  • mAChR M4 receptor positive allosteric modulator includes a compound that is a “mAChR M4 receptor allosteric potentiator” or a “mAChR M4 receptor allosteric agonist,” as well as a compound that has mixed activity comprising pharmacology of both an “mAChR M 4 receptor allosteric potentiator” and an “mAChR M 4 receptor allosteric agonist.”
  • the term “mAChR M 4 receptor positive allosteric modulator also includes a compound that is a “mAChR M 4 receptor allosteric enhancer.”
  • mAChR M 4 receptor allosteric potentiator refers to any exogenously administered compound or agent that directly or indirectly augments the response produced by the endogenous ligand (such as acetylcholine) when the endogenous ligand binds to the orthosteric site of the mAChR M4 receptor in an animal, in particular
  • the mAChR M4 receptor allosteric potentiator binds to a site other than the orthosteric site, that is, an allosteric site, and positively augments the response of the receptor to an agonist or the endogenous ligand.
  • an allosteric potentiator does not induce desensitization of the receptor, activity of a compound as an mAChR M 4 receptor allosteric potentiator provides advantages over the use of a pure mAChR M4 receptor orthosteric agonist. Such advantages can include, for example, increased safety margin, higher tolerability, diminished potential for abuse, and reduced toxicity.
  • mAChR M4 receptor allosteric enhancer refers to any exogenously administered compound or agent that directly or indirectly augments the response produced by the endogenous ligand (such as acetylcholine) in an animal, in particular a mammal, for example a human.
  • the allosteric enhancer increases the affinity of the natural ligand or agonist for the orthosteric site.
  • an allosteric enhancer increases the agonist efficacy.
  • E8a The compound of E8, or a pharmaceutically acceptable salt thereof, wherein R 8a is hydrogen. [0095] E8.2. The compound of E8, or a pharmaceutically acceptable salt thereof, wherein R 8a is C1-6alkyl. [0096] E8.3. The compound of any of E1-E8 or E8.2, or a pharmaceutically acceptable salt thereof, wherein the C1-6alkyl at R 8a is methyl, ethyl, isopropyl, or tert-butyl. [0097] E8.4. The compound of any of E1-E8 or E8.2-E8.3, or a pharmaceutically acceptable salt thereof, wherein the C 1-6 alkyl at R 8a is methyl. [0098] E8.5.
  • E1-E12 The compound of any of E1-E12, or a pharmaceutically acceptable salt thereof, wherein Z 1 is N.
  • E14 The compound of any of E1-E12, or a pharmaceutically acceptable salt thereof, wherein Z 1 is CR 1 .
  • E14.1 The compound of any of E1-E12 or E14, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
  • E14.2 The compound of any of E1-E12 or E14, or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  • E15 The compound of any of E1-E14.2, or a pharmaceutically acceptable salt thereof, wherein Z 2 is CR 2 .
  • E16 The compound of any of E1-E14.2, or a pharmaceutically acceptable salt thereof, wherein Z 2 is CR 2 .
  • Coupling of compound v with an appropriate amine compound vi provides a compound vii, which corresponds to a compound of formula (I), where R 10 is –C(R 7a )(R 7b )–Cy–OR 8 .
  • Scheme 2 [00147] As shown in Scheme 2, reaction of a compound ii with a base followed by coupling of ammonium chloride with a coupling agent such as HATU may provide compound viii, and reaction with an ortho ester R 5 –C(OR)3 may provide compound iv. Reaction with phosphorus oxychloride may provide compound v, and coupling of compound v with an appropriate amine compound vi may provide a compound vii, which corresponds to a compound of formula (I)
  • the disclosed compounds activate mAChR M4 response as an increase in calcium fluorescence in mAChR M4-transfected CHO-K1 cells in the presence of the compound, compared to the response of equivalent CHO-K1 cells in the absence of the compound.
  • a disclosed compound activates the mAChR M4 response with an EC50 of less than about 10 ⁇ M, less than about 5 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, of less than about 100 nM, or less than about 50 nM.
  • the disclosed compounds exhibit positive allosteric modulation of the mAChR M 4 response to acetylcholine with an EC50 of less than about 10 ⁇ M, less than about 5 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, or less than about 100 nM.
  • the EC50 for positive allosteric modulation is determined in CHO-K1 cells are transfected with a mAChR M4.
  • the mAChR M4 transfected human mAChR M4.
  • a disclosed compound can activate mAChR M 4 response with an EC 50 of about 5- fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100- fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500- fold less than that for mAChR M1.
  • a disclosed compound can activate mAChR M4 response with an EC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M 2 .
  • a disclosed compound can activate mAChR M 4 response with an EC 50 of about 5- fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100- fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500- fold less than that for mAChR M3.
  • a disclosed compound can activate mAChR M4 response with an EC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M 5 .
  • the compound can have an EC50 of less than about 10 ⁇ M, of less than about 5 ⁇ M, of less than about 1 ⁇ M, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also activate mAChR M 4 response with an EC 50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M 3 .
  • the compound can have an EC50 of less than about 10 ⁇ M, of less than about 5 ⁇ M, of less than about 1 ⁇ M, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also activate mAChR M4 response with EC50 of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M2-M5 receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, M2, M3, or M5 receptors, or greater than about 500-fold less than that for the mAChR M1, M2, M3, or M5 receptors.
  • compositions and Formulations [00163] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.
  • 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.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • a therapeutically effective amount of a compound of formula (I) may be about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about 950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about 850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about 750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about 650 mg/kg, about 40 mg/kg to about 600 mg/kg, about 45 mg/kg to about 550 mg/kg, about 50 mg/kg to about 500 mg/kg, about 55 mg/kg to about 450 mg/kg, about 60 mg/kg to about 400 mg/kg, about 65 mg/kg to about 350 mg/kg, about 70 mg/kg to about 300 mg/kg, about 75 mg/kg to about 250 mg/kg, about 80 mg/kg to about 200 mg/kg, about 85 mg/kg to about 150 mg/kg, and about 90 mg/kg to about
  • compositions and formulations may include pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non- toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • the compounds and their pharmaceutically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration.
  • Techniques and formulations may generally be found in “Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.).
  • Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.
  • 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.
  • 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.
  • the methods of treatment may comprise administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I).
  • the disclosure provides a method for enhancing cognition in a mammal comprising the step of administering to the mammal a therapeutically effective amount of the compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I).
  • the compounds and compositions disclosed herein may be useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with selective mAChR M4 receptor activation.
  • a treatment can include selective mAChR M 4 receptor activation to an extent effective to affect cholinergic activity.
  • a disorder can be associated with cholinergic activity, for example cholinergic hypofunction.
  • a method for the treatment of one or more disorders associated with mAChR M4 receptor activity in a subject comprising the step of administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a disorder associated with the mAChR M4 receptor.
  • the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a disorder associated with the mAChR M4 receptor.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disorder associated with the mAChR M 4 receptor.
  • the disclosure provides a method for the treatment of a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.
  • the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a neurological, psychiatric, or cognitive disorder associated with the mAChR M4 receptor, in particular, the disorders described herein.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a neurological, psychiatric, or cognitive disorder associated with the mAChR M 4 receptor, in particular, the disorders described herein.
  • the disorder is a neurological disorder selected from brain tumor, dementia with Lewy bodies, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer’s disease, Parkinson’s disease, and anti-NMDA receptor encephalitis.
  • the disorder is a psychotic disorder selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder.
  • the schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disorganized schizophrenia, and undifferentiated schizophrenia.
  • the disorder is selected from schizoid personality disorder, schizotypal personality disorder, and paranoid personality disorder.
  • the psychotic disorder is due to a general medical condition and is substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine).
  • the present disclosure provides a method for treating a cognitive disorder, comprising administering to a patient in need thereof an effective amount of a compound or a composition of the present disclosure.
  • cognitive disorders include dementia (associated with Alzheimer’s disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson’s disease, Huntington’s disease, Pick’s disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse), delirium, amnestic disorder, substance-induced persisting delirium, dementia due to HIV disease, dementia due to Huntington’s disease, dementia due to Parkinson’s disease, Parkinsonian-ALS demential complex, dementia of the Alzheimer’s type, age-related cognitive decline, and mild cognitive impairment.
  • dementia associated with Alzheimer’s disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson’s disease, Huntington’s disease, Pick’s disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse
  • delirium amnestic disorder
  • substance-induced persisting delirium dementia due to HIV disease
  • dementia due to Huntington’s disease dementia due
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • DSM-5 2013, American Psychiatric Association, Washington DC
  • NCDs neurocognitive disorders
  • NCD due to Alzheimer’s disease vascular NCD, NCD with Lewy bodies, NCD due to Parkinson’s disease, frontotemporal NCD, NCD due to traumatic brain injury, NCD due to HIV infection, substance/medication-induced NCD, NCD due to Huntington’s disease, NCD due to prion disease, NCD due to another medical condition, NCD due to multiple etiologies, and unspecified NCD.
  • the NCD category in DSM-5 encompasses the group of disorders in which the primary clinical deficit is in cognitive function, and that are acquired rather than developmental.
  • the term “cognitive disorders” includes treatment of those cognitive disorders and neurocognitive disorders as described in DSM-IV-TR or DSM-5.
  • 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 or composition of the present disclosure.
  • Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
  • DSM-IV-TR provides a diagnostic tool that includes paranoid, disorganized, catatonic, undifferentiated or residual schizophrenia, and substance- induced psychotic disorder.
  • DSM-5 eliminated the subtypes of schizophrenia, and instead includes a dimensional approach to rating severity for the core symptoms of schizophrenia, to capture the heterogeneity in symptom type and severity expressed across individuals with psychotic disorders.
  • schizophrenia or psychosis includes treatment of those mental disorders as described in DSM-IV-TR or DSM-5.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources.
  • the present disclosure provides a method for treating pain, comprising administering to a patient in need thereof an effective amount of a compound or composition of the present disclosure.
  • a compound or composition of the present disclosure are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain.
  • the compounds and compositions may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • an appropriate dosage level may be about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • the dosage level may be about 0.1 to about 250 mg/kg per day, or about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level can be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day.
  • the dosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response.
  • the mammal has been diagnosed with a need for treatment for the disorder prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment for the disorder.
  • the disorder can be selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as 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, 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.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the potentiation of muscarinic acetylcholine receptor activity in a mammal.
  • the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the potentiation of muscarinic acetylcholine receptor activity in a mammal.
  • the disclosure provides to a method for potentiation of muscarinic acetylcholine receptor activity in a cell, comprising the step of contacting the cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof.
  • the cell is mammalian (e.g., human).
  • the cell has been isolated from a mammal prior to the contacting step.
  • contacting is via administration to a mammal.
  • the invention relates to a method for enhancing cognition in a mammal comprising the step of administering to the mammal an effective amount of least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the enhancment of cognition in a mammal.
  • the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the enhancment of cognition in a mammal.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the enhancment of cognition in a mammal.
  • the mammal is a human.
  • the mammal has been diagnosed with a need for cognition enhancement prior to the administering step.
  • the method further comprises the step of identifying a mammal in need of cognition enhancement.
  • the need for cognition enhancement is associated with a muscarinic receptor dysfunction.
  • the muscarinic receptor is mAChR M 4 .
  • the cognition enhancement is a statistically significant increase in Novel Object Recognition. In some embodiments, the cognition enhancement is a statistically significant increase in performance of the Wisconsin Card Sorting Test. d. Cotherapeutic methods [00245]
  • the present invention is further directed to administration of a selective mAChR M4 activator for improving treatment outcomes in the context of cognitive or behavioral therapy. That is, in some embodiments, the invention relates to a cotherapeutic method comprising a step of administering to a mammal an effective amount and dosage of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a cotherapeutic method with cognitive or behaviorial therapy in a mammal.
  • the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a cotherapeutic method with cognitive or behaviorial therapy in a mammal.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for a cotherapeutic method with cognitive or behaviorial therapy in a mammal.
  • 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.
  • additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula (I).
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone.
  • the other drug(s) can be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a disclosed compound.
  • a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound may be used.
  • the combination therapy can also be administered on overlapping schedules.
  • the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent.
  • the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.
  • the pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • 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 invention.
  • 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 invention.
  • 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 invention is combined with another agent, the weight ratio of a disclosed compound to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. [00255] In such combinations a disclosed compound and other active agents can be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • 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 compound can be employed in combination with anti- Alzheimer’s agents, beta-secretase inhibitors, cholinergic agents, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, M1 allosteric agonists, M1 positive allosteric modulators, NSAIDs including ibuprofen, vitamin E, and anti-amyloid antibodies.
  • the subject compound can be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), 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, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clo
  • the compound 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 biperiden
  • 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 compound can be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the neuroleptic agents when used in combination with the subject compound can be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • a pharmaceutically acceptable salt for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixen
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • the subject compound can be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, ris
  • the compound 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 thereof.
  • the compounds can be coadministered with orthosteric muscarinic agonists, muscarinic potentiators, or cholinesterase inhibitors.
  • the compounds can be coadministered with 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.
  • 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.
  • Methods of treatment may include any number of modes of administering a disclosed composition.
  • Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders.
  • Iodomethane-d 3 (39 ⁇ L, 0.62 mmol) was added to the solution. After 18h, additional iodomethane-d 3 (32.6 ⁇ L) was added and the mixture was heated to 50 °C for 18 h. The mixture was cooled to ambient temperature, added to water, and extracted with EtOAc (3x). The combined organic layers were dried (MgSO 4 ), filtered, and concentrated. Purification using normal phase column chromatography (0-40% EtOAc/Hexanes) afforded the title compound (135 mg).
  • the vessel was capped, degassed and purged with nitrogen (3x) followed by addition of 1,4-dioxane (0.5mL).
  • the vial was heated to 110 °C overnight.
  • the reaction was cooled to room temperature and filtered through a pad of Celite® which was rinsed thoroughly with DCM/EtOAc.
  • the organics were concentrated and the crude residue was purified via RP-HPLC (15 - 45% MeCN in 0.1% aqueous TFA). Fractions containing product were basified with sat. NaHCO3 solution, extracted with 3:1 chloroform/IPA and concentrated to provide the title compound (13 mg).
  • the resulting polyclones were further screened to obtain monoclones of hM4–Gqi5 and rM4–Gqi5 for compound screening assay.
  • Stable monoclone cells were maintained in Ham’s F-12 medium containing 10% heat- inactivated fetal bovine serum (FBS), 1X Antibiotic/Antimycotic, 20 mM HEPES, 500 ⁇ g/mL G418 sulfate, and 200 ⁇ g/mL Hygromycin B in 37 °C humidified incubators in the presence of 5% CO2.
  • FBS heat- inactivated fetal bovine serum
  • 1X Antibiotic/Antimycotic 20 mM HEPES
  • 500 ⁇ g/mL G418 sulfate 500 ⁇ g/mL G418 sulfate
  • 200 ⁇ g/mL Hygromycin B in 37 °C humidified incubators in the presence of 5% CO2.
  • Test compound was added to cells expressing the muscarinic receptors that were loaded with calcium sensitive fluorescent dye. After a ⁇ 2.5 minute incubation period, a submaximal (EC 20 ) concentration of acetylcholine was added, and the response measured. This kinetic assay allows for simultaneous screening and potency determination of multiple pharmacological modes of action including agonist and potentiator activity.
  • 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 (Greiner Bio-One).
  • Compounds were serially diluted 1:3 into 10 point concentration response curves in DMSO using the Bravo Liquid Handler (Agilent, Santa Clara, CA), transferred to a 384 well daughter plates using an Echo acoustic liquid handler (Beckman Coulter, Indianapolis, Indiana), and diluted in assay Buffer to a 2X final concentration.
  • the agonist plates were prepared using acetylcholine (ACh, Sigma- Aldrich, St. Louis, MO) concentrations for the EC 20 and EC MAX responses by diluting in assay buffer to a 5X final concentration.
  • the 2X dye solution (2.3 ⁇ M) was prepared by mixing a 2.3 mM Fluo-4-AM stock in DMSO with 10% (w/v) pluronic acid F-127 in a 1:1 ratio in assay buffer. Using a microplate washer (BioTek, Winooski, VT), cells were washed with assay buffer for 3 times to remove medium. After the final wash, 20 L of assay buffer remained in the cell plates. Immediately, 20 L of the 2X dye solution (final 1.15 ⁇ M) was added to each well of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA).
  • DMSO vehicle was added to the control wells in the first add for assessing ACh EC20, EC80, and ECmax responses.
  • Calcium fluorescence was recorded as fold over basal fluorescence and raw data were normalized to the maximal response to ACh agonist.
  • Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition.
  • Positive allosteric modulator activity was analyzed as a concentration- dependent increase in the EC 20 acetylcholine response.
  • Antagonist activity was analyzed as a concentration-dependent decrease in the EC 80 acetylcholine response.
  • Concentration-response curves were generated using a four-parameter logistical equation using GraphPad Prism (La Jolla, CA) or the Dotmatics software platform (Woburn, MA). [00328] The above-described assay was also operated in a second mode where an appropriate fixed concentration of the present compounds was 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 the calcium response (maximum-local minima response) was measured. The EC 50 values for the agonist in the presence of test compound were determined by nonlinear curve fitting.
  • a decrease in the EC 50 value of the agonist with increasing concentrations of the present compounds 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.
  • HTRF ® Homogeneous Time-Resolved Fluorescence
  • TR-FRET Time-Resolved Resonance Energy Transfer
  • the day before assay the cells were trypsinized and resuspended in plating medium (growth medium without G418). The cells were plated to white, solid, flat-bottomed, 384 well plates at densities of 4,000 and 6,000 cells/10 L/well, of human M 4 and rat M 4 cells, respectively. The cell plates were spun at 100xg for 1 min, then immediately placed in a 37 °C incubator in the presence of 5% CO2 overnight. [00332] The next day, reagents were freshly diluted at a 2X concentration in assay buffer using F12 basal medium or stimulation buffer. All assay buffers contained 500 ⁇ M IBMX to block cAMP degradation.
  • Activation of M 4 by compounds was examined in cells stimulated with an EC 80 concentration of forskolin to induce submaximal intracellular cAMP levels.
  • Forskolin EC 80 concentrations were determined from forskolin concentration response curves (CRCs) and ranged from 1.5 to 2.5 ⁇ M.
  • Compounds (10 mM) were prepared in 100% DMSO and further serially diluted either 1:3 or 1:5 into a 13-point CRC in DMSO using a Bravo Liquid Handler in a 384 well microplate.
  • Agonist assay mode was used to assess the abilities of M 4 compounds to directly activate M 4 receptors in the absence of the agonist, acetylcholine.
  • acetylcholine CRC was also performed in the presence of an EC 80 concentration of forskolin to determine the concentrations of acetylcholine inducing maximal (EC max ) and submaximal (EC 20 ) cAMP inhibition in order to prepare for the subsequent potentiator mode assay .
  • the 10-point serially diluted compounds starting 1.1 ⁇ M as a final concentration, were transferred to a compound plate using an Echo plate reformat protocol.2X assay buffer containing an EC80 concentration of forskolin and an EC20 concentration of acetylcholine was added to the compound plate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les pyrimido[4',5':4,5]thiéno[2,3-c]pyridazin-8-amines substituées et pyrido[4',3': 4,5]thiéno[2,3-c]pyridazin-8-amines sont des modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine M4 (mAChR M4) et peuvent présenter une utilité dans le traitement de troubles neurologiques et psychiatriques associés à un dysfonctionnement du récepteur muscarinique de l'acétylcholine.
PCT/US2024/060145 2023-12-14 2024-12-13 Modulateurs allostériques positifs du récepteur muscarinique m4 de l'acétylcholine Pending WO2025129082A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363610231P 2023-12-14 2023-12-14
US63/610,231 2023-12-14

Publications (1)

Publication Number Publication Date
WO2025129082A1 true WO2025129082A1 (fr) 2025-06-19

Family

ID=94601330

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/060145 Pending WO2025129082A1 (fr) 2023-12-14 2024-12-13 Modulateurs allostériques positifs du récepteur muscarinique m4 de l'acétylcholine

Country Status (1)

Country Link
WO (1) WO2025129082A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017223290A1 (fr) * 2016-06-22 2017-12-28 Vanderbilt University Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
WO2018085813A1 (fr) * 2016-11-07 2018-05-11 Vanderbilt University Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
WO2019113179A1 (fr) * 2017-12-05 2019-06-13 Vanderbilt University Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017223290A1 (fr) * 2016-06-22 2017-12-28 Vanderbilt University Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
WO2018085813A1 (fr) * 2016-11-07 2018-05-11 Vanderbilt University Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
WO2019113179A1 (fr) * 2017-12-05 2019-06-13 Vanderbilt University Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LONG MADELINE F ET AL: "Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes - Part 2", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 53, 26 October 2021 (2021-10-26), XP086868054, ISSN: 0960-894X, [retrieved on 20211026], DOI: 10.1016/J.BMCL.2021.128416 *

Similar Documents

Publication Publication Date Title
WO2017223290A1 (fr) Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
EP3534901B1 (fr) Modulateurs allostériques positifs du récepteur muscarinique à l'acétylcholine m4
US10927126B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US10961253B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US10342782B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US12448380B2 (en) Positive modulators of the muscarinic acetylcholine receptor M4
US10736898B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US11376254B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US10189857B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US20250017935A1 (en) 7,8-dihydro-5h-1,6-naphthyridine derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor m4 for treating neurological and psychiatric disorders
WO2025129082A1 (fr) Modulateurs allostériques positifs du récepteur muscarinique m4 de l'acétylcholine
WO2024220633A1 (fr) Dérivés de pyrrolopyridine en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
WO2024220635A1 (fr) Dérivés de thiazolopyridine utilisés en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
WO2023141511A1 (fr) Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
WO2024220641A1 (fr) Dérivés de 1,6-naphtyridine utilisés en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4 utiles pour le traitement de troubles neurologiques et psychiatriques
KR20250172585A (ko) 무스카린성 아세틸콜린 수용체 m4의 양성 알로스테릭 조절제로서 피롤로피리딘 유도체
HK40014595A (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
HK40014595B (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
HK40014598B (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
HK40014598A (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24852977

Country of ref document: EP

Kind code of ref document: A1