Antagonists of the muscarinic acetylcholine receptor M4
Inventors
Lindsley, Craig W. • Bridges, Thomas M. • Conn, P. Jeffrey • Bender, Aaron M. • Engers, Darren W.
Assignees
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Publication Number
US-12600726-B2
Publication Date
2026-04-14
Expiration Date
Abstract
Disclosed herein are cyclopropylpiperidine compounds, which may be useful as antagonists of the muscarinic acetylcholine receptor M4 (niAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.
Core Innovation
The invention concerns compounds of formula (I) and pharmaceutically acceptable salts thereof within a general framework defined by a heteroaryl core A selected from thiazol-2,5-diyl, pyridazin-3,6-diyl, pyrazin-2,5-diyl, pyridin-2,5-diyl, or phthalazin-1,4-diyl. Core A is optionally substituted with halo, C1-C4 alkyl, or C1-C4 haloalkyl, and the formula further defines Q, R1, G, R2/R3, R6/Rf/Rg, and Y1 under specified ring-size and substitution constraints.
The disclosure includes pyridazin-3-amine compounds and pyridazinyl core compounds carrying a 6-azaspiro[2.5]octane-2-ylmethyl or 6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-ylmethyl scaffold. Representative examples include halo- and fluoro-substituted phenyl groups, difluorophenyl and fluorophenyl isomers, difluoromethyl/fluoro-methoxy phenyl motifs, thienyl, benzonitrile, isoquinolyl, quinolyl, benzodioxole, naphthyl, trifluoromethoxy-phenyl, trifluoromethylpyridyl, methylpyrazolyl, pyrazolyl, isoxazolyl, and thiophene substituents, with at least one explicitly specified enantiomer among the named examples.
The disclosure also encompasses pharmaceutically acceptable salts, including acid addition salts and quaternary ammonium salts, zwitterions, and pharmaceutically acceptable compositions and formulations of compounds of formula (I). The formulations support oral, topical, parenteral, ocular, and other routes/forms, and include pharmaceutically acceptable carriers comprising diluents, lubricants, binders, disintegrants, surfactants, solvents, antioxidants, and preservatives, with example formulations including spray-dried dispersions (SDD).
Claims Coverage
The consolidated claim coverage identifies three independent claim directions: a compound of formula (I), a pharmaceutical composition, and a method of antagonizing mAChR M4. Across these claims, the inventive features center on the formula (I) scaffold with constrained heteroaryl-core selection and substituent variables, and on administration of the claimed compounds for mAChR M4 antagonism.
Heteroaryl core compound of formula (I)
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is a thiazol-2,5-diyl, pyridazin-3,6-diyl, pyrazin-2,5-diyl, pyridin-2,5-diyl, or phthalazin-1,4-diyl, optionally substituted with halo, C1-C4 alkyl, or C1-C4 haloalkyl; Q is selected from NR_a, O, and CR_bR_c; and R1, G, R2/R3, R6, Rf/Rg, Y1, m, and n are defined by the stated classes and substitution constraints.
Pharmaceutical composition including a compound of formula (I)
A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
Method of antagonizing mAChR M4 by administration
A method to antagonize mAChR M4 in a subject by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The claims cover formula (I) heteroaryl-core compounds with constrained ring classes and substituent options across Q, R1, G, R2/R3, R6, Rf/Rg, and Y1, and further cover pharmaceutical compositions containing those compounds and a method of antagonizing mAChR M4 by administration.
Stated Advantages
Provides mAChR M4 antagonists.
Used for treating disorders associated with mAChR dysfunction.
Used for treating Parkinson’s disease motor symptoms such as bradykinesia, tremor, rigidity, gait dysfunction, and postural instability.
Improving solubility/bioavailability via spray-dried dispersions (SDD).
Long-term stability of formulations.
Enabling therapeutic treatment through mAChR M4 antagonism with IC50 thresholds.
Documented Applications
Treating disorders associated with mAChR dysfunction via mAChR M4 antagonism.
Treating Parkinson’s disease motor symptoms such as bradykinesia, tremor, rigidity, gait dysfunction, and postural instability.
Treating dystonia, tardive dyskinesia, catalepsy, Tourette’s syndrome, narcolepsy, ADHD, Huntington’s disease, and schizophrenia.
Pharmaceutical compositions and kits for mAChR M4 antagonism.
Pharmaceutical compositions and formulations using pharmaceutically acceptable carriers for oral, topical, parenteral, ocular, and other routes/forms.
Method to antagonize mAChR M4 in a subject by administering a therapeutically effective amount of a compound of the claim or a pharmaceutically acceptable salt thereof.
Treatment indications for neurological/psychiatric and motor disorders, including Parkinson’s disease, dystonia, tardive dyskinesia, schizophrenia, narcolepsy, ADHD, catalepsy, wakefulness, and excessive daytime sleepiness.
Cotherapeutic methods and combination therapies.
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