Antagonists of the muscarinic acetylcholine receptor M4
Inventors
Bender, Aaron M. • Spock, Matthew • Conn, P. Jeffrey • Lindsley, Craig W.
Assignees
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Publication Number
US-12516067-B2
Publication Date
2026-01-06
Expiration Date
Abstract
Disclosed herein are 1,2,3,4-tetrahydroisoquinolines and 4, 5, 6, 7-tetrahydrothieno [2, 3-cjpyridines, useful as antagonists of the muscarinic acetylcholine receptor M4 (mA·Ch·RM4). 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 relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. The scaffold includes a 6-membered 1,4-heteroarylene ring G1 containing 2 or 1 nitrogen atoms, with defined first and second substituents selected from halogen, cyano, C1-4 alkyl, C1-4 fluoroalkyl, and related substituent classes. The structure further defines variable substituents R, R1a, G1a, R2a/R2b, R3, L1, L2, G2, X1, and additional substituent variables R10, R11, R13, R14, G3, and R15 with specified ring-size and substitution constraints.
The compounds are described with tetrahydroisoquinoline and tetrahydrothieno[2,3-c]pyridine scaffold examples, including pyridazin-3-amine, pyridazinyl/heteroaryl-substituted isoquinoline, and related substituent patterns such as difluorophenyl, fluoro-methylphenyl, trifluorophenyl, and tetrahydroisoquinoline–tetrahydropyran. The content also includes preparation pathways for these isoquinoline derivatives using N-alkylation, a Minisci reaction, amide coupling, cyclopropyl-forming transformations, reductive amination, deprotection, and salt formation.
Biological evaluation is presented in an mAChR M4 framework. The compounds are characterized as antagonists of muscarinic acetylcholine receptor M4 using a cell-based functional calcium-flux assay in CHO-K1 cells expressing human or rat M4, with reported IC50 and Emax values for representative compounds.
Claims Coverage
The consolidated claim coverage identifies one independent claim framework for compounds of formula (I), or pharmaceutically acceptable salts thereof, with multiple specifically defined substituent and ring constraints. A separate therapeutic-use claim is also described, tied to antagonism of mAChR M4. Across the provided material, the inventive features center on the heteroarylene scaffold and the associated variable groups.
Compound of formula (I) with defined 1,4-heteroarylene scaffold
A compound of formula (I) or a pharmaceutically acceptable salt thereof, having a 6-membered 1,4-heteroarylene G1 containing 2 or 1 nitrogen atoms, where G1 is unsubstituted or substituted with a first substituent and a second substituent selected from the specified classes, and with optional substitution patterns on phenyl and each C3-6 cycloalkyl.
Defined variable groups R, R1a, and G1a
R is hydrogen, C1-4 alkyl, C3-4 cycloalkyl, or —C1-3 alkylene-C3-4 cycloalkyl; R1a is G1a or halogen; and G1a is a 6- to 12-membered aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, or a C3-12 carbocyclyl optionally substituted with the specified substituent classes.
Defined R2a/R2b, R3, L1, and L2 framework
R2a and R2b are hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C3-4 cycloalkyl, and can together with the attachment atom form a C3-6 cycloalkyl; R3 is selected from the defined linker-ring and alkyl/haloalkyl options; L1 is C1-5 alkylene; and L2 is 1,1-cyclopropylene.
Defined G2 and X1 with optional arene fusion
G2 is a 4- to 12-membered heterocyclyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or a C3-12 carbocyclyl optionally fused to a 6-membered arene, where G2 is unsubstituted or substituted with the specified substituents; X1 is S or —CH2—CH—.
Defined substituent variables R10, R11, R13, R14, G3, and R15
R10, R11, R13, R14, G3, and R15 are defined with specified alkyl, haloalkyl, cycloalkyl, heteroaryl, heterocyclyl, and ring-forming alternatives, including cases where two substituents together with the attachment nitrogen form a 4- to 6-membered heterocyclic ring.
mAChR M4 antagonism therapeutic use
A method for treating a disorder in a subject who would benefit from antagonism of mAChR M4 by administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
The consolidated claim coverage is directed to a broad formula (I) compound family with a constrained 1,4-heteroarylene core and multiple defined substituent variables, together with a therapeutic-use framework based on mAChR M4 antagonism.
Stated Advantages
The compounds act as antagonists of M4-mediated calcium responses in a cell-based functional calcium-flux assay.
The compounds are described with claimed IC50 and selectivity criteria relative to mAChR M1/M2/M3/M5.
Compounds and related methods are directed to antagonism of muscarinic acetylcholine receptor M4 (mAChR M4).
Therapeutic methods are directed to treating disorders such as Parkinson’s disease and dystonia and other neurodegenerative, movement, and brain disorders where mAChR M4 antagonism is described as beneficial.
Documented Applications
Cell-based functional calcium-flux assay for antagonism of muscarinic acetylcholine receptor M4 using CHO-K1 cells expressing human or rat M4.
Treatment of neurological/psychiatric disorders by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, including Parkinson’s disease, dystonia, and tardive dyskinesia.
Pharmaceutical compositions and formulation, including spray-dried dispersion and BCS class II/IV concepts.
Treating disorders (including Parkinson’s disease/dystonia) in a subject by administering a therapeutically effective amount of the claimed compound (or pharmaceutically acceptable salt) for antagonism of mAChR M4.
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