(4-(6-((2-octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazin-3-yl)phenyl)(imino)(methyl)-LAMBDA6-sulfanone derivatives and similar compounds as muscarinic acetylcholine receptor M4 antagonists for the treatment of neurodegenerative disorders
Disclosed are compounds of formula (I) wherein G 1 is as antagonists of the muscarinic acetylcholine receptor M 4 (mAChR M 4 ) for use in the treatment of e.g. a neurodegenerative disorder, a movement disorder, or a brain disorder, such as e.g. Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy. An exemplary compound is e.g. (2,5-difluoro-4-(6-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazin-3-yl)phenyl)(imino)(methyl)-λ 6 -sulfanone (e.g. example 12; compound no. 7) Pharmacological data on the activity of the compounds in an mAChR M 4 cell-based assay are provided (e.g. table 2). TABLE 2 Human M 4 Cpd. No. IC 50 (nM) E min (%)* 1 13.4 4 2 39.6 2 3 18.5 3 4 584 6 5 75.4 3 6 188 3 7 46.0 3 8 560 7 9 18.4 3 10 1.8 2 11 86.2 3 12 43.4 2 13 8.6 3 *% ACh maximum at 30 μM.
1 . A compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein:
G 1 is
R is hydrogen, C 1-4 alkyl, C 3-4 cycloalkyl, or —C 1-3 alkylene-C 3-4 cycloalkyl;
R 1 is hydrogen, C 1-4 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, —C 1-3 alkylene-C 3-4 cycloalkyl, or —C(O) C 1-4 alkyl;
R 2 is C 1-4 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, or —C 1-3 alkylene-C 3-4 cycloalkyl;
R 3 is -L 1 -G 2 , G 2 , -L 2 -G 2 , -L 2 -L 1 -G 2 , —C 2-6 alkylene-R 3a , C 3-7 alkyl, or C 3-7 haloalkyl;
R 4 , at each occurrence, is independently halogen, cyano, C 1-4 alkyl, C 1-2 fluoroalkyl, OH, —OC 1-4 alkyl, or —OC 1-2 fluoroalkyl;
n is 0, 1, 2, 3, or 4;
L 1 is C 1-5 alkylene;
L 2 is 1,1-cyclopropylene;
G 2 is a 4- to 12-membered heterocyclyl, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a C 3-12 carbocyclyl optionally fused to a 6-membered arene, wherein G 2 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, oxo, C 1-4 alkyl, C 1-4 haloalkyl, —OR 13 , —N(R 13 ) 2 , —C 1-3 alkylene-OR 13 , and —C 1-3 alkylene-N(R 13 ) 2 ;
R 3a is —OR 14 or —N(R 14 ) 2 ;
R 13 , at each occurrence, is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-4 cycloalkyl, or —C 1-3 alkylene-C 3-4 cycloalkyl, wherein alternatively two R 13 , together with a nitrogen to which the two R 13 attach form a 4- to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C 1 -4alkyl;
R 14 , at each occurrence, is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, G 3 , or —C 1-3 alkylene-G 3 , wherein alternatively two R 14 , together with a nitrogen to which the two R 14 attach form a 4- to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C 1-4 alkyl;
G 3 is phenyl, a monocyclic 5- to 6-membered heteroaryl, a monocyclic 4- to 8-membered heterocyclyl, or a monocyclic C 3-8 cycloalkyl, wherein G 3 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OR 15 , and —N(R 15 ) 2 ; and
R 15 , at each occurrence, is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-4 cycloalkyl, or —C 1-3 alkylene-C 3-4 cycloalkyl, wherein alternatively two R 15 , together with a nitrogen to which the two R 15 attach form a 4- to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C 1-4 alkyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl, C 1-2 fluoroalkyl, or —C(O)C 1-4 alkyl.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-4 alkyl.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , at each occurrence, is independently fluoro or CF 3 .
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is -L 1 _G 2 .
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 2 is the optionally substituted 4- to 12-membered heterocyclyl.
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 2 is the optionally substituted 5- to 12-membered heteroaryl.
12 . The compound of claim 11 , wherein G 2 is
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 2 is the optionally substituted C 3-12 carbocyclyl optionally fused to a 6-membered arene.
14 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is CH 2 .
16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein the CH 2 at L 1 is CD 2 .
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is CH 2 CH 2 .
18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.
19 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20 . A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M 4 , comprising administering to the mammal a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.