Antagonists of the muscarinic acetylcholine receptor M4
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 M 4 (mA·Ch·RM 4 ). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.
1 . A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
G 1 is a 6-membered 1,4-heteroarylene containing 2 or 1 nitrogen atoms, wherein G 1 is unsubstituted or substituted with a first substituent and a second substituent, the first substituent being selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, —OC 1-4 alkyl, —OC 1-4 fluoroalkyl, —OC 3-6 cycloalkyl, —OCH 2 C 3-6 cycloalkyl, —SO 2 C 1-4 alkyl, —SO 2 C 3-6 cycloalkyl, phenyl, and C 3-6 cycloalkyl, and the second substituent being selected from the group consisting of C 1-4 alkyl, C 1-4 fluoroalkyl, and C 3-6 cycloalkyl, wherein the phenyl and each C 3-6 cycloalkyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, and —OC 1-4 haloalkyl;
R is hydrogen, C 1-4 alkyl, C 3-4 cycloalkyl, or —C 1-3 alkylene-C 3-4 cycloalkyl;
R 1a is G 1a or halogen;
G 1a is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a C 3-12 carbocyclyl, wherein G 1a is substituted with 2, 1, 3, 4, or 5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, —OR 10 , —N(R 10 ) 2 , —NR 10 OC(O)R 10 , —CONR 10 R 10 , —NR 10 SO 2 R 11 , —C 1-3 alkylene-OR 10 , C 3-6 cycloalkyl, and —C1-3alkylene-C3-6cycloalkyl or G 1a is unsubstituted;
R 2a and R 2b are independently hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 3-4 cycloalkyl, or R 2a and R 2b , together with the atom to which they attach, form a C 3-6 cycloalkyl;
R 3 is -L 1 -G 2 , G 2 , -L 2 -G 2 , -L2-L 1 -G2, —C 2-6 alkylene-R 3a , C 3-7 alkyl, or C 3-7 haloalkyl;
L 1 is C 1-5 alkylene;
L 2 is 1,1-cyclopropylene;
G 2 is a 4- to 12-membered heterocyclyl, 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 unsubstituted or 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 ;
X 1 is S or —CH═CH—;
R 10 , 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 10 , together with a nitrogen to which the two R 10 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;
R 11 , at each occurrence, is independently C 1-4 alkyl, C 1-4 haloalkyl, C 3-4 cycloalkyl, or —C 1-3 alkylene-C 3-4 cycloalkyl;
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 1-4 alkyl;
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 2 is the 4- to 12-membered heterocyclyl.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 2 is the C 3-12 carbocyclyl optionally fused to a 6-membered arene.
5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 2 is the 5- to 12-membered heteroaryl.
7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 3-7 alkyl.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or C 1-4 alkyl.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1a is the 6- to 12-membered aryl.
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1a is the 5- to 12-membered heteroaryl.
13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1a is the 4- to 12-membered heterocyclyl.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen.
17 . The compound of claim 1 of formula (I-A)
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 1 of formula (I-B)
or a pharmaceutically acceptable salt thereof.
19 . A method for antagonizing mAChR M 4 in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
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 subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.