Muscarinic acetylcholine M
Provided herein, inter alia, are compounds which are useful as antagonists of the muscarinic acetylcholine receptor M 1 (mAChR M 1 ); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions.
1 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IA):
wherein:
X is a bond, —C(R 9 )(R 10 )—, —O—, or —CH 2 O—;
Y is a —CH 2 — or —CH 2 CH 2 ;
R 1 is
R 2 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
R 3 is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl; or R 2 and R 3 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, and C 1-3 alkyl; or R 3 and R 4 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 4 and R 5 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, and C 1-3 alkyl; or R 3 and R 7 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 4 and R 6 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 5 and R 7 combine to form a bond;
R 8 is
R 9 and R 10 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, heterocycloalkyl, aryl or heteroaryl; or R 3 and R 10 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 4 and R 10 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 6 and R 10 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 9 and R 10 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
each R 12 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, heterocycloalkyl, aryl, heteroaryl, or —SF 5 ;
m is 0 or 1; and
o is 0, 1, 2, or 3.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIA):
wherein:
X is a bond, —C(R 9 )(R 10 ), —O—, or —CH 2 O—;
Y is a —CH 2 — or —CH 2 CH 2 —;
R 1 is
R 2 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
R 3 is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl; or R 2 and R 3 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 8 is
R 9 and R 10 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, heterocycloalkyl, aryl or heteroaryl; or R 3 and R 10 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 9 and R 10 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
each R 12 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, heterocycloalkyl, aryl, heteroaryl, or —SF 5 ;
m is 0 or 1; and
and
o is 0, 1, 2, or 3.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula (III):
wherein:
X is a bond, —C(R 9 )(R 10 )—, —O—, or —CH 2 O—;
R 1 is
R 2 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
R 3 is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl; or R 2 and R 3 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 8 is
R 9 and R 10 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, heterocycloalkyl, aryl or heteroaryl; or R 3 and R 10 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 9 and R 10 combine to form a cycloalkyl or heterocycloalkyl ring optionally substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
each R 12 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, heterocycloalkyl, aryl, heteroaryl, or —SF 5 ;
m is 0 or 1; and
and
o is 0, 1, 2, or 3.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is a bond.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, —F, —CH 3 , —CH 2 CH 3 , —CF 2 H, —CF 3 , —CH 2 OH, —C(CH 3 ) 2 OH, or cyclopropyl.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —F, —CH 3 , —CH 2 CH 3 , —CF 2 H, —CF 3 , —CH 2 OH, —C(CH 3 ) 2 OH, or cyclopropyl.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein o is 1.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is
11 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
12 . A compound, which is
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 12 , wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 13 , wherein the compound is selected from the group consisting of
15 . A compound, which is
or a pharmaceutically acceptable salt thereof.
16 . A compound, which is
17 . The compound of claim 13 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 17 , wherein the compound is
19 . The compound of claim 13 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 19 , wherein the compound is
21 . The compound of claim 13 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 21 , wherein the compound is
23 . A pharmaceutical composition comprising the compound of claim 13 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
24 . A pharmaceutical composition comprising the compound of claim 14 and at least one pharmaceutically acceptable excipient.
25 . A pharmaceutical composition comprising the compound of claim 15 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
26 . A pharmaceutical composition comprising the compound of claim 16 and at least one pharmaceutically acceptable excipient.
27 . A pharmaceutical composition comprising the compound of claim 17 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
28 . A pharmaceutical composition comprising the compound of claim 18 and at least one pharmaceutically acceptable excipient.
29 . A pharmaceutical composition comprising the compound of claim 19 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
30 . A pharmaceutical composition comprising the compound of claim 20 and at least one pharmaceutically acceptable excipient.
31 . A pharmaceutical composition comprising the compound of claim 21 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
32 . A pharmaceutical composition comprising the compound of claim 22 and at least one pharmaceutically acceptable excipient.
33 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
34 . The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, —F, —CH 3 , —CH 2 CH 3 , —CF 2 H, —CF 3 , —CH 2 OH, —C(CH 3 ) 2 OH, or cyclopropyl.
35 . The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —F, —CH 3 , —CH 2 CH 3 , —CF 2 H, —CF 3 , —CH 2 OH, —C(CH 3 ) 2 OH, or cyclopropyl.
36 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
37 . The compound of claim 36 , or a pharmaceutically acceptable salt thereof, wherein o is 1.
38 . The compound of claim 37 , or a pharmaceutically acceptable salt thereof, wherein R 8 is