Muscarinic acetylcholine M
Provided, inter alia, are compounds which are useful as antagonists of the muscarinic acetylcholine receptor M1 (mAChR M1); 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 of Formula (IA):
wherein:
E is —CH 2 —, —CH 2 CH 2 —, —O—CH 2 —, or —CH 2 —O—;
X is a bond,
—C≡C—, —C(═O)— —CH 2 O—, —CH 2 CH 2 O—, —O—, —N(R 7 )—, —S(O) 2 —, —CH 2 N(R 7 )—, or —CH 2 CH 2 N(R 7 )—;
Y is a bond, —O—, or —N(R 8 )—;
R 1 is
wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, —CN, —N(R 10 ) 2 , C 1-6 alkyl, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
each R 2 is independently selected from hydrogen, deuterium, halogen, —OH, and C 1-6 alkyl;
each R 3 is independently selected from hydrogen, deuterium, halogen, —OH, and C 1-6 alkyl;
R 4 is
each R 5 is independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;
each R 6 is independently selected from deuterium, halogen, —CN, —N(R 10 ) 2 , C 1-6 alkyl, C 1-6 alkyl-OH, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —C(═O)(C 1-6 alkyl), —(C(R 10 ) 2 ) q —O—(C 1-6 alkyl) and —S(O) 2 R 11 ;
R 7 is hydrogen or C 1-6 alkyl;
R 8 is hydrogen or C 1-6 alkyl;
each R 9 is independently C 1-6 alkyl;
each R 10 is independently selected from H and C 1-6 alkyl;
R 11 is C 1-6 alkyl;
each R 12 is independently selected from hydrogen, deuterium, halogen, —OH, and C 1-6 alkyl;
each R 13 is independently selected from hydrogen, deuterium, halogen, —OH, and C 1-6 alkyl;
a is 1, 2, 3, 4, or 5;
m is 0, 1, 2, or 3;
n is 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3; and
each q is independently 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt or solvate thereof.
2. A compound of Formula (Ib):
wherein:
X is a bond,
—C≡C—, —C(═O)— —CH 2 O—, —CH 2 CH 2 O—, —O—, —N(R 7 )—, —S(O) 2 —, —CH 2 N(R 7 )—, or —CH 2 CH 2 N(R 7 )—;
Y is a bond, —O—, or —N(R 8 )—;
R 1 is
wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, —CN, —N(R 10 ) 2 , C 1-6 alkyl, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
each R 2 is independently selected from hydrogen, deuterium, halogen, —OH, and C 1-6 alkyl;
each R 3 is independently selected from hydrogen, deuterium, halogen, —OH, and C 1-6 alkyl;
R 4 is
each R 5 is independently selected from halogen, —CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;
each R 6 is independently selected from deuterium, halogen, —CN, —N(R 10 ) 2 , C 1-6 alkyl, C 1-6 alkyl-OH, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —C(═O)(C 1-6 alkyl), —(C(R 10 ) 2 ) q —O—(C 1-6 alkyl) and —S(O) 2 R 11 ;
R 7 is hydrogen or C 1-6 alkyl;
R 8 is hydrogen or C 1-6 alkyl;
each R 9 is independently C 1-6 alkyl;
each R 10 is independently selected from H and C 1-6 alkyl;
R 11 is C 1-6 alkyl;
m is 0, 1, 2, or 3;
n is 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3; and
each q is independently 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt or solvate thereof.
3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
4. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
5. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.
7. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
8. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond and Y is a bond.
9. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 and each R 3 are H.
10. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3.
11. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is
12. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 6 is independently selected from halogen and —CN.
13. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
14. The compound of claim 1 , selected from:
or a pharmaceutically acceptable salt or solvate thereof.
15. A compound, selected from:
or a pharmaceutically acceptable salt or solvate thereof.
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
17. A method of modulating muscarinic acetylcholine receptor M 1 activity in a subject comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.
18. The method of claim 17 , wherein the compound acts as a selective M 1 antagonist.