Antagonists of the muscarinic acetylcholine receptor M4
Disclosed herein are substituted hexahydro-1H-cyclopenta[c]pyrrole compounds, which may be useful as antagonists of the muscarinic acetylcholine receptor M 4 (mAChR M 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:
A is an arylene or a five- or six-membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from N, O, and S;
Q is selected from NR a , O, and —NR b —C(O)—;
m is 0, 1, or 2;
R 1 is aryl;
n is 1 or 2;
each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, halo, and —OR g ;
R 3 is selected from hydrogen and C 1 -C 4 alkyl;
R 4 is selected from —(CR h R i ) p —Y′, hydrogen, C 1 -C 8 alkyl, and C 2 -C 8 alkenyl;
R 5 is selected from hydrogen, C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy;
Y′ is selected from cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl;
each R a , R h , and R g is independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and aryl;
each R h is independently selected from hydrogen and C 1 -C 4 alkyl;
each R i is independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and aryl; and
p is 0, 1, 2, 3, or 4;
wherein each aryl, heteroaryl, arylene, heteroarylene, cycloalkyl, cycloalkenyl, and heterocycle is independently unsubstituted or substituted with 1-5 substituents.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
A is selected from:
wherein:
T is selected from O, S and NH;
U, V, W, X, Y and Z are independently selected from N and CR j ;
each R j is independently selected from hydrogen, C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and hydroxy;
R a and R b are independently selected from hydrogen and C 1 -C 4 alkyl;
R 1 is phenyl or a 9- to 12-membered aryl, and R 1 is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR 10 , —NR 10 COR 10 , —CONR 10 R 10 , —C 1 -C 3 alkylene-OR 10 , C 3 -C 6 cycloalkyl, and —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl;
each R 2 is independently selected from hydrogen and C 1 -C 4 alkyl;
R 4 is C 4 -C 6 alkyl or —(CR h R i ) p —Y′;
R h is hydrogen;
R i is hydrogen;
p is 0, 1, 2, or 3;
Y′ is
a) C 3 -C 10 cycloalkyl;
b) C 3 -C 8 cycloalkenyl;
c) a 6- to 12-membered aryl;
d) a 5- to 12-membered heteroaryl; or
e) a 4- to 12-membered heterocyclyl;
wherein Y′ is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR 12 , —NR 12 R 12 , —NR 12 COR 12 , and —NR 12 SO 2 R 13 ;
R 5 is selected from hydrogen and C 1 -C 4 alkyl;
R 10 , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, or —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl;
R 11 , at each occurrence, is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, or —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl;
R 12 , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, or —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl; and
R 13 , at each occurrence, is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, or —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
A is
wherein R 1 -A- is, respectively,
R a and R b are hydrogen;
R 2 is hydrogen;
R 3 is hydrogen; and
R 5 is hydrogen.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is phenyl or a 9- to 12-membered aryl, and R 1 is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR 10 , —NR 10 COR 10 , —CONR 10 R 10 , —C 1 -C 3 alkylene-OR 10 , C 3 -C 6 cycloalkyl, and —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl;
R 10 , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, or —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl; and
R 11 , at each occurrence, is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, or —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is C 4 -C 6 alkyl.
6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is —(CR h R i ) p —Y′;
R h is hydrogen;
R i is hydrogen;
p is 0, 1, 2, or 3;
Y′ is
a) C 3 -C 10 cycloalkyl;
b) C 3 -C 8 cycloalkenyl;
c) a 6- to 12-membered aryl;
d) a 5- to 12-membered heteroaryl; or
e) a 4- to 12-membered heterocyclyl;
wherein Y′ is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR 12 , —NR 12 R 12 , —NR 12 COR 12 , and —NR 12 SO 2 R 13 ;
R 12 , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, or —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl; and
R 13 , at each occurrence, is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, or —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Y′ is a C 3 -C 10 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl.
8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Y′ is a C 3 -C 8 cycloalkenyl.
9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Y′ is a phenyl or a 9- to 12-membered aryl, and optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR 12 , —NR 12 R 12 , —NR 12 COR 12 , and —NR 12 SO 2 R 13 .
10. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Y′ is a 5- to 6-membered monocyclic heteroaryl or an 8- to 12 membered bicyclic heteroaryl, and optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR 12 , —NR 12 R 12 , —NR 12 COR 12 , and —NR 12 SO 2 R 13 .
11. A method for antagonizing mAChR M 4 in a subject, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
12. A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M 4 , comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
13. A method for treating motor symptoms in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
14. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein p is 0.
15. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Q is NR a and m is 0.
16. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein Q is NR a and m is 0.
17. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Q is NR a and m is 1.
18. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein Q is NR a and m is 1.
19. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Q is O and m is 0.
20. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein Q is O and m is 0.