Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
View Patent ↗Novel MCH-1 receptor antagonists are disclosed. These compounds are used in the treatment of various disorders, including obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders. Methods of making these compounds are also described in the present invention.
1. A compound of formula I:
wherein
R 1 is selected from the group consisting of H, —S(O) q R 5 , —C(O)R 5 , —C(O)NR 4 R 5 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 7 , —NR 7 R 8 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 7 , or —NR 7 R 8 ;
R 2 is independently selected at each location from the group consisting of H, halogen, —OR 4 , —NR 4 R 5 , —NR 4 C(O)R 5 , —NR 4 C(O) 2 R 5 , —NR 5 C(O)NR 5 R 6 , —S(O) q R 5 , —CN, —C(O)R 5 , —C(O)NR 4 R 5 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 7 , —NR 7 R 8 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 7 , or —NR 7 R 8 ;
R 3 is selected from the group consisting of H, halogen, —OR 4 , —NR 4 R 5 , —NR 4 C(O)R 5 , —NR 4 C(O) 2 R 5 , NR 5 C(O)NR 5 R 6 , —S(O) q R 5 , —CN, —C(O)R 5 , —C(O)NR 4 R 5 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 7 , —NR 7 R 8 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 7 , or —NR 7 R 8 ;
R 4 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 6 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 5 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 6 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 7 and R 8 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 6 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 9 is selected from the group consisting of H, halogen, —OR 4 , —NR 4 R 5 , —NR 4 C(O)R 5 , —NR 4 C(O) 2 R 5 , NR 5 C(O)NR 5 R 6 , —S(O) q R 5 , —CN, —C(O)R 5 , —C(O)NR 4 R 5 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 7 , —NR 7 R 8 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 7 , or —NR 7 R 8 ;
X is CR 9 , C(R 9 ) 2 , N, or NR 9 ;
Y is CR 9 , C, or N;
Z is C, CH, or N;
L is —(CH 2 ) p —O—, —(CH 2 ) p —, —CH═CH—, or a bond;
B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with from 1 to 3 substituents selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C 1 -C 6 alkyl, halogen, —CF 3 , and —CN;
n is 1 or 2;
m is 0, 1, 2, or 3;
p is from 1 to 4;
q is from 0 to 2; and
represents an optional double bond,
or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
2. The compound according to claim 1 , wherein the compound has the structure
3. The compound according to claim 1 , wherein the compound has the structure
4. The compound according to claim 3 , wherein the compound has the structure
5. The compound according to claim 3 , wherein the compound is selected from the group consisting of:
6. The compound according to claim 1 , wherein the compound has the structure:
7. The compound according to claim 6 , wherein the compound is selected from the group consisting of
8. The compound according to claim 6 , wherein the compound is selected from the group consisting of
9. The compound according to claim 6 , wherein the compound is selected from the group consisting of
10. The compound according to claim 1 , wherein X is CH.
11. The compound according to claim 1 , wherein X is N.
12. The compound according to claim 1 , wherein L is a bond.
13. The compound according to claim 1 , wherein L is —CH 2 —O—.
14. The compound according to claim 1 , wherein B is aryl.
15. The compound according to claim 14 , wherein B is phenyl.
16. The compound according to claim 1 , wherein B is heteroaryl.
17. The compound according to claim 16 , wherein B is pyridinyl.
18. The compound according to claim 17 , wherein B is pyridin-2-yl.
19. The compound according to claim 17 , wherein B is pyridin-3-yl.
20. The compound according to claim 16 , wherein B is pyridazinyl.
21. The compound according to claim 20 , wherein B is pyridazin-3-yl.
22. The compound according to claim 1 , wherein B is unsubstituted.
23. The compound according to claim 1 , wherein B is substituted with at least one substituent selected from the group consisting of trifluoromethyl and fluoro.
24. The compound according to claim 1 , wherein B is selected from the group consisting of phenyl, 5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 2,4-difluorophenyl, and 4-(trifluoromethyl)phenyl.
25. A compound according to claim 1 , wherein R 1 is H.
26. A compound according to claim 1 , wherein R 1 is alkyl.
27. The compound according to claim 1 , wherein the compound is an HCl salt.
28. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.