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 6 , —C(O)R 6 , —C(O)NR 5 R 6 , 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, 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, 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 8 , —NR 8 R 9 , 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 8 , or —NR 8 R 9 ;
R 2 is selected from the group consisting of H, —S(O) q R 6 , —C(O)R 6 , —C(O)NR 5 R 6 , 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 8 , —NR 8 R 9 , 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 8 , or —NR 8 R 9 ;
R 3 is independently selected at each location from the group consisting of H, halogen, —OR 5 , —NR 5 R 6 , —NR 5 C(O)R 6 , —NR 5 C(O) 2 R 6 , —NR 6 C(O)NR 6 R 7 , —S(O) q R 6 , —CN, —C(O)R 6 , —C(O)NR 5 R 6 , 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 8 , —NR 8 R 9 , 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 8 , or —NR 8 R 9 ;
R 4 is selected from the group consisting of H, halogen, —OR 5 , —NR 5 R 6 , —NR 5 C(O)R 6 , —NR 5 C(O) 2 R 6 , —NR 6 C(O)NR 6 R 7 , —S(O) q R 6 , —CN, —C(O)R 6 , —C(O)NR 5 R 6 , 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 8 , —NR 8 R 9 , 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 8 , or —NR 8 R 9 ;
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, —C(O)R 7 , 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 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 7 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 8 and R 9 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 7 , 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 10 is selected from the group consisting of H, halogen, —OR 5 , —NR 5 R 6 , —NR 5 C(O)R 6 , —NR 5 C(O) 2 R 6 , NR 6 C(O)NR 6 R 7 , —S(O) q R 6 , —CN, —C(O)R 6 , —C(O)NR 5 R 6 , 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 8 , —NR 8 R 9 , 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 8 , or —NR 8 R 9 ;
X is CR 10 , C(R 10 ) 2 , N, or NR 10 ;
Y is CR 10 , 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 0, 1, or 2; and
represents an optional double bond, or an oxide thereof, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein R 1 is H.
3. The compound according to claim 1 , wherein R 1 is alkyl.
4. The compound according to claim 1 , wherein R 2 is H.
5. The compound according to claim 1 , wherein X is C.
6. The compound according to claim 1 , wherein X is N.
7. The compound according to claim 1 , wherein L is a bond.
8. The compound according to claim 1 , wherein L is —CH 2 —O—.
9. The compound according to claim 1 , wherein L is —CH 2 —CH 2 —.
10. The compound according to claim 1 , wherein B is aryl.
11. The compound according to claim 10 , wherein B is phenyl.
12. The compound according to claim 1 , wherein B is heteroaryl.
13. The compound according to claim 12 , wherein B is pyridinyl.
14. The compound according to claim 13 , wherein B is pyridin-2-yl.
15. The compound according to claim 13 , wherein B is pyridin-3-yl.
16. The compound according to claim 12 , wherein B is pyridazinyl.
17. The compound according to claim 16 , wherein B is pyridazin-3-yl.
18. The compound according to claim 12 , wherein B is pyrimidinyl.
19. The compound according to claim 18 , wherein B is pyrimidin-5-yl.
20. The compound according to claim 1 , wherein B is unsubstituted.
21. The compound according to claim 1 , wherein B is substituted with one substituent selected from the group consisting of methyl, trifluoromethyl, chloro and fluoro.
22. 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)pyridazin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 2-(trifluoromethyl)pyrimidin-5-yl, 6-methylpyridin-3-yl, pyridin-2-yl, 2,4-difluorophenyl, 4-chlorophenyl, 4-chloro-2-fluorophenyl, 2,4-dichlorophenyl, and 4-(trifluoromethyl)phenyl.
23. The compound according to claim 1 , wherein the compound has the formula:
24. The compound according to claim 1 , wherein the compound is selected from the group consisting of
25. The compound according to claim 1 , wherein the compound is selected from the group consisting of
26. The compound according to claim 1 , wherein the compound is selected from the group consisting of
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.