Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
View Patent ↗MCH-1 receptor antagonists are disclosed having the general formula 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 8 , —C(O)R 8 , —C(O)NR 7 R 8 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 10 , —NR 10 R 11 , 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 10 , or —NR 10 R 11 ;
R 2 and R 4 are each individually selected from the group consisting of H, —S(O) q R 8 , —C(O)R 8 , —C(O)NR 7 R 8 , 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 10 , —NR 10 R 11 , 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 10 , or —NR 10 R 11 ;
R 2 and R 3 can combine to form a 3- to 7-membered heterocycle or R 3 and R 4 can combine to form a 3- to 7-membered heterocycle, wherein at least one of R 2 and R 3 or R 3 and R 4 combine to form a 3- to 7-membered heterocycle and wherein the 3-7-membered heterocycle comprises from 1 to 2 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted with from 1 to 10 substituents independently selected at each occurrence thereof from H, halogen, —OR 7 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O) 2 R 8 , —NR 8 C(O)NR 8 R 9 , —S(O) q R 8 , —CN, —C(O)R 8 , —C(O)NR 7 R 8 , 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 10 , —NR 10 R 11 , 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 10 , or —NR 10 R 11 ; with the proviso that, when n is 0 and R 3 and R 4 combine to form a 3- to 7-membered heterocycle, R 2 cannot be C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, or heteroaryl;
R 5 is independently selected at each location from the group consisting of H, halogen, —NR 7 R 8 , —NR 7 C(O) 2 R 8 , —NR 8 C(O)NR 8 R 9 , —S(O) q R 8 , —CN, —C(O)R 8 , 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 10 , —NR 10 R 11 , 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 10 , or —NR 10 R 11 ;
R 6 is selected from the group consisting of H, halogen, —OR 7 , —NR 7 R 8 , —NR 7 C(O) 2 R 8 , —NR 8 C(O)NR 8 R 9 , —S(O) q R 8 , —CN, —C(O)R 8 , 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 10 , —NR 10 R 11 , 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 10 , or —NR 10 R 11 ;
R 7 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 9 , 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 8 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 9 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 10 and R 11 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 9 , 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 12 is selected from the group consisting of H, halogen, —OR 7 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O) 2 R 8 , —NR 8 C(O)NR 8 R 9 , —S(O) q R 8 , —CN, —C(O)R 8 , —C(O)NR 7 R 8 , 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 10 , —NR 10 R 11 , 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 10 , or —NR 10 R 11 ;
X is CR 12 , C(R 12 ) 2 , N, or NR 12 ;
Y is CR 12 , 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 0 or 1 and m is 0 or 1, wherein n+m=1;
s 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, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug 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 m is 1 and n is 0.
5. The compound according to claim 1 , wherein m is 0 and n is 1.
6. The compound according to claim 1 , wherein R 2 is H and R 3 and R 4 combine to form a 3- to 7-membered heterocycle.
7. The compound according to claim 1 , wherein R 4 is H and R 2 and R 3 combine to form a 3- to 7-membered heterocycle.
8. The compound according to claim 1 , wherein the compound has the structure:
9. The compound according to claim 1 , wherein the compound has the structure
wherein r is 1, 2, 3, 4, or 5 and R 13 , R 14 , and R 15 are selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C 1 -C 6 alkyl, halogen, —CF 3 , and —CN.
10. The compound according to claim 1 , wherein the compound has the structure
wherein r is 1, 2, 3, 4, or 5 and R 13 , R 14 , and R 15 are selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C 1 -C 6 alkyl, halogen, —CF 3 , and —CN.
11. The compound according to claim 1 , wherein the compound has the structure
wherein r is 1, 2, 3, 4, or 5 and R 13 , R 14 , and R 15 are selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C 1 -C 6 alkyl, halogen, —CF 3 , and —CN.
12. The compound according to claim 1 , wherein X is CH.
13. The compound according to claim 1 , wherein X is N.
14. The compound according to claim 1 , wherein Y is C.
15. The compound according to claim 1 , wherein Y is CH.
16. The compound according to claim 1 , wherein Y is N.
17. The compound according to claim 1 , wherein L is a bond.
18. The compound according to claim 1 , wherein L is —CH 2 —O—.
19. The compound according to claim 1 , wherein B is aryl.
20. The compound according to claim 19 , wherein B is phenyl.
21. The compound according to claim 1 , wherein B is heteroaryl.
22. The compound according to claim 21 , wherein B is pyridinyl.
23. The compound according to claim 22 , wherein B is pyridin-2-yl.
24. The compound according to claim 22 , wherein B is pyridin-3-yl.
25. The compound according to claim 1 , wherein B is unsubstituted.
26. The compound according to claim 1 , wherein B is substituted with at least one substituent selected from the group consisting of trifluoromethyl, fluoro, chloro, and methyl.
27. 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, 5-chloropyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 6-methylpyridin-3-yl, 4-(trifluoromethyl)phenyl, 2,4-difluorophenyl, 4-chloro-2-fluorophenyl, and 3,5-difluoropyridin-2-yl.
28. The compound according to claim 1 , wherein the compound is selected from the group consisting of
29. The compound according to claim 1 , wherein the compound is selected from the group consisting of
30. The compound according to claim 1 , wherein the compound is selected from the group consisting of
31. The compound according to claim 1 , wherein the compound is an HCl salt.
32. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.