Azinone-substituted azepino[
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 14 , —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 2 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 5 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 3 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 4 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 5 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
or R 2 and R 3 or R 4 and R 5 can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
R 6 is independently selected at each location from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 7 is optionally present and, if present, is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ; or R 2 and R 3 or R 4 and R 5 can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
R 8 is selected from the group consisting of H, —S(O) q R 14 , —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 9 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 10 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 11 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 12 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 13 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 15 , 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 14 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 15 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 16 and R 17 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 15 , 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 18 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 14 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 ;
G is —NR 8 —CR 9 R 10 —CR 11 R 12 —, —CR 9 R 10 —NR 8 —CR 11 R 12 —, or —CR 9 R 10 —CR 11 R 12 —NR 8 —, with the proviso that when G is —CR 9 R 10 —NR 8 —CR 11 R 12 —, R 2 and R 3 are not —C(O)NR 13 R 14 ;
X is CR 18 , C(R 18 ) 2 , N, Or NR 18 ;
Y is CR 18 , C, or N;
Z is CH, C, or N;
L is —(CH 2 ) p —O—, —(CH 2 ) p —, —CH═CH—, or a bond;
A is CH, C, or N;
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, 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 G is —NR 8 —CR 9 R 10 —CR 11 R 12 —.
3. The compound according to claim 2 , wherein R 8 is H or C 1 -C 6 alkyl, R 9 is H, R 10 is H, R 11 is H, and —R 12 is H.
4. The compound according to claim 1 , wherein G is —CR 9 R 10 —NR 8 —CR 11 R 12 —.
5. The compound according to claim 4 , wherein R 8 is H or C 1 -C 6 alkyl, R 9 is H, R 10 is H, R 11 is H, and —R 12 is H.
6. The compound according to claim 1 , wherein G is —CR 9 R 10 —CR 11 R 12 —NR 8 —.
7. The compound according to claim 6 , wherein R 8 is H or C 1 -C 6 alkyl, R 9 is H, R 10 is H, R 11 is H, and —R 12 is H.
8. The compound according to claim 1 , wherein R 1 is H.
9. The compound according to claim 1 , wherein R 1 is C 1 -C 6 alkyl.
10. The compound according to claim 1 , wherein R 1 is selected from the group consisting of H, —S(O) q R 14 , —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl.
11. The compound according to claim 1 , wherein R 8 is H or C 1 -C 6 alkyl.
12. The compound according to claim 1 , wherein R 4 and R 5 are combined to form an oxo group.
13. The compound according to claim 1 , wherein X is N, CH, or CH 2 .
14. The compound according to claim 1 , wherein Y is N, C, or CH.
15. The compound according to claim 1 , wherein L is a bond.
16. The compound according to claim 1 , wherein L is —CH 2 —O—.
17. The compound according to claim 1 , wherein L is —CH 2 —CH 2 —.
18. The compound according to claim 1 , wherein B is phenyl, pyridinyl, pyridazinyl, or pyrimidinyl.
19. The compound according to claim 1 , wherein B is unsubstituted.
20. The compound according to claim 1 , wherein B is substituted with at least one substituent selected from trifluoromethyl, chloro, fluoro, methyl, and methanethio.
21. The compound according to claim 1 , wherein B is selected from the group consisting of phenyl, 4-(trifluoromethyl)phenyl, 4-(methylthio)-phenyl, 5-(trifluoromethyl)pyridin-2-yl, 2-(trifluoromethyl)-pyrimidin-5-yl, 6-(trifluoromethyl)pyridazin-3-yl, 5-fluoro-pyridin-2-yl, 6-methylpyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 5-chloro-pyridin-2-yl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, 4-chloro-phenyl, 4-chloro-2-fluoro-phenyl, 3,5-dichloro-pyridin-2-yl, 4-fluoro-phenyl, pyridin-2-yl, and 3,5-difluoro-pyridin-2-yl.
22. The compound according to claim 1 , wherein the compound has the structure:
23. The compound according to claim 1 , wherein the compound is selected from the group consisting of
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 an HCl salt.
27. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
28. A method of treating obesity in a subject in need of weight loss comprising:
selecting a patient in need of weight loss, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
29. A method of treating obesity in a subject who has experienced weight loss comprising:
selecting a patient who has experienced weight loss, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
30. A method of treating anxiety comprising:
selecting a patient with anxiety, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
31. A method of treating depression comprising:
selecting a patient with depression, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
32. A process for the preparation of a product compound of formula (I):
wherein
R 1 is selected from the group consisting of H, —S(O) q R 14 , —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 2 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 3 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 4 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 5 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
or R 2 and R 3 or R 4 and R 5 can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
R 6 is independently selected at each location from the group consisting of H, halogen, —OR 13 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 7 is optionally present and, if present, is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ; or R 2 and R 3 or R 4 and R 5 can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
R 8 is selected from the group consisting of H, —S(O) q R 14 , —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 9 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 10 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 11 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 12 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 16 , or —NR 16 R 17 ;
R 13 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 15 , 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 14 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 15 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 16 and R 17 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 15 , 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 18 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 14 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , 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 16 , —NR 16 R 17 , 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 ;
G is —NR 8 —CR 9 R 10 —CR 11 R 12 —, —CR 9 R 10 —NR 8 —CR 11 R 12 —, or —CR 9 R 10 —CR 11 R 12 —NR 8 —, with the proviso that when G is —CR 9 R 10 —NR 8 —CR 11 R 12 —, R 2 and R 3 are not —C(O)NR 13 R 14 ;
X is CR 18 , C(R 18 ) 2 , N, Or NR 18 ;
Y is CR 18 , C, or N;
Z is C, CH, or N;
L is —(CH 2 ) p —O—, —(CH 2 ) p —, —CH═CH—, or a bond;
A is C, CH, or N;
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, 1, 2, or 3;
p is from 1 to 4;
q is 0, 1, or 2; and
represents an optional double bond,
said process comprising:
treating a first intermediate of formula (II):
wherein Q is a halogen, under conditions effective to form the compound of formula (I).