Tripyridyl carboxamide orexin receptor antagonists
View Patent ↗The present invention is directed to tripyridyl carboxamide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
1. A compound of the formula I:
wherein:
A is pyridyl;
R 1a , R 1b and R 1c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —CN,
(5) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl or naphthyl, and
(6) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl;
R 2a , R 2b and R 2c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and
(6) —C 3-6 cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(7) —NH—C 1-6 alkyl, or —N(C 1-6 alkyl)(C 1-6 alkyl), which is unsubstituted or substituted with halogen;
R 3a , R 3b and R 3c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl or naphthyl, and
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl;
R 4 is hydrogen or C 1-6 alkyl;
R 5 is hydrogen or C 1-6 alkyl; and
R 6 is hydrogen;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R 1a , R 1b and R 1c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) C 1-6 alkyl.
3. The compound of claim 1 wherein R 2a , R 2b and R 2c are independently selected from the group consisting of:
(1) hydrogen,
(2) chloro,
(3) fluoro,
(4) ethyl,
(5) isopropyl,
(6) methoxy,
(7) difluoromethyl, and
(8) cyclopropyl.
4. The compound of claim 1 wherein R 3a is hydrogen, R 3b is hydrogen and R 3c is hydrogen.
5. The compound of claim 1 wherein R 4 is hydrogen and R 5 is hydrogen.
6. A compound which is selected from the group consisting of:
5″-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide;
N-[(5,6-dimethoxypyridin-2-yl)methyl]-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide;
N-[(5,6-dimethoxypyridin-2-yl)methyl]-5″-methoxy-2,2′:5′,3″-terpyridine-3′-carboxamide;
N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-fluoro-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide;
N-[(6-ethoxy-5-methoxypyridin-2-yl)methyl]-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide;
N-[(6-ethyl-5-methoxypyridin-2-yl)methyl]-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide;
N-[(6-cyclopropyl-5-methoxypyridin-2-yl)methyl]-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide;
N-[(6-isopropyl-5-methoxypyridin-2-yl)methyl]-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide;
5″-cyano-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide;
5″-chloro-N-[(6-cyclopropyl-5-methoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide; and
5″-chloro-N-[(5,6-dimethoxypyridin-3-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide;
or a pharmaceutically acceptable salt thereof.
7. A compound which is 5″-chloro-N-[(5,6-dimethoxypridin-2-yl)methyl1]-2,2′:5′3″-terpyrididne-3′-carboxamide or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 which is 5″-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide.
9. The compound of claim 7 which is 5″-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide in the form of a pharmaceutically acceptable salt thereof.
10. A compound which is N-[(5,6-dimethoxypyridin-2-yl)methyl]-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 which is N-[(5,6-dimethoxypyridin-2-yl)methyl]-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide.
12. The compound of claim 10 which is N-[(5,6-dimethoxypyridin-2-yl)methyl]-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxamide in the form of a pharmaceutically acceptable salt thereof.
13. A compound which is 5″-cyano-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 which is 5″-cyano-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide.
15. The compound of claim 13 which is 5″-cyano-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyridine-3′-carboxamide in the form of a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition which comprises an inert carrier and a compound of claim 6 or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition which comprises an inert carrier and a compound of claim 7 or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition which comprises an inert carrier and a compound of claim 10 or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition which comprises an inert carrier and a compound of claim 13 or a pharmaceutically acceptable salt thereof.