2-pyridyloxy-4-ether orexin receptor antagonists
View Patent ↗The present invention is directed to 2-pyridyloxy-4-ether compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the 2-pyridyloxy-4-ether compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds. The present invention is also directed to uses of these pharmaceutical compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
1. A compound of the formula Ia:
wherein:
R 1a , R 1b and R 1c 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,
(6) —CN, and
(7) 1,2,3-triazolyl, which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 alkyl, —O—C 1-6 alkyl or —NO 2 , wherein only one of R 1a , R 1b and R 1c may be 1,2,3-triazolyl;
R 3 is methyl;
R 5 is selected from the group consisting of:
(1) C 1-6 alkyl, which is unsubstituted or substituted with halogen or phenyl,
(2) C 3-6 cycloalkyl, which is unsubstituted or substituted with C 1-6 alkyl, halogen or phenyl, and
(3) phenyl, which is unsubstituted or substituted with C 1-6 alkyl, halogen or phenyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is selected from the group consisting of:
(1) C 1-6 alkyl, which is unsubstituted or substituted with halogen or phenyl,
(2) C 3-6 cycloalkyl, which is unsubstituted or substituted with C 1-6 alkyl or halogen, and
(3) phenyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is selected from the group consisting of: methyl, fluoro-methyl, difluoro-methyl, ethyl, fluoroethyl, isopropyl, cyclopropyl, butyl, 2,2-difluoro-ethyl, phenyl, and benzyl.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is methyl, ethyl or isopropyl.
5. A compound which is selected from the group consisting of:
4-ethoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;
4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;
3-bromo-4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;
4-(benzyloxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;
4-(1-methylethoxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;
4-methoxy-2-{[(3R,6R)-6-methyl-1-{[4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]oxy}pyridine;
2-{[(3R,6R)-1-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-methoxypyridine;
3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)-4-(2H-1,2,3-triazol-2-yl)benzamide;
2-({(3R,6R)-1-[(2-cyclopropylphenyl)carbonyl]-6-methylpiperidin-3-yl}oxy)-4-methoxypyridine;
4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(trifluoromethyl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;
2-({(3R,6R)-1-[(2-ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}oxy)-4-methoxypyridine;
6-methoxy-3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)-2-phenylpyridine;
2-{[(3R,6R)-1-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-methoxypyridine;
6-methoxy-3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)-2-(2H-1,2,3-triazol-2-yl)pyridine;
2-{[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-methoxypyridine;
4-methoxy-2-{[(3R,6R)-1-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}pyridine;
2-cyclopropyl-6-methoxy-3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)pyridine;
2-chloro-6-methoxy-3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)pyridine;
2-{[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-(1-methylethoxy)pyridine;
2-{[(3R,6R)-1-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-(1-methyl ethoxy)pyridine;
6-methoxy-3-{[(2R,5R)-2-methyl-5-{[4-(1-methylethoxy)pyridin-2-yl]oxy}piperidin-1-yl]carbonyl}-2-(2H-1,2,3-triazol-2-yl)pyridine;
2-{[(3R,6R)-1-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-(1-methylethoxy)pyridine;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(2,2-difluoroethoxy)pyri din-2-yl)oxy)-2-methylpiperidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-((4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)piperidin-1-yl)methanone;
4-(2,2-difluoroethoxy)-2-{[(3R,6R)-6-methyl-1-({2-[(methylsulfonyl)methyl]phenyl}carbonyl)-piperidin-3-yl]oxy}pyridine;
1-(2-{[(2R,5R)-5-{[4-(2,2-difluoroethoxy)pyridin-2-yl]oxy}-2-methylpiperidin-1-yl]carbonyl}phenyl)cyclopropanecarbonitrile;
2-{[(2R,5R)-5-{[4-(2,2-difluoroethoxy)pyridin-2-yl]oxy}-2-methylpiperidin-1-yl]carbonyl}-3-(2H-1,2,3-triazol-2-yl)pyridine;
4-(2,2-difluoroethoxy)-2-{[(3R,6R)-1-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}pyridine;
4-(2,2-difluoroethoxy)-2-{[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}pyridine;
4-(2,2-difluoroethoxy)-2-{[(3R,6R)-1-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}pyridine;
4-(cyclopropyloxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}pyridine;
2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-4-(oxetan-3-yloxy)pyridine;
4-(2-methylpropoxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;
2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-4-propoxypyridine;
1-(4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-3-yl)ethanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(difluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(fluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone; and
1-(2-{[(2R,5R)-5-{[4-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylpiperidin-1-yl]carbonyl}-phenyl)cyclopropanecarbonitrile;
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.