HYDROXY-SUBSTITUTED OREXIN RECEPTOR ANTAGONISTS

• US 20160068510A1
• Filed: 04/21/2014
• Published: 03/10/2016
• Est. Priority Date: 04/23/2013
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: KUDUK, Scott D., LIVERTON, Nigel L., SKUDLAREK, Jason W.
• Granted Patent: US 9,725,434 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention is directed to hydroxy compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the 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.

Claims

1. A compound of the formula I:

2. The compound of claim 1 of the formula Ia:

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R^1a, R^1b and R^1c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C_1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(5) —

O—

C_1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(6) —

CN, and

(7) heteroaryl, wherein heteroaryl is selected from imidazolyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl, and triazolyl, which is unsubstituted or substituted with halogen, hydroxyl, C_1-6alkyl, —

O—

C_1-6alkyl or —

NO₂.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R³ is methyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁵ is selected from the group consisting of:

(1) hydrogen,

(2) chloro,

(3) fluoro, and

(4) methyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁵ and R⁶ are joined together with the carbon atoms to which they are attached to form a 5-membered carbocyclic ring.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁵ and R⁶ are joined together with the carbon atoms to which they are attached to form a 6-membered carbocyclic ring.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁶ is selected from the group consisting of:

(1) C_1-6alkyl, which is unsubstituted or substituted with fluoro, or cyclopropyl,

(2) cyclopropyl,

(3) cyclopropyl, and

(4) cyclopentyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁷ is selected from the group consisting of:

(1) hydrogen, and

(2) methyl.

11. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

14. A method for enhancing the quality of sleep in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. A method for treating insomnia in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for treating or controlling obesity in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. A compound which is selected from the group consisting of:

1-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}phenyl)ethanol;

1-(3-{[(3R,6R)-1-{[6-methoxy-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]oxy}phenyl)ethanol;

1-[3-({(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-yl}oxy)phenyl]ethanol;

2-(2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)propan-2-ol;

1,1,1-yrifluoro-2-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}phenyl)propan-2-ol;

2-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}phenyl)propan-2-ol;

(2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)methanol;

1-(2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)cyclobutanol;

2-(2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)butan-2-ol;

1-cyclopropyl-1-(2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)ethanol;

(1R)-1-cyclopropyl-1-(2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)ethanol;

(1S)-1-cyclopropyl-1-(2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)ethanol;

1,1-difluoro-2-(2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)propan-2-ol;

2-(3-methyl-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)propan-2-ol;

1-cyclopropyl-1-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}phenyl)ethanol;

1-cyclopentyl-1-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}phenyl)ethanol;

1-cyclobutyl-1-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}phenyl)ethanol;

2-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}phenyl)butan-2-ol;

4-(1-hydroxy-1-methylethyl)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}benzonitrile;

2-(4-fluoro-3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}phenyl)propan-2-ol;

2-(3-fluoro-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-yl)propan-2-ol;

5-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-1,2,3,4-tetrahydronaphthalen-1-ol;

6-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

(1R)-4-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

(1S)-4-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

(1R)-6-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

(1S)-6-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

(1R)-1-methyl-5-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-1,2,3,4-tetrahydronaphthalen-1-ol;

(1S)-1-methyl-5-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-1,2,3,4-tetrahydronaphthalen-1-ol;

(1R)-1-methyl-4-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

(1S)-1-methyl-4-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

1-methyl-6-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

(1R)-1-Methyl-6-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

(1S)-1-methyl-6-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-2,3-dihydro-1H-inden-1-ol;

2-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}phenyl)butan-2-ol; and

2-(3-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]oxy}phenyl)propan-2-ol;

or a pharmaceutically acceptable salt thereof.

12. (canceled)

13. (canceled)