Pyrrolidine orexin receptor antagonists

Patent metadata

Field	Value
Publication number	US-10150751-B2
Application number	US-201515534200-A
Country	US
Kind code	B2
Filing date	Dec 14, 2015
Priority date	Dec 19, 2014
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

The present invention is directed to pyrrolidine 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 compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

First claim

What is claimed is:

1. A compound of the formula Ib:

wherein:
R 1a and R 1b are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C l-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(5) —O—C l-6 alkyl, 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 1-6 alkyl, —O—C 1-6 alkyl or —NO 2 ;

R 2 is hydrogen;
R 3 is methyl;
R 5 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —CN,
(3) C 1-6 alkyl, which is unsubstituted or substituted with halogen or phenyl,
(4) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen or phenyl,
(5) —O—C 3-6 cycloalkyl, which is unsubstituted or substituted with C 1-6 alkyl, halogen or phenyl, and
(6) —(C═O )—O—C 1-6 alkyl ;

R 6 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —CN,
(4) C 1-6 alkyl, which is unsubstituted or substituted with halogen or phenyl,
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen or phenyl,
(6) —O—C 3-6 cycloalkyl, which is unsubstituted or substituted with C 1-6 alkyl, halogen or phenyl, and
or R 5 and R 6 may be joined together with the carbon atoms to which they are attached to form a 6-membered aromatic ring, which is unsubstituted or substituted with one or two C 1-6 alkyl;

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) hydrogen,
(2) halogen,
(3) C 1-6 alkyl, which is unsubstituted or substituted with halogen,
(4) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen, and
(5) —(C═O )—O—C 1-6 alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is selected from the group consisting of: hydrogen, fluoro, methyl, and methoxy.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 6 is selected from the group consisting of:
(1) —CN, and
(2) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 6 is selected from the group consisting of: —CN, methyl, methoxy, and difluoroethoxy.

6. A compound which is selected from the group consisting of:
1-(2-((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclobutcarbonitrile;
1-(2-((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclopropanecarbonitrile;
(2-(2H-tetrazol-2-yl)phenyl)((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone;
((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-ethoxypyridin-3-yl)methanone;
((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2,3-dihydro-1H-inden-4-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-(quinolin-2-ylamino)pyrrolidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((5-fluoropyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-(isoquinolin-1-ylamino)-2-methylpyrrolidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-chloropyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-((4-methylpyridin-2-yl)amino)pyrrolidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-fluoropyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinonitrile;
2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)isonicotinonitrile;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-isopropoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-ethoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
N-((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)-N-(4-cyanopyridin-2-yl)acetamide;
2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)(methyl)amino)isonicotinonitrile;
1-(2-((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclopropanecarbonitrile;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-((methylsulfonyl)methyl)phenyl)methanone;
(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin- 1-yl)methanone;
(4-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin- 1-yl)methanone;
2-(((3R,5R)-1-(2-(2H-tetrazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)isonicotinonitrile;
2(3R,5R)-5-methyl-1-(2-(pyrimidin-2-yl)benzoyl)pyrrolidin-3-yl)amino)isonicotinonitrile;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-bromopyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinate;
ethyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinate;
methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-ethoxynicotinate
(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,4R)-4-((4-bromopyridin-2-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)methanone;
2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-3-methylisonicotinonitrile;
2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)(methyl)amino)-3-methylisonicotinonitrile;
methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-cyanonicotinate;
2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-3-methoxyisonicotinonitrile;
(3-(1H-pyrazol-1-yl)pyridin-2-yl)((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(3-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)methanone;
((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)methanone;
(3-(1H-pyrazol-1-yl)pyrazin-2-yl)((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone;
((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(3-(pyridin-2-yl)pyrazin-2-yl)methanone;
((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)methanone;
((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-propylphenyl)methanone; and
((2S,4S)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-(trifluoromethoxy)phenyl)methanone;
or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically

Assignees

• Merck Sharp & Dohme

Inventors

• Kuduk Scott D
• Liverton Nigel
• Luo Yunfu
• Skudlarek Jason W

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title