Ethyldiamine orexin receptor antagonists

Patent metadata

Field	Value
Publication number	US-10011595-B2
Application number	US-201515532602-A
Country	US
Kind code	B2
Filing date	Dec 14, 2015
Priority date	Dec 19, 2014
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

The present invention is directed to ethyldiamne compounds which are antagonists of orexin receptors. Such compounds are of the general structural formula I:

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 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 I:

wherein:
A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, benzimidazolyl, and benzoxazolyl;
X is N or CH;
each of R 1a ,R 1b and R 1c is 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) 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 C 1-6 alkyl, which is which is unsubstituted or substituted with halo, C 3-6 cycloalkyl or phenyl;
R 3 is C 1-6 alkyl, which is which is unsubstituted or substituted with halo or hydroxyl;
R 5 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, hydroxyl 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
(7) —(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, hydroxyl 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
(7) —(C═O)—O—C 1-6 alkyl
with the proviso that at least one of R 5 and R 6 is other than hydrogen;

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 of the formula Ib:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is ethyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is methyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is selected from the group consisting of:
(1) hydrogen,
(2) methyl,
(3) —C(CH 3 ) 2 OH,
(4) —CH(OH)CF 3 ,
(5) —CH(OH)CH 3 ,
(6) —C(OH)(CF 3 )CH 3 , and
(7) —C(═O)OCH 3 .

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

8. A compound which is selected from the group consisting of:
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
2-cyclopropyl-N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethylbenzamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethyl-2-isopropoxynicotinamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-2-ethoxy-N-ethylnicotinamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethyl-2-(trifluoromethoxy)benzamide;
2-(difluoromethoxy)-N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethylbenzamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethyl-2-phenylnicotinamide;
2-(2,2-difluoroethoxy)-N-(2-(4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethylnicotinamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethyl-2-(2,2,2-trifluoroethoxy)nicotinamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethyl-4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzamide
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-2-ethoxy-N-ethylbenzamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethyl-2-(1H-pyrazol-1-yl)benzamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)ethyl)-N-ethyl-3-(2H-1,2,3-triazol-2-yl)pyrazine-2-carboxamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-propylbenzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2,2,2-trifluoroethoxy)-benzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2,2,2-trifluoroethyl)benzamide;
2-cyclopropyl-N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-6-methoxypyridine-3-carboxamide;
2-(2,2-difluoroethoxy)-N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethylbenzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2,2,2-trifluoroethyl)pyridine-3-carboxamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-3 -(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide;
2-(2,2-difluoroethyl)-N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethylbenzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(1H-pyrazol-1-yl)pyridine-3-carboxamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-3-pyrrolidin-1-ylpyrazine-2-carboxamide;
2-cyclobutyl-N-{2[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethylbenzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-3-phenylpyridine-2-carboxamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-3-(1H-pyrazol-1-yl)pyrazine-2-carboxamide;
2-(2,2-difluorocyclopropyl)-N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethylbenzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-pyrrolidin-1-ylbenzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2H-tetrazol-2-yl)benzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-pyrimidin-2-ylbenzamide;
N-{2-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-3-pyridin-2-ylpyrazine-2-carboxamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(ethyl)amino)ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-(2-((4,6-dimethylpyrimidin-2-yl)(isopropyl)amino)ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-(2-((2,2-difluoroethyl)(4,6-dimethylpyrimidin-2-yl)amino)ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-(2-((4-cyanopyridin-2-yl)(methyl)amino)ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-(2-((4-cyano-3-methylpyridin-2-yl)(methyl)amino)ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-{2-[(3-chloro-4-cyanopyridin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-{2-[(4,6-dimethoxypyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-{2-[(4-cyanopyrimidin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-(2-{[4-chloro-6-(dimethylamino)pyrimidin-2-yl](methyl)amino}ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-{2-[(6-cyanopyridin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-(2-{[5-chloro-4-(trifluoromethyl)pyrimidin-2-yl](methyl)amino}ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
N-{2-[(6-cyanopyridin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;
{2-[(4-cyanopyridin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(trifluoromethoxy)benzamide;
N-{2-[(4-cyanopyridin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-(1H-tetrazol-5-yl)benzamide;
2-(benzyloxy)-N-{2-[(4-cyanopyridin-2-yl)(methyl)amino]ethyl}-N-ethylpyridine-3-carboxamide;
N-{2-[(4-cyanopyridin-2-yl)(methyl)amino]ethyl}-N-ethyl-2-phenoxypyridine-3 -carboxamide;
N-{

Assignees

• Merck Sharp & Dohme

Inventors

• Kim Ronald M
• Kuduk Scott D
• Liverton Nigel
• Zhou Gang

Classifications

• C07D405/12

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

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

• C07D213/84

  Nitriles · CPC title

• C07D413/12 Primary

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