Pyrrolidine orexin receptor agonists

Patent metadata

Field	Value
Publication number	US-2022144771-A1
Application number	US-202017430409-A
Country	US
Kind code	A1
Filing date	Feb 11, 2020
Priority date	Feb 13, 2019
Publication date	May 12, 2022
Grant date	—

Abstract

The present invention is directed to pyrrolidine compounds which are agonists 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

1 . A compound of the formula I:

wherein:
X is —O— or —NH—, or X may be a direct bond to R 1 ;
Y is N or CH;
R 1 is selected from:
(1) —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , and
(2) —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ;

R 2 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ,
(3) —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ,
(4) -phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from R 4 , and
(5) -heteroaryl, where the heteroaryl is selected from: pyridyl, pyrimidinyl, and pyrazinyl, and the heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R 4 ;

R 2a and R 2b are independently selected from:
(1) hydrogen,
(2) hydroxyl,
(3) halogen, and
(4) —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from halogen;

R 3 is selected from:
(1) —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ,
(2) —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ,
(3) -phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from R 4 ,
(4) —NR 10 R 11 , wherein R 10 and R 11 are independently selected from:
(a) hydrogen, and
(b) C 1-6 alkyl, which is unsubstituted or substituted with one to six R 4 ;

R 4 is selected from:
(1) hydroxyl,
(2) halogen,
(3) C 1-6 alkyl, which is unsubstituted or substituted with one to six fluoro,
(4) —C 3-6 cycloalkyl,
(5) —O—C 1-6 alkyl,
(6) —O(C═O)—C 1-6 alkyl,
(7) —NH 2 ,
(8) —NH—C 1-6 alkyl,
(9) —NO 2 ,
(10) phenyl,
(11) —CO 2 H, and
(12) —CN;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein X is —O—.

3 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein X is —NH—.

4 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is selected from:
(1) methyl,
(2) ethyl,
(3) —CH 2 OH,
(4) —CH 2 CF 3 ,
(5) —CH 2 CHF 2 ,
(6) —CH(CH 3 ) 2 ,
(7) —CH 2 CH 2 CH 2 F,
(8) cyclopropyl,
(9) —CH 2 -cyclopropyl,
(10) —CH 2 -cyclobutyl, and
(11) —CH 2 O(C═O)CH 3 .

5 . The compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from:
(1) hydrogen,
(2) —CH 2 (CH 3 ) 2 ,
(3) —CF 3 ,
(4) —CH 2 CHF 2 ,
(5) —CH 2 CF 3 , and
(6) phenyl, which is unsubstituted or substituted with —CF 3 or —CH 2 CF 3 .

6 . The compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof wherein R 3 is selected from:
(1) —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro,
(2) —C 3-6 cycloalkyl,
(3) —NH 2 ,
(4) —NH(C 1-6 alkyl),
(5) —N(C 1-6 alkyl)(C 1-6 alkyl), and
(6) -phenyl.

7 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is selected from:
(1) methyl,
(2) —CF 3 ,
(3) —CH 2 F,
(4) ethyl,
(5) cyclopropyl,
(6) —CH(CH 3 ) 2 ,
(7) —NH(CH 3 ),
(8) —N(CH 3 ) 2 , and
(9) -phenyl.

8 . A compound which is selected from:
N-ethyl-3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide; (CIS)-N-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide; methyl 3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; N-(1-acetyl-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide; N-((CIS)-1-acetyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide; ethyl 3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; ethyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; isopropyl 3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; isopropyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; 2-fluoroethyl 3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; 2-fluoroethyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; 2-(3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidin-1-yl)-2-oxoethyl acetate; 2-((CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-1-yl)-2-oxoethyl acetate; N-(1-(cyclopropanecarbonyl)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide; N-((CIS)-1-(cyclopropanecarbonyl)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide; N-isopropyl-3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide; (CIS)-N-isopropyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide; 3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide; (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide; methyl 3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; 2,2-difluoroethyl 3-(methylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate; 2,2-difluoroethyl (2R,3S)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate; methyl 3-(ethylsulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (CIS)-3-(ethylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl 3-((1-methylethyl)sulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl 3-((1-methylethyl)sulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl (CIS)-3-((1-methylethyl)sulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl 3-(cyclopropanesulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl (CIS)-3-(cyclopropanesulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl 3-((fluoromethyl)sulfonamido)-2-(((4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl (CIS)-3-((fluoromethyl)sulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl 2-(((4-phenylcyclohexyl)oxy)methyl)-3-(phenylsulfonamido)pyrrolidine-1-carboxylate; methyl (CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-3-(phenylsulfonamido)pyrrolidine-1-carboxylate; methyl 3-((N-methylsulfamoyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl (CIS)-3-N-methylsulfamoyl)amino)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl 3-((N,N-dimethylsulfamoyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylat

Assignees

• Merck Sharp & Dohme

Inventors

• Bogen Stephane L
• Breslin Michael J
• Clausen Dane James
• Ginnetti Anthony
• Rudd Michael T
• Stachel Shawn J
• Stump Craig A
• Yang Dexi

Classifications

• C07D207/14 Primary

  Nitrogen atoms not forming part of a nitro radical · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title