Pyrrolidine orexin receptor agonists

Patent metadata

Field	Value
Publication number	US-12331018-B2
Application number	US-202017430409-A
Country	US
Kind code	B2
Filing date	Feb 11, 2020
Priority date	Feb 13, 2019
Publication date	Jun 17, 2025
Grant date	Jun 17, 2025

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

What is claimed is:

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 phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from 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 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 .

4. The compound of claim 1 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 .

5. A compound which is selected from: methyl 2-(((4-phenylcyclohexyl)oxy)methyl)-3-(phenylsulfonamido)pyrrolidine-1-carboxylate; methyl (CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-3-(phenylsulfonamido)pyrrolidine-1-carboxylate; 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.

Assignees

• Merck Sharp & Dohme Llc

Inventors

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

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D207/14 Primary

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