Cyclopentapyrrole orexin receptor agonists

Patent metadata

Field	Value
Publication number	US-12497362-B2
Application number	US-202118040861-A
Country	US
Kind code	B2
Filing date	Aug 16, 2021
Priority date	Aug 18, 2020
Publication date	Dec 16, 2025
Grant date	Dec 16, 2025

Abstract

The present invention is directed to cyclopentapyrrole, furopyrrole and azabicycloheptane 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;
Z is —O— or CH;
W is CH, or if Z is CH, W may be a direct bond to Z;
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 2-4 alkenyl,
(5) C 2-4 alkynyl,
(6) —C 3-6 cycloalkyl,
(7) —O—C 1-6 alkyl,
(8) —O(C═O)—C 1-6 alkyl,
(9) —NH 2 ,
(10) —NH—C 1-6 alkyl,
(11) —NO 2 ,
(12) phenyl,
(13) —CO 2 H,
(14) —SO 2 —C 1-6 alkyl,
(15) —C 3-5 cycloalkyl(SO 2 ), and
(16) —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 Z is CH and W is CH.

4 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Z is —O— and W is CH.

5 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Z is CH and W is a direct bond to Z.

6 . 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 .

7 . 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 ,
(6) phenyl, which is unsubstituted or substituted with —CF 3 , —CH 2 CF 3 , or one to three fluoro, and
(7) pyrimidinyl, which is unsubstituted or substituted with —CF 3 , —CH 2 CF 3 , or one to three fluoro.

8 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2a is hydrogen and R 2b is hydrogen.

9 . The compound of claim 1 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.

10 . A compound which is selected from:
methyl (2R,3S,3aS,6aR)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamido)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate; methyl (2R,3S,3aS,6aR)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate; methyl (2R,3S,3aS,6aR)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((N-methylsulfamoyl)amino)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate; methyl (2R,3S,3aS,6aS)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamido)hexahydro-1H-furo[3,4-b]pyrrole-1-carboxylate; methyl (2R,3S,3aS,6aS)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)hexahydro-1H-furo[3,4-b]pyrrole-1-carboxylate; methyl (2R,3S,3aS,6aS)-3-((fluoromethyl)sulfonamido)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)hexahydro-1H-furo[3,4-b]pyrrole-1-carboxylate; methyl (2R,3S,3aS,6aR)-3-(methylsulfonamido)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate; methyl (2R,3S,3aS,6aR)-2-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3-(methylsulfonamido)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate; methyl (2R,3S,3aS,6aR)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate; isopropyl (2R,3S,3aS,6aR)-2-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3-(methylsulfonamido)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate; methyl (1R,3R,4S,5S)-4-(methylsulfonamido)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)-2-azabicyclo[3.2.0]heptane-2-carboxylate;
or a pharmaceutically acceptable salt thereof.

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

12 . A method for treating narcolepsy in a mammalian subject which comprises administering to the patient an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13 . A method for treating hypersomnia in a mammalian subject which comprises administering to the patient an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Bogen Stephane L
• Clausen Dane James
• Rudd Michael T
• Xiao Dong
• Yang Dexi

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61K31/403 Primary

  condensed with carbocyclic rings, e.g. carbazole · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D491/02

  in which the condensed system contains two hetero rings · CPC title