5-alkyl pyrrolidine orexin receptor agonists

Patent metadata

Field	Value
Publication number	US-11098029-B2
Application number	US-202016787201-A
Country	US
Kind code	B2
Filing date	Feb 11, 2020
Priority date	Feb 13, 2019
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention is directed to 5-alkyl 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 Ib′″:

wherein:
X is —O— or —NH—, or X may be a direct bond to R 1 ;
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 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;

R 5 is:
(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 ;

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 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 , —CH 2 CF 3 , or one to three fluoro.

6. 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.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is selected from:
(1) al methyl,
(2) ethyl,
(3) —CHF 2 ,
(4) —CF 3 ,
(5) —CH 2 OH,
(6) —CH 2 OCH 3 , and
(7) 0 cyclopropyl.

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

9. A compound which is selected from:
(2R,3S,5R)-N-ethyl-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)-pyrrolidine-1-carboxamide;
(2R,3S,5R)-N-ethyl-5-methyl-3-(methylsulfonamido)-2-(((4-(trifluoromethyl)-cyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide;
methyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)-pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1s,4S)-4-isopropylcyclohexyl)oxy)-methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;
isopropyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;
isopropyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-((N-methylsulfamoyl)amino)pyrrolidine-1-carboxylate;
ethyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;
ethyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((4-isopropylcyclohexyl)-oxy)methyl)-5-methylpyrrolidine-1-carboxylate;
2,2-difluoroethyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;
2-fluoroethyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((4-(trifluoromethyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((4-(2,2,2-trifluoroethyl)-cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;
2,2-difluoroethyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-((N-methylsulfamoyl)amino)pyrrolidine-1-carboxylate;
2,2-difluoroethyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((4-isopropylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate;
2,2-difluoroethyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;
2,2-difluoroethyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1r,4R)-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1r,4R)-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate;
2,2-difluoroethyl (2R,3S,5R)-2-((((1r,4R)-4-(2,5-difluorophenyl)-cyclohexyl)oxy)-methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(2-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-((N-methylsulfamoyl)amino)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((fluoromethyl)sulfonamido)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1r,4R)-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-

Assignees

• Merck Sharp & Dohme

Inventors

• Bogen Stephane L
• Clausen Dane James
• Guiadeen Deodial Guy
• Rudd Michael T
• Yang Dexi

Classifications

• C07D207/16 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D409/12

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

• C07D209/54

  Spiro-condensed · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title