5-alkyl pyrrolidine orexin receptor agonists

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-3-(methylsulfonamido)-2-((((1r,4R)-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((fluoromethyl)sulfonamido)-5-methyl-2-((((1r,4R)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,5-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-(3-fluorophenyl)cyclohexyl)-oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

isopropyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate;

isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (CIS)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)-oxy)methyl)-pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)-oxy)methyl)-pyrrolidine-1-carboxylate;

methyl (CIS)-5-cyclopropyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2S,3R,5S)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (CIS)-5-ethynyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate;

methyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-5-vinylpyrrolidine-1-carboxylate;

methyl (CIS)-5-(2-hydroxyethyl)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (CIS)-5-(hydroxymethyl)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-(methoxymethyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N-(cyanomethyl)-N-methylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N-(2-cyanoethyl)-N-methylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((N-(2-methoxyethyl)-N-methylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((N-(2-hydroxyethyl)-N-methylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-((N-methyl-N-(2-(methylsulfonyl)ethyl)sulfamoyl)amino)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N-((1,1-dioxidothietan-3-yl)methyl)-N-methylsulfamoyl)-amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-((N-methyl-N-(2-(trifluoromethoxy)ethyl)sulfamoyl)amino)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((2,2-difluoroethyl)sulfonamido)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N-(2-cyanoethyl)-N-methylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-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)-2-((((1s,4S)-4-(4-cyano-3-methylphenyl)cyclohexyl)oxy)-methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1r,4R)-4-(4-cyano-3-methylphenyl)cyclohexyl)oxymethyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(2-ethylphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1r,4R)-4-(2-ethylphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S,3R,4R)-4-(3-fluorophenyl)cyclohexyl-3,4-d2)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S,3S,4S)-4-(3-fluorophenyl)cyclohexyl-3,4-d2)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1r,4R)-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1s,4S)-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1r,4R)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; and

methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,4-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

or a pharmaceutically acceptable salt thereof.

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

11. 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.

12. 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.