Bicycloheptane pyrrolidine orexin receptor agonists

1. A compound of the formula I:

wherein:

wherein n is 0 or 1;

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

Y is O or CH 2 ;

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 ,

(2) —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ; and

(3) -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from R 4 ;

R 2a and R 2b are 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, benzothiazolyl, thiazolyl and pyrazinyl, and the heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R 4 ,

Provided that at least one of R 2a and R 2b is hydrogen;

R 2c and R 2d are independently selected from:

(1) hydrogen, and

(2) fluoro;

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 ,

(5) -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from R 4 ,

(6) —CHF 2 , and

(7) —CF 3 ;

R 4 is independently selected from:

(1) hydroxyl,

(2) halogen,

(3) C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 7 ,

(4) C 2-4 alkenyl,

(5) C 2-4 alkynyl,

(6) —C 3-6 cycloalkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 7 ,

(7) —O—C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 7 ,

(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 ),

(16) —CN,

(17) -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from R 7 ,

(18) —CHF 2 , and

(19) —CF 3 ;

R 5 and R 6 are independently 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 , and

(3) —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ,

or R 5 and R 6 are joined together with the carbon atoms to which they are attached to form a —C 3-6 cycloalkyl ring, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ;

R 7 is independently selected from:

(1) halogen,

(2) C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from halo, phenyl or cycloalkyl,

(3) —CHF 2 , and

(4) —CF 3 ;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein\

wherein n is 0 or 1.

3. The compound of claim 1 , according to formula IA:

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 2a and R 2b are 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 ;

Provided that at least one of R 2a and R 2b is hydrogen;

R 2c and R 2d are independently selected from:

(1) hydrogen, and

(2) fluoro;

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 , and

(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 independently selected from:

(1) hydroxyl,

(2) halogen,

(3) C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 7 ,

(4) C 2-4 alkenyl,

(5) C 2-4 alkynyl,

(6) —C 3-6 cycloalkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 7 ,

(7) —O—C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 7 ,

(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 ),

(16) —CN,

(17) -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from R 7 ,

(18) —CHF 2 , and

(19) —CF 3 ;

R 5 and R 6 are independently 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 , and

(3) —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ,

or R 5 and R 6 are joined together with the carbon atoms to which they are attached to form a —C 3-6 cycloalkyl ring, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ;

R 7 is independently selected from:

(1) halogen,

(2) C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from halo, phenyl or cycloalkyl,

(3) —CHF 2 , and

(4) —CF 3 ;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is selected from:

(1) —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents independently selected from hydroxyl, halo, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —O(C═O)—C 1-6 alkyl, and

(2) —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R 4 .

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are selected from:

(1) hydrogen,

(2) —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro,

(3) phenyl, which is unsubstituted or substituted with one to three fluoro, —CN, or —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro, and

(4) heteroaryl, where the heteroaryl is selected from: pyridyl, pyrimidinyl, benzothiazolyl, thiazolyl and pyrazinyl, and the heteroaryl is unsubstituted or substituted with one to three substituents selected from halo, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, CN, or —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro;

Provided that at least one of R 2a and R 2b is hydrogen.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are selected from:

(1) hydrogen,

(2) —CH 2 (CH 3 ) 2 ,

(3) —CF 3 ,

(4) —CH 2 CHF 2 ,

(5) —CH 2 CF 3 ,

(6) pyridyl,

(7) pyrimidinyl,

(8) pyrazinyl,

(9) phenyl,

(10) benzothiazolyl, and

(11) thiazolyl;

Wherein said pyridyl, pyrimidinyl, pyrazinyl, phenyl, benzothiazolyl or thiazolyl is unsubstituted or substituted with halo, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, CN, or —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro;

Provided that at least one of R 2a and R 2b is hydrogen.

7. 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 four substituents independently selected from R 4 ,

(2) —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to four 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 four R 4 ,

(5) -heterocyclyl, where the heterocyclyl is azetidinyl or oxetanyl and is unsubstituted or substituted with one to three substituents independently selected from R 4 ,

(6) —CHF 2 , and

(7) —CF 3 .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 and R 6 are independently selected from:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) —CHF 2 ,

(5) —CF 3 ,

(6) —CH 2 OH,

(7) —CH 2 OCH 3 , and

(8) cyclopropyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , and R 6 is hydrogen.

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 a sleep disorder 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 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.

14. 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.

15. A compound which is selected from

methyl (2R,3S,5R)-3-((fluoromethyl)sulfonamido)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-((trifluoromethyl)sulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-(ethylsulfonamido)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((difluoromethyl)sulfonamido)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

2,2-difluoroethyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((difluoromethyl)sulfonamido)-5-methyl-2-(((6-(pyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((difluoromethyl)sulfonamido)-5-methyl-2-((((1S,3S,6R)-6-(pyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((difluoromethyl)sulfonamido)-5-methyl-2-((((1R,3R,6S)-6-(pyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5 S)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-(methoxymethyl)-3-(methylsulfonamido) pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-(((6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1R,3R,6S)-6-(5-fluoropyrimidin yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-(((6-(5-chloropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1R,3R,6S)-6-(5-chloropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-chloropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1R,3R,6S)-6-(thiazol-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1S,3S,6R)-6-(thiazol-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-(((6-(thiazol-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; and

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate;

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition which comprises an inert carrier and a compound of claim 15 or a pharmaceutically acceptable salt thereof.

17. A method for treating a sleep disorder in a mammalian subject in need which comprises administering to the patient an effective amount of the compound of claim 15 or a pharmaceutically acceptable salt thereof.

18. A method for treating narcolepsy in a mammalian subject in need which comprises administering to the patient an effective amount of the compound of claim 15 or a pharmaceutically acceptable salt thereof.

19. A method for treating hypersomnia in a mammalian subject in need which comprises administering to the patient an effective amount of the compound of claim 15 or a pharmaceutically acceptable salt thereof.

20. A compound having the structure

2,2-difluoroethyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 with the structure

2,2-difluoroethyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate.

22. A pharmaceutical composition which comprises an inert carrier and a compound of claim 20 or a pharmaceutically acceptable salt thereof.

23. A compound having the structure

methyl (2R,3S,5R)-3-((difluoromethyl)sulfonamido)-5-methyl-2-(((6-(pyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23 having the structure:

methyl (2R,3S,5R)-3-((difluoromethyl)sulfonamido)-5-methyl-2-((((1S,3S,6R)-6-(pyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

25. The compound of claim 23 having the structure:

methyl (2R,3S,5R)-3-((difluoromethyl)sulfonamido)-5-methyl-2-((((1R,3R,6S)-6-(pyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

26. The compound of claim 23 having the structure

methyl (2R,3S,5R)-3-((difluoromethyl)sulfonamido)-5-methyl-2-(((6-(pyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)pyrrolidine-1-carboxylate.

27. A pharmaceutical composition which comprises an inert carrier and a compound of claim 23 or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition which comprises an inert carrier and a compound of claim 24 or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition which comprises an inert carrier and a compound of claim 25 or a pharmaceutically acceptable salt thereof.

30. A compound having the structure

methyl (2R,3S,5R)-2-(((6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl) methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

31. The compound of claim 30 , having the structure

methyl (2R,3S,5R)-2-((((1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

32. The compound of claim 30 , having the structure

methyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

33. The compound of claim 30 , having the structure

methyl (2R,3S,5R)-2-(((6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate.

34. A pharmaceutical composition which comprises an inert carrier and a compound of claim 30 or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition which comprises an inert carrier and a compound of claim 31 or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition which comprises an inert carrier and a compound of claim 32 or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition which comprises an inert carrier and a compound of claim 33 or a pharmaceutically acceptable salt thereof.