Heterocyclic compounds as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

X is selected from the group consisting of —S—, —S(O)—, —S(O) 2 —, and —NR 9 —;

V is selected from the group consisting of:

Ar is phenyl optionally substituted with one to five R 1 substituents;

each R 1 is independently selected from the group consisting of

halogen,

cyano,

hydroxy,

C 1-6 alkyl, optionally substituted with one to five fluorines,

C 1-6 alkoxy, optionally substituted with one to five fluorines;

each R 2 is independently selected from the group consisting of

hydrogen,

hydroxy,

halogen,

cyano,

C 1-10 alkoxy, wherein alkoxy is optionally substituted with one to five substituents independently selected from fluorine and hydroxy,

C 1-10 alkyl, wherein alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxy,

C 2-10 alkenyl, wherein alkenyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxy,

(CH 2 ) n -aryl, wherein aryl is optionally substituted with one to five substituents independently selected hydroxy, halogen, cyano, nitro, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines,

(CH 2 ) n -heteroaryl, wherein heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy, halogen, cyano, nitro, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines,

(CH 2 ) n -heterocyclyl, wherein heterocyclyl is optionally substituted with one to three substituents independently selected from oxo, hydroxy, halogen, cyano, nitro, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines,

(CH 2 ) n —C 3-6 cycloalkyl, wherein cycloalkyl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, cyano, nitro, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines,

(CH 2 ) n —COOH,

(CH 2 ) n —COOC 1-6 alkyl,

(CH 2 ) n —NR 4 R 5 ,

(CH 2 ) n —CONR 4 R 5 ,

(CH 2 ) n —OCONR 4 R 5 ,

(CH 2 ) n —SO 2 NR 4 R 5 ,

(CH 2 ) n —SO 2 R 6 ,

(CH 2 ) n —NR 7 SO 2 R 6 ,

(CH 2 ) n —NR 7 CONR 4 R 5 ,

(CH 2 ) n —NR 7 COR 7 , and

(CH 2 ) n —NR 7 CO 2 R 6 ;

wherein any individual methylene (CH 2 ) carbon atom in (CH 2 ) n is optionally substituted with one to two substituents independently selected from fluorine, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines;

R 3a , R 3b , and R 3c are each independently hydrogen or C 1-4 alkyl optionally substituted with one to five fluorines;

R 4 and R 5 are each independently selected from the group consisting of

hydrogen,

(CH 2 ) m -phenyl,

(CH 2 ) m —C 3-6 cycloalkyl, and

C 1-6 alkyl, wherein alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxy and wherein phenyl and cycloalkyl are optionally substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines;

or R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is optionally substituted with one to three substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines;

each R 6 is independently cyclopropyl or C 1-6 alkyl, wherein alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxyl;

R 7 is hydrogen or R 6 ;

R 8 is selected from the group consisting of

hydrogen,

—SO 2 R 6 ,

(CH 2 ) p -phenyl,

(CH 2 ) p —C 3-6 cycloalkyl, and

C 1-6 alkyl, wherein alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxy and wherein phenyl and cycloalkyl are optionally substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines;

R 9 is selected from the group consisting of:

hydrogen,

C 1-4 alkyl wherein alkyl is optionally substituted with one to five fluorines,

C 3-6 cycloalkyl,

(CH 2 ) 1-2 -phenyl, wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, cyano, and trifluoromethyl, and

(CH 2 ) 1-2 -heteroaryl, wherein heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of fluoro, cyclopropyl, C 1-4 alkyl, and trifluoromethyl; and

each n is independently 0, 1, 2 or 3;

each m is independently 0, 1, or 2; and

each p is independently 0 or 1.

2. The compound of claim 1 wherein X is —S—, —S(O)—, or —S(O) 2 —.

3. The compound of claim 1 wherein X is —NR 9 —.

4. The compound of claim 3 wherein R 9 is selected from the group consisting of:

C 1-4 alkyl, optionally substituted with one to five fluorines;

CH 2 -phenyl, wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, and trifluoromethyl,

CH 2 CH 2 -phenyl, wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, and trifluoromethyl, and

CH 2 CH 2 -pyridyl, wherein pyridyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, and trifluoromethyl.

5. The compound of claim 4 wherein R9 is methyl.

6. The compound of claim 1 wherein V is selected from the group consisting of:

7. The compound of claim 6 wherein R 3a , R 3b , and R 3c are each hydrogen.

8. The compound of claim 1 wherein V is selected from the group consisting of:

9. The compound of claim 8 wherein R 3a , R 3b , and R 3c are each hydrogen.

10. The compound of claim 1 wherein V is selected from the group consisting of:

11. The compound of claim 10 wherein R 3a and R 3b are each hydrogen.

12. The compound of claim 1 wherein V is selected from the group consisting of:

13. The compound of claim 12 wherein R 3a and R 3b are each hydrogen.

14. The compound of claim 1 wherein V is selected from the group consisting of:

15. The compound of claim 1 wherein Ar is phenyl optionally substituted with one to three substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl, and trifluoromethoxy.

16. The compound of claim 15 wherein Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.

17. The compound of claim 1 wherein each R 2 is independently selected from the group consisting of

hydrogen,

amino,

C 1-4 alkyl, wherein alkyl is optionally substituted with one to five fluorines, and

C 3-6 cycloalkyl, wherein cycloalkyl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines.

18. The compound of claim 17 wherein each R 2 is independently selected from the group consisting of hydrogen, amino, C 1-3 alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl.

19. The compound of claim 1 wherein R 8 is selected from the group consisting of:

hydrogen,

—SO 2 R 6 ,

C 1-4 alkyl, wherein alkyl is optionally substituted with one to five fluorines, and

C 3-6 cycloalkyl, wherein cycloalkyl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines.

20. The compound of claim 19 wherein each R 8 is selected from the group consisting of hydrogen, C 1-3 alkyl, methanesulfonyl, trifluoromethanesulfonyl, and cyclopropylmethanesulfonyl.

21. The compound of claim 1 of structural formula Ia or Ib having the indicated stereochemical configuration at the two stereogenic carbon atoms marked with an *:

22. The compound of claim 21 of structural formula Ia having the indicated absolute stereochemical configuration at the two stereogenic carbon atoms marked with an *:

23. The compound of claim 21 of structural formulae Ic and Id having the indicated stereochemical configuration at the three stereogenic carbon atoms marked with an *:

24. The compound of claim 23 of structural formula Ic having the indicated absolute stereochemical configuration at the three stereogenic carbon atoms marked with an *:

25. The compound of claim 21 of structural formulae Ie and If having the indicated stereochemical configuration at the three stereogenic carbon atoms marked with an *:

26. The compound of claim 25 of structural formula Ie having the indicated absolute stereochemical configuration at the three stereogenic carbon atoms marked with an *:

27. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27 additionally comprising metformin.

29. A method for treating non-insulin dependent (Type 2) diabetes in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim 1 .