Azacycloalkane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

each m is independently an integer from 0 to 4;

each n is independently an integer from 0 to 2;

each s is independently an integer from 1 to 3;

each t is independently an integer from 1 to 3;

q is 0 or 1;

r is 0 or 1;

Z is O, S, or NR 4 ;

X—Y is N—CR a R b , CR 14 —S(O) 0-2 , or CR 13—CR a R b ;

W is heteroaryl selected from the group consisting of:

Ar is phenyl, naphthyl, or heteroaryl optionally substituted with one to five R 3 substituents;

R a and R b are each independently hydrogen or C 1-3 alkyl, wherein alkyl is optionally substituted with one to three substituents independently selected from fluorine and hydroxy;

R 1 is heteroaryl selected from the group consisting of:

wherein R c is —(CH 2 ) m CO 2 H, —(CH 2 ) m CO 2 C 1-3 alkyl, —(CH 2 ) m -Z-(CH 2 ) p CO 2 H, or —(CH 2 ) m -Z-(CH 2 ) p CO 2 C 1-3 alkyl, wherein each (CH 2 ) methylene group is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, fluorine, oxo, and hydroxy; and wherein said R 1 heteroaryl ring is optionally substituted with one substituent independently selected from the group consisting of cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfonyl, and trifluoromethyl;

each R 2 is independently selected from the group consisting of:

hydrogen,

halogen,

hydroxy,

cyano,

amino,

nitro,

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

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

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

C 1-4 alkylsulfonyl,

carboxy,

C 1-4 alkyloxycarbonyl, and

C 1-4 alkylcarbonyl;

each R 3 is independently selected from the group consisting of:

C 1-6 alkyl,

C 2-6 alkenyl,

(CH 2 ) n -phenyl,

(CH 2 ) n -naphthyl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl,

(CH 2 ) n C 3-7 cycloalkyl,

halogen,

nitro,

(CH 2 ) n OR 4 ,

(CH 2 ) n N(R 4 ) 2 ,

(CH 2 ) n C≡N,

(CH 2 ) n CO 2 R 4 ,

(CH 2 ) n NR 4 SO 2 R 4

(CH 2 ) n SO 2 N(R 4 ) 2 ,

(CH 2 ) n S(O)O 0-2 R 4 ,

(CH 2 ) n NR 4 C(O)N(R 4 ) 2 ,

(CH 2 ) n C(O)N(R 4 ) 2 ,

(CH 2 ) n NR 4 C(O)R 4 ,

(CH 2 ) n NR 4 CO 2 R 4 ,

(CH 2 ) n C(O)R 4 ,

O(CH 2 ) n C(O)N(R 4 ) 2 ,

(CH 2 ) s -Z-(CH 2 ) t -phenyl,

(CH 2 ) s -Z-(CH 2 ) t -naphthyl,

(CH 2 ) s -Z-(CH 2 ) t -heteroaryl,

(CH 2 ) s -Z-(CH 2 ) t -heterocyclyl,

(CH 2 ) s -Z-(CH 2 ) t —C 3-7 cycloalkyl,

(CH 2 ) s -Z-(CH 2 ) t —OR 4 ,

(CH 2 ) s -Z-(CH 2 ) t —N(R 4 ) 2 ,

(CH 2 ) s -Z-(CH 2 ) t —NR 4 SO 2 R 4 ,

(CH 2 ) s -Z-(CH 2 ) t —C≡N,

(CH 2 ) s -Z-(CH 2 ) t —CO 2 R 4 ,

(CH 2 ) s -Z-(CH 2 ) t —SO 2 N(R 4 ) 2 ,

(CH 2 ) s -Z-(CH 2 ) t —S(O) 0-2 R 4 ,

(CH 2 ) s -Z-(CH 2 ) t —NR 4 C(O)N(R 4 ) 2 ,

(CH 2 ) s -Z-(CH 2 ) t —C(O)N(R 4 ) 2 ,

(CH 2 ) s -Z-(CH 2 ) t —NR 4 C(O)R 4 ,

(CH 2 ) s -Z-(CH 2 ) t —NR 4 CO 2 R 4 ,

(CH 2 ) s -Z-(CH 2 ) t —C(O)R 4 ,

CF 3 ,

CH 2 CF 3 ,

OCF 3 , and

OCH 2 CF 3 ;

in which phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 3 is optionally substituted with one to two groups independently selected from fluorine, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

each R 4 is independently selected from the group consisting of

hydrogen,

C 1-6 alkyl,

(CH 2 ) n -phenyl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -naphthyl, and

(CH 2 ) n C 3-7 cycloalkyl;

wherein alkyl, phenyl, heteroaryl, and cycloalkyl are optionally substituted with one to three groups independently selected from halogen, trifluoromethyl, C 1-4 alkyl, and C 1-4 alkoxy; or two R 4 groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, NH, and NC 1-4 alkyl;

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently hydrogen, fluorine, or C 1-3 alkyl, wherein alkyl is optionally substituted with one to three substituents independently selected from fluorine and hydroxy;

R 13 is hydrogen, C 1-3 alkyl, fluorine, or hydroxy; and

each R 14 is hydrogen or C 1-3 alkyl.

2. The compound of claim 1 wherein m is 1 or 2.

3. The compound of claim 1 wherein q and r are both 1.

4. The compound of claim 1 wherein X—Y is CH—O.

5. The compound of claim 4 wherein Ar is phenyl substituted with one to three R 3 substituents.

6. The compound of claim 1 wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each hydrogen.

7. The compound of claim 1 wherein each R 2 is hydrogen.

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

wherein R c is —CH 2 CO 2 H or —CH 2 CO 2 C 1-3 alkyl.

9. The compound of claim 8 wherein R 1 is

10. The compound of claim 1 wherein q and r are both 1; X—Y is CH—O; W is:

and R 1 is heteroaryl selected from the group consisting of:

wherein R c is —CH 2 CO 2 H or —CH 2 CO 2 C 1-3 alkyl.

11. The compound of claim 10 wherein W is

and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each hydrogen.

12. A compound which is

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

14. A compound which is

or a pharmaceutically acceptable salt thereof.

15. A compound which is

or a pharmaceutically acceptable salt thereof.

16. A compound which is

or a pharmaceutically acceptable salt thereof.

17. A method for treating diabetes in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 .

18. A method for treating Type 2 diabetes in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 .

19. A method for treating obesity in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 .