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

q is 1;

r is 1;

Z is O, S, or NR 4 ;

X—Y is CR 14 —O;

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;

W is heteroaryl selected from the group consisting of:

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 any methylene (CH 2 ) carbon atom in (CH 2 ) m or (CH 2 ) p is optionally substituted with one hydroxy, one amino, or one to two fluorines; 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;

Ar is phenyl optionally substituted with one to five R 3 substituents;

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 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 SO 2 N(R 4 ) 2 ,

(CH 2 ) n S(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 ,

CF 3 ,

CH 2 CF 3 ,

OCF 3 , and

OCH 2 CF 3 ;

in which phenyl, naphthyl, and cycloalkyl, are optionally substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, optionally substituted with one to five fluorines; 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, and

(CH 2 ) n -phenyl,

wherein alkyl, and phenyl, are optionally substituted with one to three groups independently selected from halogen, 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 monocyclic 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;

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

each R 14 is hydrogen;

each m is 1;

each p is independently an integer from 1 to 3;

each n is independently an integer from 0 to 2;

each s is independently an integer from 1 to 3; and

each t is independently an integer from 1 to 3.

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

3. The compound of claim 1 wherein W is

4. 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.

5. The compound of claim 4 wherein R 1 is

6. The compound of claim 1 wherein q and r are both 1; X—Y is CH—O; W is heteroaryl selected from the group consisting of:

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.

7. The compound of claim 6 wherein W is

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

8. The compound of claim 7 wherein R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each hydrogen.

9. A compound which is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 which is

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 9 which is

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 9 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.