Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein

Z is independently selected from the group consisting of: S, S(O), S(O) 2 , O, NH and CH 2 , wherein each NH is unsubstituted or substituted with R g , and wherein CH 2 is unsubstituted or substituted with R 2 ;

B is a 5 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from NH, O and S, wherein any CH is unsubstituted or substituted with one substituent selected from R a , and wherein any NH is unsubstituted or substituted with one substituent selected from R b ;

each R 1 is independently selected from the group consisting of: hydrogen, halogen, and C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy;

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

(1) hydrogen,

(2) halogen,

(3) aryl,

(4) heteroaryl,

(5) biphenyl,

(6) C 1-6 alkyl,

(7) (CH 2 ) n OR e ,

(8) (CH 2 ) n N(R e ) 2 ,

(9) (CH 2 ) n C≡N,

(10) (CH 2 ) n COR e , and

(11) (CH 2 ) n S(O) q R e ,

wherein CH 2 , alkyl, phenyl, aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R f ;

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

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —OC 1-6 alkyl,

(5) (CH 2 ) n OR e ,

(6) (CH 2 ) n N(R e ) 2 ,

(7) (CH 2 ) n C≡N,

(8) (CH 2 ) n COR e , and

(9) (CH 2 ) n S(O) q R e ,

wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH 2 in R 3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines;

R 4 is selected from the group consisting of:

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

(1) hydrogen,

(2) halogen,

(3) cyano,

(4) C 1-4 alkyl, unsubstituted or substituted with one to five fluorines,

(5) C 1-4 alkoxy, unsubstituted or substituted with one to five fluorines,

(6) C 1-4 alkylthio, unsubstituted or substituted with one to five fluorines,

(7) C 1-4 alkylsulfonyl,

(8) —CO 2 H,

(9) C 1-4 alkyloxycarbonyl, and

(10) C 1-4 alkylcarbonyl;

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

(1) hydrogen, and

(2) C 1-4 alkyl,

wherein alkyl is unsubstituted or substituted with one to five fluorines;

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

(1) —(CH 2 ) m CO 2 H,

(2) —(CH 2 ) m CO 2 C 1-3 alkyl,

(3)—(CH 2 ) m —NR b —(CH 2 ) p CO 2 H,

(4) —(CH 2 ) m —NR b —(CH 2 ) p CO 2 C 1-3 alkyl,

(5)—(CH 2 ) m —O—(CH 2 ) p CO 2 H,

(6) —(CH 2 ) m —O—(CH 2 ) p CO 2 C 1-3 alkyl,

(7) —(CH 2 ) m —S—(CH 2 ) p CO 2 H, and

(8) —(CH 2 ) m —S—(CH 2 ) p CO 2 C 1-3 alkyl,

wherein any CH 2 in R c is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines;

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

(1) —(CH 2 ) n CO 2 H,

(2) —(CH 2 ) n CO 2 C 1-3 alkyl,

(3) —(CH 2 ) n —NR b —(CH 2 ) p CO 2 H,

(4) —(CH 2 ) n —NR b —(CH 2 ) p CO 2 C 1-3 alkyl,

(5) —(CH 2 ) n —O—(CH 2 ) p CO 2 H,

(6) —(CH 2 ) n —O—(CH 2 ) p CO 2 C 1-3 alkyl,

(7) —(CH 2 ) n —S—(CH 2 ) p CO 2 H, and

(8) —(CH 2 ) n —S—(CH 2 ) p CO 2 C 1-3 alkyl,

wherein any CH 2 in R d is unsubstituted or substituted with one to two groups independently selected from the group consisting of: halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines;

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

(1) hydrogen, and

(2) C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, —C 1-4 alkoxy, —C 1-4 alkylthio, —C 1-4 alkylsulfonyl, —CO 2 H, and —CO 2 C 1-4 alkyl;

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

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —OC 1-6 alkyl,

(5) (CH 2 ) n OR e ,

(6) (CH 2 ) n N(R e ) 2 ,

(7) (CH 2 ) n C≡N,

(8) (CH 2 ) n COR e ,

(9) (CH 2 ) n S(O) q R e , and

(10) aryl,

wherein CH 2 , alkyl and aryl are unsubstituted or substituted with one, two or three groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines;

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

(1) hydrogen, and

(2) C 1-6 alkyl;

m is an integer from 1 to 3;

n is an integer from 0 to 3;

p is an integer from 1 to 3;

q is an integer from 1 to 2;

r is an integer from 0 to 2;

s is an integer from 0 to 4;

t is an integer from 0 to 8;

d is an integer from 0 to 2; and

e is an integer from 0 to 2,

provided that d+e is 2.

2. The compound of claim 1 wherein Z is O; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 wherein d is 1; e is 1; r is 1; s is 0, 1, 2 or 3; and t is 0; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 wherein s is 0 or 1; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 4 is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein R 4 is

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein B is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 wherein B is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein B is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

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

(1) aryl,

(2) heteroaryl,

(3) biphenyl, and

(4) —C 1-6 alkyl,

wherein alkyl, biphenyl, aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R f ; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein R 2 is phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents independently selected from R f ;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 wherein:

Z is O;

B is selected from the group consisting of:

R 2 is independently selected from the group consisting of:

(1) aryl,

(2) heteroaryl,

(3) biphenyl, and

(4) —C 1-6 alkyl,

wherein alkyl, biphenyl, aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R f ;

R 3 is independently selected from the group consisting of: hydrogen and halogen;

R 4 is selected from the group consisting of:

d is 1;

e is 1;

r is 1;

s is 0 or 1; and

t is 0;

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 wherein:

Z is O;

B is selected from the group consisting of:

R 2 is phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents independently selected from R f ;

R 3 is independently selected from the group consisting of: hydrogen and halogen;

R 4 is

d is 1;

e is 1;

r is 1;

s is 0 or 1; and

t is 0;

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

16. A method of treating hyperglycemia, diabetes or insulin resistance in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim 1 .

17. A method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim 1 .