AZETIDINE DERIVATIVES AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE

1 . A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

X—Y is CH—O, CH—S, CF—O, CF—S, or CH—CR 1 R 2 ;

each of U and T is CH or N, with the proviso that at least one of U and T is N;

Ar is phenyl, benzyl, naphthyl, or pyridyl each of which is optionally substituted with one to five substituents independently selected from R 3 ;

R 1 and R 2 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;

each R 5 is independently selected from the group consisting of

(CH 2 ) n CO 2 R 4 ,

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

(CH 2 ) n COR 4 ,

(CH 2 ) n NR 4 SO 2 R 4

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

(CH 2 ) n S(O) q 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 C(O)N(OR 4 )R 4 ,

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

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

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

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

wherein any methylene (CH 2 ) carbon atom in R 5 is optionally substituted with one to two groups independently selected from fluorine, hydroxy, and C 1-4 alkyl optionally substituted with one to five fluorines; 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 3 is independently selected from the group consisting of:

halogen,

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

(CH 2 ) n OR 4 ,

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

(CH 2 ) n C≡N,

(CH 2 ) n COR 4 , and

(CH 2 ) n S(O) q R 4 ;

wherein alkyl is optionally substituted with hydroxy or one to three 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 optionally substituted with one to five fluorines; 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 ) m -phenyl,

(CH 2 ) m -heteroaryl,

(CH 2 ) m -naphthyl, and

(CH 2 ) m C 3-7 cycloalkyl;

wherein alkyl is optionally 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,

-carboxy, and —CO 2 C 1-4 alkyl; and wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from the group consisting of:

halogen,

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, optionally substituted with one to five fluorines,

C 1-4 alkylcarbonyl,

C 1-4 alkyloxycarbonyl,

amino,

mono-(Cl 1-4 alkyl)amino,

di-(Cl 1-4 alkyl)amino,

—O(CH 2 ) p CO 2 H,

—O(CH 2 ) p CO 2 C 1-4 alkyl,

—S(O) q (CH 2 ) p CO 2 H,

—S(O) q (CH 2 ) p CO 2 C 1-4 alkyl,

—NH(CH 2 ) p CO 2 H,

—NH(CH 2 ) p CO 2 C 1-4 alkyl,

—(CH 2 ) p CO 2 H,

—(CH 2 ) p CO 2 C 1-4 alkyl,

—N(R 10 )C(O)(R 10 ),

phenyl, optionally substituted with one to two substituents selected from halogen, carboxy, and C 1-4 alkyl, and

heteroaryl, optionally substituted with one to two substituents selected from halogen, carboxy, and C 1-4 alkyl;

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, and NC 1-4 alkyl;

each n is independently an integer from 0 to 2;

each m is independently an integer from 0 to 2;

each p is independently an integer from 1 to 3;

each q is independently an integer from 0 to 2;

R 6 , R 7 , R 8 , and R 9 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; and

each R 10 is independently hydrogen or C 1-4 alkyl optionally substituted with one to five fluorines.

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

3 . The compound of claim 2 wherein Ar is phenyl optionally substituted with one to two substituents independently selected from R 3 .

4 . The compound of claim 3 wherein each R 3 is halogen or trifluoromethyl.

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

6 . The compound of claim 1 wherein each R 3 is independently selected from the group consisting of halogen and trifluoromethyl.

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

CO 2 R 4 ,

OC(O)R 4 ,

COR 4 ,

NR 4 SO 2 R 4 ,

SO 2 N(R 4 ) 2 ,

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

C(O)N(R 4 ) 2 ,

C(O)N(OR 4 )R 4 ,

C(O)NR 4 NC(O)R 4 ,

NR 4 C(O)R 4 , and

NR 4 CO 2 R 4 .

8 . The compound of claim 7 wherein R 5 is —C(O)N(R 4 ) 2 .

9 . The compound of claim 8 wherein R 5 is —C(O)NHR 4 wherein R 4 is alkyl, phenyl, naphthyl, or heteroaryl each of which is optionally substituted as defined in claim 1 .

10 . The compound of claim 1 wherein T represents CH, and U represents N.

11 . The compound of claim 1 wherein T represents N, and U represents CH.

12 . The compound wherein X—Y is CH—O; T represents N; U represents CH; and Ar is phenyl optionally substituted with one to two substituents independently selected from R 3 .

13 . The compound of claim 12 wherein each R 3 is halogen or trifluoromethyl.

14 . The compound of claim 13 wherein R 6 , R 7 , R 8 , and R 9 are each hydrogen.

15 . The compound of claim 1 wherein X—Y is CH—O; T represents CH; U represents N; and Ar is phenyl optionally substituted with one to two substituents independently selected from R 3 .

16 . The compound of claim 15 wherein each R 3 is halogen or trifluoromethyl, and R 6 , R 7 , R 8 , and R 9 are each hydrogen.

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

18 - 22 . (canceled)

23 . A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

24 . 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 .

25 . 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 .