Antidiabetic bicyclic compounds

1. A compound of structural formula I:

wherein

T is CH;

U is CR 1 ;

V is CR 2 ;

W is CH;

X is N(R e );

Y is selected from the group consisting of:

(1) oxygen,

(2) C(R g )(R g ), and

(3) N(R c );

Z is C(R 5 );

A is selected from the group consisting of:

(1) aryl,

(2) heteroaryl,

(3) C 3-8 cycloalkyl, and

(4) C 2-7 cycloheteroalkyl,

wherein A is unsubstituted or substituted with one to five substituents selected from Ra;

B is selected from the group consisting of:

(1) aryl,

(2) aryl-O—,

(3) aryl-C 1-10 alkyl-,

(4) aryl-C 1-10 alkyl-O—,

(5) heteroaryl,

(6) heteroaryl-O—,

(7) heteroaryl-C 1-10 alkyl-, and

(8) heteroaryl-C 1-10 alkyl-O—,

wherein B is unsubstituted or substituted with one to five substituents selected from R b ;

R 1 and R 2 are each independently selected from:

(1) hydrogen,

(2) —C 1-6 alkyl, and

(3) —C 3-6 cycloalkyl,

wherein each alkyl and cycloalkyl is substituted with a substituent selected from R 7 and with one to three substituents selected from R 9 , provided that one of R 1 and R 2 is C 1-6 alkyl or C 3-6 cycloalkyl;

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

(1) hydrogen, and

(2) F;

R 4 is selected from the group consisting of:

(1) hydrogen,

(2) halogen, and

(3) C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh;

R 5 is 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 selected from Rh;

R 6 is 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 selected from R h ;

R 7 is selected from the group consisting of:

(1) —CO 2 R 8 , and

(2) —C 1-6 alkyl-CO 2 R 8 ;

R 8 is 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 selected from R 1 ;

each R 9 is independently selected from the group consisting of:

(1) —CO 2 C 1-6 alkyl,

(2) —C 1-10 alkyl,

(3) —C 2-10 alkenyl,

(4) —C 2-10 alkynyl,

(5) —C 3-6 cycloalkyl,

(6) —C 2-6 cycloheteroalkyl,

(7) aryl, and

(8) heteroaryl,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from C 1-6 alkyl, halogen, and —OC 1-6 alkyl;

each R a is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) halogen,

(3) —C 3-6 cycloalkyl,

(4) —C 2-5 cycloheteroalkyl, and

(5) —C 1-6 alkyl-N(R j )(R k ),

wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from —C 1-6 alkyl, halogen, —O—C 1-6 alkyl, and —CF 3 ;

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

(1) —C 1-10 alkyl,

(2) —CF 3 ,

(3) halogen,

(4) —CN,

(5) —OH, and

(6) —OC 1-10 alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;

R c is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-10 alkyl,

(3) C 2-10 alkenyl,

(4) C 3-6 cycloalkyl,

(5) C 3-6 cycloalkyl-C 1-10 alkyl-,

(6) C 2-5 cycloheteroalkyl, and

(7) C 2-5 cycloheteroalkyl-C 1-10 alkyl-,

wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from R f ;

each R d is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-4 alkyl, and

(3) halogen,

wherein each alkyl is unsubstituted or substituted with one to five halogens;

R e is 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 selected from —C 1-6 alkyl, —OC 1-6 alkyl, —CF 3 and halogen;

each R f is selected from the group consisting of:

(1) —C 1-4 alkyl,

(2) —OC 1-4 alkyl, and

(3) halogen,

each R g is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-4 alkyl, and

(3) halogen,

wherein each alkyl is unsubstituted or substituted with one to five halogens;

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

(1) —C 1-6 alkyl,

(2) —OC 1-6 alkyl, and

(3) halogen;

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

(1) —C 1-6 alkyl,

(2) —OC 1-6 alkyl, and

(3) halogen;

R j and R k are each independently selected from the group consisting of:

(1) hydrogen

(2) C 1-10 alkyl,

(3) C 2-10 alkenyl,

(4) C 3-6 cycloalkyl,

(5) C 3-6 cycloalkyl-C 1-10 alkyl-,

(6) C 2-5 cycloheteroalkyl, and

(7) C 2-5 cycloheteroalkyl-C 1-10 alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from C 1-6 alkyl, halogen, or —O—C 1-6 alkyl; and

q is independently selected from: 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein Y is selected from the group consisting of:

(1) oxygen, and

(2) C(R g )(R g );

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein A is selected from the group consisting of:

(1) aryl, and

(2) C 2-7 cycloheteroalkyl,

wherein aryl and cycloheteroalkyl are unsubstituted or substituted with one to five substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein A is aryl, wherein aryl is unsubstituted or substituted with one to five substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein B is selected from the group consisting of:

(1) aryl, and

(2) aryl-C 1-10 alkyl-,

wherein B is unsubstituted or substituted with one to five substituents selected from Rb; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein B is aryl, wherein aryl is unsubstituted or substituted with one to five substituents selected from Rb; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 1 and R 2 are each independently selected from:

(1) hydrogen, and

(2) —C 1-6 alkyl,

wherein each alkyl is substituted with a substituent selected from R 7 and with one to three substituents selected from R 9 , provided that one of R 1 and R 2 is —C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R 1 is —C 1-6 alkyl, wherein alkyl is substituted with a substituent selected from R 7 and with one to three substituents selected from R 9 ; and

R 2 is hydrogen;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; and R 6 is hydrogen; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein R 7 is —CO 2 R 8 ; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 wherein R 8 is hydrogen; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 wherein each R 9 is independently selected from the group consisting of:

(1) —C 1-10 alkyl, and

(2) —C 3-6 cycloalkyl,

wherein alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C 1-6 alkyl, halogen, and —OC 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 of structural Formula Id:

wherein

Y is selected from the group consisting of:

(1) oxygen, and

(2) C(R g )(R g );

A is selected from the group consisting of:

(1) aryl, and

(2) C 2-7 cycloheteroalkyl,

wherein aryl and cycloheteroalkyl are unsubstituted or substituted with one to five substituents selected from R a ;

B is selected from the group consisting of:

(1) aryl, and

(2) aryl-C 1-10 alkyl-,

wherein B is unsubstituted or substituted with one to five substituents selected from R b ;

R 1 and R 2 are each independently selected from:

(1) hydrogen, and

(2) —C 1-6 alkyl,

wherein each alkyl is substituted with a substituent selected from R 7 and with one to three substituents selected from R 9 , provided that one of R 1 and R 2 is C 1-6 alkyl;

R 3 , R 4 , R 5 , R 6 , and R 8 are hydrogen;

R 7 is —CO 2 R 8 ;

each R 9 is independently selected from the group consisting of:

(1) —C 1-10 alkyl, and

(2) —C 3-6 cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C 1-6 alkyl, halogen, and —OC 1-6 alkyl; and

R e is selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from —C 1-6 alkyl, —OC 1-6 alkyl, —CF 3 and halogen;

q is 1;

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 of structural Formula Ie:

wherein

Y is selected from the group consisting of:

(1) oxygen, and

(2) C(R g )(R g );

A is aryl, wherein aryl is unsubstituted or substituted with one to five substituents selected from R a ;

B is aryl, wherein aryl is unsubstituted or substituted with one to five substituents selected from R b ;

R 1 is —C 1-6 alkyl, wherein alkyl is substituted with a substituent selected from R 7 and with one to three substituents selected from R 9 ;

R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 are hydrogen;

R 7 is —CO 2 R 8 ;

each R 9 is independently selected from the group consisting of:

(1) —C 1-10 alkyl, and

(2) —C 3-6 cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C 1-6 alkyl, halogen, and —OC 1-6 alkyl;

R e is selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl,; and

q is 1;

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising

(1) a compound of claim 1 , or a pharmaceutically acceptable salt thereof;

(2) one or more compounds selected from the group consisting of:

(a) PPAR gamma agonists and partial agonists;

(b) biguanides;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors;

(e) insulin or an insulin mimetic;

(f) sulfonylureas;

(g) α-glucosidase inhibitors;

(h) agents which improve a patient's lipid profile, said agents being selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) bile acid sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) cholesterol absorption inhibitors, (vi) acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, (vii) CETP inhibitors, and (viii) phenolic anti-oxidants;

(i) PPARα/γ dual agonists,

(j) PPARδ agonists,

(k) antiobesity compounds,

(l) ileal bile acid transporter inhibitors;

(m) anti-inflammatory agents;

(n) glucagon receptor antagonists;

(o) GLP-1;

(p) GIP-1;

(q) GLP-1 analogs;

(r) HSD-1 inhibitors;

(s) SGLT-2 inhibitors; and

(t) SGLT-1/SGLT-2 inhibitors; and

(3) a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a compound selected from simvastatin, ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.