Antidiabetic bicyclic compounds

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

“a” is a single bond;

T is selected from the group consisting of:

(1) CH,

(2) N, and

(3) N-oxide;

U is selected from the group consisting of:

(1) CR 1 ,

(2) N, and

(3) N-oxide;

V is selected from the group consisting of:

(1) CR 2 ,

(2) N, and

(3) N-oxide;

W is selected from the group consisting of:

(1) CH,

(2) N, and

(3) N-oxide,

provided that no more than two of T, U, V and W are selected from N and N-oxide, further provided that if both T and W are N or N-oxide, then R 3 is absent, and further provided that both U and V are not N or N-oxide;

Y is selected from the group consisting of:

(1) oxygen,

(2) sulfur,

(3) —CR g R g ,

(4) C═O,

(5) —C(R g )OC 1-6 alkyl,

(6) —CF 2 , and

(7) —NR c ;

A is selected from the group consisting of:

(1) aryl,

(2) heteroaryl,

(3) C 3-6 cycloalkyl, and

(4) C 2-5 cycloheteroalkyl,

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

B is selected from the group consisting of:

(1) aryl,

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

(3) C 3-6 cycloalkyl,

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

(5) C 3-6 cycloalkyl-C 1-10 alkyl-O—,

(6) C 2-5 cycloheteroalkyl,

(7) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,

(8) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,

(9) heteroaryl, and

(10) heteroaryl-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 unsubstituted or substituted with one to three substituents selected from R L , and wherein one of R 1 and R 2 is substituted with a substituent selected from R 7 , or R 1 and R 2 together with the atom(s) to which they are attached form a C 3-6 cycloalkyl ring or a C 2-5 cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g , wherein each R 1 and R 2 is unsubstituted or substituted with one to three substituents selected from R L , and wherein one of R 1 and R 2 is substituted with a substituent selected from R 7 ;

R 3 is hydrogen;

R 4 is hydrogen;

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is —CO 2 R 8 ;

R 8 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 3-6 cycloalkyl, and

(4) aryl-C 1-6 alkyl,

wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted with one to three substituents selected from R j ;

R a is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) halogen,

(3) —OR e ,

(4) —NR c S(O) n R e ,

(5) —S(O) n R e ,

(6) —S(O) n NR c R d ,

(7) —NR c R d ,

(8) —C(O)R e ,

(9) —OC(O)R e ,

(10) —CO 2 R e ,

(11) —CN,

(12) —C(O)NR c R d ,

(13) —NR c C(O)R e ,

(14) —NR c C(O)OR e ,

(15) —NR c C(O)NR c R d ,

(16) —CF 3 ,

(17) —OCF 3 ,

(18) —OCHF 2 ,

(19) aryl,

(20) heteroaryl,

(21) C 3-6 cycloalkyl,

(22) —C 3-6 cycloalkenyl, and

(23) —C 2-5 cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;

R b is independently selected from the group consisting of:

(1) —C 1-10 alkyl,

(2) —C 2-10 alkenyl,

(3) —CF 3 ,

(4) halogen,

(5) —CN,

(6) —OH,

(7) —OC 1-10 alkyl,

(8) —OC 2-10 alkenyl,

(9) —O(CH 2 ) p OC 1-10 alkyl,

(10) —O(CH 2 ) p OC 3-6 cycloalkyl,

(11) —O(CH 2 ) p C 3-6 cycloalkyl-C 1-10 alkyl-,

(12) —O(CH 2 ) p C 2-5 cycloheteroalkyl,

(13) —O(CH 2 ) p C 2-5 cycloheteroalkyl-C 1-10 alkyl-,

(14) —O-aryl,

(15) —O-heteroaryl,

(16) —O-aryl-C 1-10 alkyl-,

(17) —O-heteroaryl-C 1-10 alkyl-,

(18) —O(CH 2 ) p NR c S(O) m R e ,

(19) —O(CH 2 ) p S(O) m R e ,

(20) —O(CH 2 ) p S(O) m NR c R d ,

(21) —O(CH 2 ) p NR c R d ,

(22) —C(O)R e ,

(23) —OC(O)R e ,

(24) —CO 2 R e ,

(25) —C(O)NR c R d ,

(26) —NR c C(O)R e ,

(27) —NR c C(O)OR e ,

(28) —NR c C(O)NR c R d ,

(29) —O(CH 2 ) p O—C 3-6 cycloalkyl,

(30) —O(CH 2 ) p O—C 2-5 cycloheteroalkyl,

(31) —OCF 3 ,

(32) —OCHF 2 ,

(33) —(CH 2 ) p C 3-6 cycloalkyl,

(34) —(CH 2 ) p C 2-5 cycloheteroalkyl,

(35) aryl,

(36) heteroaryl,

(37) aryl-C 1-10 alkyl-, and

(38) heteroaryl-C 1-10 alkyl-,

wherein each CH, CH 2 , alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;

R c and R d 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,

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

(8) aryl,

(9) heteroaryl,

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

(11) heteroaryl-C 1-10 alkyl-,

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

or R c and R d together with the atom(s) to which they are attached form a C 2-5 cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g , wherein each R c and R d is unsubstituted or substituted with one to three substituents independently selected from R f ;

each R e 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,

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

(8) aryl,

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

(10) heteroaryl, and

(11) heteroaryl-C 1-10 alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R h ;

each R f is selected from the group consisting of:

(1) halogen,

(2) C 1-10 alkyl,

(3) —OH,

(4) —O—C 1-4 alkyl,

(5) —S(O) m —C 1-4 alkyl,

(6) —CN,

(7) —CF 3 ,

(8) —OCHF 2 , and

(9) —OCF 3 ,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C 1-6 alkyl, cyano and S(O) 2 C 1-6 alkyl;

each R g is selected from the group consisting of:

(1) hydrogen,

(2) —C(O)R e , and

(3) —C 1-10 alkyl,

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

each R h is selected from the group consisting of:

(1) halogen,

(2) C 1-10 alkyl,

(3) —OH,

(4) —O—C 1-4 alkyl,

(5) —S(O) m —C 1-4 alkyl,

(6) —CN,

(7) —CF 3 ,

(8) —OCHF 2 , and

(9) —OCF 3 ,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C 1-6 alkyl, cyano and S(O) 2 C 1-6 alkyl;

R j is independently selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —OR e ,

(3) —NR c S(O) m R e ,

(4) halogen,

(5) —S(O) m R e ,

(6) —S(O) m NR c R d ,

(7) —NR c R d ,

(8) —C(O)R e ,

(9) —OC(O)R e ,

(10) —CO 2 R e ,

(11) —CN,

(12) —C(O)NR c R d ,

(13) —NR c C(O)R e ,

(14) —NR c C(O)OR e ,

(15) —NR c C(O)NR c R d ,

(16) —CF 3 ,

(17) —OCF 3 ,

(18) —OCHF 2 ,

(19) —C 3-6 cycloalkyl, and

(20) —C 2-5 cycloheteroalkyl;

each R L 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 n is independently selected from: 0, 1 or 2;

each m is independently selected from: 0, 1 or 2; and

each p is independently selected from: 0, 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1 wherein T is CH; U is CR 1 ; V is CR 2 ; and W is CH, N or N-oxide; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 wherein T is CH; U is CR 1 ; V is CR 2 ; and W is CH; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2 wherein T is CH; U is CR 1 ; V is CR 2 ; and W is N; or a pharmaceutically acceptable salt thereof.

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

(1) —CR g R g ,

(2) C═O,

(3) —C(R g )OC 1-6 alkyl,

(4) —CF 2 , and

(5) —NR c :

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein Y is selected from the group consisting of: —CR g R g ; or a pharmaceutically acceptable salt thereof.

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

(1) aryl, and

(2) heteroaryl,

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

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

(1) aryl, and

(2) heteroaryl,

wherein each aryl and heteroaryl is unsubstituted or substituted with one to five substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein

R 1 and R 2 are selected from:

(1) —C 1-6 alkyl, and

(2) hydrogen,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein each alkyl is substituted with a substituent selected from R 7 , provided that one of R 1 and R 2 is —C 1-6 alkyl and the other of R 1 and R 2 is hydrogen;

or a pharmaceutically acceptable salt thereof.

10. 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 unsubstituted or substituted with one to three substituents selected from R L , and wherein one of R 1 and R 2 is substituted with a substituent selected from R 7 ;

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 wherein

R 1 is selected from: —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected-from R L , and wherein R 1 is substituted with a substituent selected from R 7 ; and

R 2 is-hydrogen;

or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 wherein

R 2 is selected from: —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein R 2 is substituted with a substituent selected from R 7 ; and

R 1 is hydrogen;

or a pharmaceutically acceptable salt thereof.

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

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

wherein

T is selected from the group consisting of:

(1) CH, and

(2) N;

U is selected from the group consisting of:

(1) CR 1 , and

(2) N;

V is selected from the group consisting of:

(1) CR 2 , and

(2) N;

W is selected from the group consisting of:

(1) CH, and

(2) N,

provided that no more than two of T, U, V and W are selected from N, further provided that if both T and Ware N, then R 3 is absent, and further provided that both U and V are not N;

Y is selected from the group consisting of:

(1) —CR g R g ,

(2) C═O,

(3) —C(R g )OC 1-6 alkyl, and

(4) —CF 2 ;

A is selected from the group consisting of:

(1) aryl,

(2) hetero aryl,

(3) C 3-6 cycloalkyl, and

(4) C 2-5 cycloheteroalkyl,

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

R 7 is —CO 2 R 8 ; and

R 8 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 R j ;

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 of structural Formula Ik:

wherein

T is CH or N;

U is CR 1 ;

V is CR 2 ;

W is CH or N,

provided that T and W are both CH or one of T and W is N;

Y is selected from the group consisting of:

(1) —CR g R g ,

(2) C═O, and

(3) —CF 2 ;

A is selected from the group consisting of:

(1) aryl,

(2) heteroaryl,

(3) C 3-6 cycloalkyl, and

(4) C 2-5 cycloheteroalkyl,

wherein each aryl, heteroaryl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R a ;

R 7 is —CO 2 R 8 ; and

R 8 is hydrogen;

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 wherein

“a” is a single bond;

T is CH;

U is CR 1 ;

V is CR 2 ;

W is CH, N or N-oxide;

Y is selected from the group consisting of:

(1) —CR g R g ,

(2) C═O,

(3) —C(R g )OC 1-6 alkyl,

(4) —CF 2 , and

(5) —NR c ;

A is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein each aryl and heteroaryl is unsubstituted or substituted with one to five substituents selected from R a ;

R 3 is hydrogen;

R 4 is hydrogen;

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is —CO 2 R 8 ; and

R 8 is hydrogen;

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 wherein

“a” is a single bond;

T is CH;

U is CR 1 ;

V is CR 2 ;

W is CH;

Y is selected from the group consisting of: —CR g R g ;

A is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein each aryl and heteroaryl is unsubstituted or substituted with one to five substituents selected from R a ;

B is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein each aryl and heteroaryl 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 unsubstituted or substituted with one to three substituents selected from R L , and wherein one of R 1 and R 2 is substituted with a substituent selected from R 7 ;

R 3 is hydrogen;

R 4 is hydrogen;

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is —CO 2 R 8 ; and

R 8 is hydrogen;

or a pharmaceutically acceptable salt thereof.

18. A compound selected from:

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 of structural Formula Ik:

wherein

T is selected from the group consisting of:

(1) CH, and

(2) N;

U is selected from the group consisting of:

(1) CR 1 , and

(2) N;

V is selected from the group consisting of:

(1) CR 2 , and

(2) N;

W is selected from the group consisting of:

(1) CH, and

(2) N,

provided that no more than two of T, U, V and W are selected from N, further provided that if both T and Ware N, then R 3 is absent, and further provided that both U and V are not N;

Y is oxygen;

A is selected from the group consisting of:

(1) aryl,

(2) heteroaryl,

(3) C 3-6 cycloalkyl, and

(4) C 2-5 cycloheteroalkyl,

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

B is selected from the group consisting of:

(1) aryl,

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

(3) C 3-6 cycloalkyl,

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

(5) C 3-6 cycloalkyl-C 1-10 alkyl-O—,

(6) C 2-5 cycloheteroalkyl,

(7) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,

(8) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,

(9) heteroaryl, and

(10) heteroaryl-C 1-10 alkyl-;

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

R 7 is —CO 2 R 8 ;

R 8 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 R j ;

or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 of structural Formula Ik:

wherein

T is CH;

U is CR 1 ;

V is CR 2 ;

W is CH;

Y is oxygen;

A is selected from the group consisting of:

(1) aryl,

(2) heteroaryl, and

(3) C 2-5 cycloheteroalkyl,

wherein each aryl, heteroaryl and cycloheteroalkyl is 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 each alkyl and aryl is unsubstituted or substituted with one to five substituents selected from R b ;

R 1 and R 2 are selected from:

(1) —C 1-6 alkyl, and

(2) hydrogen,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein each alkyl is substituted with a substituent selected from R 7 , provided that one of R 1 and R 2 is —C 1-6 alkyl and the other of R 1 and R 2 is hydrogen;

R 7 is —CO 2 R 8 ;

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

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

(1) —C 1-6 alkyl,

(2) halogen,

(3) —CF 3 ,

(4) —OCF 3 , and

(5) heteroaryl,

wherein each alkyl and heteroaryl is unsubstituted or substituted with —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, and

(4) —OC 1-10 alkyl,

wherein each alkyl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ; and

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

(1) —C 1-10 alkyl,

(2) —C 2-10 alkynyl, and

(3) —C 3-6 cycloalkyl,

wherein each alkyl, alkynyl, 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.

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

22. 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.

23. 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.