Antidiabetic spirochroman compounds

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof;

wherein

T is CH;

U is CR 1 ;

V is CR 2 ;

W is CH;

X is selected from the group consisting of:

(1) oxygen,

(2) —CR b R b ,

(3) —C═O, and

(4) —C(R b )OR b , and

(5) N(R b );

Z is selected from:

Y is selected from the group consisting of:

(1) —C(R g )—,

(2) —C(F)—, and

(3) —N—;

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 C 1-6 alkyl, wherein —C 1-6 alkyl is substituted with R 7 ;

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

(1) hydrogen,

(2) halogen, —CN,

(3) —CF 3 , and

(4) —C 1-6 alkyl;

R 4 is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —CF 3 , and

(4) —C 1-6 alkyl;

R 5 is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —CN,

(4) —CF 3 ,

(5) —C 1-6 alkyl, and

(6) —C 1-5 spirocycloalkyl,

or two R 5 groups, and the carbons they are attached to, form a —C 3-6 cycloalkyl ring or a —C 2-5 cycloheteroalkyl ring;

R 6 is selected from the group consisting of:

(1) aryl,

(2) aryl-SO 2 ,

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

(4) aryl-N(R i )—,

(5) aryl-C 1-10 alkyl-N(R i )—,

(6) heteroaryl,

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

(8) heteroaryl-N(R i )—,

wherein each CH 2 is unsubstituted or substituted with 1-2 substituents selected from R a , and wherein each aryl, and heteroaryl is unsubstituted or substituted with 1-5 substituents selected from R a :

R 7 is selected from the group consisting of:

(1) —CO 2 R 8 ,

(2) —C 1-6 alkyl-CO 2 R 8 ,

(3) —C 1-6 alkyl-CONHSO 2 R m ,

(4) —C 1-6 alkyl-SO 2 NHCOR m ,

(5) —C 1-6 alkyl-tetrazolyl, and

(6) a cycloheteroalkyl selected from the group consisting of:

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) —OC 1-6 alkyl,

(3) halogen,

(4) —S(O) n R e ,

(5) —S(O) n NR c R d ,

(6) —NR c R d ,

(7) —C(O)R e ,

(8) —OC(O)R e ,

(9) —CO 2 R e ,

(10) —CN,

(11) —C(O)NR c R d ,

(12) —CF 3 ,

(13) —OCF 3 ,

(14) —OCHF 2 ,

(15) —OCH 2 CF 3 ,

(16) aryl,

(17) heteroaryl,

(18) C 3-6 cycloalkyl, and

(19) C 2-5 cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, —C 1-6 alkyl, —O—C 1-6 alkyl, —CF 3 , CO 2 H, and —CO 2 C 1-6 alkyl;

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

(1) hydrogen,

(2) —C(O)R d , and

(3) —C 1-10 alkyl,

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

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 R f substituents;

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;

R g is selected from the group consisting of:

(1) hydrogen, and

(2) —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 i is independently selected from the group consisting of:

(1) hydrogen, and

(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 k is independently selected from the group consisting of:

(1) —C 1-10 alkyl,

(2) —C 2-10 alkenyl,

(3) —C 3-6 cycloalkyl,

(4) —C 3-6 cycloalkyl-C 1-10 alkyl-,

(5) —C 2-5 cycloheteroalkyl,

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

(7) aryl,

(8) heteroaryl,

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

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

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;

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

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

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

each u is independently selected from: 0, 1, 2, or 3.

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

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

(1) —C(R b )(R b ),

(2) —C═O, and

(3) —C(R b )OR b ;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein X is —C(R b )(R b ); or a pharmaceutically acceptable salt thereof.

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

(1) —C(R g )—, and

(2) —N—;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein Y is —N—; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 6 is phenyl-CH 2 —, wherein CH 2 is unsubstituted or substituted with 1-2 substituents selected from R a , and wherein phenyl is unsubstituted or substituted with 1-3 substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

8. 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 R 7 ; and R 2 is hydrogen; or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

wherein

X is selected from the group consisting of:

(1) —C(R b )(R b ),

(2) C═O, and

(3) —C(R b )OR b ;

Z is selected from:

Y is selected from the group consisting of:

(1) —C(R g )—, and

(2) —N—;

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 C 1-6 alkyl substituted with R 7 ;

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

(1) hydrogen, and

(2) halogen;

R 4 is hydrogen;

R 5 is hydrogen;

R 6 is selected from the group consisting of:

(1) aryl,

(2) aryl-SO 2 —,

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

(4) aryl-N(R i )—,

(5) aryl-C 1-10 alkyl-N(R i )—,

(6) heteroaryl,

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

(8) heteroaryl-N(R i )—,

wherein each CH 2 is unsubstituted or substituted with 1-2 substituents selected from R a , and wherein each aryl, and heteroaryl is unsubstituted or substituted with 1-5 substituents selected from R a ;

R 7 is —CO 2 R 8 ;

R 8 is hydrogen;

each R L is independently selected from the group consisting of: —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, and —C 3-6 cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are unsubstituted or substituted with 1-4 substituents selected from C 1-6 alkyl, halogen, and —OC 1-6 alkyl;

n is 0 or 1;

m is 0, 1 or 2;

p is 0 or 2;

q is 0 or 1;

t is 0 or 1; and

u is 0 or 1;

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 of structural formula Iy:

wherein

Y is —N—;

R 1 is —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 R 7 ;

R 2 is hydrogen;

R 6 is phenyl-CH 2 —, wherein each CH 2 is unsubstituted or substituted with 1-2 substituents selected from R a , and wherein each phenyl is unsubstituted or substituted with 1-3 substituents selected from R a ;

R 7 is —CO 2 R 8 ;

R 8 is hydrogen; and

each R L is independently selected from the group consisting of: —CH 3 , and cyclopropyl;

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 13 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 method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18. 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.

19. 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.