Cyclic benzimidazole derivatives useful as anti-diabetic agents

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from:

(1) —O—,

(2) —O—CH 2 —,

(3) —S—,

(4) —S—CH 2 —,

(5) —NR d —,

(6) —NR d —CH 2 —,

(7) —CH 2 —, and

(8) —CH 2 —CH 2 —,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, —C 1-6 alkyl, —CO 2 C 1-6 alkyl, and —COC 1-6 alkyl;

Y is selected from:

(1) —C 3-7 cycloalkyl, and

(2) —C 3-6 cycloheteroalkyl,

wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ;

Z is selected from:

(1) —(CH 2 ) n CO 2 H,

(2) —(CH 2 ) n CO 2 R i ,

(3) —(CH 2 ) n NHCOR i

(4) —(CH 2 ) n SO 2 NHC(O)R i ,

(5) —(CF 12 ) n NHSO 2 R i ,

(6) —(CH 2 ) n C(O)NHSO 2 R i ,

(7) heteroaryl, and

(8) —C 2-10 cycloheteroalkyl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, and —OH, and wherein each cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c ;

each R 1 and R 2 is independently selected from:

(1) halogen,

(2) —(CH 2 ) p aryl,

(3) biphenyl, and

(4) —(CH 2 ) p heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 , and wherein each biphenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , provided that one and only one of R 1 and R 2 is halogen;

R 3 and R 4 are each independently selected from:

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —C 2-6 alkenyl,

(5) —C 2-6 alkynyl,

(6) —CN,

(7) —CF 3 ,

(8) —OC 1-6 alkyl,

(9) —SO 2 C 1-6 alkyl,

(10) —SO 2 NHC 1-6 alkyl, and

(11) —C(O)NHC 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with 1, 2 or 3 halogens;

R 5 is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —CH 2 CO 2 H, and

(4) —CH 2 CO 2 C 1-6 alkyl;

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

(1) hydrogen,

(2) halogen,

(3) —(CH 2 ) m OH,

(4) —(CH 2 ) m N(R j ) 2 ,

(5) —(CH 2 ) m CN,

(6) —C 1-6 alkyl,

(7) —(CH 2 ) m CF 3 ,

(8) —(CH 2 ) m OCF 3 ,

(9) —(CF 12 ) m SC 1-6 alkyl,

(10) —(CH 2 ) m S(O) 2 C 1-6 alkyl,

(11) —(CH 2 ) m S(O) 2 N(C 1-6 alkyl) 2 ,

(12) —(CH 2 ) m C(O)N(R j ) 2 ,

(13) —(CH 2 ) m N(R j )C(O)R f ,

(14) —(CH 2 ) m C(O)R f ,

(15) —(CH 2 ) m CO 2 R f ,

(16) —(CH 2 ) m OC(O)R f ,

(17) —(CH 2 ) m C 3-7 cycloalkyl,

(18) —(CH 2 ) m C 3-7 cycloalkenyl,

(19) —(CH 2 ) m C 2-6 cycloheteroalkyl,

(20) —(CH 2 ) m C 2-6 cycloheteroalkenyl,

(21) —(CH 2 ) m aryl, and

(22) —(CH 2 ) m heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , and —CO 2 C 1-6 alkyl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , and —CO 2 C 1-6 alkyl;

each R b is independently selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) aryl,

(4) heteroaryl,

(5) —C 3-6 cycloalkyl,

(6) —C 3-6 cycloalkenyl,

(7) —C 3-6 cycloheteroalkyl,

(8) halogen,

(9) —OH,

(10) —OC 1-6 alkyl,

(11) —CF 3 ,

(12) —CN, and

(13) —SO 2 C 1-6 alkyl,

wherein each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with 1, 2 or 3 halogens;

each R c is independently selected from:

(1) hydrogen,

(2) halogen,

(3) oxo,

(4) —(CH 2 ) r OH,

(5) —(CH 2 ) r N(R e ) 2 ,

(6) —(CH 2 ) r CN,

(7) —C 1-6 alkyl,

(8) —CF 3 ,

(9) —(CH 2 ) r C 3-7 cycloalkyl, and

(10) —(CH 2 ) r C 2-6 cycloheteroalkyl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , and —CF 3 , and wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , and —CF 3 ;

each R d is independently selected from:

(1) hydrogen, and

(2) C 1-6 alkyl;

each R e is independently selected from:

(1) hydrogen, and

(2) C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, and —OC 1-6 alkyl;

each R f is independently selected from:

(1) C 1-6 alkyl,

(2) C 4-7 cycloalkyl,

(3) C 4-7 cycloalkenyl,

(4) C 3-7 cycloheteroalkyl,

(5) C 3-7 cycloheteroalkenyl,

(6) aryl, and

(7) heteroaryl,

wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , and —CF 3 ;

each R i is independently selected from:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) C 4-7 cycloalkyl,

(4) C 4-7 cycloalkenyl,

(5) C 3-7 cycloheteroalkyl,

(6) C 3-7 cycloheteroalkenyl,

(7) aryl, and

(8) heteroaryl,

wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —OCOC 1-6 alkyl, and —OCO 2 C 1-6 alkyl;

each R j is independently selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 3-6 cycloalkyl, and

(4) —C 3-6 cycloheteroalkyl,

wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

p is 0, 1, 2, or 3; and

r is 0, 1 or 2.

2. The compound according to claim 1 , wherein X is selected from:

(1) —O—, and

(2) —O—CH 2 —,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, —C 1-6 alkyl, —CO 2 C 1-6 alkyl, and —COC 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein R 1 is independently selected from:

(1) phenyl,

(2) biphenyl, and

(3) heteroaryl,

wherein each phenyl, biphenyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein R 1 is biphenyl, wherein biphenyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R a ; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 , wherein R 2 is halogen; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein Y is —C 3-7 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 , wherein Y is selected from the group consisting of:

(1) cyclopropyl,

(2) cyclobutyl,

(3) cyclopentyl, and

(4) cyclohexyl,

wherein each cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 , wherein Y is selected from the group consisting of:

(1) cyclohexyl, and

(2) cyclobutyl,

wherein each cyclohexyl and cyclobutyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein RS is hydrogen;

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein Z is selected from the group consisting of:

(1) —(CH 2 ) n CO 2 H,

(2) —(CH 2 ) n NHCOR i ,

(3) —(CH 2 ) n NHSO 2 R i ,

(4) —(CH 2 ) n C(O)NHSO 2 R i ,

(5) heteroaryl, and

(6) —C 2-10 cycloheteroalkyl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, and —OH, and wherein each cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c ; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 , wherein Z is —CO 2 H; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein R 3 and R 4 are each independently selected from:

(1) hydrogen, and

(2) halogen;

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 , wherein R 3 is hydrogen or halogen, and R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 wherein:

X is selected from:

(1) —O—, and

(2) —O—CH 2 —;

Y is selected from the group consisting of:

(1) cyclopropyl,

(2) cyclobutyl,

(3) cyclopentyl, and

(4) cyclohexyl,

wherein each cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ;

Z is —CO 2 H;

R 1 is independently selected from:

(1) phenyl,

(2) biphenyl, and

(3) heteroaryl,

wherein each phenyl, biphenyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ;

R 2 is halogen;

R 3 and R 4 are each independently selected from:

(1) hydrogen, and

(2) halogen; and

R 5 is hydrogen;

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 wherein:

X is selected from:

(1) —O—, and

(2) —O—CH 2 —;

Y is selected from the group consisting of:

(1) cyclohexyl, and

(2) cyclobutyl,

wherein each cyclohexyl and cyclobutyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ;

Z is —CO 2 H;

R 1 is biphenyl, wherein biphenyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R a ;

R 2 is halogen;

R 3 is hydrogen or halogen;

R 4 is hydrogen; and

R 5 is hydrogen;

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , selected from:

or a pharmaceutically acceptable salt thereof

17. The compound according to claim 16 which is:

or pharmaceutically acceptable salt thereof

18. The compound according to claim 16 which is:

or pharmaceutically acceptable salt thereof

19. The compound according to claim 16 which is:

or pharmaceutically acceptable salt thereof

20. The compound according to claim 16 which is:

or pharmaceutically acceptable salt thereof

21. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

22. A composition comprising a compound according to claim 1 and a compound selected from simvastatin, ezetimibe, taranabant and sitagliptin; and a pharmaceutically acceptable carrier.

23. A method of treating a disorder, condition or disease responsive to the activation of AMP-activated protein kinase in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 , wherein the disorder, condition, or disease is Type 2 diabetes.