Cyclic benzimidazole derivatives useful as anti-diabetic agents

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is absent or selected from:

(1) —CH 2 —,

(2) —CHF—,

(3) —CF 2 —,

(4) —S—,

(5) —O—,

(6) —O—CH 2 —,

(7) —NH—,

(8) —C(O)—,

(9) —NHC(O)—,

(10) —C(O)NH—,

(11) —NHSO 2 —,

(12) —SO 2 NH—, and

(13) —CO 2 —,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from:

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

Y is selected from:

(1) C 3-10 cycloalkyl,

(2) C 3-10 cycloalkenyl,

(3) C 2-10 cycloheteroalkyl,

(4) C 2-10 cycloheteroalkenyl,

(5) aryl, and

(6) heteroaryl,

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

Z is selected from:

(1) oxo,

(2) —CN,

(3) —(CH 2 ) n CO 2 H,

(4) —(CH 2 ) n CO 2 R i ,

(5) —(CH 2 ) n OH,

(6) —(CH 2 ) n C(O)NHR g ,

(7) —(CH 2 ) n NHC(O)C 1-6 alkyl,

(8) —(CH 2 ) n NHSO 2 R i ,

(9) —(CH 2 ) n SO 2 NHR g ,

(10) —(CH 2 ) n SO 2 NHC(O)R i ,

(11) —(CH 2 ) n SO 2 NHCO 2 R i ,

(12) —(CH 2 ) n SO 2 NHCON(R g ) 2 ,

(13) —(CH 2 ) n C(O)NHSO 2 R i ,

(14) —(CH 2 ) n NHC(O)N(R g ) 2 ,

(15) —(CH 2 ) n C 3-10 cycloalkyl-CO 2 R e ,

(16) heteroaryl,

(17) —C 2-10 cycloheteroalkenyl, and

(18) —C 2-10 cycloheteroalkyl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, —OH and —NH 2 , wherein each NH is unsubstituted or substituted with 1 substituent selected from R c , and wherein each alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl 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) —CN,

(3) —CF 3 ,

(4) —C 1-6 alkyl,

(5) —(CH 2 ) p aryl,

(6) biphenyl,

(7) —(CH 2 ) p heteroaryl,

(8) —C 2-6 alkenyl-aryl,

(9) —C 2-6 alkynyl-alkyl,

(10) —C 2-6 alkynyl-aryl,

(11) —C 2-6 alkynyl-heteroaryl,

(12) —C 2-6 alkynyl-C 3-7 cycloalkyl,

(13) —C 2-6 alkynyl-C 2-7 cycloheteroalkyl, and

(14) —C 2-6 alkynyl-C 2-7 cycloheteroalkenyl,

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 ,

wherein alkyl, alkenyl and alkynyl is unsubstituted or substituted with 1, 2 or 3 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 cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ,

provided that at least one of and only one of R 1 and R 2 is selected from the group consisting of:

halogen, —CN, —CF 3 , and —C 1-6 alkyl;

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) —C 3-10 cycloalkyl,

(7) —C 3-10 cycloalkenyl,

(8) aryl,

(9) heteroaryl,

(10) —CN,

(11) —CF 3 ,

(12) —OH,

(13) —OC 1-6 alkyl,

(14) —NH 2 ,

(15) —NHC 1-6 alkyl,

(16) —N(C 1-6 alkyl) 2 ,

(17) —SC 1-6 alkyl,

(18) —SOC 1-6 alkyl,

(19) —SO 2 C 1-6 alkyl,

(20) —NHSO 2 C 1-6 alkyl,

(21) —NHC(O)C 1-6 alkyl,

(22) —SO 2 NHC 1-6 alkyl, and

(23) —C(O)NHC 1-6 alkyl;

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) halogen,

(2) oxo,

(3) —(CH 2 ) m OH,

(4) —(CH 2 ) m N(R j ) 2 ,

(5) —(CH 2 ) m NO 2 ,

(6) —(CH 2 ) m CN,

(7) —C 1-6 alkyl,

(8) —(CH 2 ) m CF 3 ,

(9) —(CH 2 ) m OCF 3 ,

(10) —OCH 2 OC 1-6 alkyl,

(11) —OCH 2 -aryl,

(12) —(CH 2 ) m C(═N—OH)N(R j ) 2 ,

(13) —(CH 2 ) m OC 1-6 alkyl,

(14) —(CH 2 ) m O-aryl,

(15) —OCH 2 phenyl,

(16) —(CH 2 ) m SC 1-6 alkyl,

(17) —(CH 2 ) m S(O)C 1-6 alkyl,

(18) —(CH 2 ) m S(O) 2 C 1-6 alkyl,

(19) —(CH 2 ) m NHS(O) 2 C 1-6 alkyl,

(20) —(CH 2 ) m C(O)R f ,

(21) —(CH 2 ) m C(O)N(R j ) 2 ,

(22) —(CH 2 ) m N(R j )C(O)R f ,

(23) —(CH 2 ) m N(R j )C(O)N(R j ) 2 ,

(24) —(CH 2 ) m CO 2 H,

(25) —(CH 2 ) m OC(O)H,

(26) —(CH 2 ) m CO 2 R f ,

(27) —(CH 2 ) m OC(O)R f ,

(28) —(CH 2 ) m C 3-7 cycloalkyl,

(29) —(CH 2 ) m C 3-7 cycloalkenyl,

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

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

(32) —(CH 2 ) m aryl, and

(33) —(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, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF2, —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 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, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl;

each R b is independently selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 3-6 cycloalkyl,

(4) —C 3-6 cycloalkenyl,

(5) —C 2-6 cycloheteroalkyl,

(6) aryl,

(7) heteroaryl,

(8) halogen,

(9) —OH,

(10) —NO 2 ,

(11) —NH 2 ,

(12) —NH(C 1-6 alkyl),

(13) —N(C 1-6 alkyl) 2 ,

(14) —OC 1-6 alkyl,

(15) —(CH 2 ) q CO 2 H,

(16) —(CH 2 ) q CO 2 C 1-6 alkyl,

(17) —CF 3 ,

(18) —CN,

(19) —SO 2 C 1-6 alkyl, and

(20) —(CH 2 ) q CON(R e ) 2 ,

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

each R c is independently selected from:

(1) halogen,

(2) oxo,

(3) —(CH 2 ) r OH,

(4) —(CH 2 ) r N(R e ) 2 ,

(5) —(CH 2 ) r CN,

(6) —C 1-6 alkyl,

(7) —CF 3 ,

(8) —C 1-6 alkyl-OH,

(9) —OCH 2 OC 1-6 alkyl,

(10) —(CH 2 ) r OC 1-6 alkyl,

(11) —OCH 2 aryl,

(12) —(CH 2 ) r SC 1-6 alkyl,

(13) —(CH 2 ) r C(O)R f ,

(14) —(CH 2 ) r C(O)N(R e ) 2 ,

(15) —(CH 2 ) r CO 2 H,

(16) —(CH 2 ) r CO 2 R f ,

(17) —(CH 2 ) r C 3-7 cycloalkyl,

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

(19) —(CH 2 ) r aryl, and

(20) —(CH 2 ) r heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R h ) 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, —C 3-7 cycloalkyl and heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —N(R h ) 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, —C 3-7 cycloalkyl and heteroaryl;

each R e , R g and R h 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, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;

each R i is independently selected from:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) C 3-6 cycloalkyl,

(4) —C(O)R i , and

(5) —SO 2 R i ,

wherein alkyl and cycloalkyl 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 ;

each R f and R i 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, —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, —C 3-7 cycloalkyl, and heteroaryl;

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

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

p is 0, 1, 2, or 3;

q is 0, 1, 2, 3 or 4; and

r is 0, 1 or 2.

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

(1) —(CH 2 ) p aryl,

(2) biphenyl,

(3) heteroaryl,

(4) —C 2-6 alkenyl-aryl,

(5) —C 2-6 alkynyl-alkyl,

(6) —C 2-6 alkynyl-aryl,

(7) —C 2-6 alkynyl-heteroaryl,

(8) —C 2-6 alkynyl-C 3-7 cycloalkyl,

(9) —C 2-6 alkynyl-C 2-7 cycloheteroalkyl, and

(10) —C 2-6 alkynyl-C 2-7 cycloheteroalkenyl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substitutents 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 , wherein each alkyl, alkenyl and alkynyl is unsubstituted or substituted with 1, 2 or 3 substitutents 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 cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , and R 2 is selected from the group consisting of: hydrogen, halogen, —CN, —CF 3 , and —C 1-6 alkyl, and provided that if R 2 is hydrogen, then at least one of R 3 and R 4 is not hydrogen; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein R a is independently selected from the group consisting of:

(1) halogen,

(2) oxo,

(3) —(CH 2 ) m OH,

(4) —(CH 2 ) m N(R j ) 2 ,

(5) —CN,

(6) —C 1-6 alkyl,

(7) —(CH 2 ) m CF 3 ,

(8) —OCF 3 ,

(9) —C(═N—OH)N(R j ) 2 ,

(10) —OC 1-6 alkyl,

(11) —SC 1-6 alkyl,

(12) —S(O)C 1-6 alkyl,

(13) —C(O)C 1-6 alkyl,

(14) —C(O)C 2-6 cycloheteroalkyl,

(15) —C(O)NH 2 ,

(16) —C(O)N(C 1-6 alkyl) 2 ,

(17) —CO 2 H, —OC(O)H,

(18) —CO 2 C 1-6 alkyl,

(19) —OC(O)C 1-6 alkyl,

(20) —(CH 2 ) m C 3-7 cycloalkyl,

(21) —C 2-6 cycloheteroalkyl,

(22) —C 2-6 cycloheteroalkenyl,

(23) aryl, and

(24) heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 H, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF2, —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, and CH 2 phenyl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF2, —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, and CH 2 phenyl; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 , wherein X is selected from:

(1) —S—,

(2) —O—,

(3) —O—CH 2 —, and

(4) —NH—,

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

5. The compound according to claim 4 , wherein Y is selected from:

(1) —C 2-10 cycloheteroalkenyl,

(2) aryl, and

(3) heteroaryl,

wherein cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 , wherein Y is phenyl, wherein phenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 , wherein Z is selected from:

(1) oxo,

(2) —CN,

(3) —(CH 2 ) n CO 2 H,

(4) —(CH 2 ) n CO 2 R i ,

(5) —(CH 2 ) n OH,

(6) —(CH 2 ) n C(O)NHR g ,

(7) —(CH 2 ) n NHC(O)C 1-6 alkyl,

(8) —(CH 2 ) n SO 2 NHR g ,

(9) —(CH 2 ) n SO 2 NHC(O)R i ,

(10) —(CH 2 ) n C(O)NHSO 2 R i ,

(11) —(CH 2 ) n NHC(O)N(R g ) 2 ,

(12) —(CH 2 ) n C 3-10 cycloalkyl-CO 2 R e ,

(13) heteroaryl,

(14) —C 2-10 cycloheteroalkenyl, and

(15) —C 2-10 cycloheteroalkyl,

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

8. The compound according to claim 7 , wherein Z is —(CH 2 ) n CO 2 H, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, —OH and —NH 2 ; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 , wherein R 3 and R 4 are each independently selected from:

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —CN,

(5) —CF 3 ,

(6) —OH,

(7) —OC 1-6 alkyl,

(8) —SOC 1-6 alkyl, and

(9) —SO 2 C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

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

11. The compound according to claim 1 of structural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from:

(1) biphenyl,

(2) aryl,

(3) heteroaryl, and

(4) —C 2 alkynyl-aryl,

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

R 2 is halogen;

R 3 is hydrogen or halogen;

R 4 and R 5 are hydrogen;

X is —O—;

Z is —CO 2 H;

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

(1) halogen,

(2) —(CH 2 ) m OH,

(3) —C 1-6 alkyl,

(4) —OC 1-6 alkyl,

(5) —CO 2 H,

(6) —C 3-7 cycloalkyl,

(7) —C 2-6 cycloheteroalkyl, and

(8) aryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF2, —CF 3 , —CO 2 H, and —CO 2 C 1-6 alkyl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, and aryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF2, —CF 3 , —CO 2 H, and —CO 2 C 1-6 alkyl;

each R b is selected from hydrogen and —C 1-6 alkyl, unsubstituted or substituted with 1 or 2 halogens; and

s is 0, 1 or 2.

12. The compound according to claim 11 , selected from:

or a pharmaceutically acceptable salt thereof.

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

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

15. The compound according to claim 12 which is:

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 12 which is:

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 12 which is:

or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 12 which is:

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 12 which is:

or a pharmaceutically acceptable salt thereof.