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) —S—,

(2) —O—,

(3) —NH—,

(4) —C(O)—,

(5) —NHC(O)—,

(6) —C(O)NH—,

(7) —NHSO 2 —,

(8) —SO 2 NH—, and

(9) —CO 2 —,

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;

Y is selected from:

(1) —CH 2 —,

(2) —CH 2 —CH 2 —,

(3) —CH 2 —CH 2 —CH 2 —,

(4) —CHF—, and

(5) —CF 2 —,

wherein each CH 2 and CHF is unsubstituted or substituted with 1 or 2 substituents selected from Rb;

Z is selected from:

(1) —CO 2 H,

(2) —C(O)NH 2 ,

(3) tetrazole, and

(4) dihydrooxadiazole,

wherein each dihydrooxadiazole and tetrazole is unsubstituted or substituted with 1, 2, or 3 substituents selected from R c ;

R 1 is independently selected from:

1) —C 3-10 cycloalkyl,

2) —C 3-7 cycloalkyl-aryl,

3) —C 3-7 cycloalkyl-heteroaryl,

4) —C 4-10 cycloalkenyl,

5) —C 4-7 cycloalkenyl-aryl,

6) —C 4-7 cycloalkenyl-heteroaryl,

7) aryl,

8) biphenyl,

9) -heteroaryl,

10) —C 2-6 alkenyl-alkyl,

11) —C 2-6 alkenyl-aryl,

12) —C 2-6 alkenyl-heteroaryl,

13) —C 2-6 alkenyl-C 3-7 cycloalkyl,

14) —C 2-6 alkenyl-C 3-7 cycloalkenyl,

15) —C 2-6 alkenyl-C 2-7 cycloheteroalkyl,

16) —C 2-6 alkenyl-C 2-7 cycloheteroalkenyl,

17) —C 2-6 alkynyl-(CH 2 ) 1-3 —O-aryl,

18) —C 2-6 alkynyl-alkyl,

19) —C 2-6 alkynyl-aryl,

20) —C 2-6 alkynyl-heteroaryl,

21) —C 2-6 alkynyl-C 3-7 cycloalkyl,

22) —C 2-6 alkynyl-C 3-7 cycloalkenyl,

23) —C 2-6 alkynyl-C 2-7 cycloheteroalkyl,

24) —C 2-6 alkynyl-C 2-7 cycloheteroalkenyl, and

25) —(CH 2 ) p C(O)phenyl,

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 each 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 , and

R 2 is selected from the group consisting of: halogen, —CN, —CF 3 , —C 2-6 alkenyl and —C 2-6 alkynyl, wherein each 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 ; or R 2 represents —C 1-6 alkyl substituted with 1, 2 or 3 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 ;

R 3 is hydrogen;

R 4 is hydrogen;

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) —O-aryl,

(12) —OCH 2 -aryl,

(13) —(CH 2 ) m C(═N—OH)N(R j ) 2 ,

(14) —(CH 2 ) m OC 1-6 alkyl,

(15) —(CH 2 ) m —O-aryl,

(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, —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, and each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is 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) halogen,

(4) —OH,

(5) —NO 2 ,

(6) —NH 2 ,

(7) —NH(C 1-6 alkyl),

(8) —N(C 1-6 alkyl) 2 ,

(9) —OC 1-6 alkyl,

(10) —CF 3 ,

(11) —CN,

(12) —SO 2 C 1-6 alkyl, and

(13) —(CH 2 ) q CON(R e ) 2 ,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 halogens, and wherein each alkyl 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 each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is 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, —C3 — 7cycloalkyl 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 j 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 1;

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

r is 0, 1 or 2.

2. The compound according to claim 1 , wherein X is absent or selected from: —S— and —O—, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 , wherein X is selected from: —S— and —O—, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 , wherein Y is selected from: —CH 2 — and —CH 2 —CH 2 —, wherein each —CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from Rb; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 , wherein Y is —CH 2 —, wherein CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 , wherein Z is —CO 2 H; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 , wherein

R 1 is selected from:

1) aryl,

2) biphenyl,

3) heteroaryl,

4) —C 2-6 alkynyl-(CH 2 ) 1-3 —O-aryl,

5) —C 2-6 alkynyl-aryl,

6) —C 2-6 alkynyl-heteroaryl,

7) —C 2-6 alkynyl-C 3-7 cycloalkyl,

8) —C 2-6 alkynyl-C 2-7 cycloheteroalkyl, and

9) —(CH 2 ) p C(O)phenyl,

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 each alkynyl 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 cycloalkyl, cycloheteroalkyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R a , and

R 2 is halogen; and

p is 1;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 , wherein each R a is independently selected from the group consisting of:

(1) halogen,

(2) —(CH 2 ) m OH,

(3) —N(R j ) 2 ,

(4) —NO 2 ,

(5) —CN,

(6) —C 1-6 alkyl,

(7) —CF 3 ,

(8) —O-aryl,

(9) —OCH 2 -aryl,

(10) —OC 1-6 alkyl,

(11) —SC 1-6 alkyl,

(12) —S(O)C 1-6 alkyl,

(13) —S(O) 2 C 1-6 alkyl,

(14) —NHS(O) 2 C 1-6 alkyl,

(15) —C(O)N(R j ) 2 ,

(16) —(CH 2 ) m N(R j )C(O)R f ,

(17) —N(R j )C(O)N(R j ) 2 ,

(18) —CO 2 H,

(19) —C 2-6 cycloheteroalkyl,

(20) aryl, and

(21) 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, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, and wherein alkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 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; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 of structural formula Ib:

wherein:

R 1 is selected from:

(1) phenyl,

(2) biphenyl,

(3) heteroaryl, and

(4) —C 2 alkynyl-phenyl,

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

R 2 is halogen;

R 3 , R 4 and R 5 are hydrogen;

X is selected from: —S— and —O—;

Z is —CO 2 H;

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

(1) —(CH 2 ) m OH,

(2) —C 1-6 alkyl,

(3) phenyl, and

(4) heteroaryl,

wherein each alkyl, phenyl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 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;

each R b is independently selected from: hydrogen, and —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1, 2 or 3 halogens; and

s is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 selected from:

or a pharmaceutically acceptable salt thereof.

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

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