Benzimidazole derivatives

1. A compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R 1 is cyclo(C 3 –C 8 )alkyl, substituted or unsubstituted;

R 2 is aryl substituted or unsubstituted;

Y is C(O);

Z 1 and Z 2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted.

2. The compound of claim 1 , wherein R 1 is cyclohexyl.

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

4. The compound of claim 1 , wherein Z 1 and Z 2 are combined to form an additional fused benzene ring.

5. The compound of claim 1 , having the formula (II):

wherein

D, E, F and G are independently CR′″, wherein each R′″ is independently selected from the group consisting of H, halogen, (C 1 –C 4 )alkyl, perfluoro(C 1 –C 4 )alkyl, (C 1 –C 4 )heteroalkyl, aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′ and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2, or combined with adjacent R′″ to form an additional fused 5-, 6-, 7- or 8-membered ring, and wherein R′ and R″ are independent selected from the group consisting of H, (C 1 –C 4 )alkyl, hetero(C 1 –C 4 )alkyl, aryl and aryl(C 1 –C 4 )alkyl.

6. The compound of claim 5 , having the formula (IIa):

wherein

R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, (C 1 –C 4 )alkyl, perfluoro(C 1 –C 4 )alkyl, (C 1 –C 4 )heteroalkyl, aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;

alternatively, R 5 , R 6 or R 7 may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7 and R 8 to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8 may be combined with R 1 to form an additional fused 5-, 6-, 7- or 8-membered ring.

7. The compound of claim 6 , wherein R 6 and R 7 are independently selected from the group consisting of H, halogen, (C 1 –C 4 )alkyl, CO 2 R′, NR′R″, OR′, OC(O)R′, N(R″)C(O)R′ and N(R″)C(O)NR′R″.

8. The compound of claim 6 , wherein R 6 is selected from the group consisting of

9. The compound of claim 6 , wherein R 8 is H or OH.

10. The compound of claim 1 , wherein R 2 is phenyl.

11. The compound of claim 1 , wherein R 2 is phenyl substituted with at least one substituent selected from the group consisting of halogen, (C 1 –C 4 )alkyl, perfluoro(C 1 –C 4 )alkyl, hetero(C 1 –C 4 )alkyl, aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O),NR′R″, S(O) m R′ and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2, and wherein R′ and R″ are independently selected from the group consistently of H, (C 1 –C 4 )alkyl, hetero(C 1 –C 4 )alkyl, aryl, aryl(C 1 –C 4 )alkyl.

12. The compound of claim 11 , wherein R 2 is phenyl substituted with at least one substituent selected from the group consisting of perfluoro(C 1 –C 4 )alkyl, aryl, heteroaryl, CONR′R″, NO 2 , S(O) m NR′R″ and S(O) m R′.

13. The compound of claim 12 , wherein R 2 is phenyl substituted with at least one substituent selected from the group consisting of CF 3 , CF 2 R′, phenyl, tetrazolyl, triazolyl, CONHR′, NO 2 , SO 2 NHR′ and SO 2 R′.

14. The compound of claim 1 , having the formula (IV):

wherein

R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, (C 1 –C 4 )alkyl, perfluoro(C 1 –C 4 )alkyl, (C 1 –C 4 )heteroalkyl, aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;

alternatively, R 5 , R 6 or R 7 may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7 and R 8 to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8 may be combined with R 1 to form an additional fused 5-, 6-, 7- or 8-membered ring.

15. A compound of claim 14 , having the formula (VII):

wherein

R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of H, halogen, (C 1 –C 4 )alkyl, perfluoro(C 1 –C 4 )alkyl, hetero(C 1 –C 4 )alkyl, aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′ and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;

alternatively, R 9 , R 10 , R 11 , R 12 or R 13 may be combined with an adjacent R group selected from the group consisting of R 9 , R 10 , R 11 , R 12 and R 13 to form an additional fused 5-, 6-, 7- or 8-membered ring.

16. The compound of claim 15 , wherein at least one of R 9 , R 10 , R 11 , R 12 and R 13 is selected from halogen, (C 1 –C 4 )alkyl, perfluoro(C 1 –C 4 )alkyl, (C 1 –C 4 )heteroalkyl, aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′ and N(R″)S(O) m R′.

17. The compound of claim 16 , wherein at least one of R 9 , R 10 , R 11 , R 12 and R 13 is selected from perfluoro(C 1 –C 4 )alkyl, aryl, heteroaryl, CONR′R″, NO 2 , S(O) m NR′R″ and S(O) m R′.

18. The compound of claim 15 , wherein R 10 is CF 3 .

19. The compound of claim 18 , having the formula (VIId):

20. The compound of claim 1 , having a formula selected from the group consisting of

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 , 2 , 3 , 4 , 5 , 8 , 9 , 10 , 13 , 14 , 15 , 17 , 18 , 19 or 20 .

22. A method of treating rheumatoid arthritis, inflammatory bowel disease, allergic disease, psoriasis, asthma, multiple sclerosis, graft rejection or sepsis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 , 2 , 3 , 4 , 5 , 8 , 9 , 10 , 13 , 14 , 15 , 17 , 18 , 19 or 20 .

23. The method of claim 22 , wherein said compound is administered orally, parenterally or topically.

24. The method of claim 22 , wherein said compound is administered in combination with a second therapeutic agent selected from the group consisting of a COX-2 inhibitor, hydroxychloroquine, D-penicillamine, infliximab, etanercept, auranofin, aurothioglucose, sulfasalazine, sulfasalazine analogs, mesalamine, corticosteroids, corticosteroid analogs, 6-mercaptopurine, cyclosporine A, methotrextate and infliximab, interferon β-1β, interferon β-1α, azathioprine, glatiramer acetate, a glucocorticoid and cyclophosphamide.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R 1 is cyclo(C 3 –C 8 )alkyl, substituted or unsubstituted;

R 2 is aryl, substituted or unsubstituted;

Y is C(O);

Z 1 and Z 2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted.

26. A method of treating rheumatoid arthritis, inflammatory bowel disease, allergic disease, psoriasis, asthma, multiple sclerosis, graft rejection or sepsis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R 1 is cyclo(C 3 –C 8 )alkyl, substituted or unsubstituted;

R 2 is aryl, substituted or unsubstituted;

Y is C(O);

Z 1 and Z 2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted.

27. A method of treating rheumatoid arthritis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R 1 is cyclo(C 3 –C 8 )alkyl, substituted or unsubstituted;

R 2 is aryl, substituted or unsubstituted;

Y is C(O);

Z 1 and Z 2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted.

28. A method of treating inflammatory bowel disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R 1 is cyclo(C 3 –C 8 )alkyl, substituted or unsubstituted;

R 2 is aryl, substituted or unsubstituted;

Y is C(O);

Z 1 and Z 2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted.

29. A method of treating multiple sclerosis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R 1 is cyclo(C 3 –C 8 )alkyl, substituted or unsubstituted;

R 2 is aryl, substituted or unsubstituted;

Y is C(O);

Z 1 and Z 2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted.