Galactopyranosyl-cyclohexyl derivauves as E-selectin antagonists

1. At least one compound chosen from glycomimetic E-selectin antagonists of Formula (I):

prodrugs of Formula (I), and pharmaceutically acceptable salts of any of the foregoing, wherein

R 1 is chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl,

groups, wherein n is chosen from integers ranging from 0 to 2, R 7 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, and C(═O)R 8 groups, and each R 8 is independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, C 6-18 aryl, and C 1-13 heteroaryl groups;

R 2 is chosen from C 1-12 alkyl groups substituted with at least one substituent chosen from —OSO 3 Q groups, wherein each Q is independently chosen from H and pharmaceutically acceptable cations;

R 3 is chosen from —OH, —OY 1 , halo, —NH 2 , —NHY 1 , —NY 1 Y 2 , —OC(═O)Y 1 , —NHC(═O)Y 1 , and —NHC(═O)NHY 1 groups, wherein Y 1 and Y 2 , which may be the same or different, are independently chosen from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 4-16 cycloalkylalkyl, C 2-12 heterocyclyl, C 6-18 aryl, and C 1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring;

R 4 is chosen from —CN, —CH 2 CN, and —C(═O)Y 3 groups, wherein Y 3 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —OZ 1 , —NHOH, —NHOCH 3 , —NHCN, and —NZ 1 Z 2 groups, wherein Z 1 and Z 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2-12 haloalkynyl, and C 7-12 arylalkyl groups, wherein Z 1 and Z 2 may join together along with the nitrogen atom to which they are attached to form a ring;

R 5 is chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2-12 haloalkynyl, C 4-16 cycloalkylalkyl, and C 6-18 aryl groups;

R 6 is chosen from —CN, C 1-12 alkyl, and C 1-12 haloalkyl groups;

L is chosen from a bond, C 6-18 aryl, and C 1-12 heteroaryl groups; and

M is chosen from linker groups.

2. The at least one compound according to claim 1 , wherein R 1 is chosen from C 1-4 alkyl,

3. The at least one compound according to claim 2 , wherein R 1 is chosen from methyl, ethyl,

4. The at least one compound according to claim 1 , wherein R 3 is chosen from —OH, —OY 1 , —OC(═O)Y 1 , and —NHC(═O)Y 1 groups, wherein Y 1 is chosen from C 1-12 alkyl, C 4-16 cycloalkylalkyl, C 2-12 heterocyclyl, C 6-18 aryl, and C 1-13 heteroaryl groups.

5. The at least one compound according to claim 4 , wherein R 3 is chosen from

6. The at least one compound according to claim 5 , wherein R 3 is chosen from

7. The at least one compound according to claim 1 , wherein R 4 is chosen from —C(═O)Y 3 groups, wherein Y 3 is chosen from —OZ 1 and —NZ 1 Z 2 groups.

8. The at least one compound according to claim 7 , wherein Z 1 and Z 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 1-12 haloalkyl, and C 7-12 arylalkyl groups.

9. The at least one compound according to claim 7 , wherein R 4 is chosen from

10. The at least one compound according to claim 7 , wherein R 4 is chosen from

11. The at least one compound according to claim 1 , wherein R 5 is chosen from C 1-12 alkyl and C 4-16 cycloalkylalkyl groups.

12. The at least one compound according to claim 11 , wherein R 5 is chosen from propyl and cyclohexylmethyl.

13. The at least one compound according to claim 1 , wherein R 6 is chosen from CN, CF 3 , and methyl.

14. The at least one compound according to claim 13 , wherein R 6 is methyl.

15. The at least one compound according to claim 1 , wherein L is a bond.

16. The at least one compound according to claim 1 , wherein L is chosen from C 6-18 aryl groups.

17. The at least one compound according to claim 16 , wherein L is:

18. The at least one compound according to claim 1 , wherein L is chosen from C 1-12 heteroaryl groups.

19. The at least one compound according to claim 18 , wherein L is:

20. The at least one compound according to claim 1 , wherein the linker group is chosen from:

21. The at least one compound according to claim 1 , wherein R 2 is chosen from C 1-12 alkyl groups substituted with at least two substituents chosen from —OSO 3 Q groups.

22. The at least one compound according to claim 1 , wherein R 2 is chosen from C 1-12 alkyl groups substituted with at least three substituents chosen from —OSO 3 Q groups.

23. The at least one compound according to claim 1 , wherein R 2 is chosen from C 1-5 alkyl groups substituted with one, two, or three substituents independently chosen from —OSO 3 Q groups.

24. The at least one compound according to claim 1 , wherein R 2 is chosen from C 1-8 alkyl groups substituted with one, two, or three substituents independently chosen from —OSO 3 Q groups.

25. The at least one compound according to claim 1 , wherein the at least one compound is chosen from

and pharmaceutically acceptable salts of any of the foregoing.

26. The at least one compound according to claim 1 , wherein the at least one compound is chosen from

and pharmaceutically acceptable salts thereof.

27. The at least one compound according to claim 1 , wherein the at least one compound is chosen from

28. The at least one compound according to claim 1 , wherein the at least one compound is

29. The at least one compound according to claim 1 , wherein each Q is independently chosen from pharmaceutically acceptable cations.

30. The at least one compound according to claim 1 , wherein each Q is a sodium cation.

31. A composition comprising at least one compound according to claim 1 and at least one additional pharmaceutically acceptable ingredient.

32. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with: or partial remission of: or ameliorating at least one disease, disorder, and/or condition where inhibition of E-selectin mediated functions is useful, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

33. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with: or partial remission of: or ameliorating at least one inflammatory disease, disorder, and/or condition, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

34. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with; or partial remission of: or ameliorating cancer, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

35. The method according to claim 34 , wherein the cancer is chosen from solid tumor cancers.

36. The method according to claim 34 , wherein the cancer is chosen from bone cancers, colorectal cancers, and pancreatic cancers.

37. The method according to claim 34 , wherein the cancer is chosen from liquid tumor cancers.

38. The method according to claim 34 , wherein the cancer is chosen from acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and multiple myeloma.

39. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with: or partial remission of: or ameliorating cancer, the method comprising administering to a subject in need thereof (a) an effective amount of at least one compound of claim 1 and (b) at least one of therapy chosen from (i) chemotherapy and (ii) radiotherapy.

40. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with: or partial remission of: or ameliorating metastasis of cancer cells, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

41. A method for inhibiting infiltration of cancer cells into the liver, lymph nodes, lung, bone, and/or bone marrow, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

42. A method for enhancing hematopoietic stem cell survival, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

43. The method according to claim 42 , wherein the subject has cancer and has received or will receive chemotherapy and/or radiotherapy.

44. A method for mobilizing cells from the bone marrow, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

45. The method according to claim 44 , wherein the cells are chosen from hematopoietic cells and tumor cells.

46. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with: or partial remission of: or ameliorating mucositis, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

47. The method according to claim 46 , wherein the mucositis is chosen from oral mucositis, esophageal mucositis, and gastrointestinal mucositis.

48. The method according to claim 46 , wherein the subject is afflicted with head and neck, breast, lung, ovarian, prostate, lymphatic, leukemic, and/or gastrointestinal cancer.

49. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with: or partial remission of: or ameliorating thrombosis, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

50. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with: or partial remission of: or ameliorating at least one cardiovascular disease or complications associated therewith, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

51. The method according to claim 50 , wherein the at least one cardiovascular disease is chosen from atherosclerosis and myocardial infarction.

52. A method of inhibiting rejection of a transplanted tissue in a subject, wherein said subject is a recipient of the transplanted tissue, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

53. A method for decreasing the likelihood of the occurrence of: or abatement, lessening, decreasing occurrence, or alleviation of symptoms of: or delay or slowing of the progression of: or prolonging the survival of a subject afflicted with: or partial remission of: or ameliorating graft versus host disease or complications associated therewith, the method comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .