Proteasome inhibitors and uses thereof
The compounds of the present invention are represented by the following compounds having Formula (I) where the substituents R, R 1 -R 5 , k, m, n, and q are as defined herein. These compounds are used in the treatment of cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders, infectious disease, or for providing immunosuppression for transplanted organs or tissues.
1. A compound of Formula (I):
wherein
R is H or C 1-6 alkyl;
R 1 is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, aryl, heteroaryl, non-aromatic heterocycle, and non-aromatic heterocycle substituted with ═O;
R 2 is independently selected at each occurrence thereof from the group consisting of C 1-2 alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and —(CH 2 ) m C(O)NHR 4 , wherein alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl;
R 3 is selected from the group consisting of H, —SO p R 5 , —C(O)(CH 2 ) k Ar, —SO 2 Ar, —SO 2 C 3-8 cycloalkyl, —C(O)(CH 2 ) k Het, and —C(O)C 1-6 alkyl, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen or C 1-6 alkyl;
R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 3-8 cycloalkyl, wherein C 3-8 cycloalkyl can be optionally substituted with —CF 3 ;
R 5 is selected from the group consisting of alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl, wherein alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl;
k is 0 or 2;
m is 1 or 2;
n is 1, 2, or 3; and
p is 1 or 2;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
2. The compound according to claim 1 , which has the Formula (Ia):
3. The compound according to claim 2 , which has the Formula (Ib):
4. The compound according to claim 2 , which has the Formula (Ic):
5. The compound according to claim 1 , wherein alkenyl is C 2-6 alkenyl.
6. The compound according to claim 1 , wherein R 1 is
7. The compound according to claim 1 , wherein R 1 is selected from the group consisting of
8. The compound according to claim 1 , wherein R 2 is selected from the group consisting of CH 3 ,
9. The compound according to claim 1 , wherein R 3 is selected from the group consisting of H,
and
R is C 1-6 alkyl.
10. The compound according to claim 1 , wherein the compound of Formula (I) is
11. The compound according to claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
12. A method of treating cancer, autoimmune disorders, or inflammatory disorders in a subject or for providing immunosuppression, said method comprising:
administering to the subject in need thereof a compound of the Formula (I):
wherein
R is H or C 1-6 alkyl;
R 1 is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, aryl, heteroaryl, non-aromatic heterocycle, and non-aromatic heterocycle substituted with ═O;
R 2 is independently selected at each occurrence thereof from the group consisting of C 1-2 alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and —(CH 2 ) m C(O)NHR 4 , wherein alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl;
R 3 is selected from the group consisting of H, —SO p R 5 , —C(O)(CH 2 ) k Ar, —SO 2 Ar, —SO 2 C 3-8 cycloalkyl, —C(O)(CH 2 ) k Het, —C(O)C 1-6 alkyl, and —C(O)OC 1-6 alkyl, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen or C 1-6 alkyl;
R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 3-8 cycloalkyl, wherein C 3-8 cycloalkyl can be optionally substituted with —CF 3 ;
R 5 is selected from the group consisting of alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl, wherein alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl;
k is 0 or 2;
m is 1 or 2;
n is 1, 2, or 3; and
p is 1 or 2;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof,
wherein the autoimmune disorder is selected from the group consisting of arthritis, colitis, multiple sclerosis, lupus, systemic sclerosis, and sjögren syndrome;
the cancer is selected from the group consisting of multiple myeloma, lymphoma, and other hematological cancers;
the inflammatory disorder is Crohn's disease or ulcerative colitis; and
the immunosuppression is provided for transplanted organs or tissues or is used to prevent transplant rejection and graft-verse-host disease.
13. The method according to claim 12 , wherein the said administering is carried out orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes.
14. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
15. A method of inhibiting chymotryptic β5i in a cell or a tissue, said method comprising:
providing a compound of Formula (I):
wherein
R is H or C 1-6 alkyl;
R 1 is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, aryl, heteroaryl, non-aromatic heterocycle, and non-aromatic heterocycle substituted with ═O;
R 2 is independently selected at each occurrence thereof from the group consisting of C 1-2 alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and —(CH 2 ) m C(O)NHR 4 , wherein alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl;
R 3 is selected from the group consisting of H, —SO p R 5 , —C(O)(CH 2 ) k Ar, —SO 2 Ar, —SO 2 C 3-8 cycloalkyl, —C(O)(CH 2 ) k Het, —C(O)C 1-6 alkyl, and —C(O)OC 1-6 alkyl, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen or C 1-6 alkyl;
R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 3-8 cycloalkyl, wherein C 3-8 cycloalkyl can be optionally substituted with —CF 3 ;
R 5 is selected from the group consisting of alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl, wherein alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl;
k is 0 or 2;
m is 1 or 2;
n is 1, 2, or 3;
p is 1 or 2; and
contacting a cell or tissue with the compound under conditions effective to inhibit chymotryptic β5i.
16. A method of treating infectious disease in a subject, said method comprising:
administering to the subject in need thereof a compound of the Formula (I):
wherein
R is H or C 1-6 alkyl;
R 1 is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, aryl, heteroaryl, non-aromatic heterocycle, and non-aromatic heterocycle substituted with ═O;
R 2 is independently selected at each occurrence thereof from the group consisting of C 1-2 alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and —(CH 2 ) m C(O)NHR 4 , wherein alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl;
R 3 is selected from the group consisting of H, —SO p R 5 , —C(O)(CH 2 ) k Ar, —SO 2 Ar, SO 2 C 3-8 cycloalkyl, —C(O)(CH 2 ) k Het, —C(O)C 1-6 alkyl, and —C(O)OC 1-6 alkyl, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen or C 1-6 alkyl;
R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 3-8 cycloalkyl, wherein C 3-8 cycloalkyl can be optionally substituted with —CF 3 ;
R 5 is selected from the group consisting of alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl, wherein alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl;
k is 0 or 2;
m is 1 or 2;
n is 1, 2, or 3; and
p is 1 or 2;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
17. The method according to claim 16 , wherein the infectious disease is caused by bacterial, viral, parasitic, and fungal infectious agents.
18. The method of claim 12 , wherein the compound of Formula (I) has the Formula (Ia):
19. The method of claim 12 , wherein the compound of Formula (I) has the Formula (Ib):
20. The method of claim 12 , wherein the compound of Formula (I) has the Formula (Ic):
21. The method of claim 12 , wherein 10 is
22. The method of claim 12 , wherein R 1 is selected from the group consisting of
23. The method of claim 12 , wherein R 2 is selected from the group consisting of CH 3 ,
24. The method of claim 12 , wherein R 3 is selected from the group consisting of H,
and
R is C 1-6 alkyl.
25. The method of claim 12 , wherein the compound of Formula (I) is
26. The method of claim 12 , wherein the compound of Formula (I) is selected from the group consisting of:
27. The method of claim 15 , wherein the compound of Formula (I) has the Formula (Ia):
28. The method of claim 15 , wherein the compound of Formula (I) has the Formula (Ib):
29. The method of claim 15 , wherein the compound of Formula (I) has the Formula (Ic):
30. The method of claim 15 , wherein R 1 is
31. The method of claim 15 , wherein R 1 is selected from the group consisting of
32. The method of claim 15 , wherein R 2 is selected from the group consisting of CH 3 ,
33. The method of claim 15 , wherein R 3 is selected from the group consisting of H,
and
R is C 1-6 alkyl.
34. The method of claim 15 , wherein the compound of Formula (I) is
35. The method of claim 15 , wherein the compound of Formula (I) is selected from the group consisting of:
36. The method of claim 16 , wherein the compound of Formula (I) has the Formula (Ia):
37. The method of claim 16 , wherein the compound of Formula (I) has the Formula (Ib):
38. The method of claim 16 , wherein the compound of Formula (I) has the Formula (Ic):
39. The method of claim 16 , wherein R 1 is
40. The method of claim 16 , wherein R 1 is selected from the group consisting of
41. The method of claim 16 , wherein R 2 is selected from the group consisting of CH 3 ,
42. The method of claim 16 , wherein R 3 is selected from the group consisting of H,
and
R is C 1-6 alkyl.
43. The method of claim 16 , wherein the compound of Formula (I) is
44. The method of claim 16 , wherein the compound of Formula (I) is selected from the group consisting of:
45. The method according to claim 16 , wherein the said administering is carried out orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes.
46. The method according to claim 16 , wherein the infectious disease is caused by bacterial, viral, parasitic, and fungal infectious agents.
47. The method according to claim 16 , wherein the infectious disease is caused by a bacteria selected from the group consisting of Escherichia coli, Salmonella, Shigella, Klebsiella, Pseudomonas, Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium avium - intracellulare, Yersinia, Francisella, Pasteurella, Brucella, Clostridia, Bordetella pertussis, Bacteroides, Staphylococcus aureus, Streptococcus pneumonia , B-Hemolytic strep., Corynebacteria, Legionella, Mycoplasma, Ureaplasma, Chlamydia, Neisseria gonorrhea, Neisseria meningitides, Hemophilus influenza, Enterococcus faecalis, Proteus vulgaris, Proteus mirabilis, Helicobacter pylori, Treponema palladium, Borrelia burgdorferi, Borrelia recurrentis, Rickettsial pathogens, Nocardia , and Actinomycetes.
48. The method according to claim 16 , wherein the infectious disease is caused by a fungal infectious agent selected from the group consisting of Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis, Paracoccicioides brasiliensis, Candida albicans, Aspergillus fumigautus, Phycomycetes ( Rhizopus ), Sporothrix schenckii, Chromomycosis , and Maduromycosis.
49. The method according to claim 16 , wherein the infectious disease is caused by a viral infectious agent selected from the group consisting of human immunodeficiency virus, human T-cell lymphocytotrophic virus, hepatitis viruses, Epstein-Barr Virus, cytomegalovirus, human papillomaviruses, orthomyxo viruses, paramyxo viruses, adenoviruses, corona viruses, rhabdo viruses, polio viruses, toga viruses, bunya viruses, arena viruses, rubella viruses, and reo viruses.