1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.
1. A method of suppressing immunosuppression or treating a disease selected from breast cancer, ovarian cancer, HIV infection, HCV infection, depression, Alzheimer's disease, Huntington's disease, trauma, age-related cataracts, organ transplant rejection, asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I or Formula F28:
or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting the disease or ameliorating the disease; wherein:
R 1 is NH 2 or CH 3 ;
R 2 is Cl, Br, CF 3 , CH 3 , or CN;
R 3 is H or F;
R 4 is F, Cl, Br, or I; and
n is 1 or 2.
2. The method of claim 1 , wherein said method is a method of treating a disease selected from breast cancer and ovarian cancer.
3. The method of claim 1 , further comprising administering an anti-viral agent, an anti-cancer vaccine, an anti-CTLA-4 antibody, a chemotherapeutic, an immunosuppressant, radiation, an anti-tumor vaccine, an anti-viral vaccine, cytokine therapy, or a tyrosine kinase inhibitor to said patient.
4. The method of claim 3 , wherein said cytokine therapy is IL-2.
5. The method of claim 3 , wherein said chemotherapeutic is a cytotoxic agent.
6. The method of claim 1 , wherein said compound is a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is NH 2 or CH 3 ;
R 2 is Cl, Br, CF 3 , CH 3 , or CN;
R 3 is H or F; and
n is 1 or 2.
7. The method of claim 6 , wherein R 1 is NH 2 .
8. The method of claim 6 , wherein R 2 is Br.
9. The method of claim 6 , wherein R 3 is F.
10. The method of claim 6 , wherein n is 2.
11. The method of claim 6 , wherein said compound is selected from:
4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;
N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;
4-({3-[(aminosulfonyl)amino]propyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;
N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide;
4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;
N-(3-chloro-4-fluorophenyl)-N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;
4-({3-[(aminosulfonyl)amino]propyl}amino)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;
N-(3-chloro-4-fluorophenyl)-N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide;
4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}-amino)-1,2,5-oxadiazole-3-carboximidamide;
4-({3-[(aminosulfonyl)amino]propyl}amino)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;
N-[4-fluoro-3-(trifluor omethyl)phenyl]-N′-hydroxy -4-({3-[(methylsulfonyl)amino]propyl}-amino)-1,2,5-oxadiazole-3-carboximidamide;
4-({2-[(aminosulfonyl)amino]ethyl}amino)-N′-hydroxy-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;
N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;
4-({3-[(aminosulfonyl)amino]propyl}amino)-N′-hydroxy-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;
N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;
N-(4-fluoro-3-methylphenyl)-N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;
4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-cyano-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide; and
N-(3-cyano-4-fluorophenyl)-N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;
or a pharmaceutically acceptable salt thereof.
12. A method of suppressing immunosuppression or treating a disease selected from breast cancer, ovarian cancer, HIV infection, HCV infection, depression, Alzheimer's disease, Huntington's disease, trauma, age-related cataracts, organ transplant rejection, asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus in a patient, comprising administering to said patient a therapeutically effective amount of 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting the disease or ameliorating the disease.
13. The method of claim 12 , further comprising administering an anti-viral agent, an anti-cancer vaccine, an anti-CTLA-4 antibody, a chemotherapeutic, an immunosuppressant, radiation, an anti-tumor vaccine, an anti-viral vaccine, cytokine therapy, or a tyrosine kinase inhibitor to said patient.
14. The method of claim 13 , wherein said cytokine therapy is IL-2.
15. The method of claim 13 , wherein said chemotherapeutic is a cytotoxic agent.
16. The method of claim 12 , wherein said compound is 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide.
17. The method of claim 1 , wherein said compound is a compound of Formula F28:
or a pharmaceutically acceptable salt thereof; wherein:
R 4 is F, Cl, Br, or I; and
n is 1 or 2.
18. A method of suppressing immunosuppression or treating a disease selected from breast cancer, ovarian cancer, HIV infection, HCV infection, depression, Alzheimer's disease, Huntington's disease, trauma, age-related cataracts, organ transplant rejection, asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus in a patient, comprising administering to said patient a therapeutically effective amount of 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-[(4-bromo-2-furyl)methyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting the disease or ameliorating the disease.
19. The method of claim 18 , further comprising administering an anti-viral agent, an anti-cancer vaccine, an anti-CTLA-4 antibody, a chemotherapeutic, an immunosuppressant, radiation, an anti-tumor vaccine, an anti-viral vaccine, cytokine therapy, or a tyrosine kinase inhibitor to said patient.
20. The method of claim 19 , wherein said cytokine therapy is IL-2.
21. The method of claim 19 , wherein said chemotherapeutic is a cytotoxic agent.
22. The method of claim 17 , wherein said compound is 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-[(4-chloro-2-furyl)methyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof.
23. A process for preparing a compound of Formula F15:
or a salt thereof, wherein R 2 is Cl, Br, CF 3 , CH 3 , or CN; R 3 is H or F; and n is 1 or 2, comprising:
a) reacting a compound of Formula F12:
or a salt thereof, with sulfamide and an organic base to afford a compound of Formula F14:
or a salt thereof, and
b) reacting said compound of Formula F14, or a salt thereof, with a base to afford said compound of Formula F15.
24. A process for preparing a compound of Formula F15:
or a salt thereof, wherein R 2 is Cl, Br, CF 3 , CH 3 , or CN; R 3 is H or F; and n is 1 or 2, comprising:
a) reacting a compound of Formula F13:
or a salt thereof, wherein Pg 1 is an amino protecting group, with an amino deprotecting agent to afford a compound of Formula F14:
or a salt thereof; and
b) reacting said compound of Formula F14 with a base to afford said compound of Formula F15.
25. The method of claim 12 , wherein said method is a method of treating breast cancer.
26. The method of claim 12 , wherein said method is a method of treating ovarian cancer.
27. The method of claim 12 , wherein said method is a method of treating HIV infection.
28. The method of claim 12 , wherein said method is a method of treating HCV infection.
29. The method of claim 12 , wherein said method is a method of treating depression.
30. The method of claim 12 , wherein said method is a method of treating Alzheimer's disease.
31. The method of claim 12 , wherein said method is a method of treating Huntington's disease.
32. The method of claim 12 , wherein said method is a method of treating trauma.
33. The method of claim 12 , wherein said method is a method of treating age-related cataracts.
34. The method of claim 12 , wherein said method is a method of treating organ transplant rejection.
35. The method of claim 12 , wherein said method is a method of treating asthma.
36. The method of claim 12 , wherein said method is a method of treating rheumatoid arthritis.
37. The method of claim 12 , wherein said method is a method of treating multiple sclerosis.
38. The method of claim 12 , wherein said method is a method of treating allergic inflammation.
39. The method of claim 12 , wherein said method is a method of treating inflammatory bowel disease.
40. The method of claim 12 , wherein said method is a method of treating psoriasis.
41. The method of claim 12 , wherein said method is a method of treating systemic lupus erythematosus.
42. The method of claim 18 , wherein said method is a method of treating breast cancer.
43. The method of claim 18 , wherein said method is a method of treating ovarian cancer.
44. The method of claim 18 , wherein said method is a method of treating HIV infection.
45. The method of claim 18 , wherein said method is a method of treating HCV infection.
46. The method of claim 18 , wherein said method is a method of treating depression.
47. The method of claim 18 , wherein said method is a method of treating Alzheimer's disease.
48. The method of claim 18 , wherein said method is a method of treating Huntington's disease.
49. The method of claim 18 , wherein said method is a method of treating trauma.
50. The method of claim 18 , wherein said method is a method of treating age-related cataracts.
51. The method of claim 18 , wherein said method is a method of treating organ transplant rejection.
52. The method of claim 18 , wherein said method is a method of treating asthma.
53. The method of claim 18 , wherein said method is a method of treating rheumatoid arthritis.
54. The method of claim 18 , wherein said method is a method of treating multiple sclerosis.
55. The method of claim 18 , wherein said method is a method of treating allergic inflammation.
56. The method of claim 18 , wherein said method is a method of treating inflammatory bowel disease.
57. The method of claim 18 , wherein said method is a method of treating psoriasis.
58. The method of claim 18 , wherein said method is a method of treating systemic lupus erythematosus.
59. The method of claim 1 , wherein the method is a method of treating breast cancer or ovarian cancer, wherein said method further comprises administering an anti-CTLA-4 antibody to said patient.
60. The method of claim 1 , wherein the method is a method of treating breast cancer or ovarian cancer, wherein said method further comprises administering an anti-PD-1 antibody to said patient.
61. The method of claim 12 , wherein the method is a method of treating breast cancer, wherein said method further comprises administering an anti-CTLA-4 antibody to said patient.
62. The method of claim 12 , wherein the method is a method of treating ovarian cancer, wherein said method further comprises administering an anti-CTLA-4 antibody to said patient.
63. The method of claim 12 , wherein the method is a method of treating breast cancer, wherein said method further comprises administering an anti-PD-1 antibody to said patient.
64. The method of claim 12 , wherein the method is a method of treating ovarian cancer, wherein said method further comprises administering an anti-PD-1 antibody to said patient.
65. The method of claim 18 , wherein the method is a method of treating breast cancer, wherein said method further comprises administering an anti-CTLA-4 antibody to said patient.
66. The method of claim 18 , wherein the method is a method of treating ovarian cancer, wherein said method further comprises administering an anti-CTLA-4 antibody to said patient.
67. The method of claim 18 , wherein the method is a method of treating breast cancer, wherein said method further comprises administering an anti-PD-1 antibody to said patient.
68. The method of claim 18 , wherein the method is a method of treating ovarian cancer, wherein said method further comprises administering an anti-PD-1 antibody to said patient.