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 inhibiting or ameliorating cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound selected from a compound of Formula I and a compound of Formula F28:
or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent; 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 the cancer is melanoma.
3. The method of claim 1 , wherein the chemotherapeutic agent is selected from dacarbazine, carmustine, cisplatin, tamoxifen, vinblastine, temozolomide, uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, gemcitabine, vinblastine, vincristine, videsine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide, navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, epidophyllotoxin, an antineoplastic enzyme, a tomoisomerase inhibitor, procarbazine, mitoxantrone, carboplatin, biological response modifiers, growth inhibitors, antihormonal therapeutic agents, leucovorin, tegafur and haematopoietic growth factors.
4. 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.
5. The method of claim 4 , wherein R 1 is NH 2 .
6. The method of claim 4 , wherein R 2 is Br.
7. The method of claim 4 , wherein R 3 is F.
8. The method of claim 4 , wherein n is 2.
9. The method of claim 4 , 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-(trifluoromethyl)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.
10. The method of claim 4 , wherein said compound is 4-({2-[(amino sulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof.
11. The method of claim 4 , wherein said compound is 4-({2-[(amino sulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide.
12. 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.
13. The method of claim 12 , wherein said compound is 4-({2-[(amino sulfonyl)amino]ethyl}amino)-N-[(4-chloro-2-furyl)methyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein said compound is 4-({2-[(amino sulfonyl)amino]ethyl}amino)-N-[(4-chloro-2-furyl)methyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide.
15. The method of claim 12 , wherein said compound is 4-({2-[(amino sulfonyl)amino]ethyl}amino)-N-[(4-bromo-2-furyl)methyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 , wherein said compound is 4-({2-[(amino sulfonyl)amino]ethyl}amino)-N-[(4-bromo-2-furyl)methyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide.
17. A method of inhibiting or ameliorating cancer in a patient, comprising administering to said patient a therapeutically effective amount of 4-({2-[(amino sulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent.
18. The method of claim 17 , wherein the cancer is melanoma.
19. The method of claim 17 , wherein the chemotherapeutic agent is selected from dacarbazine, carmustine, cisplatin, tamoxifen, vinblastine, temozolomide, uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, gemcitabine, vinblastine, vincristine, videsine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide, navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, epidophyllotoxin, an antineoplastic enzyme, a tomoisomerase inhibitor, procarbazine, mitoxantrone, carboplatin, biological response modifiers, growth inhibitors, antihormonal therapeutic agents, leucovorin, tegafur and haematopoietic growth factors.
20. A method of inhibiting or ameliorating melanoma 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, and a chemotherapeutic agent selected from dacarbazine, carmustine, cisplatin, tamoxifen, vinblastine, temozolomide, uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, gemcitabine, vinblastine, vincristine, videsine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide, navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, epidophyllotoxin, an antineoplastic enzyme, a tomoisomerase inhibitor, procarbazine, mitoxantrone, carboplatin, biological response modifiers, growth inhibitors, antihormonal therapeutic agents, leucovorin, tegafur and haematopoietic growth factors.