1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase

Patent metadata

Field	Value
Publication number	US-10653677-B2
Application number	US-201916446253-A
Country	US
Kind code	B2
Filing date	Jun 19, 2019
Priority date	Jul 8, 2008
Publication date	May 19, 2020
Grant date	May 19, 2020

Abstract

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.

First claim

What it claimed is:

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 melan

Assignees

• Incyte Corp
• Incyte Holdings Corp

Inventors

• Combs Andrew P
• Yue Eddy W
• Sparks Richard B
• Zhu Wenyu

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P31/18

  for HIV · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61K31/4245 Primary

  Oxadiazoles · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title