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 activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with 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.
2. The method of claim 1 , wherein R 1 is NH 2 .
3. The method of claim 1 , wherein R 2 is Br.
4. The method of claim 1 , wherein R 3 is F.
5. The method of claim 1 , wherein n is 2.
6. The method of claim 1 , 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.
7. A method of inhibiting activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound, which is 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.
8. A method of inhibiting activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound, which is 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide.
9. A method of inhibiting activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound, which 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.
10. The method of claim 8 , wherein the compound is a solid form having a melting point of 162° C.±3° C. to 166° C.±3° C.
11. The method of claim 8 , wherein the compound is a solid form having a DSC thermogram as shown in FIG. 2 , wherein temperature readings of said DSC thermogram vary by ±3° C.
12. The method of claim 8 , wherein the compound is a solid form having at least one XRPD peak, in terms of 2-theta, selected from 18.4°±0.2°, 18.9°±0.2°, 21.8°±0.2°, 23.9°±0.2°, 29.2°±0.2°, and 38.7°±0.2°.
13. The method of claim 8 , wherein the compound is a solid form having at least two XRPD peaks, in terms of 2-theta, selected from 18.4°±0.2°, 18.9°±0.2°, 21.8°±0.2°, 23.9°±0.2°, 29.2°±0.2°, and 38.7°±0.2°.
14. The method of claim 8 , wherein the compound is a solid form having at least three XRPD peaks, in terms of 2-theta, selected from 18.4°±0.2°, 18.9°±0.2°, 21.8°±0.2°, 23.9°±0.2°, 29.2°±0.2°, and 38.7°±0.2°.
15. The method of claim 8 , wherein the compound is a solid form having an XRPD pattern as shown in FIG. 1 , wherein peaks in said XRPD pattern vary by ±0.2° in terms of 2-theta.