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

1. 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 1.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1 is NH 2 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein, R 1 is CH 3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is Cl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is Br.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CF 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CH 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CN.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is F.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 2.

13. A compound of claim 1 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.

14. 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.

15. A compound which is 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide.

16. A solid form of the compound of claim 15 which is crystalline.

17. A solid form of the compound of claim 15 which is substantially anhydrous.

18. A solid form of the compound of claim 15 having a melting point of 162° C.±3° C. to 166° C.±3° C.

19. A solid form of the compound of claim 15 having a DSC thermogram as shown in FIG. 2 , wherein temperature readings of said DSC thermogram vary by ±3° C.

20. A solid form of the compound of claim 15 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°.

21. A solid form of the compound of claim 15 having at least two XRPD peaks, in terms of 2-theta, selected from 18.4°±0.2°, 18.9°±0.2°, 21.8°±10.2°, 23.9°±0.2°, 29.2°±0.2°, and 38.7°±0.2°.

22. A solid form of the compound of claim 15 having at least three XRPD peaks, in terms of 2-theta, selected from 18.4°±10.2°, 18.9°±0.2°, 21.8°±0.2°, 23.9°±0.2°, 29.2°±0.2°, and 38.7°±0.2°.

23. A solid form of the compound of claim 15 having an XRPD pattern as shown in FIG. 1 , wherein peaks in said XRPD pattern vary by ±0.2° in terms of 2-theta.

24. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

25. A compound which is 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.

26. A compound which 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.

27. A compound of Formula F18:

or a salt thereof, wherein n is 1 or 2.

28. The compound of claim 27 wherein n is 1.

29. The compound of claim 27 wherein n is 2.

30. 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.