MIF modulators

1. A compound according to the following formula B:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH; and R 2 is H; or

R 1 is H, and R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, C 1 alkoxy, F, Cl, or (CH 2 ) j —OH; Z 2 is H; and Z 3 is H; or

Z 1 is H; Z 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH; and Z 3 is H; or

Z 1 is H; Z 2 is H; and Z 3 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 4 is H;

Z 5 is H; and

each j is independently 0, 1, 2, 3, 4 or 5.

2. A pharmaceutical composition in dosage form comprising at least one compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

3. A compound according to the following formula B:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from OH, OCH 3 , F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ; and R 2 is H; or

R 1 is H and R 2 is selected from OH, F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 1 is selected from OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ; Z 2 is H; and Z 3 is H; or

Z 1 is H; Z 2 is selected from OH, OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ; and Z 3 is H; or

Z 1 is H; Z 2 is H; and Z 3 is selected from OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 4 is H;

Z 5 is H;

each R a is independently H, or a methyl or ethyl group which is optionally substituted with a hydroxyl group or from one to three halogen groups; and

each j is independently 0, 1, 2, or 3.

4. A compound according to the following formula B:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is CH 3 , OCH 3 , F, or OH; R 2 is H, CH 3 or OH; Z 1 is H or OCH 3 ; Z 2 is H or OH; Z 3 is H or OCH 3 ; Z 4 is H; and Z 5 is H; or

R 1 is CH 3 , OCH 3 , F, or OH; R 2 is H, CH 3 or OH; Z 1 is H or OCH 3 ; Z 2 is H, OH or OCH 3; Z 3 is H; Z 4 is H; and Z 5 is H; and wherein Z 1 is OCH 3 ; or Z 2 is OH or OCH 3 ; or; Z 3 is OCH 3 .

5. A compound or pharmaceutically acceptable salt thereof according claim 4 , wherein:

R 1 is CH 3 , R 2 is H, Z 1 is OCH 3 , Z 2 is H, Z 3 is H, Z 4 is H and Z 5 is H;

R 1 is H, R 2 is OH, Z 1 is H, Z 2 is H, Z 3 is OCH 3 , Z 4 is H and Z 5 is H;

R 1 is OH, R 2 is H, Z 1 is OCH 3 , Z 2 is OCH 3 , Z 3 is H, Z 4 is H and Z 5 is H.

6. A compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein R 1 is CH 3 , R 2 is H, Z 1 is H, Z 2 is OH, Z 3 is H, Z 4 is H and Z 5 is H.

7. A compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein R 1 is CH 3 , R 2 is H, Z 1 is H, Z 2 is OCH 3 , Z 3 is H, Z 4 is H and Z 5 is H.

8. A compound selected from the following compounds and pharmaceutically acceptable salts thereof:

3-benzyl-5-fluorobenzoxazol-2-one;

3-(2-benzyloxybenzyl)-5-methylbenzoxazol-2-one;

3-(3-cyanobenzyl)-5-chlorobenzoxazol-2-one;

3-(2,3-dimethoxybenzyl)-5-hydroxybenzoxazol-2-one;

3-(2,3-dimethoxybenzyl)-5-methylbenzoxazol-2-one;

3-(2-ethoxybenzyl)-5-methylbenzoxazol-2-one;

3-(3,5-dimethoxybenzyl)-5-methylbenzoxazol-2-one;

3-(3-ethoxybenzyl)-5-methylbenzoxazol-2-one;

3-(3-ethoxy-5-hydroxybenzyl)-5-methylbenzoxazol-2-one;

5-ethyl-3-(3-hydroxybenzyl)benzoxazol-2-one;

5-ethyl-3-(3-methoxybenzyl)benzoxazol-2-one;

3-(3-fluorobenzyl)-5-methylbenzoxazol-2-one;

3-(4-fluorobenzyl)-5-methylbenzoxazol-2-one;

5-fluoro-3-(3-hydroxybenzyl)benzoxazol-2-one;

6-fluoro-3-(3-hydroxybenzyl)benzoxazol-2-one;

5-fluoro-3-(2-methoxybenzyl)benzoxazol-2-one;

5-fluoro-3-(3-methoxybenzyl)benzoxazol-2-one;

5-fluoro-3-(4-methoxybenzyl)benzoxazol-2-one;

6-fluoro-3-(3-methoxybenzyl)benzoxazol-2-one;

3-(3-hydroxybenzyl)-5-methoxybenzoxazol-2-one;

3-(3-hydroxybenzyl)-5-methylbenzoxazol-2-one;

3-(3-hydroxybenzyl)-6-methylbenzoxazol-2-one;

3-(4-hydroxybenzyl)-5-methylbenzoxazol-2-one;

5-hydroxy-3-(3-hydroxybenzyl)benzoxazol-2-one;

5-hydroxy-3-(2-methoxybenzyl)benzoxazol-2-one;

5-hydroxy-3-(3-methoxybenzyl)benzoxazol-2-one;

6-hydroxy-3-(2-methoxybenzyl)benzoxazol-2-one;

6-hydroxy-3-(4-methoxybenzyl)benzoxazol-2-one;

5-(hydroxymethyl)-3-(3-methoxybenzyl)benzoxazol-2-one;

3-(2-methoxybenzyl)-5-methylbenzoxazol-2-one;

3-(3-methoxybenzyl)-5-methylbenzoxazol-2-one;

3-(3-methoxybenzyl)-6-methylbenzoxazol-2-one;

3-(3-methoxybenzyl)-5,6-dimethylbenzoxazol-2-one; and

5-methoxy-3-(3-methoxybenzyl)benzoxazol-2-one.

9. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

R 2 is H;

Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, C 1 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 2 is H;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

10. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j OH;

R 2 is H;

Z 1 is H;

Z 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

11. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

R 2 is H;

Z 1 is H;

Z 2 is H;

Z 3 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 4 is H; and

Z 5 is H.

12. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:

R 1 is H;

R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, Cl alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 2 is H;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

13. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:

R 1 is H;

R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 1 is H;

Z 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

14. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:

R 1 is H;

R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 1 is H;

Z 2 is H;

Z 3 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 4 is H; and

Z 5 is H.

15. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH; and R 2 is H; or

R 1 is H, and R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH; and

Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, C 1 alkoxy, F, Cl, or (CH 2 ) j —OH; Z 2 is H; and Z 3 is H; or

Z 1 is H; Z 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH and Z 3 is H; or

Z 1 is H; Z 2 is H; and Z 3 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

each j is independently 0, 1, 2, 3, 4 or 5, and

wherein said optional substituents are each independently from each other selected from alkyl, alkoxy, halogen, hydroxyl, carboxylic acid, cyano, ether, ester, acyl, nitro, amine, and amide.

16. A compound or pharmaceutically acceptable salt thereof according to claim 15 wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

R 2 is H;

Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, C 1 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 2 is H;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

17. A compound or pharmaceutically acceptable salt thereof according to claim 15 wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

R 2 is H;

Z 1 is H;

Z 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

18. A compound or pharmaceutically acceptable salt thereof according to claim 15 wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

R 2 is H;

Z 1 is H;

Z 2 is H;

Z 3 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 4 is H; and

Z 5 is H.

19. A compound or pharmaceutically acceptable salt thereof according to claim 15 wherein:

R 1 is H;

R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, Cl alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 2 is H;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

20. A compound or pharmaceutically acceptable salt thereof according to claim 15 wherein:

R 1 is H;

R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, an optionally substituted C 2 -C 8 ether, F, Cl, or (CH 2 ) j —OH;

Z 1 is H;

Z 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, a optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

21. A compound or pharmaceutically acceptable salt thereof according to claim 15 wherein:

R 1 is H;

R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 1 is H;

Z 2 is H;

Z 3 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;

Z 4 is H; and

Z 5 is H.

22. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein:

R 1 is selected from OH, OCH 3 , F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

R 2 is H;

Z 1 is selected from OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 2 is H;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

23. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein:

R 1 is selected from OH, OCH 3 , F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

R 2 is H;

Z 1 is H;

Z 2 is selected from OH, OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

24. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein:

R 1 is selected from OH, OCH 3 , F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

R 2 is H;

Z 1 is H;

Z 2 is H;

Z 3 is selected from OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 4 is H; and

Z 5 is H.

25. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein:

R 1 is H;

R 2 is selected from OH, F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Zi is selected from OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 2 is H;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

26. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein:

R 1 is H;

R 2 is selected from OH, F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 1 is H;

Z 2 is selected from OH, OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 3 is H;

Z 4 is H; and

Z 5 is H.

27. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein:

R 1 is H;

R 2 is selected from OH, F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 1 is H;

Z 2 is H;

Z 3 is selected from OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;

Z 4 is H; and

Z 5 is H.

28. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, or (CH 2 ) j —OH; and R 2 is H; or

R 1 is H, and R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl optionally substituted C 1 -C 10 alkoxy, F, or (CH 2 ) j —OH.

29. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein:

R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, or (CH 2 ) j —OH; and R 2 is H; or

R 1 is H, and R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl optionally substituted C 1 -C 10 alkoxy, or (CH 2 ) j —OH.

30. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein:

R 1 is selected from OH, OCH 3 , F, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ; and R 2 is H; or

R 1 is H and R 2 is selected from OH, F, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a .

31. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein:

R 1 is selected from OH, OCH 3 , C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ; and R 2 is H; or

R 1 is H and R 2 is selected from OH, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a .

32. A compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein:

R 1 is CH 3 , OCH 3 , or OH; R 2 is H, CH 3 or OH; Z 1 is H or OCH 3 ; Z 2 is H or OH; Z 3 is H or OCH 3 ; Z 4 is H; and Z 5 is H; or

R 1 is CH 3 , OCH 3 , or OH; R 2 is H, CH 3 or OH; Z 1 is H or OCH 3 ; Z 2 is H, OH or OCH 3 ; Z 3 is H; Z 4 is H; and Z 5 is H.