Isoxazolyl urea derivatives as kinase modulators

1. A compound of Formula (IV):

wherein:

Z 1 is N;

Z 2 is O;

each R 3 is H, alkyl, cycloalkyl, heteroaryl, or aryl;

each R 2 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or wherein two R 2 groups are linked together by an alkylene;

each R 1 is independently H, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR c , —OC(O)R c , —NO 2 , —N(R c ) 2 , —SR c , S(O) j R c where j is 1 or 2, —NR c C(O)R c , —C(O)N(R c ) 2 , —C(O) 2 R c , or —C(O)R c ;

each R c is independently H, alkyl, cycloalkyl, aryl, or heteroaryl;

Y is O or S;

L is linker —C(O)NH—; and

T is a bi-, or tricyclic, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or a stereoisomer or pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein T corresponds to Formula (V):

wherein A is a five or six-membered aryl, heterocyclyl or heteroaryl; and B is a five or six-membered arylene, heterocyclene or heteroarylene, wherein A and B together form a fused two-ring moiety.

3. The compound of claim 2 , corresponding to Formula (VI):

4. The compound of claim 3 , wherein L is —C(O)NH—.

5. The compound of claim 4 , wherein B is phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, imidazolylene, or pyrrolylene.

6. The compound of claim 5 , selected from the group consisting of:

7. The compound of claim 1 , corresponding to:

8. A compound of Formula (VII):

wherein:

Z 1 is N;

Z 2 is O;

each R 3 is H, alkyl, cycloalkyl, heteroaryl, or aryl;

each R 2 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or wherein two R 2 groups are linked together by an alkylene;

each R 1 is independently H, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR c , —OC(O)R c , —NO 2 , —N(R c ) 2 , —SR c , S(O) j R c where j is 1 or 2, —NR c C(O)R c , —C(O)N(R c ) 2 , —C(O) 2 R c , or —C(O)R c ;

each R c is independently H, alkyl, cycloalkyl, aryl, or heteroaryl;

Y is O or S;

L is —C(O)NH—;

each of X 1 , X 2 , X 3 , X 4 and X 5 is independently C, CR, N, NR, S, or O, wherein no more than three of X 1 , X 2 , X 3 , X 4 and X 5 is a heteroatom, and no two adjacent ring atoms are O or S; where

each R is independently H, halogen, alkyl, —OH, alkoxy, —OC(O)R d , —NO 2 , —N(R d ) 2 , —SR d , —S(O) j R d where j is 1 or 2, —NR d C(O)R d , —C(O) 2 R d , —C(O)N(R d ) 2 , or —C(O)R d ;

where each R d is independently H, alkyl, cycloalkyl, aryl, or heteroaryl,

or stereoisomer or pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , corresponding to Formula (VIII):

10. The compound of claim 9 , wherein

is selected from the group consisting of:

11. The compound of claim 10 selected from the group consisting of:

12. A compound of Formula (XI):

wherein:

L is —C(O)NH—;

R 7 is selected from the group consisting of H, halogen, alkyl, —OH, alkoxy, —C(O)R d , —OC(O)R d , —NO 2 , —N(R d ) 2 , —C(O)OR d and SR d ,

each R d is independently H, alkyl, cycloalkyl, aryl, or heteroaryl;

each R is independently H, halogen, alkyl, —OH, alkoxy, —OC(O)R d , —NO 2 , —N(R d ) 2 , —S(O) j R d where j is 1 or 2, —NR d C(O)R d , —C(O) 2 R d , —C(O)N(R d ) 2 , or —C(O)R d ,

or a stereoisomer or pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , selected from the group consisting of:

14. A compound corresponding to Formula (XIX):

wherein L 1 is a bond; and L is a bond or —C(O)NH—

U is selected from the group consisting of cycloalkyl, aryl, and heteroaryl; and

V is a cycloalkylene, heterocyclene, arylene, or heteroarylene.

15. The compound of claim 14 , wherein U is phenyl, thiazolyl, or pyridinyl; and V is piperidinylene, thiazolylene, imidazolylene, or thiophenylene.

16. The compound of claim 15 , wherein the compound is:

17. The compound of claim 14 , corresponding to Formula (XX):

18. The compound of claim 17 , wherein U is phenyl, C 3 -C 6 cycloalkyl, pyrimidine, or pyridine.

19. The compound of claim 14 , corresponding to Formula (XXI):

20. The compound of claim 19 , wherein U is pyrimidinyl.

21. The compound of claim 1 , corresponding to

22. A method of modulating p38 kinase, said method comprising administering an effective amount of the compound of claim 14 , or a pharmaceutically acceptable salt thereof.

23. A method of modulating MKNK2 kinase, said method comprising administering an effective amount of the compound of claim 8 , or a pharmaceutically acceptable salt thereof.

24. A method of modulating MKNK2 kinase, said method comprising administering an effective amount of the compound of claim 12 , or a pharmaceutically acceptable salt thereof.

25. A method of modulating MKNK2 kinase, said method comprising administering an effective amount of the compound of claim 14 , or a pharmaceutically acceptable salt thereof.

26. A method of modulating STK10 kinase, said method comprising administering an effective amount of the compound of claim 8 , or a pharmaceutically acceptable salt thereof.

27. A method of modulating STK10 kinase, said method comprising administering an effective amount of the compound of claim 12 , or a pharmaceutically acceptable salt thereof.

28. A method of modulating STK10 kinase, said method comprising administering an effective amount of the compound of claim 14 , or a pharmaceutically acceptable salt thereof.

29. A method of treating a cellular proliferative disorder, said method comprising administering a therapeutically effective amount of the compound of claim 8 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

30. A method of treating a cellular proliferative disorder, said method comprising administering a therapeutically effective amount of the compound of claim 12 , or a pharmaceutically acceptable salt thereof.

31. A method of treating a cellular proliferative disorder, said method comprising administering a therapeutically effective amount of the compound of claim 14 , or a pharmaceutically acceptable salt thereof.