Therapeutic kinase modulators

1. A compound of Formula (I):

and pharmaceutically acceptable salts, esters, and tautomers thereof; wherein:

each Z 1 , Z 3 , and Z 4 is CH;

Z 2 is CR 3 ;

each R 3 is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group, or

each R 3 is independently halo, CF 3 , CFN, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, COOH, polar substituent, carboxy bioisostere, CONR 2 , OOCR, COR, or NO 2 ;

Z 5 is CR 6A ;

each of R 6A , R 6B and R 6C is independently H or an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group,

or each of R 6A , R 6B and R 6C can be halo, CF 3 , OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, or NO 2 ;

wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,

and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or more N, O or S;

and each R group, and each ring formed by linking two R groups together, is optionally substituted with one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′ 2 , SR′, SO 2 R′, SO 2 NR′ 2 , NR′SO 2 R′, NR′CONR′ 2 , NR′COOR′, NR′COR′, CN, COOR′, CONR′ 2 , OOCR′, COR′, and NO 2 ,

wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;

and wherein two R′ can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S; and

R 10 is an optionally substituted five-membered or six-membered carbocyclic or heterocyclic aromatic ring.

2. The compound of claim 1 , wherein at least one R 3 is a polar substituent, wherein said polar substituent is a carboxylic acid, carboxylate salt, ester, carboxamide, tetrazole or carboxy bioisostere.

3. The compound of claim 1 , wherein Z 2 is CR 3 , where R 3 is a carboxylic acid, carboxylate salt, ester, carboxamide, tetrazole or carboxy bioisostere.

4. The compound of claim 1 , wherein R 10 is an optionally substituted six-membered carbocyclic or heterocyclic aromatic ring.

5. The compound of claim 4 , wherein R 10 is an optionally substituted phenyl or pyridyl ring.

6. The compound of claim 5 , wherein R 10 is phenyl optionally substituted with one or more halo, CN, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , or NHAc substituents.

7. The compound of claim 1 , wherein R 10 is an optionally substituted five-membered heterocyclic aromatic ring.

8. The compound of claim 7 , wherein R 10 is an optionally substituted pyrazole, isoxazole or thiophene ring.

9. The compound of claim 1 , wherein at least one of R 6B or R 6C is H.

10. The compound of claim 1 , wherein R 6B and R 6C are H.

11. The compound of claim 1 , wherein R 6A is H.

12. The compound of claim 1 having the structure of Formula (V):

and pharmaceutically acceptable salts, esters, and tautomers thereof.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

14. A composition of matter comprising a protein kinase and a compound of Formula (I) or (V).

15. The composition of claim 14 , wherein the protein kinase is a human serine-threonine kinase or a human tyrosine kinase.

16. The composition of claim 15 , wherein the protein kinase is selected from the group consisting of CK2, CK2∀2, PIM1, PIM2, PIM3, CDK1/cyclinB, c-RAF, Mer, MELK, HIPK3, HIPK2, ZIPK, FLT1, FLT2, FLT3, FLT3 (D835Y), and FLT4.

17. A compound of Formula (I), selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.