AMIDE DERIVATIVES AS KINASE MODULATORS

Title:

AMIDE DERIVATIVES AS KINASE MODULATORS

Document Type and Number:

WIPO Patent Application WO/2005/048953

Kind Code:

A2

Abstract:

The invention provides methods and compositions for treating conditions mediated by various kinases wherein derivatives of amide compounds are employed. The invention also provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.

Inventors:

MEHTA SHAMAL A (US)
GROTZFELD ROBERT M (US)
MILANOV ZDRAVKO V (US)
ANDILIY LAI G (US)
PATEL HITESH K (US)
LOCKHART DAVID J (US)

Application Number:

PCT/US2004/038433

Publication Date:

June 02, 2005

Filing Date:

November 15, 2004

Export Citation:

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Assignee:

AMBIT BIOSCIENCES CORP (US)
MEHTA SHAMAL A (US)
GROTZFELD ROBERT M (US)
MILANOV ZDRAVKO V (US)
ANDILIY LAI G (US)
PATEL HITESH K (US)
LOCKHART DAVID J (US)

International Classes:

A61K31/42; A61K31/47; A61K31/4709; A61K31/4745; A61K31/503; A61K31/517; A61K31/519; A61K31/52; C07D215/38; C07D231/12; C07D231/40; C07D261/06; C07D261/08; C07D261/14; C07D261/18; C07D277/46; C07D277/82; C07D405/12; C07D413/00; C07D413/02; C07D413/04; C07D413/12; C07D413/14; C07D417/12; C07D417/14; C07D471/04; C07D471/06; C07D473/10; C07D487/04; C07D495/04; C07D513/04; A61K; (IPC1-7): A61K/

Foreign References:

US3991071A	1976-11-09
JPS53101372A	1978-09-04

Attorney, Agent or Firm:

Haddach, Aubrey A. (650 Page Mill Road Palo Alto, CA, US)

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Claims:

WHAT IS CLAIMED IS:

1.

A compound corresponding to Formula (1) : wherein: each Z is independently C, N, NR4, O, or S, provided that no more than two Z's are heteroatoms and wherein no two adjacent Z's are O or S, where R4 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl; each Rl is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,ORC,OC (O) Rc,NO2,N (Ro) 2,SK, S (O) jRc where j is 1 or 2,NRCC (O) Rc,C (O) N (Ro) 2, C (0) 2Rc, orC (O) Rc ; or two adjacent Rl's, are taken together, to form a substituted or unsubstituted aryl or heteroaryl; where each Rz is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and Y is 0 or S ; each R2 is independently H, halogen, substituted or unsubstituted alkyl,OH, substituted or unsubstituted alkoxy, OC (O) R3,N02,N (R3) 2,SR3,NRcC (O) Rc,C (O) N (Re) 2, C (0) 2Rc, orC (O) Rc ; each R3 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ; and each n is independently 0, 1, 2,3 or 4; or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

2.	The compound of claim 1, corresponding to Formula (II) :.

3.	The compound of claim 2, corresponding to Formula (III) : wherein: Zl is CR4 or N; and Z2isOorS.

4.

The compound of claim 3, corresponding to Formula (IV): wherein: L is a linker selected from the group consisting ofC (O) NH, (substituted or unsubstituted alkylene), (substituted or unsubstituted alkenylene) , C (O) NH (substituted or unsubstituted alkylene),C (O) NH (substituted or unsubstituted alkenylene),O (substituted or unsubstituted alkylene) ,N (substituted or unsubstituted alkylene) ,C (O),NH,O,S , NHC (O) (substituted or unsubstituted alkylene),NHC (O) (substituted or unsubstituted alkylene) , a covalent bond,C (O) (substituted or unsubstituted alkenylene) ,C (O) (substituted or unsubstituted alkylene) , NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH, NHC (O) (substituted or unsubstituted alkenylene) ; and T is a mono, bi, or tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

5.	The compound of claim 4, wherein T corresponds to Formula (V): wherein A is a substituted or unsubstituted five or sixmembered aryl or heteroaryl; and B is a substituted or unsubstituted five or sixmembered arylene or heteroarylene, wherein A and B together form a fused tworing moiety.

6.	The compound of claim 5, corresponding to Formula (VI) : (VI).

7.	The compound of claim 6, wherein L isC (O) NH.

8.	The compound of claim 7, wherein B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, imidazolylene, or pyrrolylene.

9.	The compound of claim 8, selected from the group consisting of :.

10.	The compound of claim 6, wherein L isNH.

11.	The compound of claim 10, wherein B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.

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

13.	The compound of claim 4, corresponding to:.

14.

The compound of claim 4, corresponding to Formula (VII) : (VII) wherein: each of XlX5 is independently C, CR, N, NR, S, or 0, wherein no more than three of Xl X5 is a heteroatom and no 2 adjacent ring atoms are 0 ; and each R is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,ORd,OC (O) Rd,NO2,N (Rd) 2,SRd, S (O) jRd where j is 1 or 2,NRdC (O) Rd, C (O) N (Rd) 2,C (0) 2Rd, orC (O) Rd ; or two adjacent R's, are taken together, to form a substituted or unsubstituted aryl or heteroaryl; where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

15.	The compound of claim 14, corresponding to Formula (VIII): (VIII).

16.	The compound of claim 15, wherein L is a covalent bond,C (O) NH,OCH2, orOCH2CH2.

17.	The compound of claim 15, wherein x2 , xi xl is selected from the group consisting of : R R R Rw \ R N R N R R R N RN\Nt N== S\ N==/N y R R R R R R NN \ R, and R.

18.	The compound of claim 17 selected from the group consisting of :.

19.

The compound of claim 4, corresponding to Formula (IX): (IX) wherein: is selected from the group consisting of : (a) L is selected from the group consisting ofO (substituted or unsubstituted alkylene) , andC (O) (substituted or unsubstituted alkenylene) ; and each of X1X5 is independently CR, NO, or N, wherein no more than two of XlX5 is N, where each R is independently H, halogen, substituted or unsubstituted alkyl,OH, substituted or unsubstituted alkoxy,OC (O) Rc,N02,N (Rc) 2, SRc,NRcC (0) Rc, orC (O) Rc ; where each Rc is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (b) L isNH ; each of Xl, X2, X4, and X5 is independently CR or N; and X3 is independently CR6 or N, wherein no more than two of X1X5 is N, where R6 is selected from the group consisting of H, halogen, substituted or unsubstituted alkyl, substituted alkoxy,C (O) Rc,OC (O) Rc,N02, N (Rc) 2, aderz ; where each Rc is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (c) L isNH ; each of Xi, X3, and X5 is independently CR or N; and each of X2 and X4 is independently CR7 or N, wherein no more than two of X1X5 is N; where R7 is selected from the group consisting of H, halogen, unsubstituted alkyl,OH, substituted or unsubstituted alkoxy, C (O) Rc, OC (O) RC,NO2,N (Rc) 2,suc, and alkyl substituted with alkoxy, halogen, aryl, heteroaryl, amine,C (O) RC,OC (O) Rc, NO2, N (Rc) 2, or SRc ; where each Rc is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and (d) L isC (O) NH ; each of X1, X2, X4, and X5 is independently CR or N; and X3 is independently CR8 or N, wherein no more than two of X1X5 is N, and when X3 is N, at least one of Xi, X2, X3, or X5 is not CH, where R8 is selected from the group consisting of H, halogen, substituted or unsubstituted alkyl,ORC, substituted or unsubstituted alkoxy, C (O) Rc,OC (O) Rc, NO2, N (Rc) 2, andSRc, where each Rc is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

20.	The compound of claim 19, corresponding to Formula (X): (X).

21.

The compound of claim 20, wherein L isNHC (O),O (substituted or unsubstituted alkylene) , a covalent bond, (substituted or unsubstituted alkylene) , NHC (O) (substituted or unsubstituted alkylene),C (O) NH (substituted or unsubstituted alkylene) ,NHC (O) (substituted or unsubstituted alkenylene) , orC (O) NH (substituted or unsubstituted alkenylene).

22.	The compound of claim 21, corresponding to Formula (XI):.

23.	The compound of claim 22, selected from the group consisting of :.

24.	The compound of claim 20, corresponding to Formula (XII) :.

25.	The compound of claim 24, corresponding to:.

26.	The compound of claim 20, corresponding to Formula (XIII) :.

27.	The compound of claim 26, corresponding to:.

28.	The compound of claim 20, corresponding to Formula (XIV) :.

29.	The compound of claim 28, corresponding to:.

30.	The compound of claim 20, corresponding to Formula (XV):.

31.	The compound of claim 30, corresponding to:.

32.	The compound of claim 20, corresponding to Formula (XVI) :.

33.	The compound of claim 32, wherein L is a linker selected from the group consisting ofNHC (O),O (C1C3 alkyl),NHC (O) CH2SCH2C (O) NH,CHCHCH20,CH2CH2, NHC (O)(C1C4 alkene),NHC (O)(C1C3 alkyl), andCH2CH2C (O) NH.

34.	The compound of claim 33, selected from the group consisting of :.

35.	The compound of claim 2, corresponding to:.

36.	The compound of claim 4, corresponding to:.

37.

The compound of claim 4, corresponding to Formula (XVII): (XVII) wherein: L is a linker selected from the group consisting ofC (O) NH, (substituted or unsubstituted alkylene), (substituted or unsubstituted alkenylene) , C (O) NH (substituted or unsubstituted alkylene),C (O) NH (substituted or unsubstituted alkenylene),O (substituted or unsubstituted alkylene) ,N (substituted or unsubstituted alkylene),C (O),NH,O,S ,NHC (O) (substituted or unsubstituted alkylene),NHC (O) (substituted or unsubstituted alkylene) , a covalent bond,C (O) (substituted or unsubstituted alkenylene) ,C (O) (substituted or unsubstituted alkylene) , NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH, NHC (O) (substituted or unsubstituted alkenylene) ; each of X1X5 is independently C, CR, NO, or N, wherein no more than two of XlX5 is N; where each R is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,ORd,OC (O) Rd,NO2,N (Rd) 2, SRd, S (O) jRd where j is 1 or 2,NRdC (O) Rd,C (O) N (Rd) 2,C (0) 2Rd, orC (O) Rd; or two adjacent R's, are taken together, to form a substituted or unsubstituted aryl or heteroaryl; where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

38.

The compound of claim 4, corresponding to Formula (XVIII): R 1 Z K Z/z , 2 Ri (XVIII) wherein : (Y is selected from the group consisting of : (a) each of L and Li is independently a linker selected from the group consisting of a covalent bond,O (substituted or unsubstituted alkylene),S, (substituted or unsubstituted alkylene),C (O), andN (substituted or unsubstituted alkylene) ; U is a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl; and V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene; (b) L is a linker selected from the group consisting of a covalent bond, O (substituted or unsubstituted alkylene),S, (substituted or unsubstituted alkylene),O,NH,C (O),C (O) NH, andN (substituted or unsubstituted alkylene) ; Li is a linker selected from the group consisting of a covalent bond,O (substituted or unsubstituted alkylene),S, (substituted or unsubstituted alkylene),O,NH,C (O), andN (substituted or unsubstituted alkylene) ; U is selected from the group consisting of : (i) substituted or unsubstituted cycloalkyl ; (ii) unsubstituted aryl; (iii) aryl substituted at any position withCl,I, substituted or unsubstituted alkyl,OH, substituted or unsubstituted alkoxy, OC (O) R3,NO2,N (R3) 2,SR3,C (O) R3, where R3 is H,OH,N (R3) 2, or substituted or unsubstituted alkoxy, and where R3 is H or substituted or unsubstituted alkyl ; and (iv) substituted or unsubstituted heteroaryl, except pyridinyl; V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene; and (c) L is a linker selected from the group consisting of a covalent bond,O (substituted or unsubstituted alkylene),S, (substituted or unsubstituted alkylene),O,NH,C (O),C (O) NH, andN (substituted or unsubstituted alkylene) ; Li is a linker selected from the group consisting of a covalent bond,O (substituted or unsubstituted C2C5 alkylene),S, (substituted or unsubstituted alkylene),O,NH,C (O),C (O) NH, andN (substituted or unsubstituted alkylene) ; U is selected from the group consisting of substituted or unsubstituted cycloalkyl ; substituted aryl; and substituted or unsubstituted heteroaryl; and V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene.

39.	The compound of claim 38, corresponding to Formula (XIX): (XIX).

40.	The compound of claim 39, wherein Li is a bond; and L is a bond orC (O) NH.

41.	The compound of claim 40, wherein U is substituted or unsubstituted phenyl, thiazolyl, or pyridinyl; and V is substituted or unsubstituted piperidinylene, thiazolylene, imidazolylene, or thiophenylene.

42.	The compound of claim 41, selected from the group consisting of :.

43.	The compound of claim 39, corresponding to Formula (XX): (XX).

44.	The compound of claim 43, wherein Li is a bond,CH20,N (CH3) or0 ; and L isCH20orNHC (O) .

45.	The compound of claim 44, wherein U is substituted or unsubstituted phenyl, C3C6 cycloalkyl, pyrimidine or pyridine.

46.	The compound of claim 45, selected from the group consisting of :.

47.	The compound of claim 39, corresponding to Formula (XXI):.

48.	The compound of claim 47, wherein Li is aNHor0 ; and L isNHC (O).

49.	The compound of claim 48, wherein U is substituted or unsubstituted pyrmidyl.

50.	The compound of claim 49, selected from the group consisting of :.

51.	The compound of claim 39, corresponding to:.

52.

The compound of claim 4, corresponding to Formula (XXII): (XXII) wherein: L is a linker selected from the group consisting ofC (O) NH, (substituted or unsubstituted alkylene), (substituted or unsubstituted alkenylene) , C (O) NH (substituted or unsubstituted alkylene),C (O) NH (substituted or unsubstituted alkenylene),O (substituted or unsubstituted alkylene) ,N (substituted or unsubstituted alkylene),C (O),NH,O,S , NHC (O) (substituted or unsubstituted alkylene),NHC (O) (substituted or unsubstituted alkylene) , a covalent bond,C (O) (substituted or unsubstituted alkenylene) ,C (O) (substituted or unsubstituted alkylene) , NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH, NHC (O) (substituted or unsubstituted alkenylene) ; U is a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; and V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene.

53.

A method of modulating a kinase, said method comprising administering an effective amount of a compound corresponding to Formula (IB) : (IB) wherein: M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl; and Y is O or S; each Rk is independently H, halogen, substituted or unsubstituted alkyl, OH, substituted or unsubstituted alkoxy,OC (O) R2,NO2,N (R2) 2, SR2,C (O) R2,C (0) 2R2,C (O) N (R2) 2, orN (R2) C (O) R2, each R2 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R2 groups are linked together by an optionally substituted alkylene; and each n is independently 0,1, 2,3 or 4; or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

54.	The method according to claim 53, wherein said kinase is FLT3.

55.	The method according to claim 53, wherein said kinase is PDGFR.

56.	The method according to claim 53, wherein said kinase is Abl.

57.	The method according to claim 53, wherein said kinase is ckit.

58.	The method according to claim 53, wherein said kinase is p38.

59.	The method according to claim 53, wherein said kinase is MKNK2.

60.	The method according to claim 53, wherein said kinase is STK10.

61.

A method of treating a cellular proliferative disorder, said method comprising administering a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to Formula (IB) (IB) wherein: M is a substituted or unsubstituted aryl or heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and Y is O or S; each R2 is independently H, halogen, substituted or unsubstituted alkyl,OH, substituted or unsubstituted alkoxy,OC (O) R3,N02,N (R3) 2,SR3,NR3C (O) R3,C (O) N (R3) 2, C (0) 2R3, orC (O) R3; each R3 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each n is independently 0,1, 2,3 or 4; or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

62.

The method of claim 61, wherein said compound corresponds to Formula (I) : (I) wherein: each Z is independently C, CR4, N, NR4, O, or S, provided that no more than two Z's are heteroatoms and wherein no two adjacent Z's are O or S, where R4 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl; and each Rl is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,ORc,OC (O) RcNO2,N (Rc) 2,SRc, S (O) jR, where j is 1 or 2,NRcC (O) Rc,C (O) N (Rc) 2,C (0) 2Rc, orC (O) Rc ; or two adjacent Rl's, are taken together, to form a substituted or unsubstituted aryl or heteroaryl; where each rye is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

63.	The compound of claim 62, corresponding to Formula (II):.

64.	The compound of claim 63, corresponding to Formula (III) : (III) wherein: Zl is CR4 or N; and Z2 is O or S.

Description:

AMIDE DERIVATIVES AS KINASE MODULATORS This application claims priority to US Provisional Application No. 60/520,273, filed November 13,2003, US Provisional Application No. 60/527,094, filed December 3, 2003, US Provisional Application No. 60/531,243, filed December 18, 2003, and US Provisional Application No. 60/531,082, filed December 18,2003, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND Protein kinases (PKs) play a role in signal transduction pathways regulating a number of cellular functions, such as cell growth, differentiation, and cell death. PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins, and can be conveniently broken down into two classes, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). Growth factor receptors with PTK activity are known as receptor tyrosine kinases. Protein receptor tyrosine kinases are a family of tightly regulated enzymes, and the aberrant activation of various members of the family is one of the hallmarks of cancer. The protein-tyrosine kinase family, which includes Bcr-Abl tyrosine kinase, can be divided into subgroups that have similar structural organization and sequence similarity within the kinase domain. The members of the type III group of receptor tyrosine kinases include the platelet-derived growth factor (PDGF) receptors (PDGF receptors a and, B), colony-stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), FLT-3, and stem cell or steel factor receptor (c-kit). A more complete listing of the known Protein receptor tyrosine kinases subfamilies is described in Plowman et al. , DN&P, 7 (6): 334-339 (1994), which is incorporated by reference, including any drawings, as if fully set forth herein.

Furthermore, for a more detailed discussion of"non-receptor tyrosine kinases", see Bolen, Oncogene, 8 : 2025-2031 (1993), which is incorporated by reference, including any drawings, as if fully set forth herein.

Hematologic cancers, also known as hematologic or hematopoietic malignancies, are cancers of the blood or bone marrow; including leukemia and lymphoma. Acute myelogenous leukemia (AML) is a clonal hematopoietic stem cell leukemia that represents-90% of all acute leukemias in adults. See e. g., Lowenberg et al., N. Eng. J.

Med. 341: 1051-62 (1999). While chemotherapy can result in complete remissions, the long term disease-free survival rate for AML is about 14% with about 7,400 deaths from AML each year in the United States. The single most commonly mutated gene in AML

is FLT3 kinase. See e. g., Abu-Duhier et al., Br. J. Haemotol. 111: 190-05 (2000); Kiyoi et al. , Blood 93: 3074-80 (1999); Kottaridis et al., Blood 98 : 1752-59 (2001); Stirewalt et al., Blood 97: 3589-95 (2001). Such mutations also indicate a poor prognosis for the patient.

The compounds provided by the present invention are urea derivatives of substituted aryls and hetroaryls, e. g. , isoxazoles, pyrazoles and isothiazoles. Urea derivatives of pyrazoles have been reported to be selective p38 kinase inhibitors by Dumas, J. , et al., Bioorg Medic. Chem. Lett. 10: 2051-2054 (2000). Oxazoles and isopyrazoles are suggested as blockers of cytokine production in WO 00/43384 published 27 July 2000.

Urea derivatives of isoxazole and pyrazoles are described as inhibitors of RAF kinase in WO 99/32106 published 1 July 1999. Such compounds are also described as p38 kinase inhibitors by Dumas, J., et al., Bioorg. Medic. Chem. Lett. 10: 2047-2050 (2000). These compounds are also suggested as p38 kinase inhibitors in PCT publication WO 99/32111 published 1 July 1999.

There remains a need for additional compounds that are effective in inhibiting kinase activity. Given the complexities of signal transduction with the redundancy and crosstalk between various pathways, the identification of specific kinase inhibitors permits accurate targeting with limited inhibition of other pathways, thus reducing the toxicity of such inhibitory compounds.

SUMMARY OF THE INVENTION The present invention provides compounds which modulate kinase activity, and in some embodiments inhibit protein tyrosine kinases or a specific kinase or kinase class. In some embodiments, the compositions and methods for treating and preventing conditions and diseases, such as cancer, hematologic malignancies, cardiovascular disease, inflammation or multiple sclerosis. The compounds of the invention can be delivered alone or in combination with additional agents, and are used for the treatment and/or prevention of conditions and diseases. Unless otherwise stated, each of the substituents is as previously defined.

Provided herein are compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound having the structure: Ar3 Aa\/A, Ar (CH2) n3 Y (CH2) n1 Za Wa (CH2) n2 Formula A Ar2

wherein: (a) Aal is N-R3a or C-R (3a) 2 and Aa2 is N-R3a or C-R (3a) 2, wherein one of Aal or Aa2 is N and one is C wherein each R3a is independently a suitable substituent selected from hydrogen, or an alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl group unsubstituted or substituted with one or more suitable substituents independently selected from the group consisting of halogens ; -CN; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-(CH2) zCN where z is a whole integer, preferably from 0 to 4, =NH,-NHOH,-OH,-C (O) H, -OC (O) H, -C (O) OH, -OC (O) OH, -OC (O) OC (O) H, -OOH,-C (NH) NH2,-NHC (NH) NH2,-C (S) NH2,-NHC (S) NH2,-NHC (O) NH2,-S (02) H, -S (O) H, -NH2,-C (O) NH2,-OC (O) NH2, -NHC (O) H, -NHC (O) OH, -C (O) NHC (O) H, - OS (02) H, -OS (O) H, -OSH,-SC (O) H, -S (O) C (O) OH,-S02C (O) OH, -NHSH, - NHS (O) H,-NHS02H,-C (O) SH, -C (O) S (O) H, -C (O) S (02) H, -C (S) H, -C (S) OH, - C (SO) OH,-C (S02) OH,-NHC (S) H, -OC (S) H, -OC (S) OH,-OC (SO2) H, -S (02) NH2, -S (O) NH2,-SNH2,-NHCS (02) H, -NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one or more suitable substituents independently selected from the group consisting of halogens, =0,-N02,-CN,- (CH2) z-CN where z is a whole integer, preferably from 0 to 4,-ORc,-NRcOR,-NRcRc,-C (O) NRc,-C (O) ORc, -C(O)Rc, -NRcC(O)NRcRc,-NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each Re is indepenently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more R groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; or two R3a's cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with one two or three suitable substituents selected from halogen, =O ; =S;-CN ;-N02, or an alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl group unsubstituted or substituted with one or more suitable substituents independently selected from the group consisting of halogens ; =O ; =S;-CN ; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,

heteroaryl,-(CH2) zCN where z is a whole integer, preferably from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, - NHS (O) H,-NHS02H,-C (O) SH, -C (O) S (O) H, -C (O) S (02) H, -C (S) H, -C (S) OH, -C (SO) OH, -C (SO2) OH,-NHC (S) H, -OC (S) H, -OC (S) OH,-OC (S02) H, -S (02) NH2,-S (O) NH2, -SNH2,-NHCS (02) H, -NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one or more suitable substituents independently selected from the group consisting of halogens, =0,-N02,-CN,- (CH2) z-CN where z is a whole integer, preferably from 0 to 4,-ORc,-NRcORc,-NRcRc,-C (O) I\T,,-C (O) ORc, -C (O) Rc, -NRcC (O) NRcRc,-NR C (O) Rc,-OC (O) ORC,-OC (O) NRCRC,-SR, unsubstituted aLkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each R is independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more Re groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; (b) Ari, Ar2 and Ar3 are each independently an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group unsubstituted or substituted with one or more suitable substituents independently selected from the group consisting of halogens ; =O ; =S;-CN ; and-N02 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,- (CH2) zCN where z is a whole integer, preferably from 0 to 4, =NH, -NHOH, -OH, -C (O) H, -OC (O) H, -C (O) OH, -OC (O) OH, -OC (O) OC (O) H, -OOH, -C (NH) NH2, -NHC (NH) NH2,-C (S) NH2, -NHC (S) NH2,-NHC (O) NH2, -S (02) H, - (O) H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2) H, -OS (O) H, -OSH,-SC (O) H, -S (O) C (O) OH,-SO2C (O) OH, -NHSH, - NHS (O) H,-NHS02H,-C (O) SH, -C (O) S (O) H, -C (O) S (02) H, -C (S) H, -C (S) OH, - C (SO) OH,-C (SO2) OH,-NHC (S) H, -OC (S) H, -OC (S) OH,-OC (S02) H, -S (02) NH2, -S(O)NH2, -SNH2, -NHCS(O2) H, -NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one or more suitable substituents independently

selected from the group consisting of halogens, =O,-NO2,-CN,-(CH2) z-CN where z is a whole integer, preferably from 0 to 4, -ORc, -NRcORc, -NRcRc, -C(O)NRc, -C(O)ORc, - C (O) R,-NRC (O) NRcRc,-NRcC (O) Rc,-OC (O) ORc,-OC (O) NRRc,-SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each Rc is independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more Re groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; (c) nits 0, 1, 2, 3 or 4 ; (d) n2 is 0, 1,2, 3 or 4 ; (e) n3 is 0, 1, 2, 3 or 4 ; (f) Za is a bond or is selected from S, O, N, NRc, C (O) Narc, NRcC (O), and CRc, wherein Re is a suitable substituent selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl group; and (g) Wa is S or O ; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, isomer, derivative, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

Provided herein are compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound having the structure : 2b Aa A/Ar a'f n (CHs) Z R1 Rob 11 Formula B Ar2 wherein: (a) Xb and Yb are independently selected from O, N, NRcl, and CRc, wherein Rci is a suitable substituent selected from hydrogen; alkyl, alkenyl, alkynyl, aryl, cycloalkyl,

heterocycloalkyl, or heteroaryl unsubstituted or substituted with one, two, or three suitable substituents, wherein Xb and Yb are not both oxygen; (b) Rlb and R2b are each a suitable substitutent independently selected fromhydrogen, halogen, =O ; =S;-CN ;-N02, or an alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl group unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of : halogens; =O ; =S;-CN ; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-(CH2) zCN where z is a whole integer from 0 to 4, =NH,-NHOH,-OH,-C (O) H, -OC (O) H, -C (O) OH, -OC (O) OH, -OC (O) OC (O) H, - OOH,-C (NH) NH2,-NHC (NH) NH2,-C (S) NH2,-NHC (S) NH2,-NHC (O) NH2, -S (02) H, -S (O) H, -NH2,-C (O) NH2,-OC (O) NH2, -NHC (O) H, -NHC (O) OH, -C (O) NHC (O) H, - OS (02) H, -OS (O) H, -OSH,-SC (O) H, -S (O) C (O) OH,-S02C (O) OH, -NHSH, - NHS (O) H,-NHS02H,-C (O) SH, -C (O) S (O) H, -C (O) S (02) H, -C (S) H, -C (S) OH, - C (SO) OH,-C (SO2) OH,-NHC (S) H, -OC (S) H, -OC (S) OH,-OC (SO2) H, -S (02) NH2, -S (O) NH2,-SNH2,-NHCS (02) H, -NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, =0,-N02,-CN,- (CH2) z-CN where z is a whole integer from 0 to 4,-ORc,-NRcORc,-NRcRc,-C (O) NRc,-C (O) ORc,-C (O) Rc, - NRcC (O) NRcRc,-NRcC (O) Rc,-OC (O) ORc,-OC (O) NRcRc,-SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each Rc is indepenently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more Re groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.

Provided herein are compositions and methods for treating a disease by administering an effective amount of kinase modulating compound having the structure : (Rsc) n ric 1-1 1./\ roc i R1C Z, Ar2 T T [l Formula Ca wherein :

(a) Rlc is unsubstituted Cl-Cs alkyl or unsubstituted C3-C6 cycloalkyl ; (b) Acl is NH or CH2 and Asz is NH or CH2, wherein one of Acl or Axa is N and one is C ; (c) n is 0,1 or 2; and (d) Each R5c is a suitable substituent independently selected from the group consisting of halogens;-CN ; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,- (CH2) zCN where z is a whole integer from 0 to 4, NH,-NHOH,-OH,-C (O) H, -OC (O) H, -C (O) OH, -OC (O) OH, OC (O) OC (O) H, -OOH, -C (NH) NH2,-NHC (NH) NH2,-C (S) NH2, -NHC (S) NH2, -NHC (O) NH2,-S (02) H, -S (O) H,-NH2,-C (O) NH2,-OC (O) NH2, -NHC (O) H, -NHC(O) OH, -C (O) NHC (O) H, -OS (02) H, -OS (O) H, -OSH,-SC (O) H, -S (O) C (O) OH, - S02C (O) OH,-NHSH,-NHS (O) H,-NHSO2H,-C (O) SH, -C (O) S (O) H, -C (O) S (02) H, - C (S) H, -C (S) OH, -C (SO) OH,-C (S02) OH,-NHC (S) H, -OC (S) H, -OC (S) OH,-OC (SO2) H,-S (02) NH2,-S (O) NH2,-SNH2,-NHCS (02) H, -NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, 0,-N02,-CN,- (CH2) z- CN where z 0,1, 2,3, or 4,-ORc,-NRcORc,-NRcRc,-C (O) NRc,-C (O) ORc, C (O) Rc,-NRcC (O) NRcRc,-NRcC (O) Rc,-OC (O) ORc,-OC (O) NRcRc,-SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each Re is independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.

Provided herein are compositions and methods for treating a disease by administering an effective amount of kinase modulating compound having the structure: (Rsc) n "au2 f") (CHdn2 Ut ' (CH2) 2 '^""A. ni Zozo Ac'II'\ zon Formula D wherein :

(a) Rld is unsubstituted Cl-C5 alkyl or unsubstituted Cs-Cs cycloalkyl ; (b) n is 0, 1 or 2 ; (c) nl is 0,1 or 2; and wherein n2 is 0,1 or 2; wherein n1 and n2 are not both 0.

Provided herein are compositions and methods for treating a disease by administering an effective amount of a kinase modulating compound having the structure: (R5c) n 4,, Ar2 RdcAa xl A2s, SJ A A. 2 I XiYn 0 Fornula E

wherein: (a) n is 0,1 or 2; and (b) Aal is N or C-R3a and Aa2 is N or CR3a, wherein one of Aal or Aa2 is N and one is C.

Provided herein are compositions and methods for treating a disease by administering an effective amount of a kinase modulating compound having the structure: <R5c) n 3f 1- I I (CH2) 2 gAf1rA, 2s Rl1f ! ! (CH2) nl Formula F

wherein: (a) An is N or C-R (3a) 2 and Af2 is N-R3a or C-R (3a) 2, wherein one of An or Af2 is N and one is C; and (b) R3f and Rllf cyclize to form a heteroaryl or heterocycloalkyl group substituted or unsubstituted with one, two or three suitable substituents selected from the group consisting of halogen, =O ; =S;-CN ;-N02, or an alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl group unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens ; =O ; =S;-CN ; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,- (CH2) zCN where z is a whole integer from 0 to 4, =NH,-NHOH,-OH,-C (O) H, -OC (O) H, -C (O) OH, OC (O) OH, -OC (O) OC (O) H, -OOH, -C (NH) NH2, -NHC (NH) NH2,-C (S) NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O) H, -NHC (O) OH, -C (O) NHC (O) H, -OS (02) H, -OS (O) H, -OSH,-SC (O) H, -S (O) C (O) OH,-S02C (O) OH,-NHSH,-NHS (O) H,-NHS02H,-C (O) SH,-C (O) S (O) H,

-C (O) S (02) H,-C (S) H,-C (S) OH, -C (SO) OH,-C (S02) OH,-NHC (S) H,-OC (S) H, -OC (S) OH,-OC (S02) H,-S (02) NH2,-S (O) NH2,-SNH2,-NHCS (02) H,-NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, =0,-N02,-CN,- (CH2),-CN where z is a whole integer from 0 to 4, -ORc, -NRcORc, - NRcRc,-C (O) NRc,-C (O) ORc,-C (O) R,-NRC (O) NRcRc,-NRcC (O) Rc, -OC (O) ORcn-OC (O) NRCRc,-SRcp unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each Re is independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.

Provided herein are compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound having the following structure: (Rsc)" Agl, 1 l | R,. r'r" (CH2) n2 Rlc R1c t ^ I I CHa) nt I --ny Xti Yn Wa Formula G wherein: (a) R2g, R3g and R4g are each independently selected from hydrogen, unsubstituted alkyl, unsubstituted aryl, and unsubstituted heteroaryl; (b) n is 0, 1 or 2 ; (c) nl is 0, 1 or 2 ; (d) n2 is 0, 1 or 2 ; (e) Ar2 is:

wherein: (i) R6g and R7g cyclize to form a 5-or 6-membered aryl, heteroaryl, heterocycloalkyl or cycloakyl group unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of : halogens ; -CN; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,- (CH2) zCN where z is a whole integer from 0 to 4, NH, -NHOH,-OH,-C (O) H, -OC (O) H, -C (O) OH, -OC (O) OH, -OC (O) OC (O) H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, HS(O)H, -NHSO2H,-C (O) SH, -C (O) S (O) H, -C (O) S (02) H, -C (S) H, -C (S) OH, -C (SO) OH, - C (S02) OH,-NHC (S) H, -OC (S) H, -OC (S) OH,-OC (S02) H, -S (02) NH2,-S (O) NH2, - SNH2,-NHCS (02) H,-NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, =O,-N02,-CN,- (CH2) z-CN where z is a whole integer from 0 to 4, -ORc, -NRcORc, -NRcRc, -C(O)NRc, -C(O)ORc, -C(O)Rc, -NRcC(O)NRcRc, - NRcC (O) Rc,-OC (O) OR,-OC (O) NRcRc,-SR, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each R is independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; (ii) Rlog is a suitable substituent selected from hydrogen; halogens;-CN ; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,- (CH2) zCN where z is a whole integer from 0 to 4, NH,-NHOH,-OH, -C (O) H, -OC (O) H, -C (O) OH, -OC (O) OH, -OC (O) OC (O) H, -OOH, -C (NH) NH2,

-NHC (NH) NH2,-C (S) NH2,-NHC (S) NH2,-NHC (O) NH2,-S (O2) H,-S (O) H,-NH2, -C(O) NH2, -OC (O) NH2,-NHC (O) H, -NHC (O) OH, -C (O) NHC (O) H, -OS (02) H, -OS(O) H, -OSH,-SC (O) H, -S (O) C (O) OH,-SO2C (O) OH, -NHSH, NHS (O) H, - NHS02H,-C (O) SH, -C (O) S (O) H, -C (O) S (02) H, -C (S) H, -C (S) OH, -C (SO) OH, -C(SO2)OH, -NHC (S) H, -OC (S) H, -OC (S) OH,-OC (S02) H, -S (02) NH2,-S (O) NH2, - SNH2,-NHCS (02) H, -NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, =O,-NO2,-CN,-(CH2) z-CN where z is a whole integer from 0 to 4,-ORc,-NRcORc,-NRcRc,-C (O) NRc,-C (O) ORc,-C (O) Rc,-NRcC (O) NRcR, -NRcC (O) Rc,-OC (O) ORC,-OC (O) NRCRc,-SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each Rc is independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; and (iii) T1 and T2 are each independently selected from CRW and N, where Rw is a suitable substituent selected from hydrogen; halogens;-CN ; and-N02 ; and unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

Compositions and methods of Formulas A-G are provided wherein Xb is O and Yb is N and/or Xb is N and Yb is O ; and/or R2a, R2g, R3a, R3g, R4a and R4g are each hydrogen; and/or Rlb, Ric, and Rld are each an unsubstituted or substitued t-butyl and R2b and R2g are hydrogen; and/or Wa is O ; and/or Za is C (O) NH or NHC (O); and/or n is 0. In various embodiments, T1 is N and T2 is N or T1 is N and T2 is CH. In other embodiments, Ar2 is:

wherein: (i) R8g and Rgg are suitable substituents each independently selected from the group consisting of hydrogen; halogens;-CN ; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-(CH2) zCN where z is a whole integer from 0 to 4, NH,-NHOH,-OH,-C (O) H, -OC (O) H, -C (O) OH, -OC (O) OH, -OC (O) OC (O) H, -OOH, -C (NH) NH2,-NHC (NH) NH2,-C (S) NH2,-NHC (S) NH2, - NHC (O) NH2,-S (02) H,-S (O) H,-NH2,-C (O) NH2,-OC (O) NH2, -NHC (O) H, -NHC (O) OH, -C (O) NHC (O) H, -OS (02) H, -OS (O) H, -OSH,-SC (O) H, -S (O) C (O) OH, - S02C (O) OH, -NHSH, NHS (O) H,-NHS02H,-C (O) SH, -C (O) S (O) H, -C (O) S (02) H, - C (S) H, -C (S) OH, -C (SO) OH,-C (SO2) OH,-NHC (S) H, -OC (S) H, -OC (S) OH, -OC (SO2) H, -S (02) NH2,-S (O) NH2,-SNH2,-NHCS (02) H, -NHC (SO) H, -NHC (S) H, and-SH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, =0,-N02,-CN,- (CH2) z- CN where z is a whole integer from 0 to 4,-ORc,-NRcORc,-NRcRc,-C (O) NRc, - C(O)ORc, -C(O)Rc, -NRcC(O)NRcRc, -NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where each Rc is independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more R groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; and (ii) T1 is N and T2 is CH or N.

Compositions and methods of Formulas A-G are provided herein wherein R8g and Rgg are each independently selected from the group consisting of hydrogen; halogens;-CN ; and-N02 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl,

cycloalkyl, heterocycloalkyl, heteroaryl,- (CH2),, CN where z is a whole integer from 0 to 4, -OH,-C (O) H, -OC (O) H, -C (O) OH,-NH2,-C (O) NH2, -NHC (O),-OC (O) NH2, -NHC (O) H, -NHC (O) OH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group.

Compositions and methods of Fomulas A-G are provided herein wherein each R5C is a suitable substituent independently selected from the group consisting of halogens;-CN ; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-(CH2) zCN where z is a whole integer from 0 to 4, -OH,-C (O) H, -OC (O) H, -C (O) OH, -NH2,-C (O) NH2, -NHC (O),-OC (O) NH2, -NHC (O) H, -NHC (O) OH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group.

Compositions and methods of Formula A are provided herein wherein Ar3 is a 5- membered aryl, heteroaryl, heterocylcoalkyl or cycloalkyl group unsubstituted or substituted with one, two or three suitable substituents. In other embodiments, Ar3 is a 5-membered heteroaryl group unsubstituted or substituted with one, two or three suitable substituents. In still other embodiments, Ar3 is a 5-or 6-membered aryl or heteroaryl group unsubstituted or substituted with one, two or three suitable substituents.

Compositions and methods of Formula A-G are provided herein wherein n3 is 0 or 1, and/or wherein ni is 0,1 or 2, and/or n2 is 0,1 or 2. In some embodiments, R3a/R3g and R4a/R4g are each hydrogen. In other embodiments, R3a/R3g and R4a/R4g are not both substituted.

Compositions and methods of Formula A are provided herein wherein Ar3 a 5- membered heteroaryl group unsubstituted Cl-C5 alkyl or unsubstituted C3-C5 cycloalkyl ; and R2 is hydrogen. In some embodiments, Arl is an unsubstituted or substituted 6-

membered aryl group or an unsubstituted or substituted 6-membered heteroaryl group.

In other embodiments, Wa is O.

Compositions and methods of Formulas A-G wherein Za is not carbon are described herein. In some embodiments, Za is selected from S, O, N, NRc2, C (O) Narc2, and NRc2C (O), wherein Rc2 is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl group. In other embodiments, Za is C (O) NH, NHC (O), or NH.

Compositions and methods of Formulas A-G wherein Wa is S, O, or NH are described herein.

Compositions and methods of Formulas A-G are described herein wherein Arl is an aryl or heteroaryl group unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens;-CN ; and-N02 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-(CH2) zCN where z is a whole integer from 0 to 4, -OH,-C (O) H, -OC (O) H, -C (O) OH,-NH2,-C (O) NH2, -NHC (O),-OC (O) NH2, -NHC (O) H, -NHC (O) OH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl.

Compositions and methods of Formulas A-G are described herein wherein Ar2 is an aryl, heteroaryl, heterocylcoalkyl or cycloalkyl group unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens;-CN ; and-NO2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,- (CH2) zCN where z is a whole integer from 0 to 4, -OH,-C (O) H, -OC (O) H, -C (O) OH,-NH2,-C (O) NH2,-NHC (O), -OC (O) NH2, -NHC (O) H, -NHC (O) OH groups unsubstituted or substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl.

In some embodiments, Ar2 is an unsubstituted or substituted pyridinyl. In other embodiments, Ar2 is an unsubstituted or substituted quinazolinyl.

Compositions and methods of Formulas A-G are provided herein wherein Xb and Yb are each independently selected from O, N, and NRl wherein RCl is unsubstituted alkyl or unsubstituted aryl. In some emobiments, Xb is N and Yb is NRcI. In other embodiments, Xb is O and Yb is N. In other embodiments, Xb is O and Yb is N, or Xb is N and Yb is O.

Compositions and methods of Formulas A-G are provided herein wherein Ri is unsubstituted t-butyl or unsubstituted cyclopropyl.

Compositions and methods are provided herein wherein R5c is independently selected from the group consisting of halogens,-CN,-N02, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl group.

Compositions and methods of Formulas A-G are provided herein wherein Rlog is hydrogen or lower alkyl.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: (I) wherein: each Z is independently C, CR4, N, NR4, O, or S, provided that no more than two Z's are heteroatoms and wherein no two adjacent Z's are O or S, where R4 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl; each Ri is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,-ORc,-OC (O) Rc,-N02,-N (Rc) 2,-SRc, S (O) jRc where j is 1 or 2,-NRcC (O) Rc,-C (O) N (Rc) 2,-C (0) 2Rc, or-C (O) Rc ; or two adjacent Rl's are taken together to form a substituted or unsubstituted

aryl or heteroaryl; where each Re is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and Y is 0 or S ; each R2 is independently H, halogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy, -OC (O) R3,-N02,-N (R3) 2,-SR3,-NRcC (O) Rc,-C (o) N (Rc) 2, -C (0) 2Rc, or-C (O) Rc ; each R3 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each n is independently 0, 1, 2,3 or 4; or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: wherein: Z1 is CR4 or N; and Z2isOorS.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:

(IV) wherein: L is a linker selected from the group consisting of-C (O) NH-,- (substituted or unsubstituted alkylene)-,- (substituted or unsubstituted alkenylene)- , -C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)-,-O (substituted or unsubstituted alkylene)- ,-N (substituted or unsubstituted alkylene)-,-C (O)-,-NH-,-O-,-S- , -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkylene) -, a covalent bond,-C (O) (substituted or unsubstituted alkenylene) -,-C (O) (substituted or unsubstituted alkylene)- , -NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH-, -NHC (O) (substituted or unsubstituted alkenylene)- ; and T is a mono-, bi-, or tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, T is wherein A is a substituted or unsubstituted five or six-membered aryl or heteroaryl; and B is a substituted or unsubstituted five or six- membered arylene or heteroarylene, wherein A and B together form a fused two-ring moiety.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:

(VI).

In some embodiments, L is-C (O) NH-. In other embodiments, B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, imidazolylene, or pyrrolylene. In still other embodiments, L is-NH-. In yet other embodiments, B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: (VII) wherein: each of Xl-Xs is independently C, CR, N, NR, S, or O, wherein no more than three of Xi- Xs is a heteroatom and no 2 adjacent ring atoms are O or S; and each R is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,-ORd,-OC (O) Rd,-NO2,-N (Rd) 2, -SRd, S (O) jRd where j is 1 or 2,-NRdC (O) Rd,-C (O) N (Rd) 2,-C (0) 2Rd, or-C (O) Rd; or two adjacent R's, are taken together, to form a substituted or unsubstituted aryl or heteroaryl; where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: In some embodiments, L is a covalent bond,-C (O) NH-, -OCH2-, or-OCH2CH2-. In --- X2 3/xi 1 other embodiments, X4 iS selected from the group consisting of : R R R RA R \ R N R/N R Rs N N R R R R R N-0 R R ! ? . \ y R R, and R

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: is selected from the group consisting of : (a) L is selected from the group consisting of-O (substituted or unsubstituted alkylene) -, and-C (O) (substituted or unsubstituted alkenylene)- ; and each of X1-X5 is independently CR, N-O, or N, wherein no more than two of Xl-Xs is N, where each R is independently H, halogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy, -OC (O) Rc,-N02,-N (Rc) 2, -SRc,-NRcC (O) Rc, or-C (O) Rc ; where (b) L is-NH- ; each of X1, X2, X4, and X5 is independently CR or N; and X3 is independently CR6 or N, wherein no more than two of X1-X5 is N, where R6 is selected from the group consisting of H, halogen, substituted or unsubstituted alkyl, substituted alkoxy,-C (O) Rc,-OC (O) Rc,-N02,- N (Rc) 2, and-SRc ;

each Re is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (c) L is-NH- ; each of Xi, X3, and Xs is independently CR or N ; and each of X2 and X4 is independently CR7 or N, wherein no more than two of X1-X5 is N; where R7 is selected from the group consisting of H, halogen, unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy,-C (O) Rc,- OC (O) RC,-NO2,-N (Rc) 2,-suc, and alkyl substituted with alkoxy, halogen, aryl, heteroaryl, amine,-C (O) Rc,-OC (O) Rc,-N02,-N (Rc) 2, or-SRc ; each Re is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ; and (d) L is-C (O) NH- ; each of X1 X2> X4, and Xs is independently CR or N; and X3 is independently CRg or N, wherein no more than two of X1-X5 is N, and when X3 is N, at least one of Xl, X2, X3, or X5 is not CH, where R8 is selected from the group consisting of H, halogen, substituted or unsubstituted alkyl,-ORc, substituted or unsubstituted alkoxy, -C (O) Rc,-OC (O) Rc,-NO2,-N (Rc) 2 and-SRc ; each Rc is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: (X).

In some embodiments, L is-NHC (O)-,-O (substituted or unsubstituted alkylene) -, a covalent bond,- (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkylene) -,-C (O) NH (substituted or unsubstituted alkylene) -,- NHC (O) (substituted or unsubstituted alkenylene)-, or-C (O) NH (substituted or unsubstituted alkenylene).

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:

(XI).

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:

(XII).

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:

(XIII).

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: (XVI).

In some embodiments, L is a linker selected from the group consisting of-NHC (O)-,- O (C1-C3 alkyl),-NHC (O) CH2SCH2C (O) NH-,-CHCHCH20-,-CH2CH2-,-NHC (O)-(C1- C4 alkene),-NHC (O)-(C1-C3 alkyl), and-CH2CH2C (O) NH-.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: (XVII) wherein: L is a linker selected from the group consisting of-C (O) NH-,- (substituted or unsubstituted alkylene)-,- (substituted or unsubstituted alkenylene) -, -C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)-,-O (substituted or unsubstituted alkylene) -, -N (substituted or unsubstituted alkylene)-,-C (O)-,-NH-,-O-,-S-,

-NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkylene) -, a covalent bond,-C (O) (substituted or unsubstituted alkenylene) -,-C (O) (substituted or unsubstituted alkylene)- , -NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH-, -NHC (O) (substituted or unsubstituted alkenylene)- ; each of Xl-Xs is independently C, CR, N-O, or N, wherein no more than two of Xl-Xs is N; where each R is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,-ORd,-OC (O) Rd,-N02,-N (Rd) 2, -SRd, S (O) jRd where j is 1 or 2,-NRdC (O) Rd, -C (O) N (Rd) 2,-C (0) 2Rd, or-C (O) Rd; or two adjacent R's, are taken together, to form a substituted or unsubstituted aryl or heteroaryl; where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: R L L/R1 Ra Ra Z \ K Z/z R (XVIII) wherein : ('Y is selected from the group consisting of : (a) each of L and Li is independently a linker selected from the group consisting of a covalent bond,-O (substituted or unsubstituted alkylene)-,-S-,- (substituted or unsubstituted alkylene)-,-C (O)-, and-N (substituted or unsubstituted alkylene)- ;

U is a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl ; and V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene; (b) L is a linker selected from the group consisting of a covalent bond,- O (substituted or unsubstituted alkylene)-,-S-,- (substituted or unsubstituted alkylene)-,-O-,-NH-,-C (O)-,-C (O) NH-, and-N (substituted or unsubstituted alkylene)- ; Li is a linker selected from the group consisting of a covalent bond,-O (substituted or unsubstituted alkylene)-,-S-,- (substituted or unsubstituted alkylene)-,-O-,-NH-,-C (O)-, and-N (substituted or unsubstituted alkylene)- ; U is selected from the group consisting of : (i) substituted or unsubstituted cycloalkyl ; (ii) unsubstituted aryl; (iii) aryl substituted at any position with-Cl,-I, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy,- OC (O) R3,-N02,-N (R3) 2,-SR3,-C (O) R3, where R3 is H,-OH,-N (R3) 2, or substituted or unsubstituted alkoxy, and where R3 is H or substituted or unsubstituted alkyl ; and (iv) substituted or unsubstituted heteroaryl, except pyridinyl ; V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene; and (c) L is a linker selected from the group consisting of a covalent bond,-O (substituted or unsubstituted alkylene)-,-S-,- (substituted or unsubstituted alkylene)-,-O-,-NH-,-C (O)-,-C (O) NH-, and-N (substituted or unsubstituted alkylene)- ; Li is a linker selected from the group consisting of a covalent bond,-O (substituted or unsubstituted C2-Cs alkylene)-,-S-,- (substituted or unsubstituted alkylene)-,-O-,-NH-,-C (O)-,-C (O) NH-, and-N (substituted or unsubstituted alkylene)- ; U is selected from the group consisting of substituted or unsubstituted cycloalkyl ; substituted aryl; and substituted or unsubstituted heteroaryl; and

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

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: (XIX).

In some embodiments, Li is a bond; and L is a bond or-C (O) NH-. In other embodiments, U is substituted or unsubstituted phenyl, thiazolyl, or pyridinyl; and V is substituted or unsubstituted piperidinylene, thiazolylene, imidazolylene, or thiophenylene.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: (xx).

In some embodiments, Li is a bond,-CH20-,-N (CH3)- or-0- ; and L is-CH20-or - NHC (O) -. In other embodiments, U is substituted or unsubstituted phenyl, C3-C6 cycloalkyl, pyrimidine or pyridine.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:

In some embodiments, Li is a-NH-or-0- ; and L is-NHC (O)-. In other embodiments, U is substituted or unsubstituted pyrmidyl.

Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein: wherein: L is a linker selected from the group consisting of-C (O) NH-,- (substituted or unsubstituted alkylene)-,- (substituted or unsubstituted alkenylene)-, -C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)-,-O (substituted or unsubstituted alkylene)-, - N (substituted or unsubstituted alkylene)-,-C (O)-,-NH-,-O-,-S-, -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkylene) -, a covalent bond,-C (O) (substituted or unsubstituted alkenylene) -,-C (O) (substituted or unsubstituted alkylene)- , -NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH-, -NHC (O) (substituted or unsubstituted alkenylene)- ; U is a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; and V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene.

Exemplary FLT-3 Modulators Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound corresponding to the following formula are provided herein: M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl; and

Y is 0 or S ; each Rk is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy,-OC (O) R2,-N02,-N (R2) 2, -SR2,-C (O) R2,-C (0) 2R2,-C (O) N (R2) 2, or-N (R2) C (O) R2, each R2 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R2 groups are linked together by an optionally substituted alkylene ; and each n is independently 0, 1, 2,3 or 4; or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein: each Z is independently C, CR3, N, NR3, O, or S, provided that no more than two Z's are heteroatoms and wherein no two adjacent Z's are O or S, where R3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and each Ri is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl,

substituted or unsubstituted heteroaryl,-ORc-OH,-OC (O) Rc,-N02,-N (Rc) 2, -SR, S (O) j& where j is 1 or 2, -NRcC (O) R,,-C (O) N (Rc) 2, C (0) 2Rc, or- C (O) Rc ; or two adjacent Rl's, are taken together to form a substituted or unsubstituted aryl or heteroaryl, where each Re is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein Z1 is CR3 or N; and Z2 is O or S.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: each Ri is independently H, halogen, substituted or unsubstituted alkyl,-O (substituted or unsubstituted alkyl),-O (substituted or unsubstituted alkenyl),-NRcC (O) O (substituted or unsubstituted alkyl),-NRC (O) (substituted or unsubstituted alkyl),-NRcC (O) (substituted or unsubstituted alkenyl), -C (O) NRc (substituted or unsubstituted alkyl),-C (O) NRc (substituted or unsubstituted alkenyl),-N02,-S (=O) Rc,- SRc, C (O) 2Rc, or-C (O) Rc ; and each R2 is independently H or substituted or unsubstituted alkyl.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein Z1 is O or S; and Z2 is CR3 or N.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: each Ri is independently H, halogen, substituted or unsubstituted alkyl,-O (substituted or unsubstituted alkyl),-O (substituted or unsubstituted alkenyl),-NRcC (O) O (substituted or unsubstituted alkyl),-NRcC (O) (substituted or unsubstituted alkyl),-NRC (O) (substituted or unsubstituted alkenyl), -C (O) NRc (substituted or unsubstituted alkyl),-C (O) NRc (substituted or unsubstituted alkenyl),-NO2,-S (=O) Razz SRc, C (O) 2R, or-C (O) Rc ; and each R2 is independently H or substituted or unsubstituted alkyl.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)-

- NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkenylene)-,-C (O) (substituted or unsubstituted alkenylene)-, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and T is a mono-, bi, -or tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl. GEL In some embodiments, T is Ct i wherein A is a substituted or unsubstituted five or six-membered heterocyclyl, aryl, or heteroaryl; and B is a substituted or unsubstituted five or six-membered heterocyclene, arylene, or heteroarylene, wherein A and B together form a fused two ring moiety.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: In some embodiments, L of said compound is a covalent bond-C (O) NH (substituted or unsubstituted alkylene)-,-NHC (O) -,-NHC (O) (substituted or unsubstituted alkylene)-,- NH-, or-O (substituted or unsubstituted alkylene)-.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: In some embodiments, B of said compound is a substituted or unsubstituted five- membered arylene or heteroarylene. In other embodiments, B is substituted or unsubstituted thiophenylene. In still other embodiments, B is substituted or unsubstituted imidazolylene. In other embodiments, B is substituted or unsubstituted pyrrolylene. In some embodiments, B of said compound is a substituted or unsubstituted 6-membered arylene or heteroarylene. In other embodiments, B is substituted or

unsubstituted phenylene. In still other embodiments, B is substituted or unsubstituted pyridinylene, pyrimidinylene, or pyridazine.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

In some embodiments, B of said compound is a substituted or unsubstituted six- membered heteroarylene. In other embodiments, said six-membered heteroarylene is substituted or unsubstituted pyrimidinylene. In still other embodiments, L of said compound-OCH2-. In some embodiments, L of said compound is-C (O) NH.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)- -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkenylene)-,-C (O) (substituted or unsubstituted alkenylene)-, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and

each of X1-X5 is independently C, CR, N, NR, S, or O, wherein no more than three of Xl-Xs is a heteroatom, and no two adjacent ring atoms are O or S; where each R is independently H, halogen, substituted or unsubstituted alkyl,-ORd, substituted or unsubstituted alkoxy,-OC (O) Rd,-NO2,-N (Rd) 2, -SRd,-S (O) jRd where j is 1 or 2,-NRdC (O) Rd,-C (0) 2Rd,-C (O) N (Rd) 2, or-C (O) Rd, or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

In some embodiments, L of said compound is a covalent bond,-C (O) NH-, or-O (substituted or unsubstituted alkylene) -. In other embodiments, x-X2\ 1 of said compound is selected from the group consisting of :

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)- -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkenylene)-,-C (O) (substituted or unsubstituted alkenylene) -, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and each of X1-X5 is independently C, CR, N-O, or N, wherein no more than two of Xl-Xs is N, where each R is independently H, halogen, substituted or unsubstituted alkyl,-ORd, substituted or unsubstituted alkoxy,-OC (O) Rd,-NO2,-N (Rd) 2,-SRd,-S (O) jRd where j is 1 or 2,-NRdC (O) Rd, -C (0) 2Rd, -C (O) N (Rd) 2, or-C (O) Rd, or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein L is-O (substituted or unsubstituted alkylene)-or-C (O) (substituted or unsubstituted alkenylene)-.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

In some embodiments, L of said compound is-O (substituted or unsubstituted alkylene)- or-O (substituted or unsubstituted alkenylene) -. In other embodiments, L of said compound is-NHC (O) -. In yet other embodiments, L of said compound is a covalent bond, substituted or unsubstituted alkylene,-NHC (O) (substituted or unsubstituted alkylene) -,-NHC (O) (substituted or unsubstituted alkenylene) -,-NH (alkylene)-, -NHC (O) CH2SCH2C (O) NH-, and-NHC (O) (substituted alkylene) S-.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene) -,-C (O) NH (substituted or unsubstituted alkenylene)- -NHC (O) (substituted or unsubstituted alkylene) -,-NHC (O) (substituted or

unsubstituted alkenylene) -,-C (O) (substituted or unsubstituted alkenylene)-, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and each of Xl-Xs is independently C, CR, or N, wherein no more than two of Xl-X5 is N, where each R is independently H, halogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy,-OC (O) Rd,-N02,-N (Rd) 2, -SRd,-S (O) jRd where j is 1 or 2,-NRdC (O) Rd, -C (0) 2Rd,-C (O) N (Rd) 2 or-C (O) Rd, or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Z is 0 or S ; and Z2 is CR3 or N.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

(XXVII).

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

each of L and Ll is independently a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-,-C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,-N (substituted or unsubstituted alkylene) -, -C (O) NH (substituted or unsubstituted alkylene),-C (O) NH (substituted or unsubstituted alkenylene)--NHC (O) (substituted or unsubstituted alkylene)-, -NHC (O) (substituted or unsubstituted alkenylene) -,-C (O) (substituted or unsubstituted alkenylene) -, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; U is a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: each of Xl-X5 is independently C, CR, N, NR, S, or O, wherein no more than three of Xl-X5 is a heteroatom, and no two adjacent ring atoms are O or S; and each R is independently H, halogen, substituted or unsubstituted alkyl,-ORd, substituted or unsubstituted alkoxy, -OC (O) Rd,-N02,-N (Rd) 2,-SRd,-S (O) jRd where j is 1 or 2,-NRd C (O) Rd, -C (0) 2Rd, -C (O) N (Rd) 2 or-C (O) Rd, or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

In some embodiments, U is a substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted six-membered heteroaryl.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein: Z3 is NR3, O, or S; and Z4 is N or CR3.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)- -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkenylene) -,-C (O) (substituted or unsubstituted alkenylene)-, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and T is a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein: each Z is independently C, CR3, N, NR3, O, or S, provided that no more than two Z's are heteroatoms where R3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl. each Rk is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy,-OC (O) R2,-NO2,-N (R2) 2, -SR2,-C (O) R2,-C (0) 2R2,-C (O) N (R2) 2, or-N (R2) C (O) R2,

each R2 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R2 groups are linked together by an optionally substituted alkylene ; and each R1 is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,-ORc-OH,-OC (O) RC,-NO2,-N (Rc) 2,-SRc, S (O) jRc where j is 1 or 2, -NRcC (O) Rc,-C (O) N (Rc) 2, C (O) 2roc, or-C (O) Rc ; or two adjacent Rl's, are taken together to form a substituted or unsubstituted aryl or heteroaryl, where each Rc is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Methods for modulating FLT-3 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Provided herein are methods for modulating abl kinase, said methoPd comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, selected fiom the group consisting of :

Exentplary PDGER Modulators Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound corresponding to the following formula are provided herein:

wherein: M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl; and Y is 0 or S ; each Rk is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy,-OC (O) R2,-N02,-N (R2) 2, -SR2, -C(O)R2, -C(O)2R2, -C(O)N(R2)2, or -N(R2)C(O)R2, each R2 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R2 groups are linked together by an optionally substituted alkylene ; and each n is independently 0,1, 2,3 or 4; or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, spharmaceutically acceptable salt or solvate thereof.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

each Z is independently C, CR3, N, NR3, O, or S, provided that no more than two Z's are heteroatoms and wherein no two adjacent Z's are O or S, where R3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and each Ri is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,-ORc-OH,-OC (O) Rc,-N02,-N (Rc) 2, -SRe, S (O) jRc where j is 1 or 2,-NR, C (O) Ro,-C (O) N (Rc) 2, C (0) 2Rc, or- C (O) Rc ; or two adjacent Rl's, are taken together to form a substituted or unsubstituted aryl or heteroaryl, where each Re is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: each Rk is independently H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein Zl is CR3 or N; and Z2 is O or S.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein: each Ri is independently H, halogen, substituted or unsubstituted alkyl,-O (substituted or unsubstituted alkyl),-O (substituted or unsubstituted alkenyl),-NRcC (O) O (substituted or unsubstituted alkyl),-NRcC (O) (substituted or unsubstituted alkyl),-NRcC (O) (substituted or unsubstituted alkenyl), -C (O) NRc (substituted or unsubstituted alkyl),-C (O) NRc (substituted or unsubstituted alkenyl),-N02,-S (=O) Rc,- SRc, C (0) 2Rc, or-C (O) Rc ; and each R2 is independently H or substituted or unsubstituted alkyl.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein Z1 is O or S; and Z2 is CR3 or N.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein: each Ri is independently H, halogen, substituted or unsubstituted alkyl,-O (substituted or unsubstituted alkyl),-O (substituted or unsubstituted alkenyl),-NRcC (O) O (substituted or unsubstituted alkyl),-NRC (O) (substituted or unsubstituted alkyl),-NRcC (O) (substituted or unsubstituted alkenyl), -C (O) NRc (substituted or unsubstituted alkyl),-C (O) NRc (substituted or unsubstituted alkenyl),-NO2,-S (=O) Rc,- SRc, C (0) 2Rc, or-C (O) Rc ; and each R2 is independently H or substituted or unsubstituted alkyl, or two R2 groups are linked together to form an optionally substituted alkylene.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, -C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)- -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkenylene)-,-C (O) (substituted or unsubstituted alkenylene)-, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and T is a mono-, bi-, or tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl. (7r. \ In some embodiments, T is wherein A is a substituted or unsubstituted five or six-membered heterocyclyl, aryl, or heteroaryl; and B is a substituted or unsubstituted five or six-membered heterocyclene, arylene, or heteroarylene, wherein A and B together form a fused two ring moiety.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

In some embodiments, L of said compound is a covalent bond,-C (O) NH (substituted or unsubstituted alkylene), -NHC (O)-,-NHC (O) (substituted or unsubstituted alkylene)-,- NH-, or-O (substituted or unsubstituted alkylene)-.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: In some embodiments, B of said compound is a substituted or unsubstituted five- membered heteroarylene. In other embodiments, said five-membered heteroarylene is substituted or unsubstituted thiophenylene. In still other embodiments, B is substituted or unsubstituted imidazolylene. In still other embodiments, B is substituted or unsubstituted pyrrolylene. In some embodiments, B of said compound is a substituted or unsubstituted 6-membered arylene or heteroarylene. In other embodiments, B is substituted or unsubstituted phenylene. In yet other embodiments, B is substituted or unsubstituted pyridinylene or pyridazine.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: In some embodiments, B of said compound is a substituted or unsubstituted six- membered heteroarylene. In other embodiments, said six-membered heteroarylene is substituted or unsubstituted pyrimidinylene. In yet other embodiments, L of said compound-OCH2-.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)- -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkenylene)-,-C (O) (substituted or unsubstituted alkenylene)-, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and each of Xl-Xs is independently C, CR, N, NR, S, or O, wherein no more than three of Xl-Xs is a heteroatom, and no two adjacent ring atoms are 0 or S; where each R is independently H, halogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy, -OC (O) Rd,-N02,-N (Rd) 2,-SRd,-S (O) jRd where j is 1 or 2, -NRd C (O) Rd,-C (0) 2Rd, -C (O) N (Rd) 2 or-C (O) Rd, or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each Ra is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: In some embodiments, L of said compound is a covalent bond,-C (O) NH-, or-O (substituted or unsubstituted alkylene) -. In other embodiments,

said compound is selected from the group consisting of :

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)- -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkenylene)-,-C (O) (substituted or unsubstituted alkenylene)-,

and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and each of Xl-Xs is independently C, CR, N-O, or N, wherein no more than two of Xi-xi is N, where each R is independently H, halogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy,-OC (O) Rd,-N02,-N (Rd) 2,-SRd,-S (O) jRd where j is 1 or 2, -NRd C (O) Rd, -C (0) 2Rd,-C (O) N (Rd) 2 or-C (O) Rd, or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

In some embodiment, L is a linker selected from the group consisting of a covalent bond, - (substituted or unsubstituted alkylene),-NHC (O) -,-C (O) NH (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkylene)-, -C (O) NH (substituted or unsubstituted alkenylene)-,-NHC (O) (substituted or unsubstituted alkenylene)-, and-O (substituted or unsubstituted alkylene)-, Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

In some embodiments, L of said compound is-OCH2-or-OCH2CHCH-. In other embodiments, L of said compound is-NHC (O) -. In still other embodiments, L of said compound is a covalent bond, substituted or unsubstituted alkylene, -NHC (O) (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene) -,-C (O) NH (substituted or unsubstituted alkenylene)-, or- NHC (O) (substituted or unsubstituted alkenylene) -.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, -C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene)-,- N (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkylene)-,-C (O) NH (substituted or unsubstituted alkenylene)- -NHC (O) (substituted or unsubstituted alkylene)-,-NHC (O) (substituted or unsubstituted alkenylene) -,-C (O) (substituted or unsubstituted alkenylene)-, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; and each of X1-X5 is independently C, CR, NR, O, S, or N, wherein no more than two of Xl-X5 is a hetroatom, and no two adjacent ring atoms are O or S, where each R is independently H, halogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy,-OC (O) Rd,-NO2,-N (Rd) 2,-SRd,-S (O) jRd where j is 1 or 2,-NRd C (O) Rd, -C (0) 2Rd,-C (O) N (Rd) 2 or-C (O) Rd, or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Z, is 0 or S ; and Z2 is CR3 or N.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

wherein: each of L and Li is independently a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene,-C (O) NH-, -C (O)-,-NH-,-O-,-S-,-O (substituted or unsubstituted alkylene) -,-N (substituted or unsubstituted alkylene)-, -C (O) NH (substituted or unsubstituted alkylene),-C (O) NH (substituted or unsubstituted alkenylene)--NHC (O) (substituted or unsubstituted alkylene) -, -NHC (O) (substituted or unsubstituted alkenylene)-,-C (O) (substituted or unsubstituted alkenylene)-, and-NHC (O) (substituted or unsubstituted alkylene) S (substituted or unsubstituted alkylene) C (O) NH- ; U is a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene.

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:

Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: wherein: each of Xl-Xs is independently C, CR, N, NR, S, or O, wherein no more than three of Xl-xs is a heteroatom, and no two adjacent ring atoms are S or O ; and each R is independently H, halogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy, -OC (O) Rd,-NO2,-N (Rd) 2,-SRd,-S (O) jRd where j is 1 or 2, -NRd C (O) Rd,-C (0) 2Rd,-C (O) N (Rd) 2 or-C (O) Rd, or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

In some embodiments, V is a five-membered hetroarylene group. In other embodiments, U is a substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted six-membered heteroaryl.

Provided herein are methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of :

Exemplary C-KIT Modulators Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound corresponding to the following formula are provided herein:

wherein : M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl; and

Y is 0 or S ; each Rk is independently H, halogen, substituted or unsubstituted alkyl,- OH, substituted or unsubstituted alkoxy,-OC (O) R2,-NO2,-N (R2) 2,- SR2, -C (O) R2, -C (0) 2R2,-C (O) N (R2) 2, or-N (R2) C (O) R2, each R2 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R2 groups are linked together by an optionally substituted alkylene; and each n is independently 0,1, 2,3 or 4; or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.