WO2005048953A2 - Amide derivatives as kinase modulators - Google Patents

Amide derivatives as kinase modulators Download PDF

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WO2005048953A2
WO2005048953A2 PCT/US2004/038433 US2004038433W WO2005048953A2 WO 2005048953 A2 WO2005048953 A2 WO 2005048953A2 US 2004038433 W US2004038433 W US 2004038433W WO 2005048953 A2 WO2005048953 A2 WO 2005048953A2
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substituted
unsubstituted
compound
alkylene
aryl
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PCT/US2004/038433
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WO2005048953A3 (en
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Shamal A. Mehta
Robert M. Grotzfeld
Zdravko V. Milanov
Andiliy G. Lai
Hitesh K. Patel
David J. Lockhart
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Ambit Biosciences Corporation
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Definitions

  • 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 ⁇ and ⁇ ), colony-stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), FLT-3, and stem cell or steel factor receptor (c-kit).
  • Acute myelogenous leukemia 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.
  • 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.
  • 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.
  • 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:
  • Ric is unsubstituted C1-C 5 alkyl or unsubstituted C 3 -C 6 cycloalkyl
  • M is NH or CH 2 and A c2 is NH or CH 2 , wherein one of A cl or A c2 is N and one is C;
  • R 5 c is a suitable substituent independently selected from the group consisting of halogens; -CN; and -NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH 2 ) Z CN 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)NH 2 , -NHC(NH)NH 2 , -C(S)NH 2 , -NHC(S)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 ,
  • R 1( ⁇ is unsubstituted C1-C 5 alkyl or unsubstituted C 3 -C 5 cycloalkyl;
  • n 0, 1 or 2;
  • compositions and methods for treating a disease by administering an effective amount of a kinase modulating compound having the structure:
  • n 0, 1 or 2;
  • compositions and methods for treating a disease by administering an effective amount of a kinase modulating compound having the structure:
  • An is N or C-R( 3a ) 2 and Af2 is N-R 3a or C-R( 3a ) 2 , wherein one of An or A 2 is N and one is C;
  • R 2g , R g and R 4g are each independently selected from hydrogen, unsubstituted alkyl, unsubstituted aryl, and unsubstituted heteroaryl;
  • n is 0, 1 or 2;
  • n 2 is 0, 1 or 2;
  • R o g and R 7g 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 -NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH 2 ) Z CN 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)NH 2 , -NHC(NH)NH 2 , -C(S)NH 2
  • R 10g is a suitable substituent selected from hydrogen; halogens; -CN; and -NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH 2 ) Z CN 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)NH 2 , -NHC(NH)NH 2 , -C(S)NH 2 , -NHC(S)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -S(O 2 )H, -S(O)H, -NH 2 , -C
  • compositions and methods of Formulas A-G are provided wherein X b is O and Y b is N and/or X b is N and Yb is O; and/or R 2a , R 2g , R a , R 3 , Ri a and R g are each hydrogen; and/or Ri , Ric, and R 1(1 are each an unsubstituted or substitued t-butyl and R 2b and R 2g are hydrogen; and/or W a is O; and/or Z a is C(O)NH or NHC(O); and/or n is 0.
  • Ti is N and T 2 is N or T 1 is N and T 2 is CH.
  • Ar 2 is: wherein:
  • R 8g and R 9g are suitable substituents each independently selected from the group consisting of hydrogen; halogens; -CN; and -NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH 2 ) Z CN 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)NH 2 , -NHC(NH)NH 2 , -C(S)NH 2 , -NHC(S)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -S(O 2 )H, -S(O)H
  • R 8g and R 9g are each independently selected from the group consisting of hydrogen; halogens; -CN; and -NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH 2 ) Z CN where z is a whole integer from 0 to 4, -OH, -C(O)H, -OC(O)H, -C(O)OH, -NH 2 , -C(O)NH 2 , - NHC(O), -OC(O)NH 2) -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
  • each R 5C is a suitable substituent independently selected from the group consisting of halogens; -CN; and -NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH 2 ) Z CN where z is a whole integer from 0 to 4, -OH, -C(O)H, -OC(O)H, -C(O)OH, -NH 2 , -C(O)NH 2 , - NHC(O), -OC(O)NH 2 , -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 alken
  • Ar 3 is a 5- membered aryl, heteroaryl, heterocylcoalkyl or cycloalkyl group unsubstituted or substituted with one, two or three suitable substituents.
  • Ar is a 5-membered heteroaryl group unsubstituted or substituted with one, two or three suitable substituents.
  • Ar 3 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 n 3 is 0 or 1, and/or wherein ni is 0, 1 or 2, and/or n 2 is 0, 1 or 2.
  • R 3a /R 3g and R 4a /R 4g are each hydrogen. In other embodiments, R a /R 3 and are not both substituted.
  • compositions and methods of Formula A are provided herein wherein Ar 3 a 5- membered heteroaryl group unsubstituted C ⁇ -C 5 alkyl or unsubstituted C 3 -C 5 cycloalkyl; and R 2 is hydrogen, hi some embodiments, Ari is an unsubstituted or substituted 6- membered aryl group or an unsubstituted or substituted 6-membered heteroaryl group, hi other embodiments, W a is O.
  • Compositions and methods of Formulas A-G wherein Z a is not carbon are described herein.
  • Z a is selected from S, O, N, NRc 2 , C(O)NR c2 , and NRc 2 C(O), wherein R c is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl group.
  • Z a is C(O)NH, NHC(O), or NH.
  • Ar 1 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 -NO ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH 2 ) Z CN where z is a whole integer from 0 to
  • Ar 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 -NO 2 ; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH 2 ) Z CN where z is a whole integer from 0 to
  • Ar 2 is an unsubstituted or substituted pyridinyl. hi other embodiments, Ar 2 is an unsubstituted or substituted quinazolinyl.
  • Compositions and methods of Formulas A-G are provided herein wherein X b and Y b are each independently selected from O, N, and NR c i wherein R ⁇ is unsubstituted alkyl or unsubstituted aryl. In some emobiments, X is N and Y b is NR c i. other embodiments, X b is O and Y b is N.
  • X b is O and Y b is N, or X b is N and Y b 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 R 5 c is independently selected from the group consisting of halogens, -CN, -NO 2 , unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl group.
  • R 10g 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:
  • each R 2 is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R 3 , -NO 2 , -N(R 3 ) 2 , -SR 3 , -NR c C(O)Rc, -C(O)N(R c ) 2
  • each R 3 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • 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:
  • 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)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:
  • L is -C(O)NH-.
  • B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, imidazolylene, or pyrrolylene.
  • L is -NH-.
  • B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.
  • each of X 1 -X 5 is independently C, CR, N, NR, S,or O, wherein no more than three of Xi- X 5 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, -NO 2 , -N(Rd) 2 , -SRd, S(O)jRd where j is 1 or 2, -NRdC(O)Rd, -C(O)N(Rd) 2 , -C(O) 2 Rd, or -C(O)Rd; or two
  • L is a covalent bond, -C(O)NH-, -OCH 2 -, or -OCH 2 CH 2 -.
  • L is selected from the group consisting of -O(substituted or unsubstituted alkylene)-, and -C(O)(substituted or unsubstituted alkenylene)-; and each of Xi-X 5 is independently CR, N-O, or N, wherein no more than two of Xi-X 5 is N, where each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R c , -NO 2 , -N(R c ) 2 , -SRc,-NRcC(O)R c , or -C(O)R c ; where (b) L is -NH-; each of X ls X 2 , , and X 5 is independently CR or N; and X is independently CR 6 or N, wherein
  • 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:
  • 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:
  • 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:
  • 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:
  • L is a linker selected from the group consisting of -NHC(O)-, -
  • compositions and methods for treating a disease comprising administering to a subj ect in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:
  • 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)NH-, -
  • 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;
  • V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene;
  • 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 cyclo
  • 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)-;
  • L t is a linker selected from the group consisting of a covalent bond, -O(substituted or unsubstituted C 2 -C 5 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
  • Li is a bond; and L is a bond or -C(O)NH-.
  • U is substituted or unsubstituted phenyl, thiazolyl, or pyridinyl; and V is substituted or unsubstituted piperidinylene, thiazolylene, imidazolylene, or thiophenylene.
  • Li is a bond, -CH 2 O-, -N(CH 3 )- or -O-; and L is -CH 2 O- or -NHC(O)-.
  • U is substituted or unsubstituted phenyl, C 3 -C 6 cycloalkyl, pyrimidine or pyridine.
  • Li is a -NH- or -O-; 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:
  • 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)NH-, -(
  • M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl
  • N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl
  • each R k is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R 2 , -NO 2 , -N(R 2 ) 2 , -SR 2 , -C(O)R 2 , -C(O) 2 R 2 , -C(O)N(R 2 ) 2 , or -N(R 2 )C(O)R 2
  • each R 2 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 R 2 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
  • Methods for modulating FLT-3 kinase 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 comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • each Ri is independently H, halogen, substituted or unsubstituted alkyl, -O(substituted or unsubstituted alkyl), -O(substituted or unsubstituted alkenyl), -NR c C(O)O(substituted or unsubstituted alkyl), -NR c C(O) (substituted or unsubstituted alkyl), -NR c C(O)(substituted or unsubstituted alkenyl), -C(O)NR c (substituted or unsubstituted alkyl), -C(O)NR c (substituted or unsubstituted alkyl), -C(O)NR c (substituted or unsubstituted alkyl), -C(O)NR c (substituted or unsubstituted alkyl), -C(O)
  • Methods for modulating FLT-3 kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • each Ri is independently H, halogen, substituted or unsubstituted alkyl, -O(substituted or unsubstituted alkyl), -O(substituted or unsubstituted alkenyl), -NR c C(O)O(substituted or unsubstituted alkyl), -NR c C(O) (substituted or unsubstituted alkyl), -NR c C(O)(substituted or unsubstituted alkenyl), -C(O)NR c (substituted or unsubstituted alkyl), -C(O)NR c (substituted or unsubstituted alkyl), -C(O)NR c (substituted or unsubstituted alkyl), -C(O)NR c (substituted or unsubstituted alkyl), -C(O)
  • Methods for modulating FLT-3 kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • 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)-, -NHC(O)(substituted or unsubstituted alkenylene)-,
  • 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.
  • 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)-.
  • 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.
  • B is substituted or unsubstituted pyridinylene, pyrimidinylene, or pyridazine.
  • B of said compound is a substituted or unsubstituted six- membered heteroarylene.
  • said six-membered heteroarylene is substituted or unsubstituted pyrimidinylene.
  • L of said compound is -C(O)NH.
  • 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)-, -NHC(O)(substituted or unsubstituted alkenylene)-,
  • L of said compound is a covalent bond, -C(O)NH-
  • 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 alkylene)-, -NHC(O)(substituted or unsubstituted alkylene)-, -
  • Methods for modulating FLT-3 kinase 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 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 comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • L is -O(substituted or unsubstituted alkylene)- or -C(O)(substituted or unsubstituted alkenylene)-.
  • Methods for modulating FLT-3 kinase 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 comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • 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)-.
  • L of said compound is a covalent bond, substituted or unsubstituted alkylene, -NHC(O)(substiruted or unsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkenylene)-, -NH(alkylene)-, -NHC(O)CH 2 SCH 2 C(O)NH-, and -NHC(O)(substituted alkylene)S-.
  • 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)-, -NHC(O)(substituted or unsubstituted alkenylene)-,
  • Z ⁇ is O or S; and Z 2 is CR 3 orN.
  • 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)
  • Methods for modulating FLT-3 kinase 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 comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • each of X1-X 5 is independently C, CR, N, NR, S, or O, wherein no more than three of Xi-X 5 is a heteroatom, and no two adjacent ring atoms are O or S; and each R is independently H, halogen, substituted or unsubstituted alkyl, -OR d , substituted or unsubstituted alkoxy, -OC(O)R d , -NO 2 , -N(Rd) 2 , -SR d , -S(O) j R d where j is 1 or 2, -NRd C(O)R d , -C(O) 2 R d, -C(O)N(R d ) 2 or -C(O)R , or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each R is independently H, substituted or unsubstituted alkyl,
  • U is a substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted six-membered heteroaryl.
  • Z 3 is R 3 , O, or S; and Z 4 is N or CR 3 .
  • Methods for modulating FLT-3 kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • 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 imsubstituted alkylene)-, - N(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkenylene)- -NHC(O)(substituted or imsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkenylene)-, -C(O)(substituted or unsubstituted alkenylene)-,
  • each Z is independently C, CR 3 , N, NR 3 , O, or S, provided that no more than two Z's are heteroatoms where R 3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or imsubstituted heteroaryl, or substituted or unsubstituted aryl.
  • each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or imsubstituted alkoxy, -OC(O)R 2 , -NO 2 , -N(R 2 ) 2 , -SR.2, -C(O)R 2 , -C(O) 2 R 2 , -C(O)N(R 2 ) 2 , or -N(R 2 )C(O)R 2 , each R 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 R 2 groups are linked together by an optionally substituted alkylene; and each Ri is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted
  • abl kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • Exemplary PDGFR Modulators 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 K is where Y is O or S; each Ri c is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R 2 , -NO , -N(R 2 ) 2 , -SR 2 , -C(O)R 2 , -C(O) 2 R 2 , -C(O)N(R 2 ) 2 , or -N(R 2 )C(O)R 2 , each R 2 is
  • each Z is independently C, CR 3 , N, NR 3 , 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 R 3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or imsubstituted heteroaryl, or substituted or imsubstituted aryl; 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, -OR c -OH, -OC(O)Rc, -NO , -N(R c ) 2 , -SRc, S(O)j
  • each R k is independently H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
  • Methods for modulating PDGFR kinase 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 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 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 comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • 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 imsubstituted 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)-, -NHC(O)(substituted or unsubstituted alkenylene)-,
  • 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.
  • L of said compound is a covalent bond, -C(O)NH(substituted or imsubstituted alkylene), -NHC(O)-, -NHC(O)(substituted or unsubstituted alkylene)-, - NH-, or -O(substituted or imsubstituted alkylene)-.
  • B of said compound is a substituted or imsubstituted five- membered heteroarylene.
  • said five-membered heteroarylene is substituted or unsubstituted thiophenylene.
  • B is substituted or unsubstituted imidazolylene.
  • B is substituted or unsubstituted pyrrolylene.
  • B of said compound is a substituted or imsubstituted 6-membered arylene or heteroarylene.
  • B is substituted or unsubstituted phenylene.
  • B is substituted or imsubstituted pyridinylene or pyridazine.
  • B of said compound is a substituted or unsubstituted six- membered heteroarylene.
  • said six-membered heteroarylene is substituted or unsubstituted pyrimidinylene.
  • 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 imsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted 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)--,
  • Methods for modulating PDGFR kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein: (XV).
  • L of said compound is a covalent bond, -C(O)NH-,
  • said compound is selected from the group consisting of:
  • Methods for modulating PDGFR kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • 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 imsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted alkenylene)- -NHC(O)(substituted or unsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkenylene)-, -C(O)(substituted or imsubstituted alkenylene)--,
  • 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 imsubstituted alkenylene)-, -NHC(O)(substituted or imsubstituted alkenylene)-, and -O(substituted or unsubstituted alkylene)-,
  • Methods for modulating PDGFR kinase comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating PDGFR kinase 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 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 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 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 comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following fo ⁇ nula are provided herein:
  • Methods for modulating PDGFR kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • L of said compound is -OCH - or -OCH 2 CHCH-. 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 imsubstituted alkenylene)-, or - NHC(O)(substituted or unsubstituted alkenylene)-.
  • L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or imsubstituted alkylene, -C(O)NH-, -C(O)-, -NH-, -O-, -S-, -O(substiruted or unsubstituted alkylene)-, - N(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted alkenylene)- -NHC(O)(substituted or unsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkylene)-, -
  • Z ⁇ is O or S; and Z 2 is CR 3 orN.
  • 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 admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • 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 imsubstituted alkylene), -C(O)NH(substituted or unsubstituted alkenylene)- -NHC(O)(substituted or imsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkenylene)-, -C(O)(substituted or imsubstituted alkylene
  • Methods for modulating PDGFR kinase 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 comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, conesponding to the following formula are provided herein:
  • each of X ⁇ -X 5 is independently C, CR, N, NR, S, or O, wherein no more than three of X1-X5 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 imsubstituted alkoxy, -OC(O)R d , -NO 2 , -N(R d ) 2 , -SR d , -S(O) j R d where j is 1 or 2, -NRd C(O)R ⁇ ⁇ , -C(O) 2 Rd, -C(O)N(R d ) 2 or -C(O)Rd, or two adjacent R's are taken together to form a substituted or imsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or unsubstituted alkyl,
  • V is a five-membered hetroarylene group.
  • U is a substituted or imsubstituted five-membered heteroaryl, substituted or unsubstituted phenyl, or substituted or imsubstituted six-membered heteroaryl.
  • a compound, or pharmaceutically acceptable salt thereof selected from the group consisting of:
  • M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl
  • N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl
  • each R k is independently H, halogen, substituted or unsubstituted alkyl, - OH, substituted or imsubstituted alkoxy, -OC(O)R , -NO 2 , -N(R 2 ) 2 , - SR 2 , -C(O)R 2 , -C(O) 2 R 2 , -C(O)N(R 2 ) 2 , or -N(R 2 )C(O)R 2
  • each R 2 is independently H, substituted or unsubstituted alkyl, substituted or imsubstituted cycloalkyl, substituted or imsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R 2 groups are linked together by an optionally substituted alkylene; and each n is independently 0, 1, 2, 3 or 4; or an active metabolite
  • K is or where each R k is independently H, halogen, substituted or unsubstituted alkyl, or substituted or imsubstituted alkoxy.
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • L is a linker selected from the group consisting of a covalent bond, substituted or imsubstituted alkenylene, substituted or unsubstituted alkylene, -C(O)NH- , -C(O)-, -NH-, -O-, -S-, -O(substituted or imsubstituted alkylene)-, - N(substituted or imsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted 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)-
  • T is wherein A is a substituted or unsubstituted five or six-membered heterocyclyl, aryl, or heteroaryl; and B is a substituted or imsubstituted five or six-membered heterocyclene, arylene, or heteroarylene, wherein A and B together form a fused two ring moiety.
  • T of said compound is a tricyclic, substituted or unsubstituted aryl, heterocyclyl, or heteroaryl.
  • L of said compound is a covalent bond, -C(O)NH(substituted or imsubstituted alkylene),-O(substituted or unsubstituted alkylene)-, -C(O)NH-, or -
  • B of said compound is a substituted or unsubstituted five-membered heteroarylene. In still other embodiments, B of said compound is a substituted or unsubstituted 6-membered arylene or heteroarylene.
  • 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 imsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkenylene)-, -NHC(O)(substituted or imsubstituted alkylene)-, -NHC(O)(substituted or imsubstituted alkylene)-, -NHC(O)(substituted or imsubstituted alkenylene)-
  • L of said compound is a covalent bond, -C(O)NH-,
  • said compound is selected from the group consisting of:
  • 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 alkylene)-, -NHC(O)(substituted or unsubstituted alkylene)-,
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating c-kit kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, conesponding to the following formula are provided herein:
  • L of said compound is -NHC(O)-, -NHC(O)(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkylene), -C(O)NH(substituted or imsubstituted alkenylene),or -NHC(O)(substituted or unsubstituted alkenylene)-.
  • L of said compound is -O- or -
  • L of said compound is -(substituted or unsubstituted alkylene)- or -
  • Li 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 imsubstituted 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)-,
  • Li of said compound is a bond, -O(substituted or unsubstituted alkylene)-, -(substituted or unsubstituted alkylene)-, or -S-; and L of said compound is a covalent bond, -C(O)NH-,-C(O)NH(substituted or unsubstituted alkylene), or -
  • V of said compound is substituted or unsubstituted 5-membered heteroarylene.
  • each of X1-X is independently C, CR, or N, wherein no more than two of X 1 -X 5 is N; where each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)P , -NO 2 , -N(R d ) 2 , -SR d , -S(O)jR d where j is 1 or 2, -NRd C(O)Rd, -C(O) 2 Rd, -C(O)N(Rd) 2 or -C(O)R d , 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 imsubstituted cycloalkyl, substituted or unsubstituted aryl
  • U of said compound is substituted or unsubstituted pyrimidinyl or pyridinyl. In other embodiments, U of said compound is substituted or unsubstituted phenyl.
  • T is substituted or unsubstituted cycloalkyl or heterocylyl.
  • methods for modulating c-kit kinase comprising administering an effective amount of a compound, or phannaceutically acceptable salt thereof, selected from the group consisting of:
  • Exemplary ABL Modulators Methods for modulating abl 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
  • each R k is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R 2 , -NO 2 , -N(R 2 ) , -SR 2 , -C(O)R 2 , -C(O) 2 R 2 , -C(O)N(R 2 ) 2 , or -N(R 2 )C(O)R 2
  • each R 2 is independently H, substituted or imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or imsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or imsubstituted heteroaryl; or wherein two R 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 pharmaceutical
  • K is or where each Rk is independently H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
  • Methods for modulating abl kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, conesponding to the following formula are provided herein:
  • L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or imsubstituted alkylene, -C(O)NH-, -C(O)-, -NH-, -O-, -S-, -O(substituted or imsubstituted 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 imsubstituted alkenylene)-, -C(O)(substituted or imsubstituted alkenylene)-,
  • 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.
  • L of said compound is -O(substituted or unsubstituted alkylene)- , -C(O)NH-, or a covalent bond.
  • a of said compound is substituted or unsubstituted five or six-membered aryl or heteroaryl; and B of said compound is substituted or unsubstituted five or six-membered arylene or heteroarylene.
  • each X is independently C, CR, N, NR, or O, wherein no more than three X's is a heteroatom, and no two adjacent ring atoms are O; and each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)Rd, -NO 2 , -N(R d ) 2 , -SR d , -S(O)jRd where j is 1 or 2, -NR d C(O)R d , -C(O) 2 Rd, -C(O)N(Rd) 2 or -C(O)Rd, or two adjacent R's are taken together to form a substituted or imsubstituted aryl or hetroaryl, where each R d is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, where
  • Methods for modulating abl kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • each X is independently C, CR, N, NR, S or O, wherein no more than three X's is a heteroatom, and no two adjacent ring atoms are O or S; and each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or imsubstituted alkoxy, -OC(O)Rd, -NO 2 , -N(Rd)2, -SRd, -S(O)jRd where j is 1 or 2, -NRd C(O)Rd, -C(O) 2 Rd, -C(O)N(Rd) 2 or -C(O)Rd, or two adjacent R's are taken together to form a substituted or imsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti
  • Methods for modulating abl kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • Methods for modulating abl kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
  • abl kinase a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • M is a substituted or imsubstituted aryl or heteroaryl
  • N is a substituted or unsubstituted aryl or heteroaryl
  • K is , where Y is O or S; each R 2 is independently H, halogen, substituted or imsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R 3 , -NO 2 , -N(R 3 ) 2 , -SR 3 , -NR 3 C(O)R 3 , -C(O)N(R 3 ) 2 , -C(O) 2 R 3 , or -C(O)R 3 ; each R 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
  • a compound, or pharmaceutically acceptable salt thereof selected from the group consisting of:
  • MKNK2 Modulators Methods for modulating MKNK2 kinase, said method comprising administering an effective amount of a compound corresponding to the formula below are provided herein: wherein: M is a substituted or unsubstituted aryl or heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and
  • K is , where Y is O or S; each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R 3 , -NO 2 , -N(R 3 ) 2 , -SR 3 , -NR 3 C(O)R 3 , -C(O)N(R 3 ) 2 , -C(O) 2 R 3 , or -C(O)R 3 ; each R 3 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
  • Methods for modulating MKNK2 kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, conesponding to the formula below are provided herein:
  • Methods for modulating MKNK2 kinase comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the formula below are provided herein:
  • Methods for modulating MKNK2 kinase comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the formula below are provided herein:
  • M is a substituted or unsubstituted aryl or heteroaryl
  • N is a substituted or unsubstituted aryl or heteroaryl
  • K is where Y is O or S; each R 2 is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R 3 , -NO 2 , -N(R 3 ) 2 , -SR 3 , -NR 3 C(O)R 3 , -C(O)N(R 3 ) 2 , -C(O) 2 R 3 , or -C(O)R 3 ; each R is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or imsubstituted 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.
  • a compound, or pharmaceutically acceptable salt thereof selected from the group consisting of:
  • the protein kinase is selected from the group comprising Ste (sterile 20, sterile 11 and sterile 7); camk (calmodulin regulated kinases and related kinases); AGC (protein kinase A, protein kinase G and protein kinase C) and CMGC (cdk, map kinase, glycogen synthetase kinase and elk).
  • the sterile 20 kinases include, for example, PAK and CZ.
  • the protein tyrosine kinase is selected from the "HER" receptor tyrosine kinase subfamily, which includes EGFR (epithelial growth factor receptor), HER2, HER3 and HER4.
  • the protein tyrosine kinase is selected from the subfamily consisting of insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor related receptor (IRR).
  • the protein tyrosine kinase is selected from the platelet derived growth factor receptor (PDGFR) subfamily, which includes PDGFR ⁇ , PDGFR ⁇ , CSFIR, c-kit and c-fins.
  • the protein tyrosine kinase is the vascular endothelial growth factor ("VEGF") receptor subgroup.
  • VEGF vascular endothelial growth factor
  • the protein tyrosine kinase is selected from the fetus liver kinase ("flk”) receptor subfamily, which includes kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), flk-lR, flk-4 and fins-like tyrosine kinase 1 (flt-1).
  • the protein tyrosine kinase is selected from the fibroblast growth factor ("FGF") receptor subgroup, which includes the receptors FGFR1, FGFR 2, FGFR3, and FGFR4, and the ligands, FGF1, FGF2, FGF3, FGF4, FGF5, FGF6,and
  • FGF fibroblast growth factor
  • the protein tyrosine kinase is the tyrosine kinase growth factor receptor family, c-Met. In some embodiments, the protein tyrosine kinase is an fins-like tyrosine kinase 3 receptor kinase (FLT-3 kinase).
  • FLT-3 kinase fins-like tyrosine kinase 3 receptor kinase
  • the non-receptor tyrosine kinases include Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack, their respective subfamilies.
  • the non- receptor tyrosine kinase is selected from the Src subfamily, which includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • the compounds and compositions disclosed herein may be used for the prevention or treatment of cancers such as stomach, gastric, bone, ovary, colon, lung, brain, larynx, lymphatic system, genitourinary tract, ovarian, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, leukemia, glioma, colorectal cancer, genitourinary cancer gastrointestinal cancer, or pancreatic cancer, hi particular, the cancer is acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).
  • AML acute myelogenous leukemia
  • compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of an fms-like tyrosine kinase 3 (FLT-3) receptor modulating compound are provided herein.
  • the disease is cancer.
  • the cancer is a malignant tumor, or a hematologic malignancy such as leukemia and lymphoma.
  • the leukemia is acute myelogenous leukemia (AML), a B-precursor cell acute lymphoblastic leukemia, myelodysplastic leukemia, T-cell acute lymphoblastic leukemia or chronic myelogenous leukemia (CML).
  • compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a Stem Cell Factor (SCF), c-kit, receptor modulating compound are provided herein.
  • the disease is cancer.
  • the cancer is a malignant tumor, or a hematologic malignancy such as leukemia and lymphoma.
  • the cancer is small-cell lung cancer, or breast cancer.
  • the leukemia is acute myelogenous leukemia
  • the malignant tumor is a germ cell tumor, a mast cell tumor, a gastrointestinal stromal tumor (GIST), melanoma, or a neuroblastoma.
  • Compositions and methods for treating a disease comprising admimstering to a subject in need thereof an effective amount of a Bcr-Abl receptor modulating compound are provided herein.
  • the disease is cancer.
  • the cancer is a malignant tumor, or a hematologic malignancy such as leukemia and lymphoma.
  • the leukemia is chronic myeloid leukemia (CML) or acute myelogenous leukemia (AML).
  • compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a Platelet-Derived Growth Factor (PDGF) receptor modulating compound are provided herein.
  • the disease is cancer.
  • the cancer is a malignant tumor, or a hematologic malignancy such as leukemia and lymphoma.
  • the leukemia is acute lymphoblastic leukemia (ALL).
  • the lymphoma is T- cell lymphoma.
  • the malignant tumor is melanoma, or glioblastoma.
  • the disease is a nonmahgnant proliferation disease.
  • the nonmahgnant proliferation disease is atherosclerosis, or restenosis.
  • the disease is a fibroproliferative disorder.
  • the fibroproliferative disorder is obliterative bronchiolitis.
  • modulator means a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, agonist, antagonist, and the like.
  • agonist means a molecule such as a compound, a drug, an enzyme activator or a hormone that enhances the activity of another molecule or the activity of a receptor site etiehr directly or indirectly.
  • antagonist means a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone that diminishes or prevents the action of another molecule or the activity of a receptor site either directly or indirectly.
  • effective amount or “therapeutically effective amount” refer to a sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic use is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate "effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the terms “treat” or “treatment” are synonymous with the term “prevent” and are meant to indicate a postponement of development of diseases, preventing the development of diseases, and/or reducing severity of such symptoms that will or are expected to develop.
  • these terms include ameliorating existing disease symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disorder or disease, e.g., anesting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i.e., the material maybe administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • Carrier materials include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility and the release profile properties of the desired dosage form.
  • Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.
  • “Pharmaceutically compatible carrier materials” may comprise, e.g., acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4- methylbicyclo-[2.2.2]oct-2-ene-l-carbox
  • Acceptable organic bases include ethanolamine, diethanolarnine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or porymorphs.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
  • polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the term "biological sample” is broadly defined to include any cell, tissue, organ or multicellular organism.
  • a biological sample can be derived, for example, from cell or tissue cultures in vitro.
  • a biological sample can be derived from a living organism or from a population of single cell organisms.
  • linker means any divalent linking moiety used to connect, join, or attach two chemical groups.
  • linkers may be used to join two cyclic groups, such as to join two aryl groups (e.g., phenyl), an aryl group to a cycloalkyl group, an aryl group to a heterocyclyl group, a cycloalkyl group to a cycloalkyl group, a cycloalkyl group to a heterocyclyl group, and the like.
  • aryl groups e.g., phenyl
  • linkers include, but are not limited to, a covalent bond, -(substituted or unsubstituted alkylene)-, - (substituted or imsubstituted alkenylene)-, -(substituted or unsubstituted alkynylene)-, - (substituted or unsubstituted cycloalkylene)-, -(substituted or unsubstituted heterocyclylene)-, -(substituted or unsubstituted arylene)-, and -(substituted or unsubstituted heteroarylene)-.
  • linkers include - O(substituted or unsubstituted alkylene)-, -N(substituted or unsubstituted alkylene)-, - NHC(O)(substituted or unsubstituted alkylene)-, -C(O)(substituted or unsubstituted alkenylene)-, -NHC(O)(substituted or unsubstituted alkylene)S(substituted or imsubstituted alkylene)C(O)NH-, -NHC(O)(substituted or unsubstituted alkenylene)-, and the like.
  • Linkers as represented herein, embrace divalent moieties in any chemically feasible directionality.
  • compounds comprising a linker-C(O)NH- which attaches two aryl groups, Ari to Ar 2 include Ari-C(O)NH-Ar 2 as well as Ari-NHC(O)-Ar 2 .
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • alkyl means a straight chain or branched, saturated or unsaturated chain having from 1 to 10 carbon atoms.
  • Representative saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2- propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2- methyl-1-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2- ⁇ entyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, and longer alkyl groups, such as hept
  • alkyl group can be imsubstituted or substituted.
  • Unsaturated alkyl groups include alkenyl groups and alkynyl groups, discussed below.
  • Alkyl groups containing three or more carbon atoms may be straight, branched or cyclized.
  • lower alkyl means an alkyl having from 1 to 5 carbon atoms.
  • an "alkenyl group” includes a monovalent unbranched or branched hydrocarbon chain having one or more double bonds therein. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups include, but are not limited to, (C 2 -C 8 ) alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2- propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl.
  • An alkenyl group can be unsubstituted or substituted.
  • alkynyl group includes a monovalent unbranched or branched hydrocarbon chain having one or more triple bonds therein.
  • alkynyl groups include, but are not limited to, (C 2 -C 6 ) alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • the terms "trifluoromethyl,” “sulfonyl,” and “carboxyl” include CF 3 , SO 3 H, and
  • alkoxy as used herein includes -O-(alkyl), wherein alkyl is defined above.
  • alkoxyalkoxy includes -O-(alkyl)-O-(alkyl), wherein each "alkyl” is independently an alkyl group defined above.
  • alkoxycarbonyl includes-C(O)O-(alkyl), wherein alkyl is defined above.
  • alkoxycarbonylalkyl includes -(alkyl)-C(O)O-(alkyl), wherein alkyl is defined above.
  • alkoxyalkyl means -(alkyl)-O-(alkyl), wherein each "alkyl” is independently an alkyl group defined above.
  • aryl refers to a monocyclic, or fused or spiro polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having from 3 to 12 ring atoms per ring.
  • Illustrative examples of aryl groups include the following moieties:
  • heteroaryl refers to a monocyclic, or fused or spiro polycyclic, aromatic heterocycle (ring structure having ring atoms selected from carbon atoms as well as nitrogen, oxygen, and sulfur heteroatoms) having from 3 to 12 ring atoms per ring.
  • aryl groups include the following moieties:
  • cycloalkyl refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle having from 3 to 12 ring atoms per ring.
  • Illustrative examples of cycloalkyl groups include the following moieties:
  • heterocycloalkyl refers to a monocyclic, or fused or spiro polycyclic, ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring selected from C atoms and N, O, and S heteroatoms.
  • ring atoms per ring selected from C atoms and N, O, and S heteroatoms.
  • heterocycloalkyl groups include:
  • aryloxy includes -O-aryl group, wherein aryl is as defined above. An aryloxy group can be unsubstituted or substituted.
  • arylalkyl includes -(alkyl)-(aryl), wherein alkyl and aryl are defined above.
  • arylalkyloxy includes -O-(alkyl)-(aryl), wherein alkyl and aryl are defined above.
  • cycloalkyl includes a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms and having no carbon-carbon multiple bonds.
  • cycloalkyl groups mclude, but are not limited to, (C 3 -C 7 )cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
  • a cycloalkyl group can be unsubstituted or substituted.
  • the cycloalkyl group is a monocyclic ring or bicyclic ring.
  • "cycloalkyloxy" includes -O-(cycloalkyl), wherein cycloalkyl is defined above.
  • cycloalkylalkyloxy includes -O-(alkyl)-(cycloalkyl), wherein cycloalkyl and alkyl are defined above.
  • alkyhdene includes the divalent radical -C n H 2n ⁇ , wherein n is an integer from 1 to 8, such as -CH 2 -, -CH 2 CH 2 -, ⁇ CH 2 -CH 2 -CH 2 ⁇ , -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, and the like, unsubstituted or substituted with one or more alkyl groups.
  • heteroatom-containing alkyhdene includes an alkyhdene wherein at least one carbon atom is replaced by a heteroatom selected from nitrogen, oxygen, or sulfur, such as ⁇ CH 2 CH 2 OCH 2 CH 2 — , and the like, unsubstituted or substituted with one or more alkyl groups.
  • aminoalkoxy includes ⁇ O-(alkyl)-NH 2 , wherein alkyl is defined above.
  • mono-alkylamino includes — NH(alkyl), wherein alkyl is defined above.
  • di-alkylamino includes ⁇ N(alkyl)(alkyl), wherein each "alkyl” is independently an alkyl group defined above.
  • mono-alkylaminoalkoxy includes — O-(alkyl)-NH(alkyl), wherein each "alkyl” is independently an alkyl group defined above.
  • di-alkylaminoalkoxy includes ⁇ O-(alkyl)N(alkyl)(alkyl), wherein each "alkyl” is independently an alkyl group defined above.
  • arylamino includes — NH(aryl), wherein aryl is defined above.
  • arylalkylamino includes ⁇ NH-(alkyl)-(aryl), wherein alkyl and aryl are defined above.
  • alkylamino includes --NH(alkyi), wherein alkyl is defined above.
  • cycloalkylamino includes — NH-(cycloalkyl), wherein cyclohexyl is defined above.
  • cycloalkylalkylamino includes ⁇ NH-(alkyl)-(cycloalkyl), wherein alkyl and cycloalkyl are defined above.
  • aminoalkyl includes -(alkyl)-NH 2 , wherein alkyl is defined above.
  • mono-alkylaminoalkyl includes -(alkyl)-NH(alkyl),wherein each "alkyl” is independently an alkyl group defined above.
  • di-alkylaminoalkyl includes -(alkyl)-N(alkyl)(alkyl),wherein each "alkyl” is independently an alkyl group defined above.
  • the term “whole integer” is intended to include whole numbers. For example, a whole integer from 0 to 4 would include 0, 1, 2, 3, and 4.
  • Sulfonyl refers to the presence of a sulfur atom, which is optionally linked to another moiety such as an aliphatic group, an aromatic group, an aryl group, an alicyclic group, or a heterocyclic group.
  • Aryl or alkyl sulfonyl moieties have the formula -SO 2 R d
  • alkoxy moieties have the formula -O-R d , wherein R is alkyl, as defined above, or is aryl wherein aryl is phenyl, optionally substituted with 1-3 substituents independently selected from halo (fluoro, chloro, bromo or iodo), lower alkyl (1-6C) and lower alkoxy
  • the term "substituted” means that the specified group or moiety bears one or more suitable substituents.
  • the term “unsubstituted” means that the specified group bears no substituents.
  • the term “optionally substituted” means that the specified group is imsubstituted or substituted by one or more substituents.
  • Molecular embodiments of the present invention may possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti,
  • Z isomers as well as the appropriate mixtures thereof. Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem,
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with phannaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • phannaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the meanings of terms used herein will become apparent from the context of this specification in view of common usage of various terms and the explicit definitions of other terms provided in the glossary below or in the ensuing description.
  • the present invention is directed to compounds, compositions, and methods for treating conditions associated with abnormal kinase activity.
  • compounds useful in the invention are derivatives of isoxazoles, pyrazoles and isothiazoles.
  • the invention includes optically pure forms as well as mixtures of stereoisomers or enantiomers.
  • the invention provides methods for modulating various kinases by providing an effective amount of a compound of the formulas described herein. Salts of the compounds may be used for therapeutic and prophylactic purposes, where the salt is preferably a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example Q-toluenesulphonic, acids.
  • a "prodrug” refers to a drug or compound in which the pharmacological action results from conversion by metabolic processes within the body.
  • Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. Additionally, prodrugs can increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g., Fedorak et al., Am. J.
  • Prodrug forms of the above described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth above are included within the scope of the claims. Indeed, some of the above-described derivatives may be a prodrug for another derivative or active compound.
  • the invention further provides for the optical isomers of the compounds disclosed herein, especially those resulting from the chiral carbon atoms in the molecule. In additional embodiments of the invention, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion may also be useful for the applications described herein.
  • compositions containing the above described analogs and derivatives are provided.
  • the compositions are formulated to be suitable for pharmaceutical or clinical use by the inclusion of appropriate carriers or excipients.
  • Groups such as carbonyl, carboxyl, alkoxy, amino, and cyano groups, etc., as shown in the formula above, need not be directly bound to the para position; they may be included elsewhere in the alkyl, alkenyl or alkynyl substituent.
  • substituents include, for example, trifluoromethyl, difluoromethyl and fluoromethyl (alkyl substituted by halo) and trifluoromethoxy, difluoromethoxy and fluoromethoxy (alkyl where one carbon is replaced by O and is further substituted by halo).
  • Compounds of the invention which contain carboxyl groups or which contain amino groups may be supplied in the forms of their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of carboxylic acids include inorganic salts such as salts of sodium, potassium, calcium, magnesium and the like or salts formed with organic bases such as caffeine.
  • Salts of amines are acid addition salts formed from inorganic acids such as hydrochloric, sulfuric, phosphoric acids or may be salts of organic acids such as acetates, maleates, propionates, and the like.
  • the invention also provides prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce a derivative as set forth above. Indeed, some of the above described derivatives may be a prodrug for another derivative or active compound.
  • the invention further provides for the optical isomers of the compounds disclosed herein, especially those resulting from the chiral carbon atoms in the molecule.
  • compositions containing the above described analogs and derivatives are provided.
  • the compositions are formulated to be suitable for pharmaceutical or clinical use by the inclusion of appropriate carriers or excipients.
  • pharmaceutical formulations are provided comprising at least one compound described above, or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the compounds of the invention may be "conjugated" -that is they may be coupled to additional moieties that do not destroy their ability to modulate kinases.
  • the compounds might be coupled to a label such as a radioactive label, a fluorescent label and the like, or may be coupled to targeting agents such as antibodies or fragments, or to fragments to aid purification such as FLAG or a histidine tag.
  • the compounds may also be coupled to specific binding partners such as biotin for use in assay procedures or to moieties that alter their biological half-lives such as polyethylene glycol.
  • the methods of the invention employ the invention compounds per se as well as conjugates thereof.
  • the compounds of the invention are synthesized by methods well known in the art.
  • the compounds of the invention are ureas or cyclic forms thereof and can be synthesized using generally known procedures for urea synthesis.
  • an amine is reacted with an isocyanate in an aprotic solvent.
  • a molar excess of the amine is used in the presence of an aprotic solvent and the reaction is conducted at room temperature.
  • the reaction mixture is then poured into water and precipitated with salt to recover the crude product which is then purified according to standard methods.
  • the ureas are formed from two separate amine reactants in the presence of a condensing agent such as l,l,carbonyldiimidazole (CDI) in the presence of an inert nonpolar solvent such as dichloromethane.
  • a condensing agent such as l,l,carbonyldiimidazole (CDI)
  • CDI l,l,carbonyldiimidazole
  • an inert nonpolar solvent such as dichloromethane.
  • One of the amines is first added to a solution of CDI in solvent under cooling conditions and then stirred at room temperature with the other amine. After removal of solvent, the crude product can be purified using standard procedures.
  • one of the amines is added in an aprotic solvent to a solution of triphosgene and then treated with the other amine reactant dissolved in an inert solvent in the presence of base such as triethylamine. After reaction at room temperature, the mixture may be diluted with, for example, ethylacetate and washed with water and brine, dried and purified.
  • one of the amine components is treated with 4- nitrophenylchloroformate in the presence of mild base in a solvent such as N- methylpyrrolidone (NMP). The other amine is then added and the reaction mixture heated, then cooled, poured into water, extracted into chloroform and further purified.
  • NMP N- methylpyrrolidone
  • the urea may be formed by the reaction of an amine with the counterpart halo acylamine which is formed from the parent amine by treatment with phosgene and base in an inert solvent such as methylene dichloride or by reacting an amine with its counterpart amine with an acyl amine containing an alternate leaving group formed by reaction of that amine with 4-nitrophenylchloroformate in the presence of an amine base and in an inert solvent. Details of these methods can be found in Matsuno et al. J. Med. Chem. 45:3057-66 (2002); Matsuno et al. J. Med. Chem. 45:4513-23 (2002); and and Pandley et al., J. Med.
  • Cyclized forms of the ureas may be obtained by treating the formed urea with dibromo derivatives of the bridge, typically in the presence of a strong base and in an inert aprotic polar solvent.
  • the ureas may be converted to thioureas by treating with Lawesson's reagent in the presence of toluene.
  • Ar ⁇ L-Ar 2 is obtained by first protecting the amino group of p-hydroxy aniline destined to become Ar 1 with a protecting agent such as Boc and then coupling the hydroxy group of Ar 1 to an aryl alkyl halide. This coupling is conducted in the presence of strong base and in an aprotic solvent.
  • carbon electrophiles are susceptible to attack by complementary nucleophiles, including carbon nucleophiles, wherein an attacking nucleophile brings an electron pair to the carbon electrophile in order to form a new bond between the nucleophile and the carbon electrophile.
  • Suitable carbon nucleophiles include, but are not limited to alkyl, alkenyl, aryl and alkynyl Grignard, organolithium, organozinc, alkyl-, alkenyl , aryl- and alkynyl-tin reagents (organostannanes), alkyl-, alkenyl-, aryl- and alkynyl-borane reagents (organoboranes and organoboronates); these carbon nucleophiles have the advantage of being kinetically stable in water or polar organic solvents.
  • carbon nucleophiles include phosphorus ylids, enol and enolate reagents; these carbon nucleophiles have the advantage of being relatively easy to generate from precursors well known to those skilled in the art of synthetic organic chemistry.
  • Carbon nucleophiles when used in conjunction with carbon electrophiles, engender new carbon-carbon bonds between the carbon nucleophile and carbon electrophile.
  • Non-carbon nucleophiles suitable for coupling to carbon electrophiles include but are not limited to primary and secondary amines, thiols, thiolates, and thioethers, alcohols, alkoxides, azides, semicarbazides, and the like.
  • Non-carbon nucleophiles when used in conjunction with carbon electrophiles, typically generate heteroatom linkages (C- X-C), wherein X is a hetereoatom, e. g, oxygen or nitrogen.
  • the term "protecting group” refers to chemical moieties that block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Protective groups can be removed by acid, base, and hydrogenolysis.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties may be protected by conversion to simple ester derivatives as exemplified herein, or they may be blocked with oxidatively- removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in then presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a Pd 0 - catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • a protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • blocking/protecting groups may be selected from:
  • PKs Biological Activity Protein kinases
  • PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins.
  • Abnormal PK activity has been related to disorders ranging from relatively non life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer), hi addition, a variety of tumor types have dysfunctional growth factor receptor tyrosine kinases, resulting in inappropriate mitogenic signaling. Protein kinases are believed to be involved in many different cellular signal transduction pathways.
  • protein tyrosine kinases are attractive targets in the search for therapeutic agents, not only for cancer, but also against many other diseases. Blocking or regulating the kinase phosphorylation process in a signaling cascade may help treat conditions such as cancer or inflammatory processes.
  • Protein 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 includes Bcr-Abl tyrosine kinase, and 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 ⁇ and ⁇ ), colony- stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), FLT-3, and stem cell or steel factor receptor (c-kit).
  • PDGF platelet-derived growth factor
  • CSF-1R colony- stimulating factor
  • c-Fms colony- stimulating factor receptor
  • FLT-3 stem cell or steel factor receptor
  • c-kit stem cell or steel factor receptor
  • the compounds, compositions, and methods provided herein are useful to modulate the activity of kinases including, but not limited to, ERBB2, ABL1, AURKA, CDK2, EGFR, FGFR1, LCK, MAPK14, PDGFR, KDR, ABLl, BRAF, ERBB4, FLT3, KIT, and RAF1.
  • compositions and methods provided herein modulate the activity of a mutant kinase.
  • Inhibition by the compounds provided herein can be determined using any suitable assay, hi one embodiment, inhibition is determined in vitro, hi a specific embodiment, inhibition is assessed by phosphorylation assays.
  • Any suitable phosphorylation assay can be employed.
  • membrane autophosphorylation assays, receptor autophosphorylation assays in intact cells, and ELISA's can be employed. See, e.g., Gazit, et al., J. Med. Chem. (1996) 39:2170-2177, Chapter 18 in CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (Ausubel, et al., eds. 2001).
  • Cells useful in such assays include cells with wildtype or mutated forms.
  • the wildtype is a kinase that is not constirutively active, but is activated with upon dimerization.
  • the mutant FLT3 kinase is constitutively active via internal tandem duplication mutations or point mutations in the activation domain.
  • Suitable cells include those derived through cell culture from patient samples as well as cells derived using routine molecular biology techniques, e.g., retro viral transduction, transfection, mutagenesis, etc.
  • Exemplary cells include Ba/F3 or 32Dcl3 cells transduced with, e.g., MSCV retroviral constructs FLT3-
  • the compounds described herein significantly inhibit receptor tyrosine kinases.
  • a significant inhibition of a receptor tyrosine kinase activity refers to an IC 50 of less than or equal to 100 ⁇ M.
  • the compound can inhibit activity with an IC 50 of less than or equal to 50 ⁇ M, more preferably less than or equal to 10 ⁇ M, more preferably less than 1 ⁇ M, or less than 100 nM, most preferably less than 50 nM.
  • IC 50 of less than or equal to 50 ⁇ M, more preferably less than or equal to 10 ⁇ M, more preferably less than 1 ⁇ M, or less than 100 nM, most preferably less than 50 nM.
  • Lower ICso's are preferred because the IC 50 provides an indication as to the in vivo effectiveness of the compound.
  • Other factors known in the art, such as compound half- life, biodistribution, and toxicity should also be considered for therapeutic uses. Such factors may enable a compound with a lower IC 50 to have greater in vivo efficacy than a compound having a higher IC 50 .
  • a compound that inhibits activity is administered at a dose where the effective tyrosine phosphorylation, i.e., IC 5 Q, is less than its cytotoxic effects, LD 50 .
  • the compounds selectively inhibit one or more kinases. Selective inhibition of a kinase, such as FLT3, p38 kinase, STK10, MKNK2, Bcr-Abl, c- kit, or PDGFR, is achieved by inhibiting activity of one kinase, while having an insignificant effect on other members of the superfamily.
  • SCF Stem Cell Factor
  • c-kit is a receptor protein tyrosine kinase that initiates cell growth and proliferation signal transduction cascades in response to SCF binding
  • c-kit is a 145-kD transmembrane glycoprotein and is the normal cellular homolog of the v-kit retroviral oncogene
  • It is also a member of the Type III transmembrane receptor protein tyrosine kinase subfamily, which includes the macrophage colony-stimulating factor- 1 receptor, also known as the FMS receptor, the related FLT-3 receptor, and the platelet-derived growth factor (PDGF) ⁇ and ⁇ receptors.
  • FMS macrophage colony-stimulating factor- 1 receptor
  • FLT-3 receptor the related FLT-3 receptor
  • PDGF platelet-derived growth factor
  • the c-kit gene product is expressed in hematopoietic progenitor cells, mast cells, germ cells, interstitial cells of Cajal (ICC), and some human tumors.
  • Inactivating mutations of c-kit or its ligand, Steel factor (SLF) have demonstrated that the normal functional activity of the c-kit gene product is essential for maintenance of normal hematopoeisis, melanogenesis, genetogensis, and growth and differentiation of mast cells and ICC.
  • SLF is produce by human and murine hematopoietic stromal cells, including endothehal cells, fibroblasts, and bone marrow-derived stromal cells.
  • c-kit plays a role in the biological aspects of certain human cancers, including germ cell tumors, mast cell tumors, gastrointestinal stromal tumors (GIST), small-cell lung cancer, melanoma, breast cancer, acute myelogenous leukemia (AML), and neuroblastoma.
  • GIST gastrointestinal stromal tumors
  • AML acute myelogenous leukemia
  • Proliferation of tumor cell growth mediated by c-kit can occur by a specific mutation of the c-kit polypeptide that results in ligand independent activation or by autocrine stimulation of the receptor.
  • mutations that cause constitutive activation of c-kit kinase activity in the absence of SCF binding are implicated in malignant human cancers, including gastrointestinal stromal tumors, germ cell tumors, mast cell tumors, and myeloid leukemia's and in mastocytosis.
  • the activity of the c-kit receptor protein tyrosine kinase is regulated in normal cells, and as discussed the deregulated c-kit kinase activity is implicated in the pathogenesis of human cancers.
  • inhibition of c-kit activity reduces cellular proliferation, suggesting a role for use of pharmacologic inhibitors of c-kit in the treatment of c-kit dependent malignancies.
  • compositions and methods provided herein are effective to modulate the activity of c-kit.
  • compositions and methods provided herein are effective to selectively modulate the activity of c-kit.
  • Bcr-Abl c-Abl is a nonreceptor tyrosine kinase that contributes to several leukogenic fusion proteins, including the deregulated tyrosine kinase, Bcr-Abl.
  • Chronic myeloid leukemia (CML) is a clonal disease involving the pluripotent hematopoietic stem cell compartment and is associated with the Philadelphia chromosome [Nowell P. C. and Hungerford D. A.
  • the fusion gene produces a chimeric 8.5 kB transcript that codes for a 210-kD fusion protein (p210 bcr_a l ), and this gene product is an activated protein tyrosine kinase.
  • the Abelson tyrosine kinase is improperly activated by accidental fusion of the bcr gene with the gene encoding the intracellular non-receptor tyrosine kinase, c-Abl.
  • the Bcr domain interferes with the intramolecular Abl inhibitory loop and unveils a constitutive kinase activity that is absent in the normal Abl protein.
  • Bcr-Abl tyrosine kinase is a potent inhibitor of apoptosis, and it is well accepted that the oncoprotein expresses a constitutive tyrosine kinase activity that is necessary for its cellular transforming activity.
  • Constitutive activity of the fusion tyrosine kinase Bcr-Abl has been established as the characteristic molecular abnormality present in virtually all cases of chronic myeloid leukemia (CML) and up to 20 percent of adult acute lymphoblastic leukemia (ALL) [Faderl S. et al., N Engl J Med 341, 164-172 (1999); Sawyers C. L., N Engl J Med 340,1330-1340 (1999) ].
  • compositions and methods provided herein are effective to modulate the activity of Bcr-Abl. In other embodiments, compositions and methods provided herein are effective to selectively modulate the activity of Bcr-Abl.
  • compositions of Formula G inhibit the protein tyrosine kinase associated with mutated bcr-abl, which gives rise to observed clinical resistance towards treatment with STI571.
  • PDGFR Platelet-Derived Growth factor Receptors are receptor tyrosine kinases that regulate proliferative and chemotatic responses. PDGFR's have two forms- PDGFR- ⁇ (CD140a) and PDGFR- ⁇ (CD140b).
  • PDGFRs are normally found in connective tissue and glia but are lacking in most epithelia, and PDGF expression has been shown in a number of different solid tumors, from glioblastomas to prostate carcinomas.
  • PDGFR kinases are involved in various cancers such as T- cell lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), melanoma, glioblastoma and others (see Bellamy W. T. et al. , Cancer Res. 1999,59, 728-733).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • melanoma glioblastoma
  • the biological role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and angio genesis.
  • PDGF has been implicated in the pathogenesis of several nonmahgnant proliferation diseases, including atherosclerosis, restenosis following vascular angioplasty and fibroproliferative disorders such as obliterative bronchiolitis. Therefore, inhibiting the PDGFR kinase activity with small molecules may interfere with tumor growth and angiogenesis.
  • the binding of PDGFR to its receptor activates the intracellular tyrosine kinase, resulting in the autophorylation of the receptor as well as other intracellular substrates such as Src, GTPase Activating Protein (GAP), and phosphatidylinositol-3-phosphate.
  • GAP GTPase Activating Protein
  • PDGFR phospholipase C- ⁇
  • PI3K phosphatidylinositol-3-kinase
  • raf-1 phosphatidylinositol-3-kinase
  • Inhibitors of PDGFR- ⁇ frequently also inhibit additional kinases involved in tumor growth such as BCR-ABL, TEL-ABL, and PDGFR- ⁇ . See, Carroll, M., et al, Blood (1997) 90:4947-4952 and Cools, J., et al, Cancer Cell (2003) 3:450-469.
  • One class of established inhibitors of PDGFR kinase activity includes quinazoline derivatives which comprise piperazine substitutions. Such compounds are disclosed in Yu, J-C, et al, J. Pharmacol. Exp. Ther. (2001) 298:1172-1178; Pandey, A., et al, J. Med. Chem.
  • compositions and methods provided herein are effective to modulate the activity of PDGFR. In other embodiments, compositions and methods provided herein are effective to selectively modulate the activity of PDGFR.
  • FLT-3 FLT3 kinase is a tyrosine kinase receptor involved in the regulation and stimulation of cellular proliferation. See e.g., Gilliland et al., Blood 100:1532-42 (2002).
  • the FLT3 kinase is a member of the class III receptor tyrosine kinase (RTKIII) receptor family and belongs to the same subfamily of tyrosine kinases as c-kit, c-fins, and the platelet-derived growth factor and ⁇ receptors. See e.g., Lyman et al., FLT3 Ligand in THE CYTOKINE HANDBOOK 989 (Thomson et al, eds.
  • RTKIII receptor tyrosine kinase
  • the FLT3 kinase has five immunoglobulin-like domains in its extracellular region as well as an insert region of 75- 100 amino acids in the middle of its cytoplasmic domain. FLT3 kinase is activated upon the binding of the FLT3 ligand, which causes receptor dimerization. Dimerization of the FLT3 kinase by FLT3 ligand activates the intracellular kinase activity as well as a cascade of downstream substrates including Stat5, Ras, phosphatidylinositol-3-kinase (PI3K), PLC ⁇ , Erk2, Akt, MAPK, SHC, SHP2, and SHIP.
  • PI3K phosphatidylinositol-3-kinase
  • FLT3 kinase Numerous hematologic malignancies express FLT3 kinase, the most prominent of which is AML. See e.g., Yokota et al., Leukemia 11:1605-09 (1997).
  • FLT3 expressing malignancies include B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias. See e.g., Rasko et al., Leukemia 9:2058-66 (1995).
  • FLT3 kinase mutations associated with hematologic malignancies are activating mutations, hi other words, the FLT3 kinase is constitutively activated without the need for binding and dimerization by FLT3 ligand, and therefore stimulates the cell to grow continuously.
  • FLT3 kinase activity e.g., VEGF receptor (VEGFR), PDGF receptor (PDGFR), and kit receptor kinases. See e.g., Mendel et al, Clin. Cancer Res. 9:327-37 (2003); O'Farrell et al, Blood l /:3597-605 (2003); and Sun et al., J. Med. Chem.
  • the kinase is a class III receptor tyrosine kinase (RTKIII).
  • RTKIII receptor tyrosine kinase
  • the kinase is a tyrosine kinase receptor intimately involved in the regulation and stimulation of cellular proliferation.
  • the kinase is a fins-like tyrosine kinase 3 receptor (FLT-3 kinase).
  • FLT-3 kinase fins-like tyrosine kinase 3 receptor
  • inhibition and reduction of the activity of FLT-3 kinase refers to a lower level of measured activity relative to a control experiment in which the protein, cell, or subject is not treated with the test compound, whereas an increase in the activity of FLT-3 kinase refers to a higher level of measured activity relative to a control experiment.
  • the reduction or increase is at least 10%.
  • reduction or increase in the activity of FLT-3 kinase of at least 20%, 50%, 75%, 90% or 100% or any integer between 10% and 100% may be preferred for particular applications.
  • FLT3 activity includes, but is not limited to, enhanced FLT3 activity resulting from increased or de novo expression of FLT3 in cells, increased FLT3 expression or activity, and FLT3 mutations resulting in constitutive activation.
  • the existence of inappropriate or abnormal FLT3 ligand and FLT3 levels or activity can be determined using well known methods in the art. For example, abnormally high FLT3 levels can be determined using commercially available ELISA kits. FLT3 levels can be determined using flow cytometric analysis, immunohistochernical analysis, and in situ hybridization techniques.
  • An inappropriate activation of the FLT3 can be determined by an increase in one or more of the activities occurring subsequent to FLT3 binding: (1) phosphorylation or autophosphorylation of FLT3; (2) phosphorylation of a FLT3 substrate, e.g., Stat5, Ras; (3) activation of a related complex, e.g., PI3K; (4) activation of an adaptor molecule; and (5) cellular proliferation. These activities are readily measured by well known methods in the art.
  • Formulations The compounds described herein can be used to prepare a medicament, such as by fonnulation into pharmaceutical compositions for administration to a subject using techniques generally known in the art.
  • compositions may be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • the compounds of the invention can be used singly or as components of mixtures. Preferred forms of the compounds are those for systemic administration as well as those for topical or transdermal administration. Formulations designed for timed release are also within the scope of the invention. Formulation in unit dosage form is also preferred for the practice of the invention.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packeted tablets or capsules, and powders in vials or ampoules.
  • the compounds described herein may be labeled isotopically (e.g. with a radioisotope) or by any other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compositions may be in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions.
  • Suitable excipients or carriers are, for example, water, saline, dextrose, glycerol, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
  • these compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • Methods for the preparation of compositions comprising the compounds described herein include formulating the derivatives with one or more inert, pharmaceutically acceptable carriers to form either a solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • a carrier of the invention can be one or more substances which also serve to act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrating agent.
  • a carrier can also be an encapsulating material.
  • the carrier is preferably a finely divided solid in powder form which is interdispersed as a mixture with a finely divided powder from of one or more compound.
  • the carrier In tablet forms of the compositions, one or more compounds is intermixed with a carrier with appropriate binding properties in suitable proportions followed by compaction into the shape and size desired.
  • Powder and tablet form compositions preferably contain between about 5 to about 70% by weight of one or more compound.
  • Carriers that may be used in the practice of the invention include, but are not limited to, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low- melting wax, cocoa butter, and the like.
  • the compounds of the invention may also be encapsulated or microencapsulated by an encapsulating material, which may thus serve as a carrier, to provide a capsule in which the derivatives, with or without other carriers, is surrounded by the encapsulating material.
  • cachets comprising one or more compounds are also provided by the instant invention.
  • Tablet, powder, capsule, and cachet forms of the invention can be formulated as single or unit dosage forms suitable for administration, optionally conducted orally.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • One or more compounds are then dispersed into the melted material by, as a non- limiting example, stirring.
  • the non-solid mixture is then placed into molds as desired and allowed to cool and solidify.
  • Non-limiting compositions in liquid form include solutions suitable for oral or parenteral administration, as well as suspensions and emulsions suitable for oral administration.
  • sterile solutions include those comprising water, ethanol, and/or propylene glycol in forms suitable for parenteral administration.
  • a sterile solution of the invention may be prepared by dissolving one or more compounds in a desired solvent followed by sterilization, such as by filtration through a sterilizing membrane filter as a non-limiting example.
  • sterilization such as by filtration through a sterilizing membrane filter as a non-limiting example.
  • one or more compounds are dissolved into a previously sterilized solvent under sterile conditions.
  • a water based solution suitable for oral administration can be prepared by dissolving one or more compounds in water and adding suitable flavoring agents, coloring agents, stabilizers, and thickening agents as desired.
  • Water based suspensions for oral use can be made by dispersing one or more compounds in water together with a viscous material such as, but not limited to, natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and other suspending agents known to the pharmaceutical field.
  • a viscous material such as, but not limited to, natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and other suspending agents known to the pharmaceutical field.
  • the compounds of the invention are administered to a subject at dosage levels of from about 0.5 mg/kg to about 8.0 mg/kg of body weight per day.
  • a human subject of approximately 70 kg this is a dosage of from 35 mg to 560 mg per day.
  • Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the condition being treated, and the judgment of the practitioner.
  • the foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon.
  • the compounds disclosed herein can be used to treat a variety of diseases. Suitable conditions characterized by undesirable protein-kinase activity can be treated by the compounds presented herein.
  • the term "condition" refers to a disease, disorder, or related symptom where inappropriate kinase activity is present. In some embodiments, these conditions are characterized by aggressive neovasculaturization including tumors, especially acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).
  • AML acute myelogenous leukemia
  • B-precursor cell acute lymphoblastic leukemias myelodysplastic leukemias
  • T-cell acute lymphoblastic leukemias T-cell acute lymphoblastic leukemias
  • CMLs chronic myelogenous leukemias
  • a FLT3 modulating compounds may be used to treat tumors.
  • the ability of compounds that inhibit FLT3 kinase activity to treat tumors has been established.
  • Compounds having this property include SU5416 (Sugen), PKC412 (Novartis), GTP-14564 and CT53518 (Millennium). See e.g., Giles et al., Blood
  • Compounds presented herein are useful in the treatment of a variety of biologically aberrant conditions or disorders related to tyrosine kinase signal transduction. Such disorders pertain to abnormal cell proliferation, differentiation, and/or metabolism.
  • Abnormal cell proliferation may result in a wide array of diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis).
  • neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis).
  • compounds presented herein regulate, modulate, and/or inhibit disorders associated with abnormal cell proliferation by affecting the enzymatic activity of one or more tyrosine kinases and interfering with the signal transduced by said kinase.
  • the present invention is directed to compounds which regulate, modulate said kinase mediated signal transduction pathways as a therapeutic approach to cure leukemia and many kinds of solid tumors, including but not limited to carcinoma, sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma.
  • Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers.
  • compounds herein are useful in the treatment of cell proliferative disorders including cancers, blood vessel proliferative disorders, fibrotic disorders, and mesangial cell proliferative disorders.
  • Blood vessel proliferation disorders refer to angiogenic and vasculogenic disorders generally resulting in abnormal proliferation of blood vessels.
  • the formation and spreading of blood vessels, or vasculogenesis and angiogenesis, respectively, play important roles in a variety of physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration. They also play a pivotal role in cancer development.
  • blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and ocular diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness.
  • ocular diseases like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness.
  • disorders related to the shrinkage, contraction or closing of blood vessels, such as restenosis are also implicated.
  • Fibrotic disorders refer to the abnormal formation of extracellular matrix. Examples of fibrotic disorders mclude hepatic cirrhosis and mesangial cell proliferative disorders. Hepatic cinhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. Hepatic cirrhosis can cause diseases such as cinhosis of the liver.
  • An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis.
  • Lipocytes appear to play a major role in hepatic cirrhosis.
  • Other fibrotic disorders implicated include atherosclerosis (see, below).
  • Mesangial cell proliferative disorders refer to disorders brought about by abnormal proliferation of mesangial cells.
  • Mesangial proliferative disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies.
  • the cell proliferative disorders which are indications of the present invention are not necessarily independent.
  • fibrotic disorders may be related to, or overlap, with blood vessel proliferative disorders.
  • atherosclerosis results, in part, in the abnormal formation of fibrous tissue within blood vessels.
  • Compounds of the invention can be administered to a subject upon determination of the subject as having a disease or unwanted condition that would benefit by treatment with said derivative. The determination can be made by medical or clinical personnel as part of a diagnosis of a disease or condition in a subject. Non-limiting examples include determination of a risk of acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).
  • AML acute myelogenous leukemia
  • B-precursor cell acute lymphoblastic leukemias myelodysplastic leukemias
  • T-cell acute lymphoblastic leukemias T-cell acute lymphoblastic leukemias
  • the methods of the invention can comprise the administration of an effective amount of one or more compounds as disclosed herein, optionally in combination with one or more other active agents for the treatment of a disease or unwanted condition as disclosed herein.
  • the subject is preferably human, and repeated administration over time is within the scope of the present invention.
  • the present invention thus also provides compounds described above and their salts or solvates and pharmaceutically acceptable salts or solvates thereof for use in the prevention or treatment of disorders mediated by abenant protein tyrosine kinase activity such as human malignancies and the other disorders mentioned above.
  • the compounds of the present invention are especially useful for the treatment of disorders caused by abenant kinase activity such as breast, ovarian, gastric, pancreatic, non-small cell lung, bladder, head and neck cancers, and psoriasis.
  • the cancers include hematologic cancers, for example, acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).
  • AML acute myelogenous leukemia
  • B-precursor cell acute lymphoblastic leukemias for example, myelodysplastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from a disorder mediated by abenant protein tyrosine kinase activity, including susceptible malignancies, which comprises admimstering to the subject an effective amount of a compound described above or a pharmaceutically acceptable salt or solvate thereof.
  • a further aspect of the present invention provides the use of a compound described above, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of cancer and malignant tumors.
  • the cancer can be stomach, gastric, bone, ovary, colon, lung, brain, larynx, lymphatic system, gemtourinary tract, ovarian, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, leukemia, acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T- cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs), glioma, colorectal cancer, genitourinary cancer gastrointestinal cancer, or pancreatic cancer.
  • AML acute myelogenous leukemia
  • B-precursor cell acute lymphoblastic leukemias myelodysplastic leukemias
  • compounds provided herein are useful for preventing and treating conditions associated with ischemic cell death, such as myocardial infarction, stroke, glaucoma, and other neurodegenerative conditions.
  • ischemic cell death such as myocardial infarction, stroke, glaucoma, and other neurodegenerative conditions.
  • Various neurodegenerative conditions which may involve apoptotic cell death include, but are not limited to, Alzheimer's Disease, ALS and motor neuron degeneration, Parkinson's disease, peripheral neuropathies, Down's Syndrome, age related macular degeneration (ARMD), traumatic brain injury, spinal cord injury, Huntington's Disease, spinal muscular atrophy, and HIV encephalitis.
  • the compounds described in detail above can be used in methods and compositions for imparting neuroprotection and for treating neurodegenerative diseases.
  • the compounds described herein can be used in a pharmaceutical composition for the prevention and/or the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), common cold, dysmenonhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enter
  • a further aspect of the present invention provides the use of a compound described above, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of psoriasis.
  • the compounds can be administered before, during or after the occurrence of a condition or a disease, and the timing of administering the composition containing a compound can vary.
  • the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions and diseases in order to prevent the occunence of the disorder.
  • the compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, preferably within the first 48 hours of the onset of the symptoms, more preferably within the first 6 hours of the onset of the symptoms, and most preferably within 3 hours of the onset of the symptoms.
  • the initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 min. to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or a combination thereof.
  • a compound is preferably administered as soon as is practicable after the onset of a condition or a disease is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
  • the length of treatment can vary for each subject, and the length can be determined using the known criteria.
  • the compound or a formulation containing the compound can be administered for at least 2 weeks, preferably about 1 month to about 5 years, and more preferably from about 1 month to about 3 years.
  • kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method of the invention.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers can be formed from a variety of materials such as glass or plastic.
  • the container(s) can comprise one or more compounds of the invention, optionally in a composition or in combination with another agent as disclosed herein.
  • the container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods of the present invention.
  • a kit of the invention will typically may comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound of the invention.
  • materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
  • a set of instructions will also typically be included.
  • a label can be on or associated with the container.
  • a label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label can be used to indicate that the contents are to be used for a specific therapeutic application.
  • the label can also indicate directions for use of the contents, such as in the methods described herein.
  • the terms "kit” and "article of manufacture” may be used as synonyms.
  • test compound binds the kinase it competes with the immobilized ligand and prevents binding to the solid support. If the compound does not bind the kinase, phage-displayed proteins are free to bind to the solid support through the interaction between the kinase and the immobilized ligand.
  • the results are read out by quantitating the amount of fusion protein bound to the solid support, which is accomplished by either traditional phage plaque assays or by quantitative PCR (qPCR) using the phage genome as a template. To determine the affinity of the interactions between a test molecule and a kinase, the amount of phage-displayed kinase bound to the solid support is quantitated as a function of test compound concentration.
  • the concentration of test molecule that reduces the number of phage bound to the solid support by 50% is equal to the K d for the interaction between the kinase and the test molecule.
  • K d concentration of test compound that reduces the number of phage bound to the solid support by 50%.
  • data are collected for twelve concentrations of test compound and, the resultant binding curve is fit to a non- cooperative binding isotherm to calculate K d . Described in the exemplary assays below is data from bindmg with varying kinases.
  • Binding values are reported as follows "+” for representative compounds exhibiting a binding dissociation constant (K d ) of 10,000 nM or higher; "++”for representative compounds exhibiting a K d of 1,000 nM to 10,000 nM; "+++”for representative compounds exhibiting a K of 100 nM to 1,000 nM; and "++-H-"f r representative compounds exhibiting a I of less than 100 nM.
  • K d binding dissociation constant
  • ND represents non- determined values.
  • the Affinity of the Compounds for PDGFR K values for the interactions between PDGFR- ⁇ and candidate small molecule ligands were measured by a phage-display-based competitive binding assay that is described in detail in U.S. Serial No. 10/406,797 filed 2 April 2003 and incorporated herein by reference. Briefly, T7 phage displaying human PDGFR- ⁇ were incubated with an affinity matrix coated with known PDGFR- ⁇ inhibitor in the presence of various concentrations of the soluble competitor molecules.
  • Soluble competitor molecules that bind PDGFR- ⁇ prevent binding of PDGFR- ⁇ phage to the affinity matrix, hence, after washing, fewer phage are recovered in the phage eluate in the presence of an effective competitor than in the absence of an effective competitor.
  • the K d for the interaction between the soluble competitor molecule and PDGFR- ⁇ is equal to the concentration of soluble competitor molecule that causes a 50% reduction in the number of phage recovered in the eluate compared to a control sample lacking soluble competitor. K d values for the interaction between PDGFR- ⁇ and several small molecules are shown below.
  • MV4:11 was a cell line derived from a patient with acute myelogenous leukemia. It expressed a mutant FLT3 protein that was constitutively active.
  • MV4: 11 cells were grown in the presence of candidate FLT3 inhibitor molecules, resulting in significantly decreased proliferation of the leukemia-derived cells in the presence of compound. Inhibition of FLT3 kinase activity prevented proliferation of these cells, and thus the MV4: 11 cell line can be used a model for cellular activity of small molecule inhibitors of FLT3.
  • MV4.11 cells were grown in an incubator @ 37°C in 5% CO 2 in Medium 2 (RPMI, 10%FBS, 4mM glutamine, Perm/Strep). The cells were counted daily and the cell density was kept between le5 and 8e5 cells/ml. Day One: Enough cells were harvested for experiments to be conducted in 50ml conical tubes. The harvested cells were spun at 500g for 5 min at 4°C, the supernatant was then aspirated and the cells were resuspended in the starting volume of 1 x PBS. The cells were again spun at 500g for 5 min at 4°C and the supernatant again aspirated.
  • the cells were then resuspended in medium 3 (DMEM w/ glut, 10% FBS, Penn/Strep) to a density of 4e5 cells/ml and incubated @ 37°C in 5% CO 2 O/N. Day Two: The cells were counted and enough medium 3 was added to decrease density to 2e5 cells/ml. 50ul (10,000 cells) was aliquoted into each well of a 96 well optical plate using multichannel pipetman.
  • medium 3 DMEM w/ glut, 10% FBS, Penn/Strep
  • the compound plate was then set up by aliquoting 3 ⁇ l of negative control (DMSO) into column 1 of a 96 well 300ul polypropylene plate, aliquoting 3 ⁇ l of positive control (lOmM AB20121) into column 12 of plate, and aliquoting 3 ⁇ l of appropriate compounds from serial dilutions into columns 2-11.
  • DMSO negative control
  • lOmM AB20121 positive control
  • ⁇ l of appropriate compounds from serial dilutions into columns 2-11.
  • 150 ⁇ l of Medium 3 was added and 50 ⁇ l of compound/medium mixture from compound plate into rows of optical plate in duplicate.
  • the cells were then incubated @ 37°C in 5% CO 2 for 3 days.
  • Day Five MTS was thawed in a H 2 O bath. 20 ⁇ l of MTS was added to each well of optical plate and the cells were incubated @ 37°C in 5% CO for 2 hours.
  • the plate was then placed on a plate shaker for 30

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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.

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 α and β), 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:
Figure imgf000003_0001
wherein:
(a) Aai 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, -(CH )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, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)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(O2)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, -NO , -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)Rc, -NRcC(O)NRcRc,-NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRo, 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
Rc 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; -NO2, 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)2CN 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,-NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)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(O2)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, -NRJRc, -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 Rc 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 -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, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)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(O2)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)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 Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; (c) nt is 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)NRc, NRcC(O), and CRc, wherein Rc 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:
Figure imgf000006_0001
wherein: (a) X and Y are independently selected from O, N, NRci, and CRc, wherein Rd 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 X and Y are not both oxygen; (b) R^ and R2b are each a suitable substitutent independently selected fromhydrogen, halogen, =O; =S; -CN; -NO2, 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(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)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(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)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)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 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:
Figure imgf000007_0001
wherein: (a) Ric is unsubstituted C1-C5 alkyl or unsubstituted C3-C6 cycloalkyl;
(b) M is NH or CH2 and Ac2 is NH or CH2, wherein one of Acl or Ac2 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(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, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)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(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)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, -NO , -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 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. Provided herein are compositions and methods for treating a disease by administering an effective amount of kinase modulating compound having the structure:
Figure imgf000008_0001
wherein: (a) R1(ι is unsubstituted C1-C5 alkyl or unsubstituted C3-C5 cycloalkyl;
(b) n is 0, 1 or 2;
(c) ni is 0, 1 or 2; and wherein n 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:
Figure imgf000009_0001
wherein:
(a) n is 0, 1 or 2; and
(b) Aal is N or C-R3a and Aa2 is N or C-R3a, 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:
Figure imgf000009_0002
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 A 2 is N and one is C; and
(b) R3f and Rπf 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; -NO2, 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(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)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(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)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)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 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:
Figure imgf000010_0001
wherein:
(a) R2g, R g and R4g are each independently selected from hydrogen, unsubstituted alkyl, unsubstituted aryl, and unsubstituted heteroaryl;
(b) n is 0, 1 or 2;
Figure imgf000010_0002
(d) n2 is 0, 1 or 2;
(e) Ar2 is:
Figure imgf000011_0001
wherein:
(i) Rog 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(O2)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(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)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)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 Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
(ii) R10g 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(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)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(O2)NH2, -S(O)NH2,
-SNH2, -NHCS(O2)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)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 Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; and (iii) Ti and T2 are each independently selected from CRW and N, where Rw is a suitable substituent selected from hydrogen; halogens; -CN; and -NO ; 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, R a, R3 , Ria and R g are each hydrogen; and/or Ri , Ric, and R1(1 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, Ti is N and T2 is N or T1 is N and T2 is CH. In other embodiments, Ar2 is:
Figure imgf000013_0001
wherein:
(i) R8g and R9g 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(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, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)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(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)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, - RcRc, -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 Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; and
(ii) Ti is N and T2 is CH or N. Compositions and methods of Formulas A-G are provided herein wherein R8g and R9g are 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, -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, Ar is a 5-membered heteroaryl group unsubstituted or substituted with one, two or three suitable substituents. hi 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, R a/R3 and
Figure imgf000014_0001
are not both substituted. Compositions and methods of Formula A are provided herein wherein Ar3 a 5- membered heteroaryl group unsubstituted Cι-C5 alkyl or unsubstituted C3-C5 cycloalkyl; and R2 is hydrogen, hi some embodiments, Ari is an unsubstituted or substituted 6- membered aryl group or an unsubstituted or substituted 6-membered heteroaryl group, hi 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)NRc2, and NRc2C(O), wherein Rc 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 Ar1 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 -NO ; 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 Ar 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. hi 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 NRci wherein R^ is unsubstituted alkyl or unsubstituted aryl. In some emobiments, X is N and Yb is NRci. 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, -NO2, 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 R10g 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:
Figure imgf000016_0001
(I) wherein: each Z is independently C, CRj, 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, -NO2, -N(Rc)2, -SRc, S(O)jRc where j is 1 or 2, -NRcC(O)Rc, -C(O)N(Rc)2, -C(O)2Rc, or -C(O)Rc; or two adjacent Ri 's are taken together to form a substituted or unsubstituted aryl or heteroaryl; where each Rς is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and
K is
Figure imgf000017_0001
where Y is O or S; each R2 is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R3, -NO2, -N(R3)2, -SR3, -NRcC(O)Rc, -C(O)N(Rc)2,
Figure imgf000017_0002
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:
Figure imgf000017_0003
(II). 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:
Figure imgf000017_0004
(Ill) wherein:
Figure imgf000017_0005
Z2 is O or S. 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:
Figure imgf000018_0001
(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.
Figure imgf000018_0002
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:
Figure imgf000018_0003
(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:
Figure imgf000019_0001
(VII) wherein: each of X1-X5 is independently C, CR, N, NR, S,or O, wherein no more than three of Xi- X5 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(O)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:
Figure imgf000019_0002
In some embodiments, L is a covalent bond, -C(O)NH-, -OCH2-, or -OCH2CH2-. In
Figure imgf000020_0001
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:
Figure imgf000020_0002
(IX) wherein:
Figure imgf000020_0003
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 Xi-X5 is independently CR, N-O, or N, wherein no more than two of Xi-X5 is N, where each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)Rc, -NO2, -N(Rc)2, -SRc,-NRcC(O)Rc, or -C(O)Rc; where (b) L is -NH-; each of Xls X2, , and X5 is independently CR or N; and X is independently CR6 or N, wherein no more than two of Xι-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, -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; (c) L is -NH-; each of Xls X3, and X5 is independently CR or N; and each of X2 and X4 is independently CR or N, wherein no more than two of X 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) , -SRc, and alkyl substituted with alkoxy, halogen, aryl, heteroaryl, amine, -C(O)Rc, -OC(O)Rc, -NO2, -N(Rc) , or -SRc; 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 is -C(O)NH-; each of Xi, X2, X , and X5 is independently CR or N; and X3 is independently CR8 or N, wherein no more than two of Xi-X5 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, and -SR,; each Rς 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:
Figure imgf000021_0001
(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:
Figure imgf000022_0001
(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:
Figure imgf000022_0002
(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:
Figure imgf000022_0003
(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:
Figure imgf000022_0004
(XIV). 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:
Figure imgf000023_0001
(XV). 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:
Figure imgf000023_0002
(XVI).
In some embodiments, L is a linker selected from the group consisting of -NHC(O)-, -
O(Ci-C3 alkyl), -NHC(O)CH2SCH2C(O)NH-, -CHCHCH2O-, -CH2CH2-, -NHC(O)-(Cι-
C4 alkene), -NHC(O)-(Ci-C3 alkyl), and -CH2CH2C(O)NH-. Compositions and methods for treating a disease comprising administering to a subj ect in need thereof an effective amount of a kinase modulating compound according to the following formula are provided herein:
Figure imgf000023_0003
(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 Xi-X5 is independently C, CR, N-O, or N, wherein no more than two of Xi-X5 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, -NO , -N(Rd)2, -SRd, S(O)jRd where j is 1 or 2, -NRdC(O)Rd, -C(O)N(Rd)2, -C(O)2Rd, or -C(O)Rd; or two adjacent R's, are taken together, to form a substituted or imsubstituted 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:
Figure imgf000024_0001
(XVIII) wherein:
Figure imgf000024_0002
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, -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-, and -N(substituted or unsubstituted alkylene)-; Lt is a linker selected from the group consisting of a covalent bond, -O(substituted or unsubstituted C2-C5 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:
Figure imgf000026_0001
(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:
Figure imgf000026_0002
(XX). In some embodiments, Li is a bond, -CH2O-, -N(CH3)- or -O-; and L is -CH2O- 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:
Figure imgf000026_0003
(XXI). In some embodiments, Li is a -NH- or -O-; 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:
Figure imgf000027_0001
(XXII) 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:
Figure imgf000027_0002
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
Figure imgf000028_0001
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(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, 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:
Figure imgf000028_0002
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 imsubstituted 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)2Rc, or - C(O)Rc; or two adjacent Ri'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:
Figure imgf000029_0001
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:
Figure imgf000029_0002
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:
Figure imgf000029_0003
wherein Zi 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:
Figure imgf000030_0001
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), -NO2, -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:
Figure imgf000030_0002
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:
Figure imgf000030_0003
wherein Zi 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:
Figure imgf000031_0001
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), -NO2, -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:
Figure imgf000031_0002
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:
Figure imgf000031_0003
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.
In some embodiments, T is
Figure imgf000032_0001
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:
Figure imgf000032_0002
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:
Figure imgf000032_0003
hi 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. hi 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:
Figure imgf000033_0001
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:
Figure imgf000033_0002
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 Xi-X5 is independently C, CR, N, NR, S, or O, wherein no more than three of Xi-X5 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, -NR C(O)Rd, -C(O)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 R 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:
Figure imgf000034_0001
hi some embodiments, L of said compound is a covalent bond, -C(O)NH-
or -O(substituted or unsubstituted alkylene)-. In other embodiments,
Figure imgf000034_0002
of said compound is selected from the group consisting of:
Figure imgf000034_0003
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:
Figure imgf000035_0001
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 Xi-X5 is independently C, CR, N-O, or N, wherein no more than two of X1-X5 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(O)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:
Figure imgf000035_0002
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:
Figure imgf000036_0001
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:
Figure imgf000036_0002
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:
Figure imgf000036_0003
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:
Figure imgf000036_0004
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:
Figure imgf000037_0001
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:
Figure imgf000037_0002
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)(substiruted 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:
Figure imgf000037_0003
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)(substiruted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH-; and each of Xi-X5 is independently C, CR, or N, wherein no more than two of Xi-X5 is N, where each R is mdependently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)Rd, -NO2, -N(Rd)2, -SR , -S(O)jRd where j is 1 or 2, -NRdC(O)Rd, -C(O)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 O or S; and Z2 is CR3 orN. 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:
Figure imgf000038_0001
(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:
Figure imgf000038_0002
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 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:
Figure imgf000039_0001
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:
Figure imgf000039_0002
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:
Figure imgf000039_0003
wherein: each of X1-X5 is independently C, CR, N, NR, S, or O, wherein no more than three of Xi-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, -NO2, -N(Rd)2, -SRd, -S(O)jRd where j is 1 or 2, -NRd C(O)Rd, -C(O)2Rd, -C(O)N(Rd)2 or -C(O)R , or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where each R 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:
Figure imgf000040_0001
wherein: Z3 is R3, 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:
Figure imgf000040_0002
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:
Figure imgf000041_0001
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 imsubstituted alkylene)-, - N(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkenylene)- -NHC(O)(substituted or imsubstituted 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:
Figure imgf000041_0002
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 imsubstituted heteroaryl, or substituted or unsubstituted aryl. each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or imsubstituted alkoxy, -OC(O)R2, -NO2, -N(R2)2, -SR.2, -C(O)R2, -C(O)2R2, -C(O)N(R2)2, or -N(R2)C(O)R2, each R 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 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, -NO2, -N(RC)2, -SRC, S(O)jRc where j is 1 or 2, -NRcC(O)Rc, -C(O) N(RC)2, C(O)2Rc, or -C(O)Rc; or two adjacent Ri'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:
Figure imgf000042_0001
Provided herein are methods for modulating abl kinase, said methoPd comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001
43
Figure imgf000045_0001
44
Figure imgf000046_0001
45
Figure imgf000047_0001
46
Figure imgf000048_0001
Figure imgf000049_0001
48
Figure imgf000050_0001
Figure imgf000051_0001
50
Figure imgf000052_0001
51
Figure imgf000053_0001
Figure imgf000054_0001
53
Figure imgf000055_0001
54
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
57 Exemplary PDGFR Modulators Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound corresponding to the following formula are provided herein:
Figure imgf000059_0001
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 K is
Figure imgf000059_0002
where Y is O or S; each Ric is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R2, -NO , -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 imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or imsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R 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:
Figure imgf000059_0003
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 imsubstituted heteroaryl, or substituted or imsubstituted aryl; 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, -ORc -OH, -OC(O)Rc, -NO , -N(Rc)2, -SRc, S(O)jRc where j is 1 or 2, -NRcC(O)Rc, -C(O) N(Rc)2, C(O)2Rc, or - C(O)Rc; or two adjacent Ri'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 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 K is
Figure imgf000060_0001
ere each Rk is independently H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy. Methods for modulating PDGFR kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000061_0001
Methods for modulating PDGFR kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000061_0002
wherein Zi is CR 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:
Figure imgf000061_0003
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 imsubstituted alkyl), -C(O)NRc(substituted or unsubstituted alkenyl), -NO2, -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 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:
Figure imgf000062_0001
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:
Figure imgf000062_0002
wherein Zi 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:
Figure imgf000062_0003
wherein: each Ri is independently H, halogen, substituted or unsubstituted alkyl, -O(substituted or unsubstituted alkyl), -O(substituted or imsubstituted 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), -NO2, -S(=O)Rc, - SRc, C(O)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:
Figure imgf000063_0001
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:
Figure imgf000063_0002
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 imsubstituted 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 imsubstituted alkylene)C(O)NH-; and T is a mono-, bi-, or tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In some embodiments, T is
Figure imgf000063_0003
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:
Figure imgf000064_0001
In some embodiments, L of said compound is a covalent bond, -C(O)NH(substituted or imsubstituted alkylene), -NHC(O)-, -NHC(O)(substituted or unsubstituted alkylene)-, - NH-, or -O(substituted or imsubstituted 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:
Figure imgf000064_0002
In some embodiments, B of said compound is a substituted or imsubstituted 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. hi some embodiments, B of said compound is a substituted or imsubstituted 6-membered arylene or heteroarylene. In other embodiments, B is substituted or unsubstituted phenylene. In yet other embodiments, B is substituted or imsubstituted 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:
Figure imgf000064_0003
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. hi 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:
Figure imgf000065_0001
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 imsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted 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 imsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH-; and each of Xi-Xs is independently C, CR, N, NR, S, or O, wherein no more than three of Xι-X5 is a heteroatom, 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(O)2Rd, -C(O)N(Rd)2 or -C(O)Rd, or two adjacent R's are taken together to form a substituted or imsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or imsubstituted 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:
Figure imgf000066_0001
(XV). In some embodiments, L of said compound is a covalent bond, -C(O)NH-,
or -O(substituted or unsubstituted alkylene)-. hi other embodiments,
Figure imgf000066_0002
said compound is selected from the group consisting of:
Figure imgf000066_0003
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:
Figure imgf000066_0004
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 imsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted alkenylene)- -NHC(O)(substituted or unsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkenylene)-, -C(O)(substituted or imsubstituted alkenylene)-, and -NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH-; and each of Xi-X5 is independently C, CR, N-O, or N, wherein no more than two of Xι-X5 is N, 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(O)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, coπesponding to the following formula are provided herein:
Figure imgf000067_0001
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 imsubstituted alkenylene)-, -NHC(O)(substituted or imsubstituted alkenylene)-, and -O(substituted or unsubstituted alkylene)-, Methods for modulating PDGFR kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000067_0002
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:
Figure imgf000068_0001
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:
Figure imgf000068_0002
Methods for modulating PDGFR kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000068_0003
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:
Figure imgf000068_0004
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:
Figure imgf000069_0001
Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following foπnula are provided herein:
Figure imgf000069_0002
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:
Figure imgf000069_0003
hi some embodiments, L of said compound is -OCH - 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 imsubstituted 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:
Figure imgf000070_0001
wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or imsubstituted alkylene, -C(O)NH-, -C(O)-, -NH-, -O-, -S-, -O(substiruted or unsubstituted alkylene)-, - N(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted alkenylene)- -NHC(O)(substituted or unsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkenylene)-, -C(O)(substituted or imsubstituted alkenylene)-, and -NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH-; and each of Xi-X5 is independently C, CR, NR, O, S, or N, wherein no more than two of Xi-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(O)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 imsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Z\ is O or S; and Z2 is CR3 orN. 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:
Figure imgf000071_0001
Methods for modulating PDGFR kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000071_0002
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 imsubstituted alkylene), -C(O)NH(substituted or unsubstituted alkenylene)- -NHC(O)(substituted or imsubstituted alkylene)-, -NHC(O)(substituted or unsubstituted alkenylene)-, -C(O)(substituted or imsubstituted 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 admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000071_0003
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:
Figure imgf000072_0001
Methods for modulating PDGFR kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, conesponding to the following formula are provided herein:
Figure imgf000072_0002
wherein: each of Xι-X5 is independently C, CR, N, NR, S, or O, wherein no more than three of X1-X5 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 imsubstituted alkoxy, -OC(O)Rd, -NO2, -N(Rd)2, -SRd, -S(O)jRd where j is 1 or 2, -NRd C(O)R<ι, -C(O)2Rd, -C(O)N(Rd)2 or -C(O)Rd, or two adjacent R's are taken together to form a substituted or imsubstituted 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 imsubstituted five-membered heteroaryl, substituted or unsubstituted phenyl, or substituted or imsubstituted 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:
Figure imgf000073_0001
Figure imgf000074_0001
73
Figure imgf000075_0001
Figure imgf000076_0001
75
Figure imgf000077_0001
76
Figure imgf000078_0001
77
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
80
Figure imgf000082_0001
81
Figure imgf000083_0001
82 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:
Figure imgf000084_0001
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
K
Figure imgf000084_0002
where Y is O or S; each Rk is independently H, halogen, substituted or unsubstituted alkyl, - OH, substituted or imsubstituted alkoxy, -OC(O)R , -NO2, -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 imsubstituted cycloalkyl, substituted or imsubstituted 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 c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000085_0001
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 imsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or imsubstituted heterocyclyl, substituted or imsubstituted aryl, substituted or imsubstituted heteroaryl, -ORc -OH, -OC(O)Rς, -NO2, -N(Rc)2, -SRc, S(O)jRc where j is 1 or 2, -NRcC(O)Rc, -C(O)N(Rc)2; -C(O)2Rc, or -C(O) Rc; or two adjacent Ri's, are taken together to form a substituted or unsubstituted aryl or heteroaryl, 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 c-kit 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 K is
Figure imgf000085_0002
or where each Rk is independently H, halogen, substituted or unsubstituted alkyl, or substituted or imsubstituted alkoxy. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000086_0001
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000086_0002
(IH) wherein Zi is CR3 or N; and Z2 is O or S. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000086_0003
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 imsubstituted alkenyl), -NO2, -S(=O)Rc, - SRc, C(O)2Rc, or -C(O)Rc; and two adjacent Ri's, taken together, form a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and each R is independently H or substituted or unsubstituted alkyl. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000087_0001
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000087_0002
wherein Zi is O or S; and Z2 is CR3 or N. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000087_0003
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 imsubstituted alkyl), -NRcC(O) (substituted or unsubstituted alkyl), -NRcC(O)(substituted or unsubstituted alkenyl), -C(O)NRc(substituted or imsubstituted alkyl), -C(O)NRc(substituted or unsubstituted alkenyl), -NO2, -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 c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000088_0001
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000088_0002
wherein: L is a linker selected from the group consisting of a covalent bond, substituted or imsubstituted alkenylene, substituted or unsubstituted alkylene, -C(O)NH- , -C(O)-, -NH-, -O-, -S-, -O(substituted or imsubstituted alkylene)-, - N(substituted or imsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted 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.
In some embodiments, T is
Figure imgf000088_0003
wherein A is a substituted or unsubstituted five or six-membered heterocyclyl, aryl, or heteroaryl; and B is a substituted or imsubstituted five or six-membered heterocyclene, arylene, or heteroarylene, wherein A and B together form a fused two ring moiety. In some embodiments, T of said compound is a tricyclic, substituted or unsubstituted aryl, heterocyclyl, or heteroaryl. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000089_0001
In some embodiments, L of said compound is a covalent bond, -C(O)NH(substituted or imsubstituted alkylene),-O(substituted or unsubstituted alkylene)-, -C(O)NH-, or -
NHC(O)(alkylene)-. In other embodiments, B of said compound is a substituted or unsubstituted five-membered heteroarylene. In still other embodiments, B of said compound is a substituted or unsubstituted 6-membered arylene or heteroarylene. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000089_0002
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 imsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkenylene)-, -NHC(O)(substituted or imsubstituted alkylene)-, -NHC(O)(substituted or imsubstituted alkenylene)-, -C(O)(substituted or imsubstituted alkenylene)-, and -NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH-; and each of Xi-X5 is independently C, CR, N, NR, S, or O, wherein no more than three of Xi-X5 is a heteroatom, and no two adjacent ring atoms are O or S; where each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or imsubstituted alkoxy, -OC(O)Rd, -NO2, -N(Rd)2, -SRd, - S(O)jR<3 where j is 1 or 2, -NRd C(O)Rd, -C(O)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 imsubstituted aryl or substituted or unsubstituted heteroaryl. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000090_0001
In some embodiments, L of said compound is a covalent bond, -C(O)NH-,
or -O(substituted or unsubstituted alkylene)-. hi other embodiments,
Figure imgf000090_0002
said compound is selected from the group consisting of:
Figure imgf000090_0003
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000091_0001
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 Xi-X5 is independently C, CR, N, NR, S, or O, wherein no more than three of Xi-X5 is a heteroatom, and no two adjacent ring atoms are O or S; where each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or imsubstituted alkoxy, -OC(O)Rd, -NO2, -N(Rd)2, -SRd, - S(O)jRd where j is 1 or 2, -NRd C(O)Rd, -C(O)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 R is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or imsubstituted aryl or substituted or unsubstituted heteroaryl. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000091_0002
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000092_0001
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000092_0002
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000092_0003
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000092_0004
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000093_0001
Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, conesponding to the following formula are provided herein:
Figure imgf000093_0002
In some embodiments, L of said compound is -NHC(O)-, -NHC(O)(substituted or unsubstituted alkylene)-, -C(O)NH(substituted or unsubstituted alkylene), -C(O)NH(substituted or imsubstituted alkenylene),or -NHC(O)(substituted or unsubstituted alkenylene)-. In other embodiments, L of said compound is -O- or -
O(substituted or unsubstituted alkylene)-. In still other embodiments, L of said compound is -(substituted or unsubstituted alkylene)- or -
NHC(O)(alkylene)S(alkylene)C(O)NH-. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000093_0003
wherein: Li 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 imsubstituted 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 imsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH-; U is a substituted or unsubstituted cycloalkyl, hetrocycloalkyl, aryl, or heteroaryl; and V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene; Methods for modulating c-kit kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000094_0001
In some embodiments, Li of said compound is a bond, -O(substituted or unsubstituted alkylene)-, -(substituted or unsubstituted alkylene)-, or -S-; and L of said compound is a covalent bond, -C(O)NH-,-C(O)NH(substituted or unsubstituted alkylene), or -
NHC(O)(substituted or unsubstituted alkylene)-. In other embodiments, V of said compound is substituted or unsubstituted 5-membered heteroarylene. Methods for modulating c-kit kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000094_0002
wherein: each of X1-X is independently C, CR, or N, wherein no more than two of X1-X5 is N; where each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)P , -NO2, -N(Rd)2, -SRd, -S(O)jRd where j is 1 or 2, -NRd C(O)Rd, -C(O)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 imsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or imsubstituted heteroaryl. In some embodiments, U of said compound is substituted or unsubstituted pyrimidinyl or pyridinyl. In other embodiments, U of said compound is substituted or unsubstituted phenyl. Methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000095_0001
wherein T is substituted or unsubstituted cycloalkyl or heterocylyl. Provided herein are methods for modulating c-kit kinase, said method comprising administering an effective amount of a compound, or phannaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000095_0002
Figure imgf000096_0001
95
Figure imgf000097_0001
96
Figure imgf000098_0001
97
Figure imgf000099_0001
98
Figure imgf000100_0001
99
Figure imgf000101_0001
Figure imgf000102_0001
101
Figure imgf000103_0001
Figure imgf000104_0001
103
Figure imgf000105_0001
Figure imgf000106_0001
105
Figure imgf000107_0001
106
Figure imgf000108_0001
Exemplary ABL Modulators Methods for modulating abl kinase, said method comprising administering an effective amount of a compound corresponding to the following formula are provided herein:
Figure imgf000108_0002
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
Figure imgf000108_0003
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) , -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 imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or imsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or imsubstituted heteroaryl; or wherein two R 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 abl kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000109_0001
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 imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or imsubstituted aryl; and each Ri is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or imsubstituted 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(0)N( c)2, -C(O)2Rc, or - C(O)Rc; or two adjacent Ri's, are taken together to form a substituted or unsubstituted aryl or heteroaryl, each Rc is independently H, substituted or imsubstituted alkyl, substituted or imsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000109_0002
wherein K is
Figure imgf000110_0001
or where each Rk is independently H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy. Methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000110_0002
Methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, conesponding to the following formula are provided herein:
Figure imgf000110_0003
wherein Zi is CR3 or N; and Z2 is O or S. Methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000110_0004
wherein: L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or imsubstituted alkylene, -C(O)NH-, -C(O)-, -NH-, -O-, -S-, -O(substituted or imsubstituted 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 imsubstituted alkenylene)-, -C(O)(substituted or imsubstituted 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.
hi some embodiments, T is
Figure imgf000111_0001
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 abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000111_0002
In some embodiments, L of said compound is -O(substituted or unsubstituted alkylene)- , -C(O)NH-, or a covalent bond. In other embodiments, A of said compound is substituted or unsubstituted five or six-membered aryl or heteroaryl; and B of said compound is substituted or unsubstituted five or six-membered arylene or heteroarylene. Methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000111_0003
wherein: each X is independently C, CR, N, NR, or O, wherein no more than three X's is a heteroatom, and no two adjacent ring atoms are 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(O)2Rd, -C(O)N(Rd)2 or -C(O)Rd, or two adjacent R's are taken together to form a substituted or imsubstituted 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 abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000112_0001
Methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000112_0002
wherein: each X is independently C, CR, N, NR, S or O, wherein no more than three X's is a heteroatom, and no two adjacent ring atoms are O or S; and each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or imsubstituted alkoxy, -OC(O)Rd, -NO2, -N(Rd)2, -SRd, -S(O)jRd where j is 1 or 2, -NRd C(O)Rd, -C(O)2Rd, -C(O)N(Rd)2 or -C(O)Rd, or two adjacent R's are taken together to form a substituted or imsubstituted aryl or hetroaryl, where each Rd is independently H, substituted or imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Methods for modulating abl kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000113_0001
Methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000113_0002
Methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the following formula are provided herein:
Figure imgf000113_0003
Provided herein are methods for modulating abl kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000114_0001
Exemplary p38 Modulators Methods for modulating p38 kinase, said method comprising admimstering an effective amount of a compound corresponding to the formula below are provided herein:
Figure imgf000114_0002
wherein: M is a substituted or imsubstituted aryl or heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and
K is
Figure imgf000114_0003
, where Y is O or S; each R2 is independently H, halogen, substituted or imsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R3, -NO2, -N(R3)2, -SR3, -NR3C(O)R3, -C(O)N(R3)2, -C(O)2R3 , or -C(O)R3; each R 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. Methods for modulating p38 kinase, said method comprising administering an effective amount of a compound corresponding to the formula below are provided herein:
Figure imgf000115_0001
Methods for modulating p38 kinase, said method comprising administering an effective amount of a compound corresponding to the formula below are provided herein:
Figure imgf000115_0002
Methods for modulating p38 kinase, said method comprising administering an effective amount of a compound corresponding to the formula below are provided herein:
Figure imgf000115_0003
Methods for modulating p38 kinase, said method comprising admimstering an effective amount of a compound corresponding to the formula below are provided herein:
Figure imgf000116_0001
Provided herein are methods for modulating p38 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000116_0002
Exemplary MKNK2 Modulators Methods for modulating MKNK2 kinase, said method comprising administering an effective amount of a compound corresponding to the formula below are provided herein:
Figure imgf000117_0001
wherein: M is a substituted or unsubstituted aryl or heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and
K is
Figure imgf000117_0002
, where Y is O or S; each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R3, -NO2, -N(R3)2, -SR3, -NR3C(O)R3, -C(O)N(R3)2, -C(O)2R3 , or -C(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. Methods for modulating MKNK2 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the formula below are provided herein:
Figure imgf000117_0003
Methods for modulating MKNK2 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, conesponding to the formula below are provided herein:
Figure imgf000117_0004
Methods for modulating MKNK2 kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the formula below are provided herein:
Figure imgf000118_0001
Methods for modulating MKNK2 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, corresponding to the formula below are provided herein:
Figure imgf000118_0002
Provided herein are methods for modulating MKNK2 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, of a compound selected from the group consisting of:
Figure imgf000118_0003
Exemplary STK-10 Modulators Methods for modulating STK10 kinase, said method comprising administering an effective amount of a compound according to the formula below are provided herein:
Figure imgf000119_0001
wherein: M is a substituted or unsubstituted aryl or heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and
K is
Figure imgf000119_0002
where Y is O or S; each R2 is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R3, -NO2, -N(R3)2, -SR3, -NR3C(O)R3, -C(O)N(R3)2, -C(O)2R3 , or -C(O)R3; each R is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or imsubstituted 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. Methods for modulating STK10 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, according to the formula below are provided herein:
Figure imgf000119_0003
Methods for modulating STK10 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, according to the formula below are provided herein:
Figure imgf000120_0001
Methods for modulating STK10 kinase, said method comprising admimstering an effective amount of a compound, or pharmaceutically acceptable salt thereof, according to the formula below are provided herein:
Figure imgf000120_0002
Provided herein are methods for modulating STK10 kinase, said method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000120_0003
In some embodiments, the protein kinase is selected from the group comprising Ste (sterile 20, sterile 11 and sterile 7); camk (calmodulin regulated kinases and related kinases); AGC (protein kinase A, protein kinase G and protein kinase C) and CMGC (cdk, map kinase, glycogen synthetase kinase and elk). The sterile 20 kinases include, for example, PAK and CZ. In some embodiments, the protein tyrosine kinase is selected from the "HER" receptor tyrosine kinase subfamily, which includes EGFR (epithelial growth factor receptor), HER2, HER3 and HER4. In further embodiments, the protein tyrosine kinase is selected from the subfamily consisting of insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor related receptor (IRR). In some embodiments, the protein tyrosine kinase is selected from the platelet derived growth factor receptor (PDGFR) subfamily, which includes PDGFR α, PDGFR β, CSFIR, c-kit and c-fins. In another embodiment, the protein tyrosine kinase is the vascular endothelial growth factor ("VEGF") receptor subgroup. In some embodiments, the protein tyrosine kinase is selected from the fetus liver kinase ("flk") receptor subfamily, which includes kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), flk-lR, flk-4 and fins-like tyrosine kinase 1 (flt-1). In further embodiments, the protein tyrosine kinase is selected from the fibroblast growth factor ("FGF") receptor subgroup, which includes the receptors FGFR1, FGFR 2, FGFR3, and FGFR4, and the ligands, FGF1, FGF2, FGF3, FGF4, FGF5, FGF6,and
FGF7. In a still further embodiment, the protein tyrosine kinase is the tyrosine kinase growth factor receptor family, c-Met. In some embodiments, the protein tyrosine kinase is an fins-like tyrosine kinase 3 receptor kinase (FLT-3 kinase). The present invention provides compounds which modulate the activity, and in some embodiments, preferentially inhibit non-receptor tyrosine kinases. In some embodiments, the non-receptor tyrosine kinases include Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack, their respective subfamilies. In a futher embodiemnt, the non- receptor tyrosine kinase is selected from the Src subfamily, which includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The compounds and compositions disclosed herein may be used for the prevention or treatment of cancers such as stomach, gastric, bone, ovary, colon, lung, brain, larynx, lymphatic system, genitourinary tract, ovarian, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, leukemia, glioma, colorectal cancer, genitourinary cancer gastrointestinal cancer, or pancreatic cancer, hi particular, the cancer is acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs). Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of an fms-like tyrosine kinase 3 (FLT-3) receptor modulating compound are provided herein. In one embodiment, the disease is cancer. In other embodiments, the cancer is a malignant tumor, or a hematologic malignancy such as leukemia and lymphoma. hi some embodiments, the leukemia is acute myelogenous leukemia (AML), a B-precursor cell acute lymphoblastic leukemia, myelodysplastic leukemia, T-cell acute lymphoblastic leukemia or chronic myelogenous leukemia (CML). Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a Stem Cell Factor (SCF), c-kit, receptor modulating compound are provided herein. In one embodiment, the disease is cancer. In other embodiments, the cancer is a malignant tumor, or a hematologic malignancy such as leukemia and lymphoma. hi some embodiments, the cancer is small-cell lung cancer, or breast cancer. In some embodiments, the leukemia is acute myelogenous leukemia
(AML). In some embodiments, the malignant tumor is a germ cell tumor, a mast cell tumor, a gastrointestinal stromal tumor (GIST), melanoma, or a neuroblastoma. Compositions and methods for treating a disease comprising admimstering to a subject in need thereof an effective amount of a Bcr-Abl receptor modulating compound are provided herein. In one embodiment, the disease is cancer. In other embodiments, the cancer is a malignant tumor, or a hematologic malignancy such as leukemia and lymphoma. In some embodiments, the leukemia is chronic myeloid leukemia (CML) or acute myelogenous leukemia (AML). Compositions and methods for treating a disease comprising administering to a subject in need thereof an effective amount of a Platelet-Derived Growth Factor (PDGF) receptor modulating compound are provided herein. In one embodiment, the disease is cancer. In other embodiments, the cancer is a malignant tumor, or a hematologic malignancy such as leukemia and lymphoma. hi some embodiments, the leukemia is acute lymphoblastic leukemia (ALL). In some embodiments, the lymphoma is T- cell lymphoma. In some embodiments, the malignant tumor is melanoma, or glioblastoma.
In a further embodiment, the disease is a nonmahgnant proliferation disease. In some embodiments, the nonmahgnant proliferation disease is atherosclerosis, or restenosis. hi a still further embodiment, the disease is a fibroproliferative disorder. In some embodiments, the fibroproliferative disorder is obliterative bronchiolitis. These and other aspects of the present invention will become evident upon reference to the following detailed description. In addition, various references are set forth herein which describe in more detail certain procedures or compositions, and are incorporated by reference in their entirety. DISCLOSURE OF THE INVENTION To more readily facilitate an understanding of the invention and its prefened embodiments, the meanings of terms used herein will become apparent from the context of this specification in view of common usage of various terms and the explicit definitions of other terms provided in the glossary below or in the ensuing description. Glossary of Terms Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg (1992) "ADVANCED ORGANIC CHEMISTRY 3RD ED." Vols. A and B, Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed. The term "modulator" means a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, agonist, antagonist, and the like. The term "agonist" means a molecule such as a compound, a drug, an enzyme activator or a hormone that enhances the activity of another molecule or the activity of a receptor site etiehr directly or indirectly. The term "antagonist" means a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone that diminishes or prevents the action of another molecule or the activity of a receptor site either directly or indirectly. The terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. As used herein, the terms "treat" or "treatment" are synonymous with the term "prevent" and are meant to indicate a postponement of development of diseases, preventing the development of diseases, and/or reducing severity of such symptoms that will or are expected to develop. Thus, these terms include ameliorating existing disease symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disorder or disease, e.g., anesting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. By "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material which is not biologically or otherwise undesirable, i.e., the material maybe administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. "Carrier materials" include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Pharmaceutically compatible carrier materials" may comprise, e.g., acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,
Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999). As used herein, the term "subject" encompasses mammals and non-mammals.
Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the present invention, the mammal is a human. The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4- methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4,- methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolarnine, triethanolamine, tromethamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or porymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. As used herein, the term "biological sample" is broadly defined to include any cell, tissue, organ or multicellular organism. A biological sample can be derived, for example, from cell or tissue cultures in vitro. Alternatively, a biological sample can be derived from a living organism or from a population of single cell organisms. As used herein, the term "linker" means any divalent linking moiety used to connect, join, or attach two chemical groups. For example, linkers may be used to join two cyclic groups, such as to join two aryl groups (e.g., phenyl), an aryl group to a cycloalkyl group, an aryl group to a heterocyclyl group, a cycloalkyl group to a cycloalkyl group, a cycloalkyl group to a heterocyclyl group, and the like. Representative linkers include, but are not limited to, a covalent bond, -(substituted or unsubstituted alkylene)-, - (substituted or imsubstituted alkenylene)-, -(substituted or unsubstituted alkynylene)-, - (substituted or unsubstituted cycloalkylene)-, -(substituted or unsubstituted heterocyclylene)-, -(substituted or unsubstituted arylene)-, and -(substituted or unsubstituted heteroarylene)-. Exemplary linkers also include -O-, -S-, -S(O)-, -S(O)2-, - S(O)3-, -C(O)-, -NH-, -N=, -N=N-, =N-N=,
-C(O)NH-, -S(O)NH-, and the like. Additional examples of linkers include - O(substituted or unsubstituted alkylene)-, -N(substituted or unsubstituted alkylene)-, - NHC(O)(substituted or unsubstituted alkylene)-, -C(O)(substituted or unsubstituted alkenylene)-, -NHC(O)(substituted or unsubstituted alkylene)S(substituted or imsubstituted alkylene)C(O)NH-, -NHC(O)(substituted or unsubstituted alkenylene)-, and the like. Linkers, as represented herein, embrace divalent moieties in any chemically feasible directionality. For example, compounds comprising a linker-C(O)NH- which attaches two aryl groups, Ari to Ar2, include Ari-C(O)NH-Ar2 as well as Ari-NHC(O)-Ar2. As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine. As used herein, "alkyl" means a straight chain or branched, saturated or unsaturated chain having from 1 to 10 carbon atoms. Representative saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2- propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2- methyl-1-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-ρentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, and longer alkyl groups, such as heptyl, and octyl. An alkyl group can be imsubstituted or substituted. Unsaturated alkyl groups include alkenyl groups and alkynyl groups, discussed below. Alkyl groups containing three or more carbon atoms may be straight, branched or cyclized. As used herein, "lower alkyl" means an alkyl having from 1 to 5 carbon atoms. As used herein, an "alkenyl group" includes a monovalent unbranched or branched hydrocarbon chain having one or more double bonds therein. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to, (C2-C8) alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2- propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted or substituted. As used herein, "alkynyl group" includes a monovalent unbranched or branched hydrocarbon chain having one or more triple bonds therein. The triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to, (C2-C6) alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substituted. The terms "trifluoromethyl," "sulfonyl," and "carboxyl" include CF3, SO3H, and
CO H, respectively. The term "alkoxy" as used herein includes -O-(alkyl), wherein alkyl is defined above. As used herein, "alkoxyalkoxy" includes -O-(alkyl)-O-(alkyl), wherein each "alkyl" is independently an alkyl group defined above. As used herein, "alkoxycarbonyl" includes-C(O)O-(alkyl), wherein alkyl is defined above. As used herein, "alkoxycarbonylalkyl" includes -(alkyl)-C(O)O-(alkyl), wherein alkyl is defined above. As used herein, "alkoxyalkyl" means -(alkyl)-O-(alkyl), wherein each "alkyl" is independently an alkyl group defined above. As used herein, the term "aryl" (Ar) refers to a monocyclic, or fused or spiro polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having from 3 to 12 ring atoms per ring. Illustrative examples of aryl groups include the following moieties:
Figure imgf000128_0002
like. As used herein, the term "heteroaryl" (heteroAr) refers to a monocyclic, or fused or spiro polycyclic, aromatic heterocycle (ring structure having ring atoms selected from carbon atoms as well as nitrogen, oxygen, and sulfur heteroatoms) having from 3 to 12 ring atoms per ring. Illustrative examples of aryl groups include the following moieties:
Figure imgf000128_0003
and the like.
Figure imgf000128_0004
As used herein, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle having from 3 to 12 ring atoms per ring. Illustrative examples of cycloalkyl groups include the following moieties:
Figure imgf000128_0005
Figure imgf000129_0001
and the like.
Figure imgf000129_0002
As used herein, the term "heterocycloalkyl" refers to a monocyclic, or fused or spiro polycyclic, ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring selected from C atoms and N, O, and S heteroatoms. Illustrative examples of heterocycloalkyl groups include:
Figure imgf000129_0003
and the like.
Figure imgf000129_0004
As used herein, "aryloxy" includes -O-aryl group, wherein aryl is as defined above. An aryloxy group can be unsubstituted or substituted. As used herein, "arylalkyl" includes -(alkyl)-(aryl), wherein alkyl and aryl are defined above. As used herein, "arylalkyloxy" includes -O-(alkyl)-(aryl), wherein alkyl and aryl are defined above. As used herein, "cycloalkyl" includes a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms and having no carbon-carbon multiple bonds. Examples of cycloalkyl groups mclude, but are not limited to, (C3-C7)cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes. A cycloalkyl group can be unsubstituted or substituted. Preferably, the cycloalkyl group is a monocyclic ring or bicyclic ring. As used herein, "cycloalkyloxy" includes -O-(cycloalkyl), wherein cycloalkyl is defined above. As used herein, "cycloalkylalkyloxy" includes -O-(alkyl)-(cycloalkyl), wherein cycloalkyl and alkyl are defined above. As used herein, the term "alkyhdene" includes the divalent radical -CnH2n~, wherein n is an integer from 1 to 8, such as -CH2-, -CH2CH2-, ~CH2-CH2-CH2~, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and the like, unsubstituted or substituted with one or more alkyl groups. As used herein, "heteroatom-containing alkyhdene" includes an alkyhdene wherein at least one carbon atom is replaced by a heteroatom selected from nitrogen, oxygen, or sulfur, such as ~CH2CH2OCH2CH2— , and the like, unsubstituted or substituted with one or more alkyl groups. As used herein, "aminoalkoxy" includes ~O-(alkyl)-NH2, wherein alkyl is defined above. As used herein, "mono-alkylamino" includes — NH(alkyl), wherein alkyl is defined above. As used herein, "di-alkylamino" includes ~N(alkyl)(alkyl), wherein each "alkyl" is independently an alkyl group defined above. As used herein, "mono-alkylaminoalkoxy" includes — O-(alkyl)-NH(alkyl), wherein each "alkyl" is independently an alkyl group defined above. As used herein, "di-alkylaminoalkoxy" includes ~O-(alkyl)N(alkyl)(alkyl), wherein each "alkyl" is independently an alkyl group defined above. As used herein, "arylamino" includes — NH(aryl), wherein aryl is defined above. As used herein, "arylalkylamino" includes ~NH-(alkyl)-(aryl), wherein alkyl and aryl are defined above. As used herein, "alkylamino" includes --NH(alkyi), wherein alkyl is defined above. As used herein, "cycloalkylamino" includes — NH-(cycloalkyl), wherein cyclohexyl is defined above. As used herein, "cycloalkylalkylamino" includes ~NH-(alkyl)-(cycloalkyl), wherein alkyl and cycloalkyl are defined above. As used herein, "aminoalkyl" includes -(alkyl)-NH2, wherein alkyl is defined above. As used herein, "mono-alkylaminoalkyl" includes -(alkyl)-NH(alkyl),wherein each "alkyl" is independently an alkyl group defined above. As used herein, "di-alkylaminoalkyl" includes -(alkyl)-N(alkyl)(alkyl),wherein each "alkyl" is independently an alkyl group defined above. The term "whole integer" is intended to include whole numbers. For example, a whole integer from 0 to 4 would include 0, 1, 2, 3, and 4. Sulfonyl refers to the presence of a sulfur atom, which is optionally linked to another moiety such as an aliphatic group, an aromatic group, an aryl group, an alicyclic group, or a heterocyclic group. Aryl or alkyl sulfonyl moieties have the formula -SO2Rd, and alkoxy moieties have the formula -O-Rd, wherein R is alkyl, as defined above, or is aryl wherein aryl is phenyl, optionally substituted with 1-3 substituents independently selected from halo (fluoro, chloro, bromo or iodo), lower alkyl (1-6C) and lower alkoxy
(1-6C). As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents. As used herein, the term "unsubstituted" means that the specified group bears no substituents. As used herein, the term "optionally substituted" means that the specified group is imsubstituted or substituted by one or more substituents. Molecular embodiments of the present invention may possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem,
Rev, 1996, 96, 3147-3176 and references cited therein. In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with phannaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. To more readily facilitate an understanding of the invention and its prefened embodiments, the meanings of terms used herein will become apparent from the context of this specification in view of common usage of various terms and the explicit definitions of other terms provided in the glossary below or in the ensuing description. Compounds In one aspect, the present invention is directed to compounds, compositions, and methods for treating conditions associated with abnormal kinase activity. In one embodiment, compounds useful in the invention are derivatives of isoxazoles, pyrazoles and isothiazoles. When the compounds of the invention contain one or more chiral centers, the invention includes optically pure forms as well as mixtures of stereoisomers or enantiomers. Thus, the invention provides methods for modulating various kinases by providing an effective amount of a compound of the formulas described herein. Salts of the compounds may be used for therapeutic and prophylactic purposes, where the salt is preferably a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example Q-toluenesulphonic, acids. A "prodrug" refers to a drug or compound in which the pharmacological action results from conversion by metabolic processes within the body. Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. Additionally, prodrugs can increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al, Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., hit. J. Pharmaceutics, 47, 103 (1988); Sinkula et al, J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. Prodrug forms of the above described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth above are included within the scope of the claims. Indeed, some of the above-described derivatives may be a prodrug for another derivative or active compound. The invention further provides for the optical isomers of the compounds disclosed herein, especially those resulting from the chiral carbon atoms in the molecule. In additional embodiments of the invention, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion may also be useful for the applications described herein. hi another aspect, compositions containing the above described analogs and derivatives are provided. Preferably, the compositions are formulated to be suitable for pharmaceutical or clinical use by the inclusion of appropriate carriers or excipients. Groups such as carbonyl, carboxyl, alkoxy, amino, and cyano groups, etc., as shown in the formula above, need not be directly bound to the para position; they may be included elsewhere in the alkyl, alkenyl or alkynyl substituent. Thus, also acceptable substituents are the following representative forms: -CH2NHCH3;-CH2θCH3; -CH2SCH3; -NHCH3; -CH2CH3; -OCH2CH3; -SCH2CH2CH3; -CH=CHCH2NH2; -CH2CH2OH; ' -CH2CH2CH2SH; -CH2OC(0)CH3; -CH2 HC(0)CH2C(0)CH3; -NHC(0)CH2CH2CH3
Figure imgf000133_0001
each of which may further be substituted with a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group. It will also be evident that these substituents include, for example, trifluoromethyl, difluoromethyl and fluoromethyl (alkyl substituted by halo) and trifluoromethoxy, difluoromethoxy and fluoromethoxy (alkyl where one carbon is replaced by O and is further substituted by halo). Compounds of the invention which contain carboxyl groups or which contain amino groups may be supplied in the forms of their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of carboxylic acids include inorganic salts such as salts of sodium, potassium, calcium, magnesium and the like or salts formed with organic bases such as caffeine. Salts of amines are acid addition salts formed from inorganic acids such as hydrochloric, sulfuric, phosphoric acids or may be salts of organic acids such as acetates, maleates, propionates, and the like. The invention also provides prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce a derivative as set forth above. Indeed, some of the above described derivatives may be a prodrug for another derivative or active compound. The invention further provides for the optical isomers of the compounds disclosed herein, especially those resulting from the chiral carbon atoms in the molecule. In additional embodiments of the invention, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are provided. In another aspect of the invention, compositions containing the above described analogs and derivatives are provided. Preferably, the compositions are formulated to be suitable for pharmaceutical or clinical use by the inclusion of appropriate carriers or excipients. In yet another aspect of the invention, pharmaceutical formulations are provided comprising at least one compound described above, or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. The compounds of the invention, especially when used in the invention methods and compositions, may be "conjugated" -that is they may be coupled to additional moieties that do not destroy their ability to modulate kinases. For example, the compounds might be coupled to a label such as a radioactive label, a fluorescent label and the like, or may be coupled to targeting agents such as antibodies or fragments, or to fragments to aid purification such as FLAG or a histidine tag. The compounds may also be coupled to specific binding partners such as biotin for use in assay procedures or to moieties that alter their biological half-lives such as polyethylene glycol. Thus, the methods of the invention employ the invention compounds per se as well as conjugates thereof. Synthesis of Compounds Compounds of the present invention may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. See, e.g., March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 3rd Ed., Vols. A and B (Plenum 1992), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 2nd Ed. (Wiley 1991). General methods for the preparation of compound as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. The compounds of the invention are synthesized by methods well known in the art. The compounds of the invention are ureas or cyclic forms thereof and can be synthesized using generally known procedures for urea synthesis. In one group of methods, an amine is reacted with an isocyanate in an aprotic solvent. Typically, in some embodiments, a molar excess of the amine is used in the presence of an aprotic solvent and the reaction is conducted at room temperature. The reaction mixture is then poured into water and precipitated with salt to recover the crude product which is then purified according to standard methods. In alternative methods, the ureas are formed from two separate amine reactants in the presence of a condensing agent such as l,l,carbonyldiimidazole (CDI) in the presence of an inert nonpolar solvent such as dichloromethane. One of the amines is first added to a solution of CDI in solvent under cooling conditions and then stirred at room temperature with the other amine. After removal of solvent, the crude product can be purified using standard procedures. In still another method, one of the amines is added in an aprotic solvent to a solution of triphosgene and then treated with the other amine reactant dissolved in an inert solvent in the presence of base such as triethylamine. After reaction at room temperature, the mixture may be diluted with, for example, ethylacetate and washed with water and brine, dried and purified. In still another method, one of the amine components is treated with 4- nitrophenylchloroformate in the presence of mild base in a solvent such as N- methylpyrrolidone (NMP). The other amine is then added and the reaction mixture heated, then cooled, poured into water, extracted into chloroform and further purified. Alternatively, the urea may be formed by the reaction of an amine with the counterpart halo acylamine which is formed from the parent amine by treatment with phosgene and base in an inert solvent such as methylene dichloride or by reacting an amine with its counterpart amine with an acyl amine containing an alternate leaving group formed by reaction of that amine with 4-nitrophenylchloroformate in the presence of an amine base and in an inert solvent. Details of these methods can be found in Matsuno et al. J. Med. Chem. 45:3057-66 (2002); Matsuno et al. J. Med. Chem. 45:4513-23 (2002); and and Pandley et al., J. Med. Chem. 45:3772-93 (2002). Cyclized forms of the ureas may be obtained by treating the formed urea with dibromo derivatives of the bridge, typically in the presence of a strong base and in an inert aprotic polar solvent. The ureas may be converted to thioureas by treating with Lawesson's reagent in the presence of toluene. For compounds having the moiety Ar^L-Ar2 is obtained by first protecting the amino group of p-hydroxy aniline destined to become Ar1 with a protecting agent such as Boc and then coupling the hydroxy group of Ar1 to an aryl alkyl halide. This coupling is conducted in the presence of strong base and in an aprotic solvent. After deprotection, the urea is formed by reaction with the isoxazole isocyanate. These techniques are exemplified below. Selected examples of covalent linkages and precursor functional groups which yield them are given in the Table entitled "Examples of Covalent Linkages and Precursors Thereof." Precursor functional groups are shown as electrophilic groups and nucleophilic groups. The functional group on the organic substance maybe attached directly, or attached via any useful spacer or linker as defined below. Table 1: Examples of Covalent Linka es and Precursors Thereof
Figure imgf000136_0001
Figure imgf000137_0001
In general, carbon electrophiles are susceptible to attack by complementary nucleophiles, including carbon nucleophiles, wherein an attacking nucleophile brings an electron pair to the carbon electrophile in order to form a new bond between the nucleophile and the carbon electrophile. Suitable carbon nucleophiles include, but are not limited to alkyl, alkenyl, aryl and alkynyl Grignard, organolithium, organozinc, alkyl-, alkenyl , aryl- and alkynyl-tin reagents (organostannanes), alkyl-, alkenyl-, aryl- and alkynyl-borane reagents (organoboranes and organoboronates); these carbon nucleophiles have the advantage of being kinetically stable in water or polar organic solvents. Other carbon nucleophiles include phosphorus ylids, enol and enolate reagents; these carbon nucleophiles have the advantage of being relatively easy to generate from precursors well known to those skilled in the art of synthetic organic chemistry. Carbon nucleophiles, when used in conjunction with carbon electrophiles, engender new carbon-carbon bonds between the carbon nucleophile and carbon electrophile. Non-carbon nucleophiles suitable for coupling to carbon electrophiles include but are not limited to primary and secondary amines, thiols, thiolates, and thioethers, alcohols, alkoxides, azides, semicarbazides, and the like. These non-carbon nucleophiles, when used in conjunction with carbon electrophiles, typically generate heteroatom linkages (C- X-C), wherein X is a hetereoatom, e. g, oxygen or nitrogen. The term "protecting group" refers to chemical moieties that block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable. Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester derivatives as exemplified herein, or they may be blocked with oxidatively- removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in then presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd0- catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. Typically blocking/protecting groups may be selected from:
Figure imgf000139_0001
allyl Bn Cbz alloc Me H2 H3C p^z H2 o H3C^ ^- (H3C)3C^ (H3C)3C'Si^ {C akfiT ^ Et t-butyl TBDMS
(CHafeC ( βHδ C
Figure imgf000139_0003
Figure imgf000139_0002
Boc pMBn trityl acetyl Fmoc Other protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incoφorated herein by reference in its entirety.
Biological Activity 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. Abnormal PK activity has been related to disorders ranging from relatively non life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer), hi addition, a variety of tumor types have dysfunctional growth factor receptor tyrosine kinases, resulting in inappropriate mitogenic signaling. Protein kinases are believed to be involved in many different cellular signal transduction pathways. In particular, protein tyrosine kinases (PTK) are attractive targets in the search for therapeutic agents, not only for cancer, but also against many other diseases. Blocking or regulating the kinase phosphorylation process in a signaling cascade may help treat conditions such as cancer or inflammatory processes. Protein 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 includes Bcr-Abl tyrosine kinase, and 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 α and β), colony- stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), FLT-3, and stem cell or steel factor receptor (c-kit). The compounds, compositions, and methods provided herein are useful to modulate the activity of kinases including, but not limited to, ERBB2, ABL1, AURKA, CDK2, EGFR, FGFR1, LCK, MAPK14, PDGFR, KDR, ABLl, BRAF, ERBB4, FLT3, KIT, and RAF1. In some embodiments, the compositions and methods provided herein modulate the activity of a mutant kinase. Inhibition by the compounds provided herein can be determined using any suitable assay, hi one embodiment, inhibition is determined in vitro, hi a specific embodiment, inhibition is assessed by phosphorylation assays. Any suitable phosphorylation assay can be employed. For example, membrane autophosphorylation assays, receptor autophosphorylation assays in intact cells, and ELISA's can be employed. See, e.g., Gazit, et al., J. Med. Chem. (1996) 39:2170-2177, Chapter 18 in CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (Ausubel, et al., eds. 2001). Cells useful in such assays include cells with wildtype or mutated forms. In one embodiment, the wildtype is a kinase that is not constirutively active, but is activated with upon dimerization. For example, the mutant FLT3 kinase is constitutively active via internal tandem duplication mutations or point mutations in the activation domain. Suitable cells include those derived through cell culture from patient samples as well as cells derived using routine molecular biology techniques, e.g., retro viral transduction, transfection, mutagenesis, etc. Exemplary cells include Ba/F3 or 32Dcl3 cells transduced with, e.g., MSCV retroviral constructs FLT3-
ITD (Kelly et al., 2002); Molm-13 and Molml4 cell line (Fujisaki Cell Center, Okayama, Japan); HL60 (AML-M3), AML193 (AML-M5), KG-1, KG-la, CRL-1873, CRL-9591, and THP-1 (American Tissue Culture Collection, Bethesda, MD); or any suitable cell line derived from a patient with a hematopoietic malignancy. In some embodiments, the compounds described herein significantly inhibit receptor tyrosine kinases. A significant inhibition of a receptor tyrosine kinase activity refers to an IC50 of less than or equal to 100 μM. Preferably, the compound can inhibit activity with an IC50 of less than or equal to 50 μM, more preferably less than or equal to 10 μM, more preferably less than 1 μM, or less than 100 nM, most preferably less than 50 nM. Lower ICso's are preferred because the IC50 provides an indication as to the in vivo effectiveness of the compound. Other factors known in the art, such as compound half- life, biodistribution, and toxicity should also be considered for therapeutic uses. Such factors may enable a compound with a lower IC50 to have greater in vivo efficacy than a compound having a higher IC50. Preferably, a compound that inhibits activity is administered at a dose where the effective tyrosine phosphorylation, i.e., IC5Q, is less than its cytotoxic effects, LD50. In some embodiments, the compounds selectively inhibit one or more kinases. Selective inhibition of a kinase, such as FLT3, p38 kinase, STK10, MKNK2, Bcr-Abl, c- kit, or PDGFR, is achieved by inhibiting activity of one kinase, while having an insignificant effect on other members of the superfamily. c-kit The Stem Cell Factor (SCF) receptor c-kit is a receptor protein tyrosine kinase that initiates cell growth and proliferation signal transduction cascades in response to SCF binding, c-kit is a 145-kD transmembrane glycoprotein and is the normal cellular homolog of the v-kit retroviral oncogene, It is also a member of the Type III transmembrane receptor protein tyrosine kinase subfamily, which includes the macrophage colony-stimulating factor- 1 receptor, also known as the FMS receptor, the related FLT-3 receptor, and the platelet-derived growth factor (PDGF) α and β receptors. The c-kit gene product is expressed in hematopoietic progenitor cells, mast cells, germ cells, interstitial cells of Cajal (ICC), and some human tumors. Inactivating mutations of c-kit or its ligand, Steel factor (SLF), have demonstrated that the normal functional activity of the c-kit gene product is essential for maintenance of normal hematopoeisis, melanogenesis, genetogensis, and growth and differentiation of mast cells and ICC. SLF is produce by human and murine hematopoietic stromal cells, including endothehal cells, fibroblasts, and bone marrow-derived stromal cells. In addition to its importance in normal cellular physiologic activities, c-kit plays a role in the biological aspects of certain human cancers, including germ cell tumors, mast cell tumors, gastrointestinal stromal tumors (GIST), small-cell lung cancer, melanoma, breast cancer, acute myelogenous leukemia (AML), and neuroblastoma. Proliferation of tumor cell growth mediated by c-kit can occur by a specific mutation of the c-kit polypeptide that results in ligand independent activation or by autocrine stimulation of the receptor. In the former case, mutations that cause constitutive activation of c-kit kinase activity in the absence of SCF binding are implicated in malignant human cancers, including gastrointestinal stromal tumors, germ cell tumors, mast cell tumors, and myeloid leukemia's and in mastocytosis. The activity of the c-kit receptor protein tyrosine kinase is regulated in normal cells, and as discussed the deregulated c-kit kinase activity is implicated in the pathogenesis of human cancers. In some types of tumors, inhibition of c-kit activity reduces cellular proliferation, suggesting a role for use of pharmacologic inhibitors of c-kit in the treatment of c-kit dependent malignancies. In one embodiment, compositions and methods provided herein are effective to modulate the activity of c-kit. hi other embodiments, compositions and methods provided herein are effective to selectively modulate the activity of c-kit. Bcr-Abl c-Abl is a nonreceptor tyrosine kinase that contributes to several leukogenic fusion proteins, including the deregulated tyrosine kinase, Bcr-Abl. Chronic myeloid leukemia (CML) is a clonal disease involving the pluripotent hematopoietic stem cell compartment and is associated with the Philadelphia chromosome [Nowell P. C. and Hungerford D. A. , Science 132,1497 (I960)], a reciprocal translocation between chromosomes 9 and 22 ([(9:22) (q34; ql 1)]) [Rowley J. D., Nature 243,290-293 (1973)]. The translocation links the c-Abl tyrosine kinase oncogene on chromosome 9 to the 5, half of the bcr (breakpoint cluster region) gene on chromosome 22 and creates the fusion gene bcr/abl. The fusion gene produces a chimeric 8.5 kB transcript that codes for a 210-kD fusion protein (p210bcr_a l ), and this gene product is an activated protein tyrosine kinase. Thus, the Abelson tyrosine kinase is improperly activated by accidental fusion of the bcr gene with the gene encoding the intracellular non-receptor tyrosine kinase, c-Abl. The Bcr domain interferes with the intramolecular Abl inhibitory loop and unveils a constitutive kinase activity that is absent in the normal Abl protein. Bcr-Abl tyrosine kinase is a potent inhibitor of apoptosis, and it is well accepted that the oncoprotein expresses a constitutive tyrosine kinase activity that is necessary for its cellular transforming activity. Constitutive activity of the fusion tyrosine kinase Bcr-Abl has been established as the characteristic molecular abnormality present in virtually all cases of chronic myeloid leukemia (CML) and up to 20 percent of adult acute lymphoblastic leukemia (ALL) [Faderl S. et al., N Engl J Med 341, 164-172 (1999); Sawyers C. L., N Engl J Med 340,1330-1340 (1999) ]. Mutations present in the kinase domain of the Bcr-Abl gene of patients suffering from CML or Ph+ ALL account for the biological resistance of these patients towards STI571 treatment in that said mutations lead to resistance of the Bcr- Abl tyrosine kinase towards inhibition by STI571. Novel therapies for CML need to address this emerging problem of clinical resistance to STI571 (Gleevec). Because tumor progression in patients receiving STI571 seem to be mediated by amplification of or mutation in the Bcr-Abl gene that causes the tyrosine kinase to be less efficiently inhibited by the drug, newer tyrosine kinase inhibitors may be susceptible to the same mechanisms of resistance. None the less, these findings are extremely valuable in the development of new compounds or combinations of compounds which are capable to overcome resistance towards treatment with STI571. Furthermore, in view of the large number of protein kinase inhibitors and the multitude of proliferative and other PK-related diseases, there is an ever-existing need to provide novel classes of compounds that are useful as PK inhibitors and thus in the treatment of these PTK related diseases. In one embodiment, compositions and methods provided herein are effective to modulate the activity of Bcr-Abl. In other embodiments, compositions and methods provided herein are effective to selectively modulate the activity of Bcr-Abl. In a further embodiment, compositions of Formula G, e.g., compounds described in Examples M and O, inhibit the protein tyrosine kinase associated with mutated bcr-abl, which gives rise to observed clinical resistance towards treatment with STI571. PDGFR Platelet-Derived Growth factor Receptors (PDGFR' s) are receptor tyrosine kinases that regulate proliferative and chemotatic responses. PDGFR's have two forms- PDGFR-α (CD140a) and PDGFR-β (CD140b). PDGFRs are normally found in connective tissue and glia but are lacking in most epithelia, and PDGF expression has been shown in a number of different solid tumors, from glioblastomas to prostate carcinomas. For instance, PDGFR kinases are involved in various cancers such as T- cell lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), melanoma, glioblastoma and others (see Bellamy W. T. et al. , Cancer Res. 1999,59, 728-733). In these various tumor types, the biological role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and angio genesis. Furthermore, PDGF has been implicated in the pathogenesis of several nonmahgnant proliferation diseases, including atherosclerosis, restenosis following vascular angioplasty and fibroproliferative disorders such as obliterative bronchiolitis. Therefore, inhibiting the PDGFR kinase activity with small molecules may interfere with tumor growth and angiogenesis. The binding of PDGFR to its receptor activates the intracellular tyrosine kinase, resulting in the autophorylation of the receptor as well as other intracellular substrates such as Src, GTPase Activating Protein (GAP), and phosphatidylinositol-3-phosphate. Upon autophorylation the PDGFR also forms complexes with other signaling moieties including phospholipase C-γ (PLC-γ), phosphatidylinositol-3-kinase (PI3K), and raf-1. It appears to be involved in communication between endothehal cells and pericytes, a communication that is essential for normal blood vessel development. It has been found previously that the disruption of the PDGFR-β in mice oblates neovascular pericytes that from part of the capillary wall. See Lindahl, P., et al., Science (1997) 227:242-245; Hellsxrom, M., et al, Development (1999) 126:3047-3055. A recent study by Bergers, G., et al., J. Clin. Invest. (2003) 111:1287-1295 has suggested that inhibition of PDGFR kinase activity by certain compounds such as SU6668 or ST1571/Gleevec inhibits tumor growth and that these compounds combined with VEGFR inhibitor SU5416 were very effective in reducing tumor growth. Further, inhibition of PDGFR-β by Gleevec enhanced tumor chemotherapeutic efficacy in mice.
Pietras, K., et al, Cancer Res. (2002) 62:5476-5484. A review of PDGFR receptors as cancer drug targets by Pietras, K., et al, appears in Cancer Cell. (2003) 3:439-443. Inhibition of this kinase activity is also effective where abnormal forms of PDGFR, such as the TEL/PDGFR-β fusion protein associated with chronic myelomonocytic leukemia (CMML) is produced. See also, Grisolano, J. L., et al, Proc. Natl. Acad. Sci. USA.
(2003) 100:9506-9511. Inhibitors of PDGFR-β frequently also inhibit additional kinases involved in tumor growth such as BCR-ABL, TEL-ABL, and PDGFR-α. See, Carroll, M., et al, Blood (1997) 90:4947-4952 and Cools, J., et al, Cancer Cell (2003) 3:450-469. One class of established inhibitors of PDGFR kinase activity includes quinazoline derivatives which comprise piperazine substitutions. Such compounds are disclosed in Yu, J-C, et al, J. Pharmacol. Exp. Ther. (2001) 298:1172-1178; Pandey, A., et al, J. Med. Chem. (2002) 45:3772-3793 Matsuno, K., et al, J. Med. Chem. (2002) 45: 4413-4523 and Matsuno, K., et al, ibid., 3057-3066. Still another class is represented by 2-phenyl pyrimidines as disclosed by Buchdunger, E., et al, Proc. Natl. Acad. Sci. USA. (1995) 92:2558-2562. However, there remains a need for additional compounds that are effective in inhibiting PDGFR kinase activity. Given the complexities of signal transduction with the redundancy and crosstalk between various pathways, the identification of specific PDGFR tyrosine kinase inhibitors permits accurate targeting with limited or no unwanted inhibition of the pathways, thus reducing the toxicity of such inhibitory compounds, hi one embodiment, compositions and methods provided herein are effective to modulate the activity of PDGFR. In other embodiments, compositions and methods provided herein are effective to selectively modulate the activity of PDGFR.
FLT-3 FLT3 kinase is a tyrosine kinase receptor involved in the regulation and stimulation of cellular proliferation. See e.g., Gilliland et al., Blood 100:1532-42 (2002). The FLT3 kinase is a member of the class III receptor tyrosine kinase (RTKIII) receptor family and belongs to the same subfamily of tyrosine kinases as c-kit, c-fins, and the platelet-derived growth factor and β receptors. See e.g., Lyman et al., FLT3 Ligand in THE CYTOKINE HANDBOOK 989 (Thomson et al, eds. 4th Ed.) (2003). The FLT3 kinase has five immunoglobulin-like domains in its extracellular region as well as an insert region of 75- 100 amino acids in the middle of its cytoplasmic domain. FLT3 kinase is activated upon the binding of the FLT3 ligand, which causes receptor dimerization. Dimerization of the FLT3 kinase by FLT3 ligand activates the intracellular kinase activity as well as a cascade of downstream substrates including Stat5, Ras, phosphatidylinositol-3-kinase (PI3K), PLCγ, Erk2, Akt, MAPK, SHC, SHP2, and SHIP. See e.g., Rosnet et al, Acta Haematol. 95:218 (1996); Hayakawa et al., Oncogene 19:624 (2000); Mizuki et al., Blood 96:3907 (2000); and Gilliand et al., Curr. Opin. Hematol. 9: 274-81 (2002). Both membrane-bound and soluble FLT3 ligand bind, dimerize, and subsequently activate the FLT3 kinase. In normal cells, immature hematopoietic cells, typically CD34+ cells, placenta, gonads, and brain express FLT3 kinase. See, e.g., Rosnet, et al., Blood 82:1110-19 (1993); Small et al., Proc. Natl. Acad. Sci. U.S.A. 91:459-63 (1994); and Rosnet et al., Leukemia 10:238-48 (1996). However, efficient stimulation of proliferation via FLT3 kinase typically requires other hematopoietic growth factors or interleukins. FLT3 kinase also plays a critical role in immune function through its regulation of dendritic cell proliferation and differentiation. See e.g., McKenna et al., Blood 95:3489-97 (2000). Numerous hematologic malignancies express FLT3 kinase, the most prominent of which is AML. See e.g., Yokota et al., Leukemia 11:1605-09 (1997). Other FLT3 expressing malignancies include B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias. See e.g., Rasko et al., Leukemia 9:2058-66 (1995). FLT3 kinase mutations associated with hematologic malignancies are activating mutations, hi other words, the FLT3 kinase is constitutively activated without the need for binding and dimerization by FLT3 ligand, and therefore stimulates the cell to grow continuously. Several studies have identified inhibitors of FLT3 kinase activity that also inhibit the kinase activity of related receptors, e.g., VEGF receptor (VEGFR), PDGF receptor (PDGFR), and kit receptor kinases. See e.g., Mendel et al, Clin. Cancer Res. 9:327-37 (2003); O'Farrell et al, Blood l /:3597-605 (2003); and Sun et al., J. Med. Chem.
46:1116-19 (2003). Such compounds effectively inhibit FLT3 kinase-mediated phosphorylation, cytokine production, cellular proliferation, resulting in the induction of apoptosis. See e.g., Spiekermann et al., Blood 101:1494-1504 (2003). Moreover, such compounds have potent antitumor activity in vitro and in vivo. In some embodiments, the kinase is a class III receptor tyrosine kinase (RTKIII). In other embodiments, the kinase is a tyrosine kinase receptor intimately involved in the regulation and stimulation of cellular proliferation. In still other embodiments, the kinase is a fins-like tyrosine kinase 3 receptor (FLT-3 kinase). hi this context, inhibition and reduction of the activity of FLT-3 kinase refers to a lower level of measured activity relative to a control experiment in which the protein, cell, or subject is not treated with the test compound, whereas an increase in the activity of FLT-3 kinase refers to a higher level of measured activity relative to a control experiment. In particular embodiments, the reduction or increase is at least 10%. One of skill in the art will appreciate that reduction or increase in the activity of FLT-3 kinase of at least 20%, 50%, 75%, 90% or 100% or any integer between 10% and 100% may be preferred for particular applications. Compounds provided herein are useful in treating conditions characterized by inappropriate FLT3 activity such as proliferative disorders. FLT3 activity includes, but is not limited to, enhanced FLT3 activity resulting from increased or de novo expression of FLT3 in cells, increased FLT3 expression or activity, and FLT3 mutations resulting in constitutive activation. The existence of inappropriate or abnormal FLT3 ligand and FLT3 levels or activity can be determined using well known methods in the art. For example, abnormally high FLT3 levels can be determined using commercially available ELISA kits. FLT3 levels can be determined using flow cytometric analysis, immunohistochernical analysis, and in situ hybridization techniques. An inappropriate activation of the FLT3 can be determined by an increase in one or more of the activities occurring subsequent to FLT3 binding: (1) phosphorylation or autophosphorylation of FLT3; (2) phosphorylation of a FLT3 substrate, e.g., Stat5, Ras; (3) activation of a related complex, e.g., PI3K; (4) activation of an adaptor molecule; and (5) cellular proliferation. These activities are readily measured by well known methods in the art. Formulations The compounds described herein can be used to prepare a medicament, such as by fonnulation into pharmaceutical compositions for administration to a subject using techniques generally known in the art. A summary of such pharmaceutical compositions may be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. The compounds of the invention can be used singly or as components of mixtures. Preferred forms of the compounds are those for systemic administration as well as those for topical or transdermal administration. Formulations designed for timed release are also within the scope of the invention. Formulation in unit dosage form is also preferred for the practice of the invention. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packeted tablets or capsules, and powders in vials or ampoules. The compounds described herein may be labeled isotopically (e.g. with a radioisotope) or by any other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compositions may be in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. Suitable excipients or carriers are, for example, water, saline, dextrose, glycerol, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like. Of course, these compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth. Methods for the preparation of compositions comprising the compounds described herein include formulating the derivatives with one or more inert, pharmaceutically acceptable carriers to form either a solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. A carrier of the invention can be one or more substances which also serve to act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrating agent. A carrier can also be an encapsulating material. In powder forms of the invention' s compositions, the carrier is preferably a finely divided solid in powder form which is interdispersed as a mixture with a finely divided powder from of one or more compound. In tablet forms of the compositions, one or more compounds is intermixed with a carrier with appropriate binding properties in suitable proportions followed by compaction into the shape and size desired. Powder and tablet form compositions preferably contain between about 5 to about 70% by weight of one or more compound. Carriers that may be used in the practice of the invention include, but are not limited to, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low- melting wax, cocoa butter, and the like. The compounds of the invention may also be encapsulated or microencapsulated by an encapsulating material, which may thus serve as a carrier, to provide a capsule in which the derivatives, with or without other carriers, is surrounded by the encapsulating material. In an analogous manner, cachets comprising one or more compounds are also provided by the instant invention. Tablet, powder, capsule, and cachet forms of the invention can be formulated as single or unit dosage forms suitable for administration, optionally conducted orally. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted. One or more compounds are then dispersed into the melted material by, as a non- limiting example, stirring. The non-solid mixture is then placed into molds as desired and allowed to cool and solidify. Non-limiting compositions in liquid form include solutions suitable for oral or parenteral administration, as well as suspensions and emulsions suitable for oral administration. Sterile aqueous based solutions of one or more compounds, optionally in the presence of an agent to increase solubility of the derivative(s), are also provided. Non-limiting examples of sterile solutions include those comprising water, ethanol, and/or propylene glycol in forms suitable for parenteral administration. A sterile solution of the invention may be prepared by dissolving one or more compounds in a desired solvent followed by sterilization, such as by filtration through a sterilizing membrane filter as a non-limiting example. In another embodiment, one or more compounds are dissolved into a previously sterilized solvent under sterile conditions. A water based solution suitable for oral administration can be prepared by dissolving one or more compounds in water and adding suitable flavoring agents, coloring agents, stabilizers, and thickening agents as desired. Water based suspensions for oral use can be made by dispersing one or more compounds in water together with a viscous material such as, but not limited to, natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and other suspending agents known to the pharmaceutical field. In therapeutic use, the compounds of the invention are administered to a subject at dosage levels of from about 0.5 mg/kg to about 8.0 mg/kg of body weight per day. For example, a human subject of approximately 70 kg, this is a dosage of from 35 mg to 560 mg per day. Such dosages, however, may be altered depending on a number of variables, not limited to the activity of the compound used, the condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the condition being treated, and the judgment of the practitioner. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon.
Methods of Use By modulating kinase activity, the compounds disclosed herein can be used to treat a variety of diseases. Suitable conditions characterized by undesirable protein-kinase activity can be treated by the compounds presented herein. As used herein, the term "condition" refers to a disease, disorder, or related symptom where inappropriate kinase activity is present. In some embodiments, these conditions are characterized by aggressive neovasculaturization including tumors, especially acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs). In some embodiments, a FLT3 modulating compounds may be used to treat tumors. The ability of compounds that inhibit FLT3 kinase activity to treat tumors has been established. Compounds having this property include SU5416 (Sugen), PKC412 (Novartis), GTP-14564 and CT53518 (Millennium). See e.g., Giles et al., Blood
102:795-801 (2003); Weisberg et al, Cancer Cell 1:433-43 (2002); Murata et al., J. Biol. Chem. 278:32892-98 (2003); and Kelly et al., Cancer Cell 1:421-32 (2002). Compounds presented herein are useful in the treatment of a variety of biologically aberrant conditions or disorders related to tyrosine kinase signal transduction. Such disorders pertain to abnormal cell proliferation, differentiation, and/or metabolism.
Abnormal cell proliferation may result in a wide array of diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis). In various embodiments, compounds presented herein regulate, modulate, and/or inhibit disorders associated with abnormal cell proliferation by affecting the enzymatic activity of one or more tyrosine kinases and interfering with the signal transduced by said kinase. More particularly, the present invention is directed to compounds which regulate, modulate said kinase mediated signal transduction pathways as a therapeutic approach to cure leukemia and many kinds of solid tumors, including but not limited to carcinoma, sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers. In other embodiments, compounds herein are useful in the treatment of cell proliferative disorders including cancers, blood vessel proliferative disorders, fibrotic disorders, and mesangial cell proliferative disorders. Blood vessel proliferation disorders refer to angiogenic and vasculogenic disorders generally resulting in abnormal proliferation of blood vessels. The formation and spreading of blood vessels, or vasculogenesis and angiogenesis, respectively, play important roles in a variety of physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration. They also play a pivotal role in cancer development. Other examples of blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and ocular diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness. Conversely, disorders related to the shrinkage, contraction or closing of blood vessels, such as restenosis, are also implicated. Fibrotic disorders refer to the abnormal formation of extracellular matrix. Examples of fibrotic disorders mclude hepatic cirrhosis and mesangial cell proliferative disorders. Hepatic cinhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. Hepatic cirrhosis can cause diseases such as cinhosis of the liver. An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis. Other fibrotic disorders implicated include atherosclerosis (see, below). Mesangial cell proliferative disorders refer to disorders brought about by abnormal proliferation of mesangial cells. Mesangial proliferative disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies. The cell proliferative disorders which are indications of the present invention are not necessarily independent. For example, fibrotic disorders may be related to, or overlap, with blood vessel proliferative disorders. For example, atherosclerosis results, in part, in the abnormal formation of fibrous tissue within blood vessels. Compounds of the invention can be administered to a subject upon determination of the subject as having a disease or unwanted condition that would benefit by treatment with said derivative. The determination can be made by medical or clinical personnel as part of a diagnosis of a disease or condition in a subject. Non-limiting examples include determination of a risk of acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs). The methods of the invention can comprise the administration of an effective amount of one or more compounds as disclosed herein, optionally in combination with one or more other active agents for the treatment of a disease or unwanted condition as disclosed herein. The subject is preferably human, and repeated administration over time is within the scope of the present invention. The present invention thus also provides compounds described above and their salts or solvates and pharmaceutically acceptable salts or solvates thereof for use in the prevention or treatment of disorders mediated by abenant protein tyrosine kinase activity such as human malignancies and the other disorders mentioned above. The compounds of the present invention are especially useful for the treatment of disorders caused by abenant kinase activity such as breast, ovarian, gastric, pancreatic, non-small cell lung, bladder, head and neck cancers, and psoriasis. The cancers include hematologic cancers, for example, acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs). A further aspect of the invention provides a method of treatment of a human or animal subject suffering from a disorder mediated by abenant protein tyrosine kinase activity, including susceptible malignancies, which comprises admimstering to the subject an effective amount of a compound described above or a pharmaceutically acceptable salt or solvate thereof. A further aspect of the present invention provides the use of a compound described above, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of cancer and malignant tumors. The cancer can be stomach, gastric, bone, ovary, colon, lung, brain, larynx, lymphatic system, gemtourinary tract, ovarian, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, leukemia, acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T- cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs), glioma, colorectal cancer, genitourinary cancer gastrointestinal cancer, or pancreatic cancer. In accordance with the present invention, compounds provided herein are useful for preventing and treating conditions associated with ischemic cell death, such as myocardial infarction, stroke, glaucoma, and other neurodegenerative conditions. Various neurodegenerative conditions which may involve apoptotic cell death, include, but are not limited to, Alzheimer's Disease, ALS and motor neuron degeneration, Parkinson's disease, peripheral neuropathies, Down's Syndrome, age related macular degeneration (ARMD), traumatic brain injury, spinal cord injury, Huntington's Disease, spinal muscular atrophy, and HIV encephalitis. The compounds described in detail above can be used in methods and compositions for imparting neuroprotection and for treating neurodegenerative diseases. The compounds described herein, can be used in a pharmaceutical composition for the prevention and/or the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), common cold, dysmenonhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recunent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including types I and II diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders, and septic shock, arthritis, fever, common cold, pain and cancer in a mammal, preferably a human, cat, livestock or a dog, comprising an amount of a compound described herein or a phannaceutically acceptable salt thereof effective in such prevention and/or treatment optionally with a pharmaceutically acceptable carrier. A further aspect of the present invention provides the use of a compound described above, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of psoriasis. As one of skill in the art will recognize, the compounds can be administered before, during or after the occurrence of a condition or a disease, and the timing of administering the composition containing a compound can vary. Thus, for example, the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions and diseases in order to prevent the occunence of the disorder. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, preferably within the first 48 hours of the onset of the symptoms, more preferably within the first 6 hours of the onset of the symptoms, and most preferably within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 min. to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or a combination thereof. A compound is preferably administered as soon as is practicable after the onset of a condition or a disease is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. As one of skill in the art will recognize, the length of treatment can vary for each subject, and the length can be determined using the known criteria. For example, the compound or a formulation containing the compound can be administered for at least 2 weeks, preferably about 1 month to about 5 years, and more preferably from about 1 month to about 3 years. Kits/Articles of Manufacture For use in the therapeutic applications described herein, kits and articles of manufacture are also within the scope of the invention. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method of the invention. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. For example, the container(s) can comprise one or more compounds of the invention, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods of the present invention. A kit of the invention will typically may comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound of the invention. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein. The terms "kit" and "article of manufacture" may be used as synonyms. EXAMPLES The present invention is further illustrated by the following examples, which should not be construed as limiting in any way. The experimental procedures to generate the data shown are discussed in more detail below. For all fonnulations herein, multiple doses may be proportionally compounded as is known in the art. The invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Thus, it will be appreciated by those of skill in the art that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, one of skill in the art will also appreciate that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 5th ed. (2001). Example A: Synthesis of Isoxazole- Amides Compounds Al through A240 are synthesized by methods known in the art or described herein. The structures are shown below in Table A: Table A
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Example B: Exemplary Synthesis of Isoxazole- Amides
Figure imgf000169_0002
3-fert-Butyl-isoxazol-5-ylarmne
Figure imgf000169_0003
Figure imgf000169_0004
In a 40mL vial, lmL of thionyl chloride was added to 0.2 mmol para-substituted phenylacetic acid. The vial was capped and stirred at 80°C for approximately three hours. The completion of the reaction was checked by TLC. The excess thionyl chloride was removed in vacuo. The residue was dissolved in dichloromethane and added to a mixture of 3-tert-butyl-isoxazol-5-ylamine (0.2 mmol) and DIEA (0.2 mmol). The reaction was stirred overnight at 45°C. The solvent was removed under vacuum and the product was purified by HPLC.
Synthesis of Compound Bl: N-(3-tert-butylisoxazol-5-yl)-2-(4-(benzyloxy)phenyl)acetamide
Figure imgf000170_0001
(4-Benzyloxy-phenyl)-acetic acid (50mg, 0.2 mmol, leq) was stnred with lmL of thionyl chloride at 80°C for approximately three hours. The completion of the reaction was checked by TLC. Excess thionyl chloride was removed in vacuo, the residue was dissolved in dichloromethane and added to a mixture of 3-tert-butyl-isoxazol-5-ylamine (28mg, 0.2 mmol, leq) and DLEA (35μL, 0.2 mmol, leq). The reaction was stkred overnight at 45°C. The solvent was removed and the product purified by HPLC. Yield: 42mg (57%), LC/MS [MH+] 365. Compounds B2 through B16 were synthesized in a manner analogous to Compound Bl using similar starting materials and reagents. The structures are shown below in Table B:
Table B
Figure imgf000171_0001
Figure imgf000172_0001
Example C: Synthesis of thiazole-amides Synthesis of Compound Cl: 2-(4-(benzyloxy)phenyl)-N-(5-methylthiazol-2-yl)acetamide
Figure imgf000172_0002
Compound Cl was prepared in strict analogy to compound Bl using 2-amino-5- methylthiazole as starting material instead of 3-tert-butyl-isoxazol-5-ylamine. Compounds C2 through C6 were synthesized in a manner analogous to Compound Cl using similar starting materials and reagents. The structures are shown below in Table C: Table C
Figure imgf000173_0002
Example E: Synthesis of Di-Phenyl Ureas Synthesis of Compound El: 2-(4-Fluoro-phenyl)-N-(5-methyl-2-phenyl-2H-pyrazol- 3-yl)-acetamide
Figure imgf000173_0001
Compound El was prepared in strict analogy to compound Bl using 5-methyl-2- phenyl-2H-pyrazol-3-ylamine and 4-fluorophenylacetic acid as starting materials. Compounds E2 through E20 were synthesized in a manner analogous to Compound El using similar starting materials and reagents. The structures are shown below in Table E: Table E
Figure imgf000174_0001
Figure imgf000175_0001
Example F: Synthesis of Isoxazole-Bis-Amides
Figure imgf000176_0001
In a vial thionyl chloride was added to a para-substituted phenylacetic acid. The vial was capped and stined at 80°C for approximately three hours. The completion of the reaction was checked by TLC, and the excess thionyl chloride removed in vacuo. The residue was dissolved in dichloromethane and added to a mixture 5-tert-butyl-isoxazol-3- ylamine and DIE A. The reaction was stined overnight at 45°C. The solvent was removed under vacuum and the product was purified by HPLC.
Figure imgf000176_0002
For the case of R= NO2, reduction to the amine was carried out prior to reaction with an activated carboxylic acid. 1.5 gm of l-(5-tert-butyl-isoxazol-3-yl)-3-(4-nitro-phenyl)- amide was dissolved in 50ml THF and 0.1 g of 10% Pd/C is added. The solution was stirred under hydrogen at 50 psi. for 24 hours then filtered through a Celite pad. The organic solvent was evaporated under vacuum and the resulting residue was triturated with ethyl acetate.
Figure imgf000176_0003
1 equivalent of the carboxylic acid and 1.1 equivalent of CDI were dissolved in dry DMF and stined at 40°C for 2 h, then 1 equivalent of the substituted aniline was added. The reaction mixture was stined at 40°C overnight and the final product was purified by preparative HPLC. R-COOH SOCI2, 50°C, 3h R-COCI
Figure imgf000177_0001
Alternatively, 1 equivalent of the carboxylic acid and 1.1 equivalent of thionyl chloride were heated in a sealed tube at 50 C for 3h. The excess thionyl chloride was evaporated, 1 equivalent of aniline in DMF was added, and the solution stined at room temperature for 8h. The final product was purified by preparative HPLC. Compounds FI through F5 are synthesized in a manner analogous to those shown above using similar starting materials and reagents. The structures are shown below in Table F: Table F
Figure imgf000177_0002
Figure imgf000178_0001
Binding Constant (Kd) Measurements for Small-Molecule- Kinase Interactions
Methods for measuring binding affinities for interactions between small molecules and kinases including FLT3, c-KIT, ABL(T334I) [a.k.a. ABL(T315I)], VEGFR2 (a.k.a. KDR), and EGFR are described in detail in US Application No. 10/873,835, which is incorporated by reference herein in its entirety. The components of the assays mclude human kinases expressed as fusions to T7 bacteriophage particles and immobilized ligands that bind to the ATP site of the kinases. For the assay, phage-displayed kinases and immobilized ATP site ligands are combined with the compound to be tested. If the test compound binds the kinase it competes with the immobilized ligand and prevents binding to the solid support. If the compound does not bind the kinase, phage-displayed proteins are free to bind to the solid support through the interaction between the kinase and the immobilized ligand. The results are read out by quantitating the amount of fusion protein bound to the solid support, which is accomplished by either traditional phage plaque assays or by quantitative PCR (qPCR) using the phage genome as a template. To determine the affinity of the interactions between a test molecule and a kinase, the amount of phage-displayed kinase bound to the solid support is quantitated as a function of test compound concentration. The concentration of test molecule that reduces the number of phage bound to the solid support by 50% is equal to the Kd for the interaction between the kinase and the test molecule. Typically, data are collected for twelve concentrations of test compound and, the resultant binding curve is fit to a non- cooperative binding isotherm to calculate Kd. Described in the exemplary assays below is data from bindmg with varying kinases. Binding values are reported as follows "+" for representative compounds exhibiting a binding dissociation constant (Kd) of 10,000 nM or higher; "++"for representative compounds exhibiting a Kd of 1,000 nM to 10,000 nM; "+++"for representative compounds exhibiting a K of 100 nM to 1,000 nM; and "++-H-"f r representative compounds exhibiting a I of less than 100 nM. The term "ND" represents non- determined values. The Affinity of the Compounds for Abl Compound E7 and B15 were tested against abl using the results are outlined below:
Figure imgf000179_0001
The Affinity of the Compounds for MKNK2 Compound F2 was tested against MKNK2 using the procedure outlined above and showed activity towards the target of less than 50 nM.
The Affinity of the Compounds for PDGFR K values for the interactions between PDGFR-β and candidate small molecule ligands were measured by a phage-display-based competitive binding assay that is described in detail in U.S. Serial No. 10/406,797 filed 2 April 2003 and incorporated herein by reference. Briefly, T7 phage displaying human PDGFR-β were incubated with an affinity matrix coated with known PDGFR-β inhibitor in the presence of various concentrations of the soluble competitor molecules. Soluble competitor molecules that bind PDGFR-β prevent binding of PDGFR-β phage to the affinity matrix, hence, after washing, fewer phage are recovered in the phage eluate in the presence of an effective competitor than in the absence of an effective competitor. The Kd for the interaction between the soluble competitor molecule and PDGFR-β is equal to the concentration of soluble competitor molecule that causes a 50% reduction in the number of phage recovered in the eluate compared to a control sample lacking soluble competitor. Kd values for the interaction between PDGFR-β and several small molecules are shown below.
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Binding Constand (Kd) Measurements for Small-Molecule c-Kit Interactions
Figure imgf000183_0001
The Affinity of the Compounds for FLT3 The ability of FLT3 kinase inhibitors to inhibit cellular proliferation was also examined. MV4:11 was a cell line derived from a patient with acute myelogenous leukemia. It expressed a mutant FLT3 protein that was constitutively active. MV4: 11 cells were grown in the presence of candidate FLT3 inhibitor molecules, resulting in significantly decreased proliferation of the leukemia-derived cells in the presence of compound. Inhibition of FLT3 kinase activity prevented proliferation of these cells, and thus the MV4: 11 cell line can be used a model for cellular activity of small molecule inhibitors of FLT3.
FLT3 assay using MV4, 11 cells MV4.11 cells were grown in an incubator @ 37°C in 5% CO2 in Medium 2 (RPMI, 10%FBS, 4mM glutamine, Perm/Strep). The cells were counted daily and the cell density was kept between le5 and 8e5 cells/ml. Day One: Enough cells were harvested for experiments to be conducted in 50ml conical tubes. The harvested cells were spun at 500g for 5 min at 4°C, the supernatant was then aspirated and the cells were resuspended in the starting volume of 1 x PBS. The cells were again spun at 500g for 5 min at 4°C and the supernatant again aspirated. The cells were then resuspended in medium 3 (DMEM w/ glut, 10% FBS, Penn/Strep) to a density of 4e5 cells/ml and incubated @ 37°C in 5% CO2 O/N. Day Two: The cells were counted and enough medium 3 was added to decrease density to 2e5 cells/ml. 50ul (10,000 cells) was aliquoted into each well of a 96 well optical plate using multichannel pipetman. The compound plate was then set up by aliquoting 3 μl of negative control (DMSO) into column 1 of a 96 well 300ul polypropylene plate, aliquoting 3 μl of positive control (lOmM AB20121) into column 12 of plate, and aliquoting 3 μl of appropriate compounds from serial dilutions into columns 2-11. To each well, 150 μl of Medium 3 was added and 50 μl of compound/medium mixture from compound plate into rows of optical plate in duplicate. The cells were then incubated @ 37°C in 5% CO2 for 3 days. Day Five: MTS was thawed in a H2O bath. 20 μl of MTS was added to each well of optical plate and the cells were incubated @ 37°C in 5% CO for 2 hours. The plate was then placed on a plate shaker for 30 seconds on high speed. Data for some of the compounds is provided below:
Figure imgf000185_0001
Figure imgf000185_0002
Figure imgf000186_0002
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
All references cited herein, including patents, patent applications, and publications, are herby incorporated by reference in their entireties, whether previously specifically incorporated or not. Having now fully described this invention, it will be appreciated by those skilled in the art that the same can be performed within a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While this invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications. This application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth.

Claims

WHAT IS CLAIMED IS:
1. A compound conesponding to Formula (I):
Figure imgf000190_0001
wherein: each Z is independently C, CR , 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 R is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl; each R\ is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or imsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORc, -OC(O)Rc, -NO2, -N(Rc) , -SRc, S(O)jRc where j is 1 or 2, -NRcC(O)Rc, -C(O)N(Rc)2, -C(O)2Rc, or -C(O)Rc; or two adjacent Ri'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; and
K is
Figure imgf000190_0002
where Y is O or S; each R2 is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or imsubstituted alkoxy, -OC(O)R3, -NO2, -N(R3)2, -SR3, -NRcC(O)Rc, -C(O)N(Rc)2, -C(O)2Rc, or -C(O)Rc; each R is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or imsubstituted 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.
The compound of claim 1, conesponding to Formula (IT):
Figure imgf000191_0001
(II).
The compound of claim 2, conesponding to Formula (III):
Figure imgf000191_0002
(HI) wherein:
Figure imgf000191_0003
Z2 is O or S.
The compound of claim 3, conesponding to Formula (IV):
Figure imgf000191_0004
(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 imsubstituted 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 imsubstituted 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 imsubstituted 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.
The compound of claim 4, wherein T conesponds to Formula (V) :
Figure imgf000192_0001
(V) wherein A is a substituted or imsubstituted 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.
The compound of claim 5, conesponding to Formula (VI):
Figure imgf000192_0002
(VI).
7. The compound of claim 6, wherein L is -C(O)NH-
8. The compound of claim 7, wherein B is substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, imidazolylene, or pynolylene.
The compound of claim 8, selected from the group consisting of:
Figure imgf000192_0003
10. The compound of claim 6, wherein L is -NH-.
11. The compound of claim 10, wherein B is substituted or imsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.
12. The compound of claim 11, selected from the group consisting of:
Figure imgf000193_0001
13. The compound of claim 4, conesponding to :
Figure imgf000193_0002
14. The compound of claim 4, conesponding to Formula (VII):
Figure imgf000193_0003
(VII) wherein: each of X1-X5 is independently C, CR, N, NR, S,or O, wherein no more than three of Xi- X5 is a heteroatom and no 2 adjacent ring atoms are O; 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 imsubstituted aryl, substituted or unsubstituted heteroaryl, -OR , -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(O)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.
15. The compound of claim 14, conesponding to Formula (VIII) :
Figure imgf000194_0001
(VIII).
16. The compound of claim 15, wherein L is a covalent bond, -C(O)NH-, -OCH2- or -OCH2CH2-.
17. The compound of claim 15 , wherein
Figure imgf000194_0002
is selected from the group consisting of:
Figure imgf000194_0003
18. The compound of claim 17 selected from the group consisting of:
Figure imgf000194_0004
Figure imgf000195_0001
19. The compound of claim 4, conesponding to Formula (IX):
Figure imgf000195_0002
(IX) wherein:
Figure imgf000195_0003
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 Xi-Xs is N, where each R is independently H, halogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)Rc, -NO2, -N(Rc)2, -SRc, -NRcC(O)Rc, or -C(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 is -NH-; each of Xl5 X2, X4, and X5 is independently CR or N; and X is independently CR6 or N, wherein no more than two of X1-X5 is N, where R$ is selected from the group consisting of H, halogen, substituted or unsubstituted alkyl, substituted alkoxy, -C(O)Rc, -OC(O)Rc, -NO2, - N(Rc)2, and -SRc; where each Rc is independently H, substituted or imsubstituted alkyl, substituted or imsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (c) L is -NH-; each of X\, X3, and X5 is independently CR or N; and each of X2 and X 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, -SRc, 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 imsubstituted aryl, or substituted or unsubstituted heteroaryl; and (d) L is -C(O)NH-; each of Xls X2, X , and X5 is independently CR or N; and X3 is independently CR8 or N, wherein no more than two of Xι-X5 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, and -SRc, 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, conesponding to Formula (X):
Figure imgf000196_0001
(X).
21. The compound of claim 20, wherein 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).
22. The compound of claim 21 , conesponding to Formula (XI) :
Figure imgf000196_0002
(XI).
23. The compound of claim 22, selected from the group consisting of:
Figure imgf000197_0001
Figure imgf000197_0002
24. The compound of claim 20, conesponding to Formula (XII):
Figure imgf000197_0003
(XII).
25. The compound of claim 24, conesponding to :
Figure imgf000197_0004
26. The compound of claim 20, conesponding to Formula (XIII):
Figure imgf000198_0001
27. The compound of claim 26, conesponding to:
Figure imgf000198_0002
28. The compound of claim 20, conesponding to Formula (XIV):
Figure imgf000198_0003
(XIV).
29. The compound of claim 28, conesponding to:
Figure imgf000198_0004
30. The compound of claim 20, conesponding to Formula (XV) :
Figure imgf000198_0005
(XV).
31. The compound of claim 30, conesponding to :
Figure imgf000199_0001
32. The compound of claim 20, conesponding to Formula (XVI):
Figure imgf000199_0002
(XVI).
33. The compound of claim 32, wherein L is a linker selected from the group consisting of -NHC(O)-, -O(Cι-C3 alkyl), -NHC(O)CH2SCH2C(O)NH-, -CHCHCH2O-, -CH2CH2- -NHC(O)-(Cι-C4 alkene), -NHC(O)-(C1-C3 alkyl), and -CH2CH2C(O)NH-.
34. The compound of claim 33, selected from the group consisting of:
Figure imgf000199_0003
Figure imgf000199_0004
Figure imgf000200_0001
35. The compound of claim 2, conesponding to :
Figure imgf000200_0002
36. The compound of claim 4, conesponding to:
Figure imgf000200_0003
37. The compound of claim 4, conesponding to Formula (XVII):
Figure imgf000200_0004
(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 imsubstituted alkylene)- , -N(substituted or unsubstituted alkylene)-, -C(O)-, -NH-, -O-, -S- , -NHC(O)(substituted or imsubstituted alkylene)-, -NHC(0)(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 Xι-X5 is independently C, CR, N-O, or N, wherein no more than two of Xι-X 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 imsubstituted 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(O)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 imsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
38. The compound of claim 4, conesponding to Formula (XVIII) :
Figure imgf000201_0001
(XVIII) wherein:
Figure imgf000201_0002
i .s 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 imsubstituted 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, -NO2, -N(R3)2, -SR3, -C(O)R3, where R is H, -OH, -N(R )2, or substituted or imsubstituted 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 imsubstituted alkylene)-, -O-, -NH-, -C(O)-, -C(O)NH-, and -N(substituted or imsubstituted alkylene)-; L\ is a linker selected from the group consisting of a covalent bond, -O(substituted or unsubstituted C2-C5 alkylene)-, -S-, -(substituted or unsubstituted alkylene)-, -O-, -NH-, -C(O)-, -C(O)NH-, and -N(substituted or imsubstituted 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 imsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene.
39. The compound of claim 38, conesponding to Formula (XIX):
Figure imgf000202_0001
(XIX).
40. The compound of claim 39, wherein Li is a bond; and L is a bond or -C(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:
Figure imgf000203_0001
43. The compound of claim 39, conesponding to Formula (XX):
Figure imgf000203_0002
(XX).
44. The compound of claim 43, wherein Li is a bond, -CH2O-, -N(CH3)- or -O-; and L is -CH2O- or -NHC(O)-.
45. The compound of claim 44, wherein U is substituted or unsubstituted phenyl, C3-C6 cycloalkyl, pyrimidine or pyridine.
46. The compound of claim 45, selected from the group consisting of:
Figure imgf000203_0003
47. The compound of claim 39, conesponding to Formula (XXI):
Figure imgf000204_0001
(XXI).
48. The compound of claim 47, wherein Li is a -NH- or -O-; and L is -NHC(O)-
49. The compound of claim 48, wherein U is substituted or imsubstituted pyrmidyl.
50. The compound of claim 49, selected from the group consisting of:
Figure imgf000204_0002
51. The compound of claim 39, conesponding to :
Figure imgf000204_0003
52. The compound of claim 4, conesponding to Formula (XXII):
Figure imgf000205_0001
(XXII) 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 imsubstituted alkylene)-, -C(O)NH(substituted or imsubstituted 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 imsubstituted alkenylene)-; U is a substituted or imsubstituted 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 conesponding to Formula (IB):
Figure imgf000205_0002
wherein: M is substituted or unsubstituted heteroaryl, or substituted or imsubstituted aryl; N is a substituted or unsubstituted aryl, or substituted or imsubstituted hetroaryl; and
Figure imgf000205_0003
where 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(O)2R2, -C(O)N(R2)2, or -N(R2)C(O)R2, each R2 is independently H, substituted or imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R 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 FLT-3.
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 c-kit.
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 STK-10.
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, conesponding to Formula (IB)
Figure imgf000206_0001
(IB) wherein: M is a substituted or unsubstituted aryl or heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and
K
Figure imgf000206_0002
where Y is O or S; each R2 is independently H, halogen, substituted or imsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, -OC(O)R3, -NO2, -N(R3)2, -SR3, -NR3C(O)R3, -C(O)N(R3)2, -C(O)2R3, or -C(O)R3; each R3 is independently H, substituted or imsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or imsubstituted aryl, or substituted or unsubstituted heteroaryl; and each n is independently 0, 1, 2, 3 or 4; or an active metabolite, or a phannaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.
62. The method of claim 61, wherein said compound conesponds to Formula (I):
Figure imgf000207_0001
(i) wherein: each Z is independently C, CR4, N, NR , 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 imsubstituted 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 imsubstituted aryl, substituted or imsubstituted heteroaryl, -ORc, -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)2Rc, or -C(O)Rc; or two adjacent Ri '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.
63. The compound of claim 62, conesponding to Formula (II):
Figure imgf000207_0002
(II).
64. The compound of claim 63, conesponding to Formula (10):
Figure imgf000208_0001
(III) wherein: Z\ is CR4 or N; and Z2 is O or S.
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Publication number Priority date Publication date Assignee Title
JP2009506125A (en) * 2005-08-29 2009-02-12 ジェラルド・エム・ハウシー Theramutein modulator
EP2070916A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft 2-Arylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070925A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2-substituted tiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070924A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2 hetarylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
JP2009529002A (en) * 2006-03-02 2009-08-13 アストラゼネカ アクチボラグ Quinoline derivatives
WO2010098866A1 (en) 2009-02-27 2010-09-02 Supergen, Inc. Cyclopentathiophene/cyclohexathiophene dna methyltransferase inhibitors
US7834039B2 (en) 2006-12-15 2010-11-16 Abbott Laboratories Oxadiazole compounds
US8034806B2 (en) 2007-11-02 2011-10-11 Vanderbilt University Bicyclic mGluR5 positive allosteric modulators and methods of making and using same
CN102656140A (en) * 2009-10-28 2012-09-05 多姆皮公司 2-aryl-propionamide derivatives useful as bradykinin receptor antagonists and pharmaceutical compositions containing them
US8604069B2 (en) 2011-04-28 2013-12-10 Japan Tobacco Inc. Amide compound and medicinal use thereof
US8853392B2 (en) 2007-06-03 2014-10-07 Vanderbilt University Benzamide mGluR5 positive allosteric modulators and methods of making and using same
US8883819B2 (en) 2011-09-01 2014-11-11 Irm Llc Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
US9073921B2 (en) 2013-03-01 2015-07-07 Novartis Ag Salt forms of bicyclic heterocyclic derivatives
US9296722B2 (en) 2010-05-27 2016-03-29 Ambit Biosciences Corporation Azolyl urea compounds and methods of use thereof
US9382239B2 (en) 2011-11-17 2016-07-05 Dana-Farber Cancer Institute, Inc. Inhibitors of c-Jun-N-terminal kinase (JNK)
US9518064B2 (en) 2012-04-26 2016-12-13 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyridazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US9688695B2 (en) 2012-04-26 2017-06-27 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
JP2017519818A (en) * 2014-06-03 2017-07-20 ジ・アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・ザ・ユニバーシティー・オブ・アリゾナ Benzimidazole analogs and related methods
US9862730B2 (en) 2012-04-26 2018-01-09 Bristol-Myers Squibb Company Imidazothiadiazole derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US9889102B2 (en) 2012-07-19 2018-02-13 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
JP2020517677A (en) * 2017-04-27 2020-06-18 アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ C5-anilinoquinazoline compounds and their use in the treatment of cancer
US11117870B2 (en) 2017-11-01 2021-09-14 Drexel University Compounds, compositions, and methods for treating diseases
US11498903B2 (en) 2017-08-17 2022-11-15 Bristol-Myers Squibb Company 2-(1,1′-biphenyl)-1H-benzodimidazole derivatives and related compounds as apelin and APJ agonists for treating cardiovascular diseases

Families Citing this family (114)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
EP2298311B1 (en) 1999-01-13 2012-05-09 Bayer HealthCare LLC w-Carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors
SE0102764D0 (en) * 2001-08-17 2001-08-17 Astrazeneca Ab Compounds
SI1478358T1 (en) 2002-02-11 2013-09-30 Bayer Healthcare Llc Sorafenib tosylate for the treatment of diseases characterized by abnormal angiogenesis
US20030216396A1 (en) 2002-02-11 2003-11-20 Bayer Corporation Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors
GB0226930D0 (en) 2002-11-19 2002-12-24 Astrazeneca Ab Chemical compounds
JP2007511203A (en) 2003-05-20 2007-05-10 バイエル、ファーマシューテイカルズ、コーポレイション Diarylurea with kinase inhibitory activity
SI1663978T1 (en) 2003-07-23 2008-02-29 Bayer Pharmaceuticals Corp Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
EP1684762A4 (en) 2003-11-13 2009-06-17 Ambit Biosciences Corp Urea derivatives as kinase modulators
EP2228369A1 (en) 2003-12-23 2010-09-15 Astex Therapeutics Ltd. Pyrazole derivatives as protein kinase modulators
KR20070007104A (en) * 2004-02-18 2007-01-12 아스트라제네카 아베 Compounds
EP1718624B1 (en) * 2004-02-18 2009-03-25 AstraZeneca AB Benzamide derivatives and their use as glucokinase activating agents
JP4790704B2 (en) * 2004-04-12 2011-10-12 トレント・ファーマシューティカルズ・リミテッド 2-propen-1-one as an HSP70 inducer
WO2005110994A2 (en) 2004-04-30 2005-11-24 Bayer Pharmaceuticals Corporation Substituted pyrazolyl urea derivatives useful in the treatment of cancer
TW200600086A (en) * 2004-06-05 2006-01-01 Astrazeneca Ab Chemical compound
KR20070085371A (en) 2004-10-16 2007-08-27 아스트라제네카 아베 Process for making phenoxy benzamide compounds
GB0423043D0 (en) * 2004-10-16 2004-11-17 Astrazeneca Ab Compounds
EP1831228A1 (en) * 2004-12-20 2007-09-12 AstraZeneca AB Novel pyrazole derivatives and their use as modulators of nicotinic acetylcholine receptors
CA2592118C (en) 2004-12-23 2015-11-17 Deciphera Pharmaceuticals, Llc Urea derivatives as enzyme modulators
EP1833832A1 (en) * 2004-12-31 2007-09-19 GPC Biotech AG Napthyridine compounds as rock inhibitors
US7771382B2 (en) * 2005-01-19 2010-08-10 Gi Dynamics, Inc. Resistive anti-obesity devices
US8227455B2 (en) * 2005-04-18 2012-07-24 Rigel Pharmaceuticals, Inc. Methods of treating cell proliferative disorders
WO2006125958A1 (en) * 2005-05-24 2006-11-30 Astrazeneca Ab 2-phenyl substituted imidazol [4 , 5b] pyridine/ pyrazine and purine derivatives as glucokinase modulators
TW200714597A (en) * 2005-05-27 2007-04-16 Astrazeneca Ab Chemical compounds
JP2008543919A (en) * 2005-06-21 2008-12-04 アステックス・セラピューティクス・リミテッド Pharmaceutical compounds
JP2008546751A (en) 2005-06-22 2008-12-25 アステックス・セラピューティクス・リミテッド Pharmaceutical composition
US8541461B2 (en) 2005-06-23 2013-09-24 Astex Therapeutics Limited Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
NZ575512A (en) * 2005-07-09 2009-11-27 Astrazeneca Ab Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes
EP2027113A1 (en) * 2005-07-09 2009-02-25 AstraZeneca AB Heteroaryl benzamide derivatives for use as glk activators in the treatment of diabetes
US20110053910A1 (en) * 2005-07-09 2011-03-03 Mckerrecher Darren 2 -heterocyclyloxybenzoyl amino heterocyclyl compounds as modulators of glucokinase for the treatment of type 2 diabetes
JP5072595B2 (en) * 2005-08-05 2012-11-14 中外製薬株式会社 Multikinase inhibitor
US9202182B2 (en) * 2005-08-11 2015-12-01 International Business Machines Corporation Method and system for analyzing business architecture
KR20080075837A (en) * 2005-10-28 2008-08-19 아이알엠 엘엘씨 Compounds and compositions as protein kinase inhibitors
TW200738621A (en) 2005-11-28 2007-10-16 Astrazeneca Ab Chemical process
CN101336244B (en) * 2005-12-08 2011-11-30 雅培制药有限公司 9-membered heterobicyclic compounds as inhibitors of protein kinases
EP1966174A1 (en) * 2005-12-22 2008-09-10 AstraZeneca AB Chemical compounds
JP4610668B2 (en) * 2006-03-17 2011-01-12 アムビト ビオスシエンセス コルポラチオン Imidazolothiazole compounds for treating diseases
PL1999114T3 (en) 2006-03-22 2015-12-31 Hoffmann La Roche Pyrazoles as 11-beta-hsd-1
WO2008005457A2 (en) * 2006-06-30 2008-01-10 Sunesis Pharmaceuticals Pyridinonyl pdk1 inhibitors
FR2903105A1 (en) 2006-07-03 2008-01-04 Sanofi Aventis Sa 2-BENZOYL-IMIDAZOPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2903107B1 (en) 2006-07-03 2008-08-22 Sanofi Aventis Sa IMIDAZOPYRIDINE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
US8188113B2 (en) 2006-09-14 2012-05-29 Deciphera Pharmaceuticals, Inc. Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US7790756B2 (en) * 2006-10-11 2010-09-07 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
TW200825063A (en) * 2006-10-23 2008-06-16 Astrazeneca Ab Chemical compounds
SA07280576B1 (en) * 2006-10-26 2011-06-22 استرازينيكا ايه بي Benzoyl amino heterocyclyl compounds as glucokinase (GLK) activators
WO2008060866A1 (en) * 2006-11-14 2008-05-22 Smithkline Beecham Corporation Novel compounds
CN101595104A (en) 2006-12-21 2009-12-02 阿斯利康(瑞典)有限公司 New crystalline compound as the GLK activator
US7737149B2 (en) * 2006-12-21 2010-06-15 Astrazeneca Ab N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide and salts thereof
UY30892A1 (en) * 2007-02-07 2008-09-02 Smithkline Beckman Corp AKT ACTIVITY INHIBITORS
GB0704932D0 (en) 2007-03-14 2007-04-25 Astex Therapeutics Ltd Pharmaceutical compounds
RU2455994C2 (en) * 2007-04-16 2012-07-20 Хатчисон Медифарма Энтерпрайзис Лимитед Pyrimidine derivatives
US20110189167A1 (en) * 2007-04-20 2011-08-04 Flynn Daniel L Methods and Compositions for the Treatment of Myeloproliferative Diseases and other Proliferative Diseases
EP2146716A4 (en) * 2007-04-20 2010-08-11 Deciphera Pharmaceuticals Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
TWI437988B (en) * 2007-09-19 2014-05-21 Ambit Biosciences Corp Solid forms comprising n-(5-tert-butyl-isoxazol-3-yl)-n'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea, compositions thereof, and uses therewith
FR2925900B1 (en) * 2008-01-02 2011-03-04 Sanofi Aventis DERIVATIVES OF N-PHENYL-IMIDAZO-1,2-α-PYRIDINE-2-CARBOXAMIDES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
CA2972138A1 (en) 2008-03-17 2009-09-24 Ambit Biosciences Corporation Raf kinase modulator compounds and methods of use thereof
US20110118234A1 (en) * 2008-05-05 2011-05-19 Kaustav Biswas Urea Compounds as Gamma Secretase Modulators
BRPI0914233A2 (en) * 2008-06-19 2015-11-03 Astrazeneca Ab compound, use of a compound, methods for producing a gffr inhibitory effect and for producing an anticancer effect in a warm-blooded animal, pharmaceutical composition, and method for treating a disease
JP2011525538A (en) * 2008-06-24 2011-09-22 バレアント プハルマセウトイカルス インターナショナル Benzyloxyanilide derivatives useful as potassium channel modulators
MX2011001333A (en) 2008-08-04 2011-03-15 Astrazeneca Ab Pyrazolo [3,4] pyrimidin-4-yl derivatives and their uses to treat diabetes and obesity.
GB0818033D0 (en) 2008-10-02 2008-11-05 Respivert Ltd Novel compound
MY159230A (en) 2008-10-02 2016-12-30 Respivert Ltd P38 map kinase inhibitors
KR20110099687A (en) * 2008-10-29 2011-09-08 데시페라 파마슈티칼스, 엘엘씨. Cyclopropane amides and analogs exhibiting anti-cancer and anti-proliferative activities
CA2746354A1 (en) 2008-12-11 2010-06-17 Respivert Limited P38 map kinase inhibitors
JP2012516344A (en) * 2009-01-30 2012-07-19 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー Crystalline N-{(1S) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1H-pyrazol-5-yl) -2-thiophenecarboxamide hydrochloride
GB0902434D0 (en) * 2009-02-13 2009-04-01 Astrazeneca Ab Chemical process
GB0902406D0 (en) * 2009-02-13 2009-04-01 Astrazeneca Ab Crystalline polymorphic form
GB0905955D0 (en) 2009-04-06 2009-05-20 Respivert Ltd Novel compounds
WO2010116176A1 (en) * 2009-04-09 2010-10-14 Astrazeneca Ab Pyrazolo [4, 5-e] pyrimidine derivative and its use to treat diabetes and obesity
AR076220A1 (en) 2009-04-09 2011-05-26 Astrazeneca Ab DERIVATIVES OF PIRAZOL [4,5 - E] PYRIMIDINE
AR076753A1 (en) 2009-05-07 2011-07-06 Gruenenthal Chemie DERIVATIVES OF CARBOXAMIDE AND UREA AROMATICS REPLACED AS LIGANDOS OF THE VANILLOID RECEIVER.
WO2011150201A2 (en) * 2010-05-27 2011-12-01 Ambit Biosciences Corporation Azolyl amide compounds and methods of use thereof
NZ604018A (en) 2010-06-07 2015-02-27 Novomedix Llc Furanyl compounds and the use thereof
CN106986856A (en) 2010-09-03 2017-07-28 福马Tm有限责任公司 It is used as 4 { [(ylmethyl of pyridine 3) amino carbonyl] amino } Benzosulfone derivatives of the NAMPT inhibitor for treating diseases such as cancer
CN102731413A (en) * 2011-04-15 2012-10-17 上海医药工业研究院 Urea compound and its preparation method, intermediate and use
HUE030791T2 (en) 2011-05-13 2017-06-28 Array Biopharma Inc Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as trka kinase inhibitors
BR112014011262B1 (en) * 2011-11-09 2022-02-15 Medifron Dbt Inc SUBSTITUTED PYRAZOLIL-BASED CARBOXAMIDES AND UREA DERIVATIVES, THEIR USE, AND PHARMACEUTICAL COMPOSITION
WO2013148365A1 (en) * 2012-03-28 2013-10-03 Neuropore Therapies, Inc. Phenyl-urea and phenyl-carbamate derivatives as inhibitors of protein aggregation
US8461179B1 (en) 2012-06-07 2013-06-11 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
AU2013323206B2 (en) 2012-09-28 2017-07-20 Fred Hutchinson Cancer Center Compounds and methods for preventing, treating and/or protecting against sensory hair cell death
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
DK2922844T3 (en) 2012-11-13 2018-03-05 Array Biopharma Inc N-PYRROLIDINYL, N'-PYRAZOLYL-URINE, THIOURINE, GUANIDINE AND CYANOGUANIDE COMPOUNDS AS TRKA-KINASE INHIBITORS
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
AU2013344886B2 (en) 2012-11-13 2017-06-29 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
WO2014078328A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-bicyclic aryl,n'-pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078331A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078322A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US20140179712A1 (en) 2012-12-21 2014-06-26 Astrazeneca Ab Pharmaceutical formulation of n-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide
EP2970190A1 (en) 2013-03-14 2016-01-20 Respivert Limited Kinase inhibitors
WO2014162121A1 (en) 2013-04-02 2014-10-09 Topivert Pharma Limited Kinase inhibitors based upon n-alkyl pyrazoles
US9822418B2 (en) 2013-04-22 2017-11-21 Icahn School Of Medicine At Mount Sinai Mutations in PDGFRB and NOTCH3 as causes of autosomal dominant infantile myofibromatosis
WO2015175788A1 (en) 2014-05-15 2015-11-19 Array Biopharma Inc. 1-((3s,4r)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1h-pyrazol-5-yl)urea as a trka kinase inhibitor
US10065934B2 (en) * 2014-07-17 2018-09-04 Sunshine Lake Pharma Co., Ltd. Substituted urea derivatives and pharmaceutical uses thereof
UY36391A (en) * 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO1), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
CA2974395C (en) 2015-02-06 2023-08-22 University Of Washington Compounds and methods for preventing or treating sensory hair cell death
RU2721419C2 (en) * 2015-08-28 2020-05-19 СиЭйчДиАй ФАУНДЕЙШН, ИНК. Probing proteins of hentingin protein
WO2018102455A1 (en) 2016-12-01 2018-06-07 Ignyta, Inc. Methods for the treatment of cancer
WO2018217766A1 (en) 2017-05-22 2018-11-29 Whitehead Institute For Biomedical Research Kcc2 expression enhancing compounds and uses thereof
MX2019014436A (en) * 2017-06-01 2020-02-10 Oncostellae S L Pyridoquinazoline derivatives useful as protein kinase inhibitors.
WO2019126613A1 (en) * 2017-12-22 2019-06-27 Board Of Trustees Of Michigan State University Chemical inhibitors of mycobacterium tuberculosis dosrst signaling and persistence
SG11202007287XA (en) 2018-01-31 2020-08-28 Deciphera Pharmaceuticals Llc Combination therapy for the treatment of mastocytosis
KR20240140193A (en) 2018-01-31 2024-09-24 데시페라 파마슈티칼스, 엘엘씨. Combination therapy for the treatment of gastrointestinal stromal tumors
US11952370B2 (en) 2018-06-11 2024-04-09 Northeastern University Selective ligands for modulation of GIRK channels
EP3818044A1 (en) * 2018-07-03 2021-05-12 IFM Due, Inc. Compounds and compositions for treating conditions associated with sting activity
EP3870177A1 (en) * 2018-10-26 2021-09-01 Arrien Pharmaceuticals LLC Pyrazolyl compounds and methods of use thereof
CA3150433A1 (en) 2019-08-12 2021-02-18 Deciphera Pharmaceuticals, Llc Ripretinib for treating gastrointestinal stromal tumors
TW202122082A (en) 2019-08-12 2021-06-16 美商迪賽孚爾製藥有限公司 Methods of treating gastrointestinal stromal tumors
AU2020419197B2 (en) 2019-12-30 2023-08-31 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
KR20220123058A (en) 2019-12-30 2022-09-05 데시페라 파마슈티칼스, 엘엘씨. 1-(4-Bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl ) -3-Phenylurea composition
US11161852B1 (en) 2020-05-08 2021-11-02 Halia Therapeutics, Inc. Inhibitors of NEK7 kinase
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3991071A (en) * 1973-06-21 1976-11-09 The Boots Company Limited Fungicidal compositions containing substituted imidazoles

Family Cites Families (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US556245A (en) * 1896-03-10 Box-fastener
CH579614A5 (en) 1972-08-17 1976-09-15 Ciba Geigy Ag
JPS5031039A (en) 1973-07-27 1975-03-27
US4062861A (en) * 1973-07-27 1977-12-13 Shionogi & Co., Ltd. 3-Isoxazolylurea derivatives
JPS53101372A (en) 1977-02-15 1978-09-04 Kanebo Ltd Preparation of imidazole-4(5)-carboxylic acid
JPS5386033A (en) 1977-10-20 1978-07-29 Shionogi & Co Ltd Herbicides
US5710158A (en) 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5480883A (en) * 1991-05-10 1996-01-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5721237A (en) 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
US5714493A (en) 1991-05-10 1998-02-03 Rhone-Poulenc Rorer Pharmaceuticals, Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US6645969B1 (en) 1991-05-10 2003-11-11 Aventis Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
GB9300059D0 (en) * 1992-01-20 1993-03-03 Zeneca Ltd Quinazoline derivatives
US5506245A (en) * 1992-10-12 1996-04-09 Adir Et Compagnie Thiazolidinedione compounds
US5656643A (en) * 1993-11-08 1997-08-12 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
GB9510757D0 (en) 1994-09-19 1995-07-19 Wellcome Found Therapeuticaly active compounds
TW321649B (en) 1994-11-12 1997-12-01 Zeneca Ltd
US5773459A (en) * 1995-06-07 1998-06-30 Sugen, Inc. Urea- and thiourea-type compounds
ZA986732B (en) 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitiors of tyrosine kinases
KR100622138B1 (en) 1997-12-22 2006-09-13 바이엘 코포레이션 Inhibition of raf kinase using aryl and heteroaryl substituted heterocyclic ureas
KR100571588B1 (en) * 1997-12-22 2006-04-17 바이엘 코포레이션 Inhibition of RAF Kinase with Substituted Heterocyclic Urea
IL136737A0 (en) 1997-12-22 2001-06-14 Bayer Ag Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
MXPA00006233A (en) 1997-12-22 2002-09-18 Bayer Ag INHIBITION OF p38 KINASE ACTIVITY USING SUBSTITUTED HETEROCYCLIC UREAS.
SK14982000A3 (en) * 1998-04-08 2001-05-10 Eli Lilly And Company Methods for inhibiting mrp1
US6303645B1 (en) * 1998-05-22 2001-10-16 Avanir Pharmaceuticals Benzimidazole derivatives as modulators of IgE
US6246702B1 (en) 1998-08-19 2001-06-12 Path 1 Network Technologies, Inc. Methods and apparatus for providing quality-of-service guarantees in computer networks
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
US7928239B2 (en) 1999-01-13 2011-04-19 Bayer Healthcare Llc Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridyl ureas
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
EP1177181B1 (en) * 1999-05-05 2009-01-28 Aventis Pharma Limited Substituted bicyclic compounds
DE60009480T2 (en) * 1999-05-05 2005-09-01 Aventis Pharma Ltd., West Malling UREAES AS MODULATORS OF CELL ADHESION
KR20020032612A (en) 1999-09-21 2002-05-03 다비드 에 질레스 Quinazoline Derivatives And Their Use As Pharmaceuticals
SK3832002A3 (en) 1999-09-21 2002-11-06 Astrazeneca Ab Quinazoline compounds and pharmaceutical compositions containing them
AU2001236698A1 (en) 2000-02-07 2001-08-14 Abbott Gesellschaft Mit Beschrankter Haftung & Company Kommanditgesellschaft 2-benzothiazolyl urea derivatives and their use as protein kinase inhibitors
US6645990B2 (en) * 2000-08-15 2003-11-11 Amgen Inc. Thiazolyl urea compounds and methods of uses
JP3551905B2 (en) 2000-09-01 2004-08-11 オムロン株式会社 Management station, network system, and communication method in network system
US20030028018A1 (en) * 2000-09-11 2003-02-06 Chiron Coporation Quinolinone derivatives
KR100728797B1 (en) * 2000-09-11 2007-06-19 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 Quinolinone derivatives as tyrosine kinase inhibitors
HU230302B1 (en) * 2000-10-20 2015-12-28 Eisai R&D Management Co., Ltd. Nitrogenous aromatic ring compounds and pharmaceutical compositions containing them
US7238813B2 (en) * 2000-11-29 2007-07-03 Smithkline Beecham Corporation Chemical compounds
JP4285996B2 (en) * 2001-02-21 2009-06-24 田辺三菱製薬株式会社 Quinazoline derivatives
US20020135808A1 (en) * 2001-03-22 2002-09-26 Parry Travis J. Method and apparatus for printing video data
PL209822B1 (en) * 2001-04-27 2011-10-31 Kirin Pharma Kk Quinoline derivative having azolyl group and quinazoline derivative
AU2002345574A1 (en) 2001-06-05 2002-12-16 Cetacean Networks, Inc. Real-time network scheduled packet routing system
EP1401831A1 (en) * 2001-07-03 2004-03-31 Chiron Corporation Indazole benzimidazole compounds as tyrosine and serine/threonine kinase inhibitors
AU2002325381A1 (en) 2001-07-31 2003-02-24 Bayer Healthcare Ag Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists
EP1435948A1 (en) 2001-08-06 2004-07-14 Pharmacia Italia S.p.A. Aminoisoxazole derivatives active as kinase inhibitors
CA2810339A1 (en) 2001-08-10 2003-02-20 Novartis Ag Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia
JP2005508904A (en) * 2001-09-11 2005-04-07 スミスクライン ビーチャム コーポレーション Furo- and thienopyrimidine derivatives as angiogenesis inhibitors
EP1612813A3 (en) * 2001-09-11 2009-12-09 JTEKT Corporation Magnetizing device with pole array, and magnetizing method
EP2343366A1 (en) 2001-10-05 2011-07-13 Novartis AG Mutated Abl kinase domains
JP2005508953A (en) 2001-10-10 2005-04-07 スージェン・インコーポレーテッド 3- [4- (Substituted heterocyclyl) -pyrrol-2-ylmethylidene] -2-indolinone derivatives as kinase inhibitors
CN1582150B (en) 2001-10-30 2011-09-07 诺瓦提斯公司 Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity
WO2003039082A1 (en) 2001-10-31 2003-05-08 Siemens Aktiengesellschaft Method for communication of a real-time data exchange in a collision-recognition based communication network, corresponding memory medium and communication network
CA2465068A1 (en) * 2001-11-03 2003-05-15 Astrazeneca Ab Quinazoline derivatives as antitumor agents
PT1487424E (en) 2002-03-15 2007-01-31 Novartis Ag 4-(4-methylpiperazin-1-ylmethyl)-n-(4-methyl-3(4-pyridin-3-yl)pyrimidin-2-yl-amino)phenyl)-benzamide for treating ang ii-mediated diseases
US20030236287A1 (en) * 2002-05-03 2003-12-25 Piotrowski David W. Positive allosteric modulators of the nicotinic acetylcholine receptor
AR037647A1 (en) 2002-05-29 2004-12-01 Novartis Ag USED DIARILUREA DERIVATIVES FOR THE TREATMENT OF DEPENDENT DISEASES OF THE PROTEIN KINase
US7576074B2 (en) 2002-07-15 2009-08-18 Rice Kenneth D Receptor-type kinase modulators and methods of use
WO2004013091A2 (en) 2002-08-01 2004-02-12 Yissum Research Development Company Of The Hebrew University Of Jerusalem 4-anilido substituted quinazolines and use thereof as inhibitors of epidermal growth factor receptor kinases
AU2003255482A1 (en) 2002-10-02 2004-04-23 Merck Patent Gmbh Use of 4 amino-quinazolines as anti cancer agents
AU2003298608A1 (en) 2002-10-29 2004-05-25 Activx Biosciences, Inc. Nucleotide-binding protein-directed probes and methods of their synthesis and use
JO2785B1 (en) 2003-05-27 2014-03-15 شركة جانسين فارماسوتيكا ان. في Quinazoline derivatives
US20060178318A1 (en) 2003-07-03 2006-08-10 Shubha Anand Use of aurora kinase inhibitors for reducing the resistance of cancer cells
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
ES2651730T3 (en) 2003-09-26 2018-01-29 Exelixis, Inc. C-Met modulators and methods of use
WO2005040125A1 (en) 2003-10-06 2005-05-06 Gpc Biotech Ag Quinazoline derivatives for the treatment of herpesviral infections
EP1684762A4 (en) * 2003-11-13 2009-06-17 Ambit Biosciences Corp Urea derivatives as kinase modulators
US7193838B2 (en) * 2003-12-23 2007-03-20 Motorola, Inc. Printed circuit dielectric foil and embedded capacitors
CA2551495A1 (en) * 2004-01-07 2005-07-28 Ambit Biosciences Corporation Conjugated small molecules
WO2005076861A2 (en) 2004-02-04 2005-08-25 University Of Virginia Patent Foundation Compounds that inhibit hiv particle formation
MXPA06012613A (en) * 2004-05-07 2007-01-31 Amgen Inc Protein kinase modulators and method of use.
WO2005115145A2 (en) 2004-05-20 2005-12-08 Wyeth Quinone substituted quinazoline and quinoline kinase inhibitors
US7810168B2 (en) * 2004-12-10 2010-10-12 L-3 Insight Technology Incorporated Method and apparatus for mounting a vision system
US7576090B2 (en) * 2004-12-27 2009-08-18 4Sc Ag Benzazole analogues and uses thereof
CA2592900A1 (en) * 2005-01-03 2006-07-13 Myriad Genetics Inc. Nitrogen containing bicyclic compounds and therapeutical use thereof
EP1833511A4 (en) 2005-01-03 2011-01-19 Myriad Genetics Inc Method of treating brain cancer
EP1746096A1 (en) * 2005-07-15 2007-01-24 4Sc Ag 2-Arylbenzothiazole analogues and uses thereof in the treatment of cancer
JP4157564B2 (en) * 2006-03-09 2008-10-01 東芝サムスン ストレージ・テクノロジー株式会社 Optical disc apparatus and disc discrimination method
AU2007249762A1 (en) 2006-05-15 2007-11-22 Senex Biotechnology, Inc Identification of CDKI pathway inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3991071A (en) * 1973-06-21 1976-11-09 The Boots Company Limited Fungicidal compositions containing substituted imidazoles

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009506125A (en) * 2005-08-29 2009-02-12 ジェラルド・エム・ハウシー Theramutein modulator
JP2009529002A (en) * 2006-03-02 2009-08-13 アストラゼネカ アクチボラグ Quinoline derivatives
US7834039B2 (en) 2006-12-15 2010-11-16 Abbott Laboratories Oxadiazole compounds
US8853392B2 (en) 2007-06-03 2014-10-07 Vanderbilt University Benzamide mGluR5 positive allosteric modulators and methods of making and using same
US8034806B2 (en) 2007-11-02 2011-10-11 Vanderbilt University Bicyclic mGluR5 positive allosteric modulators and methods of making and using same
EP2070924A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2 hetarylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070925A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2-substituted tiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070916A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft 2-Arylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
WO2010098866A1 (en) 2009-02-27 2010-09-02 Supergen, Inc. Cyclopentathiophene/cyclohexathiophene dna methyltransferase inhibitors
CN102656140A (en) * 2009-10-28 2012-09-05 多姆皮公司 2-aryl-propionamide derivatives useful as bradykinin receptor antagonists and pharmaceutical compositions containing them
US9296722B2 (en) 2010-05-27 2016-03-29 Ambit Biosciences Corporation Azolyl urea compounds and methods of use thereof
US8604069B2 (en) 2011-04-28 2013-12-10 Japan Tobacco Inc. Amide compound and medicinal use thereof
US8883819B2 (en) 2011-09-01 2014-11-11 Irm Llc Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
US9751876B2 (en) 2011-09-01 2017-09-05 Novartis Ag Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
US9382239B2 (en) 2011-11-17 2016-07-05 Dana-Farber Cancer Institute, Inc. Inhibitors of c-Jun-N-terminal kinase (JNK)
US10822343B2 (en) 2012-04-26 2020-11-03 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor4 (PAR4) inhibitors for treating platelet aggregation
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US9862730B2 (en) 2012-04-26 2018-01-09 Bristol-Myers Squibb Company Imidazothiadiazole derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
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US10428077B2 (en) 2012-04-26 2019-10-01 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor4 (PAR4) inhibitors for treating platelet aggregation
US9889102B2 (en) 2012-07-19 2018-02-13 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US10314795B2 (en) 2012-07-19 2019-06-11 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US9073921B2 (en) 2013-03-01 2015-07-07 Novartis Ag Salt forms of bicyclic heterocyclic derivatives
JP2017519818A (en) * 2014-06-03 2017-07-20 ジ・アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・ザ・ユニバーシティー・オブ・アリゾナ Benzimidazole analogs and related methods
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