WO2006071940A2 - Enzyme modulators and treatments - Google Patents

Enzyme modulators and treatments Download PDF

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WO2006071940A2
WO2006071940A2 PCT/US2005/047270 US2005047270W WO2006071940A2 WO 2006071940 A2 WO2006071940 A2 WO 2006071940A2 US 2005047270 W US2005047270 W US 2005047270W WO 2006071940 A2 WO2006071940 A2 WO 2006071940A2
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c6alkyl
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WO2006071940A3 (en
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Daniel L. Flynn
Peter A. Petillo
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Deciphera Pharmaceuticals LLC
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Deciphera Pharmaceuticals LLC
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Priority to JP2007548595A priority Critical patent/JP5197016B2/ja
Priority to AU2005321946A priority patent/AU2005321946B2/en
Priority to EP05855777A priority patent/EP1835934A4/en
Priority to CA2592118A priority patent/CA2592118C/en
Publication of WO2006071940A2 publication Critical patent/WO2006071940A2/en
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Publication of WO2006071940A3 publication Critical patent/WO2006071940A3/en
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Definitions

  • the present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of C-AbI, c-Kit, VEGFR, PDGFR, Raf and P38 kinases and disease polymorphs thereof.
  • proliferative diseases include cancer, rheumatoid arthritis, atherosclerosis, and retinopathies.
  • Important examples of kinases which have been shown to cause or contribute to the pathogensis of these diseases include C-AbI kinase and the oncogenic fusion protein BCR-AbI kinase; PDGF receptor kinase; VEGF receptor kinases; MAP kinase p38 ⁇ ; and the RAF kinase family.
  • C-AbI kinase is an important non-receptor tyrosine kinase involved in cell signal transduction. This ubiquitously expressed kinase — upon activation by upstream signaling factors including growth factors, oxidative stress, integrin stimulation, and ionizing radiation- — localizes to the cell plasma membrane, the cell nucleus, and other cellular compartments including the actin cytoskeleton (Van Etten, Trends Cell Biol. (1999) 9: 179). There are two normal isoforms of AbI kinase: AbI-IA and AbI-IB.
  • the N-terminal half of c-Abl kinase is important for autoinhibition of the kinase domain catalytic activity (Pluk et al, Cell (2002) 108: 247). Details of the mechanistic aspects of this autoinhibition have recently been disclosed (Nagar et al, Cell (2003) 112: 859).
  • the N-terminal myristolyl amino acid residue of AbI-IB has been shown to intramolecularly occupy a hydrophobic pocket formed from alpha-helices in the C-lobe of the kinase domain.
  • Such intramolecular binding induces a novel binding area for intramolecular docking of the SH2 domain and the SH3 domain onto the kinase domain, thereby distorting and inhibiting the catalytic activity of the kinase.
  • an intricate intramolecular negative regulation of the kinase activity is brought about by these N-terminal regions of c-Abl kinase.
  • An aberrant dysregulated form of c-Abl is formed from a chromosomal translocation event, referred to as the Philadelphia chromosome (P. C. Nowell et al. Science (1960) 132: 1497; J.D. Rowley, Nature (1973) 243: 290).
  • Bcr-AbI AbI kinase gene
  • BCR breakpoint cluster region
  • CML chronic myeloid leukemia
  • CML is a malignancy of pluripotent hematopoietic stem cells.
  • the p210 form of Bcr-Abl is seen in 95% of patients with CML, and in 20% of patients with acute lymphocytic leukemia.
  • a pl85 form has also been disclosed and has been linked to being causative of up to 10% of patients with acute lymphocytic leukemia .
  • Growth factor receptor kinases contribute to the growth and metastasis of tumors by stimulating the proliferation of endothelial cells, fibroblasts, smooth muscle cells, and matrix proteins. Conditions such as hypoxia can induce tumor cells to secrete growth factors which subsequently result in the growth of new blood vessels to support the tumor.
  • growth factors include platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), which subsequently stimulate secretion of other growth factors including vascular endothelial growth factor (VEGF), fibroblast growth factor, and epidermal growth factor (EGF).
  • PDGF platelet derived growth factor
  • TGF-beta transforming growth factor-beta
  • VEGF vascular endothelial growth factor
  • fibroblast growth factor fibroblast growth factor
  • EGF epidermal growth factor
  • VEGFR2 also known as the kinase insert domain- containing receptor tyrosine kinase or KDR
  • KDR kinase insert domain- containing receptor tyrosine kinase
  • Ras-RAF-MEK-ERK-MAP kinase pathway A major signaling pathway downstream of cell surface growth factor receptor activation is the Ras-RAF-MEK-ERK-MAP kinase pathway (Peyssonnaux, C. et al, Biol. Cell (2001) 93: 53-62, Cancers arise when mutations occur in one or more of the proteins involved in this signaling cascade. Cell proliferation and differentiation become dysregulated and cell survival mechanisms are activated which allow unregulated cancer cells to override protective programmed cell death surveillance. Mutations in the p21-Ras protein have been shown to be a major cause of dysregulation of this signaling pathway, leading to the development of human cancers. P21-Ras mutations have been identified in approximately 30% of human cancers (Bolton et al, Ann. Rep. Med. Chem.
  • RAF kinase isoforms are all activated by Ras, and thus are activated in cancers that result from mutated and upregulated p21-Ras protein activity.
  • mutations have also been found in BRAF kinase which results in activation of the cascade downstream from p21-Ras (Davies, H., et al, Nature
  • a dominant single site mutation at position 599 in the BRAF kinase was shown to be particularly aggressive and linked to approximately 80% of the observed human malignant melanomas. This mutation substitutes the negatively charged amino acid glutamic acid for the normally occurring neutral amino acid valine. This single site mutation is sufficient to render the mutated BRAF kinase constituitively active, resulting in signaling pathway dysregulation and human cancer.
  • small molecule inhibitors of BRAF kinase are a rational approach to the treatment of human malignancy, whether the signaling mutation is at the level of the upstream p21-Ras protein or at the level of BRAF kinase.
  • the MAP kinase p38 ⁇ has recently been identified as an important mechanistic target for the treatment of inflammatory diseases. Inhibition of the MAP kinase p3S-alpha has been demonstrated to result in the suppression the production and release the proinflammatory mediators TNF-alpha, IL-I beta, IL-6, IL-8 and other proinflammatory cytokines (Chen, Z. et al, Chem. Rev. (2001) 101: 2449).
  • p38-alpha kinase has been implicated in the regulation of tissue factor expression in monocytes, suggesting a role for inhibition of p38- alpha kinase in the treatment of thrombotic disorders and atherosclerosis (Chu, A.J., et al, J. Surg. Res. (2001) 101 : 85-90; Eto, M., et al, Circulation (2002) 105: 1756-1759).
  • the p38- alpha kinase has also been shown to be involved in thrombin-induced proinflammatory conditions (V. Marin, et al, Blood, August 1, 2001, 98: 667-673).
  • Enbrel a soluble TNF receptor
  • etanercept a soluble TNF receptor
  • Amgen for the treatment of rheumatoid arthritis
  • Ro 45-2081 a recombinant soluble TNF-alpha receptor chimeric protein
  • Ro 45-2081 a recombinant soluble TNF-alpha receptor chimeric protein, has also shown effectiveness in the treatment of the acute phase of lung injury and in animal models of allergic lung disease (Renzetti, et al, Inflamm Res. (1997) 46: S143).
  • Remicade is a monoclonal TNF-alpha antibody that has shown effectiveness in the treatment of rheumatoid arthritis and Crohn's disease (Bondeson, J. et al, Int. J. Clin. Pracf. (2001) 55: 211).
  • Gleevec is an inhibitor of BCR-AbI kinase (J. Zimmermann et al, WO 99/03854; N. von Bubnoff et al, Cancer Research (2003) 63: 6395; B. J. Druker et al, Nature Medicine (1996) 2: 561; J. Zimmermann et al, Bioorganic and Medicinal Chemistry Letters (1997) 7: 187).
  • Gleevec has been shown to produce clinical remissions in CML patients. However, resistance to the effects of Gleevec have often been encountered (M. E.
  • kinases are regulated by a common activation/deactivation mechanism wherein a specific activation loop sequence of the kinase protein binds into a specific pocket on the same protein which is referred to as the switch control pocket.
  • a specific activation loop sequence of the kinase protein binds into a specific pocket on the same protein which is referred to as the switch control pocket.
  • Such binding occurs when specific amino acid residues of the activation loop are modified for example by phosphorylation, oxidation, or nitrosylation.
  • the binding of the activation loop into the switch pocket results in a conformational change of the protein into its active form (Huse, M. and Kuriyan, J. Cell (109) 275-282.)
  • the present invention describes novel potent and selective inhibitors of CAbI kinase, VEGFR2/KDR kinase, and BRAF kinase.
  • the compounds of this invention inhibit kinase activity in a novel way by binding into the "switch pocket" remote from the ATP-cofactor pocket with or without concomitant binding into the "DFG-in-conformation” pocket.
  • X-ray structures determined from small molecule/BRAF co-crystals have confirmed this novel mode of binding to the kinase by the compounds of this present invention, and illustrate the novel features of this binding mode when compared to inhibitors which anchor or bind into the ATP pocket of BRAF kinase.
  • novel inhibitors of the present invention in some cases also exhibit a preference for inhibiting the oncogenic mutant form of a kinase (V599E- BRAF) and a sparing of normal wild-type kinase that lack the cancer-causing mutation, wherein the oncogenic mutation is a modification of a critical binding amino acid residue of the switch control pocket.
  • V599E- BRAF a kinase
  • An example of this profile has been identified for BRAF, wherein mutation of the valine 599 residue to a glutamic acid residue results in an oncogenic form of BRAF and for which it has been found that compounds of this invention inhibit the oncogenic mutant form of BRAF but not the wild type BRAF.
  • This desirable feature of inhibitor selectivity enables the use of a BRAF inhibitor to treat mammalian cancer caused by mutant V559E BRAF kinase, while sparing the normal wildtype BRAF kinase present in non-cancerous cells.
  • Enhanced safety and selectivity realized from this "wild-type kinase- sparing" provides safer inhibitors that target the cancer-causing forms of BRAF kinase.
  • Figures 1 and 2 further illustrates the novel binding interaction for the compounds of this invention with kinases.
  • the known interactions of kinase inhibitors reported previously are defined as directed to a combination of the ATP binding domain, an adjacent binding area known as the ATP binding domain hinge region, and in some cases a third domain known as the "DFG-in conformation" kinase pocket.
  • Figure 1 Illustration of the kinase binding domains of known kinase inhibitors
  • the binding modality of the compounds of this invention is illustrated in Figure 2.
  • the unique feature is the necessary engagement of another binding domain within the kinase referred to as the switch pocket.
  • Compounds of this invention uniquely and necessarily bind within the switch pocket, and optionally the "DFG-in conformation" domain, and optionally to the ATP binding domain hinge region.
  • This unique binding modality confers upon compounds of this invention a novel mechanism to modulate kinase activity as well as significant advantages over previously described kinase inhibitors in achieving a therapeutically important degree of selectivity for the preferred target over inhibitors which occupy the ATP binding domain.
  • the novel binding modality of the compounds of this invention also avoids mutations within the ATP binding domain which commonly confer resistance to inhibition by compounds which require interaction with the ATP binding domain.
  • Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma.
  • Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.
  • Carbocyclyl refers to monocyclic saturated carbon rings taken from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptanyl;
  • Aryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized ⁇ electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring; preferred aryl rings are taken from phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl;
  • Heteroaryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring; heteroaryl rings are taken from, but not limited to, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolony
  • Heterocyclyl refers to monocyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms; heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, homotropanyl;
  • Poly-aryl refers to two or more monocyclic or fused bicyclic ring systems characterized by delocalized ⁇ electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring wherein the rings contained therein are optionally linked together.
  • Poly-heteroaryl refers to two or more monocyclic or fused bicyclic systems characterized by delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring wherein the rings contained therein are optionally linked together, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heteroaryl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;
  • Poly-heterocyclyl refers to two or more monocyclic or fused bicyclic ring systems containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms wherein the rings contained therein are optionally linked, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heterocyclyl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;
  • Lower alkyl refers to straight or branched chain C1-C6alkyls
  • Substituted in connection with a moiety refers to the fact that a further substituent may be attached to the moiety to any acceptable location on the moiety.
  • salts embraces pharmaceutically acceptable salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutical ly-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared, from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic , ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, (3- hydroxybutyric, galactaric
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group Ha) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine.
  • prodrug refers to derivatives of active compounds which revert in vivo into the active form.
  • a carboxylic acid form of an active drug may be esterified to create a prodrug, and the ester is subsequently converted in vivo to revert to the carboxylic acid form. See Ettmayer et. al, J. Med. Chem, 2004, 47(10), 2393-2404 and Lorenzi et. al, J. Pharm. Exp. Therpeutics, 2005, 883-8900 for reviews.
  • PGDF platelet-derived growth factor
  • PGDFR platelet-derived growth factor receptor
  • VEGF vascular endothelial growth factor
  • VEGFR vascular endothelial growth factor receptor
  • MAP kinase mitogen-activated protein kinase
  • BCR breakpoint cluster region
  • CML chronic myeloid leukemia
  • TGF-beta transforming growth factor beta
  • EGF epidermal growth factor
  • KDR refers to kinase insert domain-containing receptor
  • TNF refers to tumor necrosis factor
  • ATP adenosine triphosphate
  • DFG-in-conformation refers to the tripeptide sequence aspartylphenylalanylglycyl in the kinase protein sequence
  • V599E refers to the mutational replacement of valine 599 of BRAF kinase by glutamic acid
  • FGFR refers to fibroblast growth factor receptor
  • V599E refers to the mutational replacement of valine
  • the invention includes compounds of the formula
  • A2 is selected from the group cons sting of bicyclic fused aryl, bicyclic fused heteroaryl, and bicyclic fused heterocyclyl rings, each A2 moiety presenting a proximal ring bonded with Al and a distal ring attached to the proximal ring, and either the distal ring has a heteroatom in the ring structure thereof and/or the distal ring has Z2 or Z3 substituents;
  • Al is selected from the group consisting of R2' and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2' -substituted monocyclic heterocyclyl moieties;
  • W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
  • X is O, S, or NR3;
  • D comprises a member of the group consisting of Z5- or Z6-substituted mono- and poly-aryl, of Z5- or Z6-substituted mono- and poly-heteroaryl, of Z5- or Z6-substituted mono- and poly-heterocyclyl, of Z5- or Z6-substituted mono- and poly-arylalkyl, of Z5- or Z6- substituted mono- and poly-aryl branched alkyl, of Z5- or Z6-substituted mono- and poly- heteroarylalkyl, of Z5- or Z6-substituted mono- and poly-heteroaryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heterocyclylalkyl, of Z5- or Z6-substituted mono- and poly- heterocyclyl branched alkyl, alkyl, and carbocyclyl moieties;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
  • Z3 contains an alkyl or alkylene moiety
  • such moieties may be further substituted with one or more C1-C6alkyls; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • each Z5 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , - N(R3)-(CH 2 )q-N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O- Alkyl, -N(R3)-(CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each Z6 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N-, -N(R3)COR8, (R4) 2 N-, -R5, -N(R4)COR8, -N(R3)SO 2 R6-, -CON(R3) 2 , -CON(R4) 2 , -COR5, -SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroaryl amino, and heterocyclylamino;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1- C6alkyl, and heterocyclylC1-C6alkyl;
  • each R5 is independently and individually selected from the group consisting of
  • each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • the compounds of formula I above contain D moieties of the formula
  • El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein El is directly linked to the Y group of formula I;
  • E2 is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazo
  • Additional preferred D moieties comprise carbocyclyls and a moiety of the formula
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
  • More preferred D moieties from 1.1.1b comprise the compounds of Formula III wherein the E2 ring is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, be
  • Preferred A2 moieties of Formula I are selected from the group consisting of
  • each Z3 and Z5 may be independently attached to either of the rings making up the foregoing bicyclic structures; each R9 is independently and individually selected from the group consisting of H, F, C1- C6alkyl, branched C4-C7alkyl, carbocyclyl, phenyl, phenyl C1-C6alkyl, heterocyclyl and heterocyclylC 1 -C6alkyl ;
  • each Rl 3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N-CO, (R4) 2 N-CO-C1 -C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1- C6alkoxycarbonylC1-C6alkyl, (R4) 2 N-C2-C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) q , R5- C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N-C2-C6alkylO-(CH 2 ) q , R5-C2-C6alkyl-O-(CH 2 ) q , - (CH
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Rl 3 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R14 is independently and respectively selected from the group consisting of H and C1- C6alkyl
  • V, Vl, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • More preferred A2 moieties are selected from the group consisiting of
  • each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
  • Still more preferred A2 moieties are selected from the group consisting of
  • Al moieties are selected from the group consisting of
  • each R7 is selected from the group consisting of halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy.
  • Preferred Al moieties are selected from the group consisting of
  • Still more preferred Al moieties are selected from the group consisting of wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
  • A2 is selected from the group consisting of
  • each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
  • Al is selected from the group consisting of
  • X is O, S, or NR3;
  • El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein El is directly linked to the Y group of formula I;
  • each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C ⁇ alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
  • R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1- C6alkyl, and heterocyclylC1-C6alkyl; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyal
  • each R5 is independently and individually selected from the group consisting of
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • each R13 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N-CO, (R4) 2 N-CO-C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1- C6alkoxycarbonylC1-C6alkyl, (R4) 2 N-C2-C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) q , R5- C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N-C2-C6alkyl0-(CH 2 ) q , R5-C2-C6alkyl-O-(CH 2 ) q , -(CH 2 )
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R14 is independently and respectively selected from the group consisting of H and C1- C6alkyl;
  • V, Vl, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
  • each Z3 is independently and individually selected from the group consisting of H, C1- C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N-, (R4) 2 N-, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , R8CO-, (R4) 2 N-CO-C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , -SO 2 R3, SOR3, (R4) 2 NSO 2 , -SO 2 R4,
  • Z3 contains an alkyl or alkylene moiety
  • such moieties may be further substituted with one or more C1-C6alkyls; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • Each Z6 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N-, -N(R3)COR8, (R4) 2 N-, -R5, -N(R4)COR8, -N(R3)SO 2 R6-, -CON(R3) 2 , -CON(R4) 2 , -COR5, -SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. C- AbI kinase, BCR-AbI kinase.
  • the kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing.
  • the method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 1.1 and 1.1.6a.
  • the kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e.
  • kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
  • the methods of the invention may also involve the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase, especially C-AbI kinase or BCR-AbI kinase, to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
  • the second compound may interact at a substrate, co-factor or regulatory site on the kinase, with the second site being distinct from the site of interaction of the first compound.
  • the second site may be an ATP co-factor site.
  • the second compounds may be taken from the group consisting of N-(4- memyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylarnino)phenyl)-4-((4-methylpiperazin-1- yl)methyl)benzamide(Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2- hydroxyethyl)piperazin- 1 -yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS- 354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-
  • the methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 1.1 and 1.1.6a. Exemplary conditions include chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier.
  • the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.
  • the invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
  • the compounds are advantageously selected from the groups defined in sections 1.1 and 1.1.6a.
  • A2 is selected from the group cons sting of a Zl -substituted phenyl, Zl -substituted pyridyl, Zl -substituted pyrimidinyl, Zl-substituted thienyl, Zl or Z4' -substituted monocyclic heterocyclyl rings, and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4- oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the Al ring;
  • Al is selected from the group consisting of R2' and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2' -substituted monocyclic heterocyclyl moieties;
  • W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
  • X is O, S, or NR3;
  • cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the Al ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring; wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4' may cyclize to form a C3-C7 heterocyclyl ring;
  • each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
  • each R3' is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1- C6alkyl, and heterocyclic 1-C6alkyl;
  • each R5 is independently and individually selected from the group consisting of and wherein the symbol (##) is the point of attachment to respective R8, RlO, Zl, Z4', Z5, Z6 or A2 ring moieties containing a R5 moiety;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4- C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclic 1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • D comprises a moiety taken from group consisting of moieties of the formula
  • E2 is taken from the group consisting of poly-aryl, poly-heteroaryl, mono- and poly heterocyclyl, and carbocyclyl;
  • El is taken from the group consisting of mono- and poly-aryl, mono- and poly- heteroaryl, mono- and poly heterocyclyl and carbocyclyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alky], or a direct bond wherein either El or E2 is directly linked to the Y group of formula I; and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
  • the compounds of formula I in 1.2 contain D moieties wherein El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
  • E2 is comprises the group consisting of cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, and hetero
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
  • More preferred D moieties of 1.2.1b are wherein E2 is cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpy ⁇ midinyl, t ⁇ azolylpy ⁇ midmyl, oxadiazoylpy ⁇ midinyl, thiadiazoylpy ⁇ midinyl, morphohnylpy ⁇ midinyl, dioxothiomorphohnylpy ⁇ midinyl, thiomorphohnylpy ⁇ midinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadiny
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O-Alkyl, -N(R3)- (CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • More preferred A2 moieties are selected from the group consisting of
  • A2 moieties are selected from the group consisting of
  • the invention includes compounds of the formula
  • A2 is selected from the group cons sting of
  • Al is selected from the group consisting of
  • X is O, S, or NR3;
  • D comprises a member of wherein El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein El is directly linked to the Y group of formula I;
  • cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the Al ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
  • alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
  • the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring; in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
  • R3 moieties are independently and individually taken from the group'consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4' may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4' may cyclize to form a C3-C7 heterocyclyl ring;
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O-Alkyl, -N(R3)- (CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • Each Z6 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N-, -N(R3)COR8, (R4) 2 N-, -R5, -N(R4)COR8, -N(R3)SO 2 R6-, -CON(R3) 2 , -CON(R4) 2 , -COR5, -SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl; each R3' is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1- C6alkyl, and heterocyclylC1-C6alkyl;
  • each R5 is independently and individually selected from the group consisting of
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl; each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4- C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. C- AbI kinase, BCR-AbI kinase.
  • the kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing.
  • the method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 1.2 and 1.2.6a.
  • the kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e.
  • kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
  • the methods of the invention may also involve the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase, especially C-AbI kinase or BCR-AbI kinase, to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
  • the second compound may interact at a substrate, co-factor or regulatory site on the kinase, with the second site being distinct from the site of interaction of the first compound.
  • the second site may be an ATP co-factor site.
  • the second compounds may be taken from the group consisting of N-(4- methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1- yl)methyl)benzamide(Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2- hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS- 354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-
  • the methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 1.2 and 1.2.6a. Exemplary conditions include chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers. 1.2.9 Kinase/Compound Adducts
  • the invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
  • the compounds are advantageously selected from the groups defined in sections 1.2 and 1.2.6a.
  • A2 is selected from the group cons sting of a Z7-substituted phenyl, Z7-substituted pyridyl, Z7-substituted pyrimidinyl, Zl -substituted thienyl, Zl or Z4'-substituted monocyclic heterocyclyl rings and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4- oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the Al ring;
  • Al is selected from the group consisting of R2' and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2' -substituted monocyclic heterocyclyl moieties;
  • W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
  • X is O, S, or NR3;
  • each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl; each R3' is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1- C6alkyl, and heterocyclylC1-C6alkyl;
  • each R5 is independently and individually selected from the group consisting of
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • D comprises a moiety taken from group consisting of
  • ElA is taken from the groups consisting of carbocyclyl, mono- and poly- heterocyclyl and mono- and poly- heteroaryl;
  • ElB is taken from the groups consisting of phenyl and naphthyl
  • E2A is taken from the group consisting of naphthyl, a 5-membered ring heteroaryl, or a fused bicyclic heteroaryl; wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein ElA or ElB or E2A or E2B are directly linked to the Y group of formula I;
  • carbon atoms of -(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
  • X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
  • the compounds of formula I in 1.3 contain D moieties wherein ElA is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
  • E2A is comprises the group consisting of cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl,
  • X2 is selected from the grou consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2A or E2B is directly linked to the Y group of formula I.
  • More preferred D moieties of 1.3.1b are wherein the E2A ring is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazo
  • More preferred A2 moieties are selected from the group consisting of
  • A2 moieties are selected from the grou consisting of
  • the invention includes compounds of the formula
  • A2 is selected from the group consisting of
  • Al is selected from the group consisting of wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
  • X is O, S, or NR3;
  • ElA is taken from the groups consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
  • ElB is taken from the groups consisting of phenyl and naphthyl
  • E2A is taken from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and f fused bicyclic rings selected from the group consisting of indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl
  • E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein El is directly linked to the Y group of formula I;
  • each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
  • X3 may be further substituted by one or more C1-C6alkyl;
  • X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
  • R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1 -C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1 -C6alkyl, heteroarylC 1 - C6alkyl, and heterocyclylC1-C6alkyl;
  • R4 moieties independently and individually taken from the group consisting of C1 -C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
  • each R5 is independently and individually selected from the group consisting of
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4- C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocydylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1 -C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
  • the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring; in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O-AlkyI, -N(R3)- (CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • Each Z6 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N-, -N(R3)COR8, (IM) 2 N-, -R5, -N(R4)COR8, -N(R3)SO 2 R6-, -CON(R3) 2 , -CON(R4) 2 , -COR5, -SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the Al ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
  • alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring; and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. C- AbI kinase, BCR-AbI kinase.
  • the kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing.
  • the method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 1.3 and 1.3.6a.
  • the kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e.
  • kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
  • the methods of the invention may also involve the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase, especially C-AbI kinase or BCR-AbI kinase, to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
  • the second compound may interact at a substrate, co-factor or regulatory site on the kinase, with the second site being distinct from the site of interaction of the first compound.
  • the second site may be an ATP co-factor site.
  • the second compounds may be taken from the group consisting of N-(4- methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1- yl)methyl)benzamide(Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2- hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS- 354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-
  • the methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 1.3 and 1.3.6a. Exemplary conditions include chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier.
  • the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.
  • the invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild- type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
  • the compounds are advantageously selected from the groups defined in sections 1.3 and 1.3.6a.
  • the invention includes compounds of formula I as defined in section 1.1, wherein each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-
  • R19 substituted C3-C8carbocyclyl wherein R19 is H, or C1-C6alkyl, C1- C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents,
  • Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 )p, (R4) 2 N-C2-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) p N(R4)C(O)R8 , aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl' may cyclize to form a C3-C7 heterocyclyl ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
  • each Z3 is independently and individually selected from the group consisting of H, C1- C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N-, (R4) 2 N-, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , R8CO-, (R4) 2 N-CO-C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , -SO 2 R3, SOR3, (R4) 2 NSO 2 , -SO 2 R4,
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • More preferred compounds of Formula I as defined above in section 2.1.1b contain D moieties as defined in section 1.1.1c.
  • each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
  • Still more preferred compounds of Formula I as defined above in section 2.1 have A2 moieties selected from group consisting of
  • each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • A2 is selected from the group consisting of
  • each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
  • Al is selected from the group consisting of
  • X is O, S, or NR3;
  • D comprises a member of 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4- chlorophenyl, 3-chlorophenyl, 3-bromophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4- difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5- trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 4-cyanophenyl, 3-(R8SO 2 )- phenyl, 3-phenoxyphenyl, 4 phenoxyphenyl, wherein El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl,
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein El is directly linked to the Y group of formula I;
  • each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
  • each R5 is independently and individually selected from the group consisting of
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl; each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4- C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • each R13 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N-CO, (R4) 2 N-CO-C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1- C6alkoxycarbonylC1-C6alkyl, (R4) 2 N-C2-C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) q , R5- C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N-C2-C6alkyl0-(CH 2 ) q , R5-C2-C6alkyl-O-(CH 2 ) q , -(CH 2 )
  • each R14 is independently and respectively selected from the group consisting of H and C1- C6alkyl
  • Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) p N(R4)C(O)R8 , aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl' may cyclize to form a C3-C7 heterocyclyl ring;
  • each Z3 is independently and individually selected from the group consisting of H, C1- C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N-, (R4) 2 N-, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , R8CO-, (R4) 2 N-CO-C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , -SO 2 R3, SOR3, (R4) 2 NSO 2 , -SO 2 R4,
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • such moieties may be further substituted with one or more C1-C6alkyls; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O-Alkyl, -N(R3)- (CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • Each Z6 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N-, -N(R3)COR8, (R4) 2 N-, -R5, -N(R4)COR8, -N(R3)SO 2 R6-, -CON(R3) 2 , -CON(R4) 2 , -COR5, -SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • V, Vl, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb, FGFRl, FGFR2, FGFR3, FGFR4, TrkA, TrkB, EGFR, EPHAl, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHAlO, EPHBl, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHB7, EPHB8.
  • receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb, FGFRl, FGFR2, FGFR3, FGFR4, TrkA, TrkB, EGFR, EPHAl, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8,
  • the kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing.
  • the method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 2.1 and 2.1.6a.
  • the kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation.
  • the kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
  • the methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization. These methods comprise administering to such individuals compounds of the invention, and especially those of section 2.1 and 2.1.6a.
  • Exemplary conditions include glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier.
  • the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.
  • the invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
  • the compounds are advantageously selected from the groups defined in sections 2.1 and 2.1.6a.
  • each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3- C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, or C1-C6alkyl, C1- C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents;
  • cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the Al ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) p N(R4)C(O)R8 , aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl' may cyclize to form a C3-C7 heterocyclyl ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of ZA' may cyclize to form a C3-C7 heterocyclyl ring;
  • two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4' may cyclize to form a C3-C7 heterocyclyl ring;
  • the compounds of formula I in 2.2 contain D moieties wherein El and E2 are as defined in section 1.2.1
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl' may cyclize to form a C3-C7 heterocyclyl ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O-Alkyl, -N(R3)- (CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • More preferred A2 moieties are selected from the group consisting of
  • A2 moieties are selected from the group consisting of
  • A2 is selected from the group consisting of
  • Al is selected from the group consisting of
  • X is O, S, or NR3;
  • El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein El is directly linked to the Y group of formula I;
  • each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
  • R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1- C6alkyl, and heterocyclylC1-C6alkyl;
  • each R4 is independently and individually selected from the group consisting of
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4- C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
  • alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) p N(R4)C(O)R8 , aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O-Alkyl, -N(R3)- (CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • Each Z6 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N-, -N(R3)COR8, (R4) 2 N-, -R5, -N(R4)COR8, -N(R3)SO 2 R6-, -CON(R3) 2 , -CON(R4) 2 , -COR5, -SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb,
  • kinases e.g. receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb,
  • EPHA5 EPHA6, EPHA7, EPHA8, EPHA9, EPHAlO, EPHBl, EPHB2, EPHB3, EPHB4,
  • the kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing.
  • the method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 2.2 and 2.2.6a.
  • the kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation.
  • the kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
  • the methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization. These methods comprise administering to such individuals compounds of the invention, and especially those of section 2.2 and 2.2.6a. Exemplary conditions include glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier.
  • the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.
  • the invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
  • the compounds are advantageously selected from the groups defined in sections 2.2 and 2.2.6a.
  • each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
  • site of attachment to the A2 ring is meta to the point of attachment to the Al ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl may cyclize to form a C3-C7 heterocyclyl ring;
  • Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl' may cyclize to form a C3-C7 heterocyclyl ring;
  • cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the Al ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
  • alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
  • such moieties may be further substituted with one or more C1-C6alkyls; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
  • the compounds of formula I in 2.3 contain D moieties wherein El and E2 are as defined in section 1.3.1a.
  • D moieties of 2.2.1b are wherein E2 is defined as in section 1.3.1c.
  • A2 moieties are selected from the group consisting of
  • A2 is selected from the group consisting of
  • Al is selected from the group consisting of
  • X is O, S, or NR3;
  • D comprises a member of 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4- chlorophenyl, 3-chlorophenyl, 3-bromophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4- difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5- trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 4-cyanophenyl, 3-(R8SO 2 )- phenyl, 3-phenoxyphenyl, 4 phenoxyphenyl, wherein ElA is taken from the groups consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl
  • E2A is taken from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benzimi
  • E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein El is directly linked to the Y group of formula I; each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
  • carbon atoms of -(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
  • X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
  • R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1- C6alkyl, and heterocyclic 1-C6alkyl; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl,
  • each R5 is independently and individually selected from the group consisting of
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4- C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) P N(R4)C(O)R8 , aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl' may cyclize to form a C3-C7 heterocyclyl ring;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of TA may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O-Alkyl, -N(R3)- (CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • Each Z6 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N-, -N(R3)COR8, (R4) 2 N-, -R5, -N(R4)COR8, -N(R3)SO 2 R6-, -CON(R3) 2 , -CON(R4) 2 , -COR5, -SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the Al ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
  • alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
  • such moieties may be further substituted with one or more C1-C6alkyls; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb,
  • kinases e.g. receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb,
  • EPHA5 EPHA6, EPHA7, EPHA8, EPHA9, EPHAlO, EPHBl, EPHB2, EPHB3, EPHB4,
  • the kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing.
  • the method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 2.3 and 2.3.6a.
  • the kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation.
  • the kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
  • the methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization. These methods comprise administering to such individuals compounds of the invention, and especially those of section 2.3 and 2.3.6a.
  • Exemplary conditions include glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier.
  • the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.
  • the invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
  • the compounds are advantageously selected from the groups defined in sections 2.3 and 2.3.6a.
  • the invention includes compounds of formula I as defined in section 2.1, wherein each R2 is independently and individually selected from the group consisting of C1-C6alkyl, branched
  • C3-C7alkyl C1-C6fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, monocyclic heteroaryl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1- C6alkyl.
  • Preferred compounds of Formula I as defined above in section 3.1 contain D moieties as defined in section 1.1.1a.
  • More preferred compounds of Formula I as defined above in section 3.1.1b contain D moieties as defined in section 1.1.1c.
  • each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
  • Still more preferred compounds of Formula I as defined above in section 3.1 have A2 moieties selected from group consisting of
  • each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
  • A2 is selected from the group consisting of
  • each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
  • X is O, S, or NR3;
  • D comprises a member of 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4- difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5- trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 3-phenoxyphenyl, 4- phenoxyphenyl, cyclohexyl,
  • El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
  • X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein El is directly linked to the Y group of formula I;
  • Each R2 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C1-C6fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, monocyclic heteroaryl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
  • each R2' is selected from the group consisting of halogen and R2;
  • each R3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
  • R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
  • each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1- C6alkyl, and heterocyclylC1-C6alkyl;
  • each R4 is independently and individually selected from the group consisting of
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R6 is independently and individually selected from the group consisting of C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
  • each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1- C3alkoxy;
  • each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4- C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
  • each RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO-N(R4) 2 , OH, C1-C6alkoxy, -N(R4) 2 ;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of RlO may cyclize to form a C3-C7 heterocyclyl ring;
  • each R13 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N-CO, (R4) 2 N-CO-C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1- C6alkoxycarbonylC1-C6alkyl, (R4) 2 N-C2-C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) q , R5- C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N-C2-C6alkyl0-(CH 2 ) q , R5-C2-C6alkyl-O-(CH 2 ) q , - (CH 2 )
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
  • each R 14 is independently and respectively selected from the group consisting of H and C1- C6alkyl
  • ZV is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(CH 2 )p, (R4) 2 N-CO-C1- C6alkyl, carboxyC1 -C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1 -C6alkyl, heterocyclyl, heterocyclylC1 -C6alkyl, aryloxyC1 -
  • R4 moieties independently and individually taken from the group consisting of C1 -C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Zl' may cyclize to form a C3-C7 heterocyclyl ring;
  • each Z3 is independently and individually selected from the group consisting of H, C1- C6alkyl, hydroxyl, hydroxyC1 -C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N-, (IU) 2 N-, (R4) 2 NC1 -C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , R8C0-, (R4) 2 N-CO-C1 -C6alkyl, carboxyl, carboxyC1 -C6alkyl, C1-C6alkoxycarbonyl, C 1-C6alkoxycarbonylC1 -C6alkyl, (R3) 2 NSO 2 , -SO 2 R3, SOR3, (R4) 2 NSO 2 , -
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
  • such moieties may be further substituted with one or more C1-C6alkyls; wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
  • Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, -N(R3) 2 , -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q- N(R4) 2 , -R5, -O-(CH 2 )q-O-Alkyl, -O-(CH 2 )q-N(R4) 2 , -N(R3)-(CH 2 )q-O-Alkyl, -N(R3)- (CH 2 )q-N(R4) 2 , -O-(CH 2 )q-R5, and -N(R3)-(CH 2 )q-R5;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
  • Each Z6 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N-, -N(R3)COR8, (IU) 2 N-, -R5, -N(R4)COR8, -N(R3)SO 2 R6-, -CON(R3) 2 , -CON(R4) 2 , -COR5, -SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
  • R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring; wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
  • V, Vl, and V2 are each independently and respectively selected from the group consisting of
  • the invention includes methods of modulating kinase activity of RAF kinases and other kinases in the RAS- RAF-MEK-ERK-MAP kinase pathway including, but not limited to, A- Raf, B-Raf, and C-Raf.
  • the kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing.
  • the method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 3.1 and 3.1.6a.
  • the kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation.
  • the kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
  • the methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 3.1 and 3.1.6a. condition being melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastisis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis characterized by the in-growth of a vascularized pannus, or a disease caused by a mutation in the RAS- RAF- MEK-ERK-MAP kinase pathway.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier.
  • the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

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WO2008046003A2 (en) 2006-10-11 2008-04-17 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
WO2008051757A1 (en) * 2006-10-20 2008-05-02 Irm Llc Compositions and methods for modulating c-kit and pdgfr receptors
WO2008058037A1 (en) * 2006-11-03 2008-05-15 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2008034008A3 (en) * 2006-09-14 2008-07-10 Deciphera Pharmaceuticals Llc Kinase inhibitors useful for the treatment of proliferative diseases
WO2008097428A3 (en) * 2007-02-02 2008-09-25 Irm Llc Compounds and compositions as modulators of gpr119 activity
WO2008131253A1 (en) * 2007-04-20 2008-10-30 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
JP2010503701A (ja) * 2006-09-14 2010-02-04 デシファラ ファーマスーティカルズ， エルエルシー 増殖性疾患の治療に有用なキナーゼ阻害剤
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