US20070078121A1 - Enzyme modulators and treatments - Google Patents

Enzyme modulators and treatments

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Publication number
US20070078121A1
US20070078121A1 US11/318,399 US31839905A US2007078121A1 US 20070078121 A1 US20070078121 A1 US 20070078121A1 US 31839905 A US31839905 A US 31839905A US 2007078121 A1 US2007078121 A1 US 2007078121A1
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c6alkyl
group
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Daniel Flynn
Peter Petillo
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Deciphera Pharmaceuticals LLC
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Deciphera Pharmaceuticals LLC
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Priority to US11/318,399 priority Critical patent/US20070078121A1/en
Assigned to DECIPHERA PHARMACEUTICALS, LLC reassignment DECIPHERA PHARMACEUTICALS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FLYNN, DANIEL L., PETILLO, PETER A.
Publication of US20070078121A1 publication Critical patent/US20070078121A1/en
Priority to US11/963,740 priority patent/US8163756B2/en
Abandoned legal-status Critical Current

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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-Abl, 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-Abl kinase and the oncogenic fusion protein BCR-Abl kinase; PDGF receptor kinase; VEGF receptor kinases; MAP kinase p38 ⁇ ; and the RAF kinase family.
  • C-Abl 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 Abl kinase: Abl-1A and Abl-1B.
  • 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 Abl-1B 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-Abl This abnormal chromosomal translocation leads aberrant gene fusion between the Abl kinase gene and the breakpoint cluster region (BCR) gene, thus encoding an aberrant protein called Bcr-Abl (G. Q. Daley et al, Science (1990) 247: 824; M. L. Gishizky et al, Proc. Natl. Acad. Sci. USA (1993) 90: 3755; S. Li et al, J. Exp. Med . (1999) 189: 1399).
  • Bcr-Abl fusion protein does not include the regulatory myristolylation site (B.
  • 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 p185 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 (2002) 417: 949-954).
  • 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 p38-alpha has been demonstrated to result in the suppression the production and release the proinflammatory mediators TNF-alpha, IL-1 beta, IL-6, IL-8 and other proinflammatory cytokines (Chen, Z. et al, Chem. Rev . (2001) 101: 2449). Recently, 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.
  • Enbrel a soluble TNF receptor
  • a soluble TNF receptor has been developed by Immunex, Inc., and marketed currently by Amgen for the treatment of rheumatoid arthritis (Brower et al, Nature Biotechnology (1997) 15: 1240; Pugsley, M. K., Curr. Opin. Invest. Drugs (2001) 2: 1725).
  • 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.
  • 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. Pract . (2001) 55: 211).
  • Gleevec is an inhibitor of BCR-Abl 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 CAbl 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
  • 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.
  • 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.
  • FIGS. 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.
  • the binding modality of the compounds of this invention is illustrated in FIG. 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.
  • FIG. 1 is an illustration of the kinase binding domains of known kinase inhibitors.
  • FIG. 2 is an illustration of the binding modality of compounds of the present invention to kinases.
  • 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 pharmaceutically-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 and gal
  • 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 IIa) 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 wherein A2 is selected from the group consisting of bicyclic fused aryl, bicyclic fused heteroaryl, and bicyclic fused heterocyclyl rings, each A2 moiety presenting a proximal ring bonded with A1 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;
  • A1 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
  • the compounds of formula I above contain D moieties of the formula wherein E1 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; wherein the symbol (***) is the point of attachment to the Y group of formula I;
  • X1 is selected from the group consisting of O, S, NR3, —C( ⁇ O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—
  • 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. 1.1.1c
  • 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 and wherein the symbol (**) is the point of attachment to the A1 ring of formula I; and wherein indicates either a saturated or an unsaturated bond; wherein 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 heterocyclylC1-C6alkyl; 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-C
  • More preferred A2 moieties are selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring for formula I; wherein 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 and wherein the symbol (**) is the point of attachment to the A1 ring of formula I; wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
  • A1 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; 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 A1 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. 1.1.4c
  • Still more preferred A1 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.
  • symbol (*) denotes the attachment to the W moiety of formula I
  • symbol (**) denotes the attachment to the A2 moiety of formula I.
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring; wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • D is selected from the group consisting of 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophen
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. C-Abl kinase, BCR-Abl 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-Abl kinase or BCR-Abl 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-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955);
  • 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 pharmaceutically 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.
  • the invention includes compounds of the formula wherein A2 is selected from the group consisting of a Z1-substituted phenyl, Z1-substituted pyridyl, Z1-substituted pyrimidinyl, Z1-substituted thienyl, Z1 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 A1 ring;
  • A1 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 monocycl
  • the compounds of formula I in 1.2 contain D moieties wherein E1 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;
  • E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrol
  • 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
  • D moieties of formula I in 1.2 comprise a formula wherein 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. 1.2.1c
  • 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, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrol
  • each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C( ⁇ NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C
  • More preferred A2 moieties are selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring for formula I. 1.2.2c
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • the invention includes compounds of the formula wherein A2 is selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
  • A1 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;
  • D comprises a member of wherein E1 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; wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
  • X1 is selected from the group consisting
  • 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 Z1 may cyclize to form a C3-C7 heterocyclyl ring;
  • each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. C-Abl kinase, BCR-Abl 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-Abl kinase or BCR-Abl 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-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955);
  • 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 pharmaceutically 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 1.2 and 1.2.6a.
  • A2 is selected from the group consisting of a Z7-substituted phenyl, Z7-substituted pyridyl, Z7-substituted pyrimidinyl, Z1-substituted thienyl, Z1 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 A1 ring;
  • A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and
  • the compounds of formula I in 1.3 contain D moieties wherein E1A 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,
  • D moieties of formula I in 1.3 comprise a formula X2 is selected from the group 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. 1.3.1c
  • 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
  • the compounds of formula I in section 1.3 contain A2 moieties as defined in section 1.2.2a.
  • More preferred A2 moieties are selected from the group consisting of wherein the symbol (**) is the point of attachment to the A1 ring for formula I. 1.3.2c
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • the invention includes compounds of the formula wherein A2 is selected from the group consisting of wherein the symbol (**) denotes the attachment to the A1 moiety of formula I; A1 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;
  • D comprises a member of 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 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-tri
  • 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 Z1 may cyclize to form a C3-C7 heterocyclyl ring;
  • each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. C-Abl kinase, BCR-Abl 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-Abl kinase or BCR-Abl 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-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955);
  • 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 pharmaceutically 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-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,
  • Z1′ 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-C6alkylO—(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
  • each Z2 is independently and individually selected from the group consisting of hydroxyl, hydroxyC1-C6alkyl, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)—(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C( ⁇ O)—, (R4) 2 N—C( ⁇ O)—, (R4) 2 N—C( ⁇ O)—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6
  • Preferred compounds of Formula I as defined above in section 2.1 contain D moieties as defined in section 1.1.1a.
  • More preferred compounds of Formula I as defined above in section 2.1.1b contain D moieties as defined in section 1.1.1c.
  • Still more preferred compounds of Formula I as defined above in section 2.1 have A2 moieties selected from group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring of formula I; wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
  • A2 moieties selected from group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring of formula I; wherein 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;
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring; wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • 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,
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFR1, VEGFR2, FLT-1, FLT-3, PDGFRa, PDGFRb, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, TrkB, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHB7, EPHB8.
  • 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 pharmaceutically 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.
  • the invention includes compounds of the formula I as defined in section 1.2 wherein 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; each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl
  • the compounds of formula I in 2.2 contain D moieties wherein E1 and E2 are as defined in section 1.2.1
  • each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6al
  • More preferred A2 moieties are selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring for formula I. 2.2.2c
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • D comprises a member of wherein E1 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 naphthy
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFR1, VEGFR2, FLT-1, FLT-3, PDGFRa, PDGFRb, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, TrkB, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHB7, EPHB8.
  • 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 pharmaceutically 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.
  • the invention includes compounds of the formula I as defined in section 1.3 wherein 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; wherein each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6
  • the compounds of formula I in 2.3 contain D moieties wherein E1 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.
  • More preferred A2 moieties are selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring for formula I. 2.3.2c
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • 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-trifluor
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFR1, VEGFR2, FLT-1, FLT-3, PDGFRa, PDGFRb, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, TrkB, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHB7, EPHB8.
  • 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 pharmaceutically 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.
  • Still more preferred compounds of Formula I as defined above in section 3.1 have A2 moieties selected from group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring of formula I; wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring. 3.1.3 Preferred Classes of Compounds 3.1.3a
  • 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;
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring; wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • 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
  • 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-Rat, 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 pharmaceutically 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 3.1 and 3.1.6a.
  • the invention includes compounds of the formula I as defined in section 2.2, 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;
  • the compounds of formula I in 3.2 contain D moieties wherein E1 and E2 are as defined in section 1.2.1
  • More preferred A2 moieties are selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring for formula I. 3.2.2c
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • D comprises a member of wherein E1 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 naphthy
  • 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 3.2 and 3.2.6a.
  • 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 and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 3.2 and 3.2.6a. 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 pharmaceutically 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 3.2 and 3.2.6a.
  • the invention includes compounds of the formula I as defined in section 2.3 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.
  • the compounds of formula I in 3.3 contain D moieties wherein E1 and E2 are as defined in section 1.3.1a.
  • D moieties of 3.2.1b are wherein E2 is defined as in section 1.3.1c.
  • More preferred A2 moieties are selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring for formula I. 3.3.2c
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • 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, wherein E1A is taken
  • 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 3.3 and 3.3.6a.
  • 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 and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 3.3 and 3.3.6a. 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 pharmaceutically 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 3.3 and 3.3.6a.
  • the invention includes compounds of formula I as defined in section 2.1, wherein R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
  • Preferred compounds of Formula I as defined above in section 4.1 contain D moieties as defined in section 1.1.1a.
  • More preferred compounds of Formula I as defined above in section 4.1.1b contain D moieties as defined in section 1.1.1c.
  • Still more preferred compounds of Formula I as defined above in section 4.1 have A2 moieties selected from group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring of formula I; wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring. 4.1.3 Preferred Classes of Compounds 4.1.3a
  • 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;
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring; wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • D comprises a member of 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chlorophenyl, 2,3,4-trifluorophenyl, 2,
  • the invention includes methods of modulating kinase activity of the p38 family of kinases including, but not limited to p38-alpha and other MAP kinases.
  • 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 4.1 and 4.1.6a.
  • 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 also include treating individuals suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease.
  • These methods comprise administering to such individuals compounds of the invention, and especially those of section 4.1 and 4.1.6a, said condition being human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral,
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharmaceutically 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 4.1 and 4.1.6a.
  • the invention includes compounds of the formula I as defined in section 2.2, wherein R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
  • the compounds of formula I in 4.2 contain D moieties wherein E1 and E2 are as defined in section 1.2.1
  • More preferred A2 moieties are selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring for formula I. 4.2.2c
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • D comprises a member of wherein E1 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 naphthy
  • the invention includes methods of modulating kinase activity of the p38 family of kinases including, but not limited to p38-alpha and other MAP kinases.
  • 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 4.2 and 4.2.6a.
  • 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 also include treating individuals suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease.
  • These methods comprise administering to such individuals compounds of the invention, and especially those of section 4.2 and 4.2.6a, said condition being human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral,
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharmaceutically 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 4.2 and 4.2.6a.
  • the invention includes compounds of the formula I as defined in section 2.3 wherein R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
  • the compounds of formula I in 4.3 contain D moieties wherein E1 and E2 are as defined in section 1.3.1a.
  • D moieties of 3.2.1b are wherein E2 is defined as in section 1.3.1c.
  • More preferred A2 moieties are selected from the group consisting of and wherein the symbol (**) is the point of attachment to the A1 ring for formula I. 4.3.2c
  • W and Y are each NH, and X ⁇ O; (2) W ⁇ NH, Y ⁇ CHR4 and X ⁇ O; or (3) W ⁇ CHR4, Y ⁇ NH, and X ⁇ O.
  • W and Y are each NH and X ⁇ O.
  • A2 is selected from the group consisting of wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
  • A1 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;
  • D comprises a member of 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chlorophenyl, 2,3,4-trifluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,
  • the invention includes methods of modulating kinase activity of the p38 family of kinases including, but not limited to p38-alpha and other MAP kinases.
  • 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 4.3 and 4.3.6a.
  • 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 also include treating individuals suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease.
  • These methods comprise administering to such individuals compounds of the invention, and especially those of section 4.3 and 4.3.6a, said condition being human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
  • the administration method is not critical, and may be from the group consisting of oral, parenteral,
  • the compounds of the invention may form a part of a pharmaceutical composition by combining one or more such compounds with a pharmaceutically 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 4.3 and 4.3.6a.
  • the synthesis method comprises the steps: providing a ring compound of the formula wherein s is 3 or 4, the ring compound has two double bonds and one reactable ring NH moiety, Q is independently and individually selected from the group consisting of N and CR2, and R15 is selected from the group consisting of lower alkyl, branched lower alkyl, benzyl, substituted benzyl, or other suitable carboxylic acid protecting group; each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated; reacting said ring compound with a compound of the formula A3P-M
  • A3P is a protected form of A3
  • A3 comprises a member of the group consisting of mono- and poly-aryl, mono- and poly-heteroaryl, mono- and poly-heterocyclyl moieties
  • P is a protective group wherein A3 is chemically protected so as not to interfere with the reaction of A3P-M with wherein A3P-M is taken from the group consisting of A3P—B(OH) 2 , -A3P—B(OR16) 2 , -A3P—B(R17) 3 M2, -A3P—Si(R18) 3 , or A3P—Sn(R16) 3 , wherein R16 is taken from lower alkyl or branched lower alkyl, R17 is halogen, R18 is lower alkoxy, and M2 is Li, K, or Na, and from the formulae wherein v is 1 or 2; said reaction generating an intermediate compound of the formula converting said intermediate compound to the carboxylic acid form thereof subjecting said carboxylic acid to a Curt
  • first step of the method involves using a ring compound taken from the group consisting of A3P-M is taken from A3P—B(OH) 2 , A3P—B(OR16) 2 , or boroxines (A3PBO) 3 ; said reaction generating an intermediate compound of the formula and being catalyzed by a copper(II) catalyst, in an inert solvent taken from the group consisting of dichloromethane, dichloroethane, and N-methylpyrrolidinone, in the presence of a base taken from the group consisting of triethylamine and pyridine, at temperatures ranging from ambient to about 130° C., wherein the reaction is exposed to an atmosphere containing oxygen; Converting said intermediate compound to the carboxylic acid form thereof and subjecting said acid form compound to a Curtiuss rearrangement in the presence of a compound of formula D1-NH 2 , such rearrangement mediated by the use of diphenylphosphoryl azidate in an inert solvent
  • the starting ring compound is selected from the group consisting of A3P-M is taken from A3P—B(OH) 2 , A3P—B(OR15) 2 , or boroxines (A3PBO) 3 ; said reaction generating an intermediate compound of the formula said catalyst comprising copper(II) acetate, said reaction being carried in an inert solvent, selected from the group consisting of dichloromethane, dichloroethane, and N-methylpyrrolidinone, in the presence of a base from the group consisting of triethylamine and pyridine, and in the presence of 4 angstrom sieves at ambient temperature, wherein the reaction is exposed to air, to generate an intermediate compound of the formula converting said intermediate compound to the carboxylic acid form thereof subjecting said carboxylic acid form intermediate to a Curtiuss rearrangement in the presence of a compound of formula D1-NH 2 , such rearrangement mediated by the use of diphenylphosphoryl azidate in an iner
  • A2P refers to a protected form of A2, as defined above, wherein the Z1, Z2, Z3, or Z4 moieties or heteroatoms attached to A2 are suitably protected to allow their use in multi-step chemistry.
  • Scheme 1 illustrates the preparation of hydrazines 2. If the amine precursors 1 are readily available, they are converted to the hydrazines 2 by a diazotization/reduction sequence. Preferred conditions react 1 with NaNO 2 in aqueous HCl to form the diazonium salt at about 0C in aqueous solvent or an aqueous/organic cosolvent. The diazonium salt is not isolated, but directly reduced by reaction with SnCl 2 .2H 2 0 under acidic conditions, preferably aqueous HCl at between about 0C and room temperature.
  • the hydrazines 2 are isolated as the HCl addition salts. If the amine precursors 1 are not directly available, they can be formed from the nitro-substituted A2P precursors 3 by reduction, preferably with iron/HCl, SnCl 2 .2H 2 0, or catalytic hydrogenation, to give the requisite amines 1. Conversion to the hydrazines 2 is accomplished as described above.
  • reaction of the aryl or heteroaryl bromides 4 with benzophenone hydrazone and a palladium catalyst, preferably with Pd(OAc) 2 and DPPF as ligand, can afford the protected hydrazines 5, which are deprotected under acidic conditions, preferably p-toluenesulfonic acid or ethanolic HCl, to give rise to the desired hydrazines 2 (Hartwig, J. F., et al, Angew. Chem. Int. Ed . (1998) 37: 2090; Haddad, N., et al, Tetrahedron Letters (2002) 43: 2171-2173).
  • reaction of the aryl or heteroaryl iodides 6 with t-butylcarbazate and a copper (I) catalyst, preferably CuI in DMF at about 80C with Cs 2 CO 3 base and a ligand such as 1,10-phenanthroline, can afford the BOC-protected hydrazines 7, which are converted to the desired hydrazines 2 by treatment with acid (M. Woltor et al, Organic Letters (2001) 3: 3803-3805).
  • pyrazoles 9 and 11 are illustrated in Scheme 2.
  • Reaction of hydrazines 8 with beta-ketonitriles in an alcoholic solvent, preferably EtOH, and an acid catalyst, preferably HCl or p-toluenesulfonic acid, at about 80C gives aminopyrazoles 9.
  • Analogous treatment of hydrazines 8 with the ethyl 2-(methoxyimino)-4-oxobutanoates 10 affords the pyrazole ethyl esters 11 (Lam, P. Y., Journal of Medicinal Chemistry (2003) 46: 4405-4418).
  • the aminopyrazoles 9 are converted into the desired pyrazole ureas 12 of Formula I (see Scheme 3) by methods described in Scheme 30 for the conversion of the aminothiophene into ureas of Formula I.
  • pyrazole ureas of Formula I can be formed from the pyrazole ethyl esters 11 by a sequence illustrated in Scheme 4. Conversion of esters 11 to the carboxylic acids 13 is accomplished by saponification or by treatment with aqueous acid. Curtius-type rearrangement of 13, preferably by treatment with ethyl chloroformate and base, preferably triethylamine, in an organic solvent, preferably THF at about 0C, and then forming the acyl azide by reaction with sodium azide, and quenching of the in situ rearranged isocyanate with D-NH 2 gives rise to the desired pyrazole ureas 14 of Formula I (E1 Haddad, M. et al, Journal of Heterocyclic Chemistry (2000) 37: 1247-1252).
  • the aminopyrazoles 20 are converted into the desired pyrazole ureas 21 of Formula I by methods described in Scheme 30.
  • Scheme 11 illustrates the preparation of imidazole intermediate 50. Reaction of 48 with 49, affords 50 (cf. Little, T. L. et al. J. Org. Chem. 1994, 59 (24), 7299-7305).
  • Cross-coupling reaction of 50 is accomplished by two different methods.
  • Scheme 12 illustrates the method of Kiyomori, A. et al. ( Tetrahedron Lett. 1999, 40 (14), 2657) wherein 50 is reacted with a suitable A2P—I in the presence of Cs 2 CO 3 as base and Cu(OTf) 2 as catalyst.
  • 50 is cross-coupled with an A2P—B(OH) 3 under Cu(OAc) 2 catalysis in the presence of pyridine (Chan, D. M. T. et al. Tetrahedron Lett. 2003, 44 (19), 3863).
  • nucleophilic aromatic substitution between 50 and A2P—F (or Cl) in the presence of an inorganic base also provides 51.
  • Scheme 14 illustrates the preparation of oxazole intermediates 56.
  • Readily available acid chlorides 54 are converted to the corresponding acyl nitrites 55 by the action of cyanide anion, according to the method of Tanaka, M. et al. ( Synthesis 1981, 12, 973-4).
  • Scheme 16 illustrates the preparation of oxazole intermediates 61.
  • the aldehyde function is elaborated through a Strecker synthesis (Kendall, E. C. et al. Org. Synth . CV 1, 21) to provide amino-nitriles 59.
  • Acylation with R2COCl in the presence of a base generates intermediate 60.
  • 59 can be coupled with R2COOH in the presence of a peptide-coupling or dehydrating agent and a base to also give 60.
  • treatment of 60 with a strong organic acid (cf. EP 816347) or mineral acid afford the desired aminooxazoles 61.
  • A2P-containing hydrazines, 68 are acylated with R2COCl in the presence of a base to generate intermediates 69.
  • 68 can be coupled with R2COOH in the presence of a peptide-coupling or dehydrating agent and a base to also give 69.
  • Halogenation under the conditions of Joseph, B. et al. J. Carbohydrate Chem. 1993, 12, 1127-38) or Sakamoto, T. et al. ( Chem. Pharm. Bull. 1988, 36, 800-802) afford hydrazinoyl halides 70.
  • Treatment with base generates the reactive 1,3-dipoles 71 which are trapped with cyanamide to give aminotriazoles 72, in accordance with precedent (EP 285893).
  • 79 may be obtained by cross-coupling with a stannane in the presence of a palladium catalyst.
  • the cross-coupling may be accomplished under Suzuki conditions with an appropriate boronic acid.
  • 77 is converted to a boronate species, 78, which is then subjected to Suzuki coupling conditions with the requisite A2P—X. Deprotonation of 79 and quenching of the anion with CO 2 delivers acid 80. Subjecting 80 to Curtius rearrangement conditions in the presence of D-NH 2 to trap the intermediate isocyanate provides 81 using methods analogous to that illustrated in Scheme 4.
  • Scheme 24 illustrates the preparation of furan intermediates 85.
  • the 1,4-dicarbonyl starting materials 82 are reacted with para-methylbenzenesulphonic acid (TsOH) in a suitable solvent such as toluene to afford furan 83.
  • TsOH para-methylbenzenesulphonic acid
  • Nitration of 83 affords 84, which is reduced with iron/HCl, tin (II) chloride, or catalytic hydrogenation conditions to give the 3-aminofuran intermediates 85.
  • the aminofurans 85 are converted into the desired furanyl ureas 86 of Formula I by methods described in Scheme 30.
  • Scheme 26 illustrates the preparation of 4,5-disubstituted 2-aminothiophenes 92 according to methods reported by Knoll et al (Knoll, A. et al, Synthesis (1984) 51-53; Knoll, A. et al, J. Prakt. Chem . (1985), 327: 463-470).
  • the compound 87 is reacted with an excess of formamide derivatives 88 in methanol to afford N-(3-aminothioacryloyl)-formamidines 89.
  • a protic solvent such as methanol or ethanol
  • the product thiophene-imines, 91 are treated with aqueous acid to obtain the thiophene-amines 92.
  • the aminothiophenes 92 are converted into the desired thiophenyl ureas of Formula I by methods described in Scheme 30.
  • Scheme 28 illustrates the preparation of 1,4-dicarbonyl starting materials 96 for the preparation of compounds of Formula I, wherein A1 is A1-13.
  • One preferred method utilizes a 1,4-conjugate addition procedure, Scheme 28 (a), to transform 94 to 96 by reaction with the unsaturated ketone 95 in the presence of a suitable base such as a lithium, sodium, or potassium amide or hydride base.
  • a suitable base such as a lithium, sodium, or potassium amide or hydride base.
  • Scheme 28 (b) makes use of a transmetallation reaction, converting 97, wherein X1 is halogen, to an organometallic species 98 wherein the metal is magnesium, nickel, or cadmium.
  • the 1,4-dicarbonyl starting materials 96 are reacted with Lawesson's reagent in a suitable solvent such as THF or toluene to afford thiophene 103. Nitration of 103 affords 104, which is reduced with iron/HCl, tin (II) chloride, or catalytic hydrogenation conditions to give the 3-aminothiophene intermediates 105 (Scheme 29).
  • Scheme 31 illustrates the preparation of 2,4-disubstituted N-protected-anilines 117.
  • the commercially available starting materials 113 are converted to 4-substituted anilines 114 by nitration, followed by reduction with iron/HCl, tin (II) chloride, or catalytic hydrogenation conditions.
  • the reaction of 4-substituted anilines 114 with bromine in acetic acid gives 2-brominated anilines 115.
  • the amino groups of 115 are protected to allow their use in Suzuki coupling reactions to obtain 117.
  • the Suzuki coupled intermediates 117 are converted into the desired phenyl ureas 118 of Formula I by methods described in Scheme 30.
  • Scheme 33 illustrates the preparation of 2,5-disubstituted 2-aminopyridines 125.
  • the commercially available starting material 119 is reacted with sodium nitrate to afford 1-methyl-3,5-dinitro-2-pyridone 120.
  • the reaction of 120 with ketones 121 in the presence of NH 3 gives alkyl and/or aryl-substituted 3-nitropyridine derives 122 (Tohda, Y. et al, Bull. Chem. Soc. of Jpn (1990), 63: 2820-2827).
  • Reduction followed by selective bromination of 122 affords 123 (Canibano, V. et al, Synthesis (2001) 14: 2175-2179).
  • the amino group of 123 is protected to give 124.
  • 124 is reacted with a variety of Suzuki coupling reagents to obtain 125.
  • the aminopyridines 125 are converted into the desired pyridyl ureas 126 of Formula I by methods described in Scheme 30.
  • Scheme 35 illustrates the preparation of 2,4-disubstituted 5-aminopyridines 132.
  • the commercially available starting materials 127 are converted to 2-substituted-4-nitropyridines 128 under standard nitration conditions. Reduction followed by a second nitration of 128 gives 4-amino-2-substituted-5-nitropyridines 129 which can purified by silica column chromatography from the other isomers.
  • the 4-amino-2-substituted-5-nitropyridines 129 are reacted with HBr and NaNO2 to afford 4-bromopyridines 130.
  • the bromopyridine 130 is reacted with a variety of Suzuki coupling reagents to produce 131.
  • the aminopyridines 132 are converted into the desired pyridyl ureas 133 of Formula I by methods described in Scheme 30.
  • Scheme 36 demonstrates the preparation of substituted pyridines 138.
  • Amination of 134 and subsequent bromination affords 135 as previously reported ( J. Am. Chem. Soc., 1990, 112, 8024 and Heterocycles, 1986, 24, 1815).
  • 3-alkyl pyridines 134 upon reaction with sodamide gives pyridines 135, which are brominated with bromine to give pyridines 136.
  • the amine functionalities of 136 are acetylated using acetyl chloride or acetic anhydride to give 137.
  • the brominated intermediates 137 are utilized in Suzuki cross coupling reactions to give cross-coupled intermediates 138 utilizing procedures describe above in Scheme 23.
  • ester functionalities of 148 are hydrolyzed to acids 149, which are utilized in a Curtius rearrangement reaction sequence in the presence of amines D-NH 2 using methods reported above in Scheme 4, to give the desired ureas 150 of Formula I.
  • 170 is subjected to a Curtius-type rearrangement in the presence of amines D-NH 2 , to give 171.
  • 170 is first converted to the primary amides 172, which are then subjected to a modified Hoffman-type rearrangement utilizing bis-trifluoroacetoxyiodobenzene to afford rearranged amines that are trapped with an isocyanate D-N ⁇ C ⁇ O.
  • Scheme 44 illustrates the preparation of intermediates A2P corresponding to A2-1 through A2-6.
  • Readily available halogenated substituted benzenes, pyridines, pyrimidines, or triazines 172 through 177 are obtained commercially or are available through diazotization/H-Q2 quench (Sandmeyer reaction) of the corresponding substituted aryl- or heteroaryl-amines 178 through 183.
  • substituted hydrazines are either derived from readily available hydrazines or are derived from the substituted aryl- or heteroaryl-amines 178 through 183 by diazotization of the amino groups followed by reduction of the diazonium salts to the corresponding hydrazines 1184 through 189.
  • Scheme 45 illustrates the preparation of intermediates A2P corresponding to A2-7.
  • Thiourea is reacted with readily available alpha-halocarbonyl compounds 190, wherein Q2 is chloro or bromo, to afford aminothiazoles 191.
  • Aminothiazoles 191 are converted to thiazolylhydrazines 192 by a standard diazotization/reduction sequence.
  • aminothiazoles 191 are converted to thiazolyl halides 193, wherein Q2 is chloro or bromo, by a standard Sandmeyer reaction sequence involving H-Q2 trapping of an in situ formed diazonium salt.
  • Scheme 46 illustrates the preparation of intermediates A2P corresponding to A2-8.
  • Readily available aminonitriles 194 are reacted with aldehydes 195 in the presence of sulfur and base, affording intermediate aminothiazoles 196 after an acid work-up.
  • Aminothiazoles 196 are converted to the thiazolylhydrazines 197 by a standard diazotization/reduction sequence.
  • aminothiazoles 196 are converted to thiazolyl halides 198, wherein Q2 is chloro or bromo, by a standard Sandmeyer reaction sequence involving H-Q2 trapping of an in situ formed diazonium salt.
  • beta-keto esters 199 wherein Q3 is a halogen leaving group, are reacted with substituted thioamides to afford thiazolyl esters 200.
  • Esters 200 are hydrolyzed to their corresponding acids 201, which are then converted into thiazolyl amines 202 by a Curtius-type rearrangement, or are converted into thiazolyl halides 203 by a Hunsdiecker reaction.
  • Scheme 47 illustrates the preparation of intermediates A2P corresponding to A2-9.
  • thioamides 204 and beta-halo-alpha-keto esters 205 undergo a Hantzch cyclization to afford thiazolyl esters 206.
  • Esters 206 are hydrolyzed to their corresponding acids 207, which undergo a Curtius-type rearrangement to afford the requisite aminothiazoles 208, which then undergo a standard diazotization/reduction sequence to give thiazolyl hydrazines 209.
  • acids 207 undergo a Hunsdiecker reaction to afford the corresponding thiazolyl halides 210, wherein Q2 is chloro or bromo.
  • Scheme 48 illustrates the preparation of intermediates A2P corresponding to A2-10.
  • Ketal-protected amino ketones 211 are converted to the oxazolyl esters 212 by reaction with ethyl oxalyl chloride. Hydrolysis of the esters 212 affords acids 213.
  • Acids 213 are converted to the hydrazines 215 and halides 216 by reaction sequences described above in Scheme 47.
  • Scheme 49 illustrates the preparation of intermediates A2P corresponding to A2-11.
  • Readily available aminonitriles 217 are reacted with substituted acid chlorides 218 in the presence of base, affording intermediate N-acyl aminonitriles 219.
  • Cyclization of 219 affords the aminooxazoles 220.
  • Conversion of 220 to the oxazolyl hydrazines 221 or the oxazolyl halides 222 is effected as described above in Scheme 45.
  • Scheme 50 illustrates the preparation of intermediates A2P corresponding to A2-12.
  • Acyl nitriles 223 are reacted with aldehydes 195 in the presence of ammonium acetate/acetic acid to give the aminooxazoles 224 using conditions reported above in Scheme 46.
  • the aminooxazoles 224 are converted to the hydrazines 225 under standard diazotization/reduction conditions.
  • alpha-amino-beta-ketoesters 226 are acylated to give intermediates 227, which are cyclized to the oxazolyl esters 228 in the presence of a cyclodehydrating reagent such as thionyl chloride, triphenyl phosphine/carbon tetra-chloride, or Burgess reagent.
  • a cyclodehydrating reagent such as thionyl chloride, triphenyl phosphine/carbon tetra-chloride, or Burgess reagent.
  • Hydrolysis of esters 228 gives rise to acids 229, which are converted to oxazolyl hydrazines 231 and oxazolyl halides 232 by employing reaction conditions described above in Scheme 47.
  • Scheme 51 illustrates the preparation of intermediates A2P corresponding to A2-13. Aminoketones 232 are reacted with cyanamide to afford the aminoimidazoles 233. Conversion of 233 to the corresponding hydrazines 234 and the halides 235 is accomplished by employing reaction conditions described above in Scheme 45.
  • Scheme 52 illustrates the preparation of intermediates A2P corresponding to A2-14.
  • Alpha, beta-diketoesters 236 are reacted with substituted aldehydes 195 in the presence of ammonium acetate/acetic acid to give rise to imidazolyl esters 237.
  • Imidazole NH protection (wherein P denotes suitable protection of the imidazole NH bond), followed by ester hydrolysis affords imidazole acids 238/239, which are converted to the corresponding hydrazines 242/243 and halides 244/245 by employing reaction conditions described above in Scheme 47.
  • R7 is a suitable moiety that conforms to the generic definition of Z4 or a protected form of such moiety.
  • Compounds 267 and 268 are prepared by reductive alkylation of 265 or 266 with an appropriate aldehyde and sodium triacetoxyborohydride as the reducing agent.
  • 269 and 270 are synthesized from 265 or 266 by simple amide formation using an acid chloride and base, preferably triethylamine or pyridine.
  • 271 and 272 are synthesized by amidine or guanidine formation utilizing a thioamide or a thiourea, respectively.
  • Intermediates 273, 274, 279, 280, 285 and 286 are prepared by palladium-catalyzed bromide substitution with benzophenone hydrazone as described by Haddad et al. ( Tetrahedron Lett. 2002, 43, 2171-2173).
  • 273, 274, 279, 280, 285 and 286 are either directly implemented by reaction with a suitable A1-containing intermediate, or, if required, first hydrolyzed to hydrazines 275, 276, 281, 282, 287 and 288, respectively, under acidic conditions.
  • the bromide functionalities in 267 to 272 are substituted by boronic acid affording 277, 278, 283, 284, 289 and 290, respectively.
  • the bromide is transformed into an organometallic species such as a grignard compound, and subsequently reacted with trimethyl borate to afford 277, 278, 283, 284, 289 and 290 after acid hydrolysis.
  • organometallic species such as a grignard compound
  • 400 can be reduced with LAH to yield 403 and subsequently protected as the trifluoroacetamide (404), which is converted to the hydrazine (405, R18, V ⁇ H2) or iodide (406, R18, V ⁇ H2) (Scheme 66) using the same methodology outlined in Scheme 53.
  • 404 trifluoroacetamide
  • Structures 415 and 416 can be obtained when the bromide is reacted with benzophenone hydrazone under palladium catalysis as described by Haddad et al. ( Tetrahedron Lett. 2002, 43, 2171-2173).
  • 415 and 416 can either be directly implemented for reaction with a suitable A1 intermediate or, if required, first hydrolyzed to hydrazines 417 and 418 under acidic conditions.
  • the bromide in 413 and 414 can be substituted by a boronic acid affording 419 and 420.
  • the bromide is transformed into an organometallic species such as a grignard compound and subsequently reacted with trimethyl borate to afford 419 and 420 after acid hydrolysis.
  • the boronic acid can be mildly introduced with bis(pinacolato)diboron and Pd(dppf).
  • 474, 475, 486 and 487 are prepared by palladium-catalyzed bromide substitution with benzophenone hydrazone as described by Haddad et al. ( Tetrahedron Lett. 2002, 43, 2171-2173). 474, 475, 486 and 487 are either directly implemented by reaction with a suitable A1-containing intermediate, or, if required, first hydrolyzed to hydrazines 476, 477, 488 and 489, respectively, under acidic conditions. The bromide functionalities in 470, 471, 482 and 483 are substituted by a boronic acid affording 478, 479, 490 and 491.
  • the bromide is transformed into an organometallic species such as a grignard compound and subsequently reacted with trimethyl borate to afford 478, 479, 490 and 491 after acid hydrolysis.
  • organometallic species such as a grignard compound
  • the boronic acids are mildly formed from the bromides by utilizing a procedure employing bis(pinacolato)diboron and Pd(dppf).
  • Nitration of 516 under standard conditions gives 517, which are subjected to reduction to afford the amino-substituted pyrazolylpyridines 518.
  • Conversion of 518 to hydrazines 519 or halides 520 is effected as described in Scheme 41. A2-98, V ⁇ O
  • Scheme 75 illustrates the preparation of intermediates containing A2-98 wherein V is O.
  • the commercially available starting material 7-nitro-3,4-dihydronaphthalen-1(2H)-one 521 is reacted with hydroxylamine, followed by PCl5, to give lactam 522.
  • the nitro functionality of 522 is reduced under catalytic hydrogenation conditions to afford amine 523.
  • the aminobenzoazepinone 523 is converted into the hydrazine 524, bromide 525 or boronic acid 526 as described in Scheme 59.
  • Scheme 77 illustrates the preparation of intermediates containing A2-99 wherein V1 and V2 are O.
  • the commercial available starting material 2-(2-carboxyethyl)benzoic acid 533 is reacted with fuming nitric acid to give the nitrobenzoic acid 534.
  • the nitrobenzoic acid 534 is treated with trifluoroacetamide in the presence of HOBt and EDCI to give the cyclic imide 535 (Nazar, F. et al, Tetrahedron Lett ., (1999), 40: 3697-3698).
  • the by-products and excess substituted resin and a tertiary amine-substituted resin (Flynn, D. L. et al, J. Am. Chem.
  • an acid-activating reagent such as EDCI/HOBt in the presence of base, preferably triethylamine (TEA)
  • TAA triethylamine
  • a Ring Closing Metathesis (RCM) reaction of 543 utilizing Grubbs' catalyst gives the benzazepinedione 544.
  • Reduction of 544 under catalytic hydrogenation conditions produces 545 (Knobloch, K. et al, European J. of Org. Chem ., (2001), 17: 3313-3332).
  • Intermediate 545 is converted into the hydrazine 546, bromide 547 or boronic acid 548 as described in Scheme 77.
  • intermediate 544 is selectively reduced at the nitro functionality, preferably with stannous chloride, to afford amine-substituted benzazepinedione 549, wherein the ring C—C bond is unsaturated.
  • Intermediate 549 is converted into the hydrazine 550, bromide 551 or boronic acid 552 as described in Scheme 77.
  • A2-99, V1 and V2 H 2
  • Reduction of 570 under catalytic hydrogenation conditions yields the tetrahydrobenzoazepineone 571 which is reduced at the ring C—C bond and nitro group, with concomitant removal of the PMB protecting group (Knobloch, K. et al, European J. of Org. Chem ., (2001), 17: 3313-3332).
  • 571 is converted into the hydrazine 572, bromide 573 or boronic acid 574 as described in Scheme 78.
  • intermediate 570 is selectively reduced at the nitro functionality, preferably with stannous chloride, to afford amine-substituted benzazepinedione 575, wherein the ring C—C bond is unsaturated.
  • Intermediate 575 is converted into the hydrazine 576, bromide 577 or boronic acid 578 as described in Scheme 78.
  • A2-100, V1 and V2 O
  • Scheme 82 illustrates the preparation of intermediates containing A2-100 wherein V1 and V2 are O.
  • the commercially available starting material 1,2-phenylendiacetic acid 579 is coupled with trifluoroacetamide under HOBt and EDCI conditions to give the cyclic imide 580 (Nazar, F. et al, Tetrahedron Lett ., (1999), 40: 3697-3698).
  • the by-products and excess of reagents can be removed by using a mixed resin containing sulfonic acid-substituted resin and a tertiary amine-substituted resin (Flynn, D. L. et al, J. Am. Chem.
  • Nitration of 580 produces 581.
  • Reduction of the nitro functionality of 581 under catalytic hydrogenation conditions affords the amine-substituted benzazepinedione 582.
  • the amine-substituted benzazepindione 582 is converted to the hydrazine 583, bromide 584, or boronic acid 585 using the methodology described in Scheme 59.
  • A2-100, V1 and V2 H2
  • Scheme 86 illustrates the preparation of intermediates containing A2-101 wherein V1 and V2 are O.
  • the commercially available starting material 2-amino-4-nitrobenzoic acid 610 is converted into 2-iodo-4-nitrobenzoic acid 611 by a Sandmeyer reaction sequence.
  • the iodobenzoic acid 611 is reacted with acrylonitrile under Heck conditions to give the unsaturated nitrile 612 (Bumagin, N. A. et al, J. Organometallic Chem . (1989), 371: 397-401).
  • Intermediate 612 is converted into the acid chloride 613 and then subjected to acid-catalyzed cyclization, giving the ring closure product 614 (Puar, M. S.
  • Scheme 91 illustrates the preparation of intermediates containing A2-102 wherein V is O, using the methodology reported by Schultz, C. et al ( J. Med. Chem . (1999), 42: 2909-2919).
  • the commercially available starting material 2-amino-5-nitrobenzoic acid 657 is converted into the ester 658.
  • the ester 658 is treated with ethyl 4-chloro-oxobutanoate in the presence of pyridine to yield 659. Dieckman cyclization of 659 using potassium hydride as base in mixture of toluene and DMF affords the dihydrobenzazepineone 660.
  • R′ is Br or I
  • 691 or 692 may be used directly in a metal-mediated cross-coupling, such as a Heck, Suzuki or Stille protocol (see Scheme 23).
  • R′ is Br or I
  • it may be subjected to Pd-mediated alkoxycarbonylation using a published procedure (Stille, J. K. et al, J. Org. Chem. 1975, 40 (4), 532; Heck, R. F., et al., J. Org. Chem. 1974, 39 (23), 3318) to give an ester.
  • This functionality is saponified or reduced to afford the carboxylic acid or aldehyde, respectively.
  • R′ when R′ is Br or I, it may be converted to a boronic ester as shown previously in Scheme 23.
  • R′ is NO 2
  • hydrogenation provides the amine.
  • Diazotization, followed by reduction provides the hydrazine.
  • intermediates 741 can be subjected to the various reactions described in Scheme 57 to afford Z4-substituted analogs 743 (scheme 104).
  • benzdiazepines 749 Concomitant reduction of the lactam carbonyl and nitro functional groups with LAH gives rise to intermediate benzdiazepines 749.
  • 748 is converted into Z4-substituted benzdiazepineones 751 by a sequence involving amine deprotection and derivatization with Z4 moieties as described in Scheme 57.
  • 749 is converted into regioisomeric Z4-substituted benzdiazepineones 752 using methods described in Scheme 57.
  • Cyclization of 756 to benzdiazepinediones 757 is effected by EDCI/HOBT in the presence of base, preferably triethylamine. Amide nitrogen deprotection, followed by reduction of the ring carbonyl functionalities by LAH or borane affords the requisite benzdiazepines 758.
  • R5 is pyrrolidine (R5-1) [CAS 123-75-1], piperidine (R5-2) [CAS 110-98-4], azepine [CAS 11-49-9], morpholine (R5-3) [CAS 110-91-8] or thiomorpholine (R5-4) [CAS 123-90-0], these materials are purchased from a number of commercial sources.
  • R5 is 2-substituted pyrrolidine (R5-12), 2-substituted piperidine (R5-13), HN(CH 2 CON(R4)) 2 (R5-14), HN(CH 2 CO 2 R4) 2 (R5-15), or 4-substituted oxazolidinone (R5-16), these are prepared from commercially available precursors using standard methods and performed by one of ordinary skill in the art.
  • R5 is thiomorpholinsulphone (R5-5) [790, CAS 39093-93-1]
  • the synthesis is shown in Scheme 114.
  • Benzylamine 787 and divinylsulphone 788 are reacted together in refluxing methylenechloride to yield benzyl-protected thiomorpholinesulphone 789, which upon hydrogenation yields 790.
  • R5 is 4-alkyl-4-piperdinol (R5-6)
  • the synthesis proceeds as shown in Scheme 115.
  • N-Boc-4-piperdone is reacted with the requisite Grignard or alkyllithium reagent to yield N-Boc-4-alkyl-4-piperdinol 791, which is readily deprotected to yield species of type 792.
  • Example A1 (1 g, 3.09 mmol) and 1,2-dichloro-3-isocyanatobenzene (0.7 g, 3.71 mmol) were combined to afford ethyl 3- ⁇ 3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]-1H-pyrazol-1-yl ⁇ benzoate (0.6 g, 41% yield).
  • Example A2 (80 mg, 0.17 mmol) was reduced to afford 1-[3-t-butyl-1-(3-hydroxymethyl-phenyl)-1H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (50 mg, 68% yield).
  • Example A2 To a solution of Example A2 (100 mg, 0.21 mmol) in fresh THF (10 mL) was added dropwise a solution of MeMgBr (1.5 mL, 1.4 in toluene/THF) at 0° C. under N 2 . After stirring for 1 h, the resulting mixture was allowed to rise to RT and stirred for 1 h. The reaction mixture was quenched by addition of aqueous 1N HCl (5 mL) and the mixture was extracted with EtOAc (3 ⁇ ).
  • Example A1 To a solution of Example A1 (14.4 g, 50 mmol) and formamide (4.5 g, 0.1 mol) in DMF (50 mL) was added NaOMe (5.4 g 0.1 mol) at RT. The mixture was stirred at 100° C. for 2 h, concentrated and the residue dissolved in EtOAc (150 mL). The organic layer was washed with H 2 O and brine, dried (Na 2 SO 4 ), filtered and purified by column chromatography to afford 3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)benzamide (6 g, 48% yield).
  • Example A3 A solution of Example A3 and the appropriate isocyanate (general method A) or the appropriate aniline (general method B) were converted to the target compound.
  • Example 9 (80 mg, 0.19 mmol) was suspended in conc. HCl (0.93 mL) and briskly stirred. More conc. HCl (1 mL) was added several times to maintain good stirring and keep the solids wetted. The reaction was stirred at RT for 5 h and 24 h at 40° C. The reaction was cooled to RT, diluted with H 2 O and EtOAc and the layers separated. The aqueous was extracted with EtOAc (2 ⁇ ). Solids in the aqueous layer were collected by filtration, rinsed sparingly with H 2 O and dried.
  • Example A4 Using general method A, a solution of Example A4 (70 mg, 0.29 mmol) and the appropriate isocyanate (0.29 mmol) were converted to the target compound.
  • Example 19 (100 mg, 0.21 mmol) in fresh THF (10 mL) was transformed to 1- ⁇ 3-t-butyl-1-[4-(2-hydroxypropan-2-yl)phenyl]-1H-pyrazol-5-yl ⁇ -3-(2,3-dichlorophenyl)urea (50 mg, 52% yield).
  • Example A5 (1.08 g, 3.18 mmol) was transformed to ethyl 2-(3-(3-t-butyl-5-((prop-1-en-2-yloxy)carbonyl)-1H-pyrazol-1-yl)phenyl)acetate (1.23 g, 100% yield).
  • Example A6 150 mg, 0.39 mmol
  • Example A7 108 mg, 0.39 mmol
  • N-methylpyrrolidine 8.9 mg, 0.10 mmol
  • the crude reaction mixture was chromatographed on silica gel to provide ethyl 2-(3-(3-t-butyl-5-(3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)ureido)-1H-pyrazol-1-yl)phenyl)acetate (236 mg, 100% yield) as a straw-colored solid.
  • Example A5 6.0 g, 20 mmol
  • formamide 1.8 g, 40 mmol
  • DMF 20 mL
  • NaOMe 2.1 g, 40 mmol
  • the mixture was heated at reflux for 1 h, concentrated and the residue was purified via column chromatography to afford 2-[3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl]acetamide (2.0 g, 40% yield).
  • Example A10 (2.0 g, 6.6 mmol) and 1,2-dichloro-3-isocyanato-benzene (1.1 g, 7.5 mmol) were combined to afford ethyl 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)acetate (2.2 g, 68% yield).
  • Example 23 (100 mg, 0.21 mmol) was reduced to yield 1- ⁇ 3-t-butyl-1-[3-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl ⁇ -3-(2,3-dichlorophenyl)urea (60 mg, 64% yield).
  • Example A8 A solution of Example A8 and the appropriate amine were converted to the target compound using the general method indicated.
  • General method B 459 ⁇ 9.23 (s, 1H), 8.75 (s, 1H), 8.04 (m, 1H), 7.50 (brs, 1H), 7.45-7.25 (m, 7H), 6.90 (brs, 1H), 6.36 (s, 1H), 3.42 (s, 2H), 1.24 (s, 9H) 1-(1-(3-(2-amino-2- oxoethyl)phenyl)-3-t- butyl-1H-
  • Example A14 (0.600 g, 1.7 mmol, 1.0) and 7N N 3 in MeOH (9.8 ml, 69 mmol, 40 eq) was heated in a sealed screw-cap vial at 60° C. for 36 h. More 7N N 3 in MeOH (9.8 ml, 69 mmol, 40 eq) was added and the reaction heated at 60° C. 24 h. The solution was concentrated to a purple residue of 2-(3-(5-amino-3-cyclopentyl-1H-pyrazol-1-yl)phenyl)acetamide. MS (ESI) m/z: 285.2 (M+H + ).
  • Example A15 (0.1000 g, 0.218 mmol, 1.00 eq) and 4-(4-aminophenyl)isoindolin-1-one (0.0488 g, 0.218 mmol, made according to literature procedures) were combined to yield 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea (51.7 mg, 44.5% yield).
  • Example A15 (0.0805 g, 0.175 mmol, 1.00 eq) and Example A11 (0.0442 g, 0.175 mmol) were combined to yield 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (18.3 mg, 19% yield).
  • Example 23 (80 mg, 0.17 mmol) was saponified to afford 3- ⁇ 3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]-1H-pyrazol-1-yl ⁇ benzoic acid (60 mg, 79% yield).
  • Example 34 To a stirred solution of Example 34 (0.150 g, 0.325 mmol, 1.0 eq), (3S)-( ⁇ )-3-(dimethylamino)pyrrolidine (0.0446 g, 0.390 mmol, 1.2 eq) and TBTU (0.125 g, 0.390 mmol, 1.2 eq) in DMF (3 mL) was added I-PR2NET (0.173 ml, 0.975 mmol, 3.0 eq). The resulting solution was stirred at RT. Upon completion, the reaction was quenched with 3N HCl (pH 1-2) and extracted with EtOAc (1 ⁇ ). This extract was set aside.
  • Example 34 To a stirred solution of Example 34 (130 mg, 0.282 mmol), in DMF (3 mL) was added HOBT (48 mg, 0.310 mmol) and EDC (68 mg, 0.352 mmol). The mixture was stirred for 15 min and then treated with (S)-3-aminopropane-1,2-diol (32 mg, 0.352 mmol), stirred at RT overnight, and then diluted with H 2 O (20 mL).
  • HOBT 48 mg, 0.310 mmol
  • EDC 68 mg, 0.352 mmol
  • Example 34 (100 mg, 0.20 mmol) and 2-aminoEtOH (2 mL) were combined to afford 1-(3-t-butyl- ⁇ 1-[3-(2-hydroxyethylamino)-2-oxo-thyl]-phenyl ⁇ -1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)-urea (70 mg, 69% yield).
  • Example A6 145 mg, 0.38 mmol
  • Example A16 80 mg, 0.40 mmol
  • Example A6 145 mg, 0.38 mmol
  • Example A16 80 mg, 0.40 mmol
  • Methyl 2-(3-nitrophenyl)acetate (9.6 g, 49 mmol) was treated with conc. NH 4 OH (24 ml, 172 mmol). The suspension was stirred briskly at RT until complete, then chilled thoroughly in an ice bath. The solids were collected by filtration, rinsed sparingly with ice H 2 O and dried to yield pure 2-(3-nitrophenyl)acetamide as an off-white solid (7.47 g, 84% yield).
  • N-(3-nitrophenethyl)-2,2,2-trifluoroacetamide (0.215 g, 101% yield) as an oil that solidified on standing.
  • N-(3-nitrophenethyl)-2,2,2-trifluoroacetamide 9.05 g, 34.5 mmol
  • MeOH MeOH
  • 10% Pd/C 50% H 2 O wet
  • the resulting suspension was placed under H 2 (3 atm) at RT overnight.
  • the reaction was filtered through Celite® and the cake rinsed with MeOH.
  • the filtrate was concentrated to provide N-(3-aminophenethyl)-2,2,2-trifluoroacetamide as an oil (7.83 g, 98% yield).
  • N-(3-aminophenethyl)-2,2,2-trifluoroacetamide hydrochloride (0.27 g, 1.0 mmol) was suspended in 6M HCl (2.0 mL) and cooled thoroughly in an ice bath. This was rapidly stirred while a solution of NaNO 2 (73 mg) in H 2 O (1.0 mL) was added slowly. The mixture was stirred at 0-5° C. for 45 min and was then treated with SnCl 2 .2H 2 O (1.3 g, 5.8 mmol) in 6N HCl (4.0 mL). The resulting suspension was stirred at 0-5° C. for 3 h and then carefully quenched with 3N NaOH (15 mL) to pH 7-8.
  • Example A17 (0.180 g, 0.51 mmol) and 2,3-dichlorophenyl isocyanate (82 mg, 0.53 mmol) were combined to yield 1-(3-t-butyl-1-(3-(2-(2,2,2-trifluoro-acetamido)ethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichloro-phenyl)urea as an orange foam (0.134 g, 52% yield).
  • Example 39 To a stirring solution of Example 39 (54.2 mg, 0.121 mmol) in MeOH (1.2 mL) at RT was added aq. formaldehyde (37 wt %, 0.036 mL, 0.49 mmol) and conc. formic acid (0.037 mL, 0.97 mmol). The reaction was stirred at 60-65° C. overnight, then cooled to RT, diluted with 1N HCl and filtered. The filtrate was made basic (pH 13) with 3N NaOH and extracted with CH 2 Cl 2 (2 ⁇ ).
  • Example 5 Using general method C, Example 5 (0.17 g, 0.39 mmol) was reduced to yield 1-(1-[3-(aminomethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl)-3-(3-bromophenyl)urea as the HCl salt (0.131 g, 70% yield).
  • Example 9 (50 mg, 0.12 mmol) was reduced to afford 1- ⁇ 1-[3-(aminomethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl ⁇ -3-(2,3-dichloro-phenyl)urea as a white solid (20.6 mg, 41% yield).

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US8163756B2 (en) 2012-04-24
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AU2005321946A1 (en) 2006-07-06
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