- AURORA KINASE MODULATORS AND METHOD OF USE
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The present invention relates to chemical compounds having a general formula (I) wherein A1-5 and 7-8, D', L1, L2, R1, R3, R6-8, n and o are defined herein, and synthetic intermediates, which are capable of modulating the activity of Aurora kinase proteins and, thereby, influencing various disease states and conditions related to the activities of Aurora kinases. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.
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- Pyrrolotriazine inhibitors of kinases
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The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2, FGFR-1, PDGFR, HER-1, HER-2, thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases associated with signal transduction pathways operating through growth factor receptors.
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Page/Page column 20-21
(2008/06/13)
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- Discovery of the pyrrolo[2,1-f][1,2,4]triazine nucleus as a new kinase inhibitor template
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The pyrrolo[2,1-f][1,2,4]triazine nucleus was identified as a novel kinase inhibitor template which effectively mimics the well-known quinazoline kinase inhibitor scaffold. Attachment of a 4-((3-chloro-4-fluorophenyl)amino) substituent to the template provided potent biochemical inhibitors of the tyrosine kinase activity of EGFR, as well as inhibition of cellular proliferation of the human colon tumor cell line DiFi. Attachment of a 4-((3-hydroxy-4-methylphenyl)amino) substituent provided potent inhibitors of VEGFR-2 which also showed effects on the VEGF-dependent proliferation of human umbilical vein endothelial cells. Biological activity was maintained with substitution at positions 5 or 6, but not 7, suggesting that the former positions are promising sites for introducing side chains which modulate physicochemical. properties. Preliminary inhibition studies with varying ATP concentrations suggest that, like the quinazoline-based kinase inhibitors, the pyrrolotriazine-based inhibitors bind in the ATP pocket.
- Hunt, John T.,Mitt, Toomas,Borzilleri, Robert,Gullo-Brown, Johnni,Fargnoli, Joseph,Fink, Brian,Han, Wen-Ching,Mortillo, Steven,Vite, Gregory,Wautlet, Barri,Wong, Tai,Yu, Chiang,Zheng, Xiaoping,Bhide, Rajeev
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p. 4054 - 4059
(2007/10/03)
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- Methods of treating p38 kinase-associated conditions and pyrrolotriazine compounds useful as kinase inhibitors
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Methods of treating one or more conditions associated with p38 kinase activity are disclosed comprising administering to a patient in need thereof at least one compound having the formula (I): 1or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein R3 is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, or NH2, preferably methyl, and X, R1 through R6, and Z are as described in the specification. Advantageously the groups —ZR4R5 taken together comprise an —NH-substituted aryl.
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