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Organic compoundsOrganic compounds description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20090069360, Organic compounds. Brief Patent Description - Full Patent Description - Patent Application Claims
SUMMARY
The present invention relates to the discovery that certain compounds inhibit, regulate and/or modulate tyrosine and serine/threonine kinase and kinase-like proteins, such as RAF kinase, a serine/threonine kinase that functions in the MAP kinase signaling pathway, and is concerned with compositions which contain these compounds, and methods of using them to treat tyrosine and serine/threonine kinase and kinase-like dependent diseases, such as angiogenesis, cancer and cardiac hypertrophy. BACKGROUNDCells communicate various aspects of their extracellular environment to the nucleus by using various signal transduction pathways. Many of these, signals are transmitted by protein kinases which activate various factors through the transfer of phosphate groups. Disruption of signal transduction by inhibiting appropriate kinase activity can have a clinical benefit as has been demonstrated by imatinib, an inhibitor of bcr-abl kinase, which is marketed as its mesylate salt under the brand GLEEVEC (in the United States) or GLIVEC. The MAP kinase signaling pathway is known in the art as one of the pathways for growth factors to send their signal to proliferate from the extracellular environment to the cell nucleus. The growth factors activate transmembrane receptors located on the cell surface which in turn start a cascade whereby RAS is activated and recruits RAF kinase to the membrane where it is activated and in turn activates MEK kinase which then activates ERK kinase. Activated ERK kinase can move to the nucleus where it activates various gene transcription factors. Aberrations in this pathway can lead to altered gene transcription, cellular growth and contribute to tumorogenicity by negatively regulating apoptosis and transmitting proliferative and angiogenic signals. Inhibitors of RAF kinase have been shown to block signaling through the MAP kinase signaling pathway. The RAF kinase family is known to have three members designated C-RAF, also known as RAF-1, B-RAF and A-RAF. It has been reported that B-RAF kinase is commonly activated by one of several somatic point mutations in human cancer, including 59% of the melanoma cell lines tested. See, Davies, H. et al, Nature 417, 949-954 (2002). This invention relates to the discovery of a class of compounds that efficiently inhibit one or more members of the RAF kinase family. The RAF kinase inhibiting property of the compounds makes them useful as therapeutic agents for the treatment for proliferative diseases characterized by an aberrant MAP kinase signaling pathway, particularly many cancers characterized by overexpression of RAF kinase or an activating mutation of RAF kinase, such as melanoma having mutated B-RAF, especially wherein the mutated B-RAF is the V599E mutant. The present invention also provides a method of treating other conditions characterized by an aberrant MAP kinase signaling pathway, particularly where B-RAF is mutated, for example benign Nevi moles having mutated B-RAF, with the compounds. DESCRIPTIONA first aspect of the present invention provides a compound of formula (I)
or a pharmaceutical acceptable salt, ester or prodrug thereof for use as a pharmaceutical wherein
each of A1, A2, A3, A4 is independently selected from N or C—R3 where R3 represents H or a substituent moiety of C and where at least one of A1, A2 and A4 is N;
X is a linking moiety selected from N—H, substituted amino, O or S;
R1 is a substituent of the aromatic ring and n is an integer from 0 to 4;
Y and D are independently selected from O, S, CH2, NH, R8-substituted C, or R6-substituted N,
R6 is a substituent of the ring which contains Y and D and r is an integer from 0 to the maximum number of available valencies of the ring;
R2 is a substituted or unsubstituted moiety selected from hydrocarbyl and heterocyclic;
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