Tyrosine kinase inhibitors. 16. 6,5,6-tricyclic benzothieno [3,2-d]pyrimidines and pyrimido[5,4-b]- and -[4,5-b]indoles as potent inhibitors of the epidermal growth factor receptor tyrosine kinase

Several elaborations of the fundamental anilinopyrimidine pharmacophore hav e been reported as potent and selective inhibitors of the epidermal growth factor receptor (EGFr) tyrosine kinase. This paper reports on a series of i nhibitors whereby some 6,5-bicyclic heteroaromatic systems were fused throu gh their C-2 and C-3 positions to this anilinopyrimidine pharmacophore. Alt hough the resulting tricycles did not produce the enormous potency of some of the (5/6),6,6-bicyclic systems, the best of them had IC(50)s for the EGF r TK around 1 nM. Investigation of 4-position side chains in the indolopyri midines confirmed that m-bromoaniline was an optimal substituent for potenc y. Investigation of substitution within the C-(benzo)ring of benzothieno-py rimidines confirmed that introduction of an extra ring can change sharply t he effects of substituents when compared to similar bicyclic nuclei, and on ly two substituents were found which even moderately enhanced inhibitory ac tivity over the parent compound for this series.