4-Anilino-6,7-dialkoxyquinolime-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors

The synthesis and SAR of a series of 4-anilino-6,7-dialkoxyquinoline-3-carb onitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3,4-dialkoxyanilines with ethyl (ethoxymethylene )cyano acetate followed by thermal cyclization gave, regiospecifically, 6,7 -dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitriles. Chlorination (POCl3) followed by the reaction with substituted anilines furnished the 4-anilino- 6,7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alterna te synthesis of these compounds starts with a methyl 3,4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH4Cl, MeOH-H2O) gave a methyl 2-amino -4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cycli zation using LiCH2CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3- carbonitrile, which was transformed as before. Compounds containing acid, e ster, amide, carbinol, and aldehyde groups at the 3-position of the quinoli ne ring were also prepared for comparison, as were several 1-anilino-6,7-di methoxyisoquinoline-4-carbonitiriles The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF- R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position wa s studied. The compounds were further evaluated for their ability to inhibi t the growth of cell lines that overexpress EGF-R or HER-2. It was found th at 4-anilino quinoline-3-carbonitriles are effective inhibitors of EGF-R ki nase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EG;F-R kinase was constructed based on the X-ray s tructures of Hck and FGF receptor-1 kinase. The model suggests that with th e quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water m olecule which, in turn, interacts with Thr 830. It is proposed that the qui noline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.