The synthesis and SAR of a series of 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3, 4-dialkoxyanilines with ethyl (ethoxymethylene)cyanoacetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1, 4-dihydroquinoline-3-carbonitriles. Chlorination (POCl(3)) followed by the reaction with substituted anilines furnished the 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3, 4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH(4)Cl, MeOH-H(2)O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH(2)CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitriles. 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 was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilinoquinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EGF-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.

中文翻译：

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表皮生长因子受体激酶的4-Anilino-6,7-二烷氧基喹啉-3-甲腈抑制剂及其与4-anilino-6,7-二烷氧基喹唑啉抑制剂的生物立体关系。

描述了表皮生长因子受体（EGF-R）激酶的一系列4-苯胺基-6，7-二烷氧基喹啉-3-甲腈抑制剂的合成和SAR。将3，4-二烷氧基苯胺与（乙氧基亚甲基）氰基乙酸乙酯缩合，然后热环化，区域特异性地得到6，7-二烷氧基-4-氧代-1，4-二氢喹啉-3-甲腈。氯化（POCl（3）），然后与取代的苯胺反应，提供了EGF-R激酶的4-苯胺基-6，7-二烷氧基喹啉-3-甲腈抑制剂。这些化合物的另一种合成方法是从3，4-二烷氧基苯甲酸甲酯开始。硝化然后还原（Fe，NH（4）Cl，MeOH-H（2）O），得到2-氨基-4,5-二烷氧基苯甲酸甲酯。使用DMF-乙缩醛形成formation，然后使用LiCH（2）CN环化，得到6,7-二烷氧基-4-氧代-1,4-二氢喹啉-3-腈 像以前一样进行了改造。还制备了在喹啉环的3-位上含有酸，酯，酰胺，甲醇和醛基的化合物，以及几种1-苯胺基-6,7-二甲氧基异喹啉-4-腈。评价化合物抑制EGF-R催化结构域的自磷酸化的能力。就6,7-烷氧基，苯胺取代基和3-位取代基的性质而言，研究了这些抑制剂的SAR。进一步评估了化合物抑制过表达EGF-R或HER-2的细胞系生长的能力。已经发现4-苯胺基喹啉-3-甲腈是EGF-R激酶的有效抑制剂，其活性与基于4-苯胺基喹唑啉的抑制剂相当。基于Hck和FGF受体-1激酶的X射线结构，构建了新的EGF-R激酶同源模型。该模型表明，在基于喹唑啉的抑制剂中，N3原子与水分子发生氢键结合，而水分子又与Thr 830相互作用。有人提出，喹啉-3-腈以类似的方式与水结合分子被与相同的Thr残基相互作用的氰基取代。