5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases

Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.

Graphical abstract5-((4-Aminopiperidin-1-yl)methyl)-pyrrolotriazine dual EGFR and HER2 protein tyrosine kinase inhibitor, 1c, exhibited potent kinase inhibition, antiproliferative activity, and good oral efficacy in EGFR/HER2 driven human tumor xenograft models. A broad range of potent pyrrolotriazine dual EGFR and HER2 kinase inhibitors are possible with the C5 aminopiperidine solubilizing group.Figure optionsDownload full-size imageDownload as PowerPoint slide