Synthesis of 4-(Phenylamino)pyrimidine Derivatives as ATP-Competitive Protein Kinase Inhibitors with Potential for Cancer Chemotherap

The 4-(phenylamino)pyrimidine pharmacophore is found in a variety of different compounds that function as ATP-competitive inhibitors of several important protein kinase enzymes. Specific inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have received the most attention, and several elaborations of the fundamental 4-(phenyl­amino)­­pyrimidine pharma­co­phore have now been reported as potent and selective inhibitors of this class of enzyme. Three separate pharmaceutical companies have now entered quinazoline EGFR inhibitors into clinical trials for the treatment of cancer, demonstrating the competitive nature of this area. Recent work with vascular endothelial growth factor (VEGF) and cyclin-dependent kinase (CDK) inhibitors has shown that the field is still expanding, and will undoubtably continue to show potential for some time to come. This review article concentrates on the synthetic approaches and chemical procedures that have been used for the production of these novel pharmaceutical agents.