Synthesis of 4-(phenylamino)pyrimidine derivatives as ATP-competitive protein kinase inhibitors with potential for cancer chemotherapy

The 4-(phenylamino)pyrimidine pharmacophore is found in a variety of differ ent compounds that function as ATP-competitive inhibitors of several import ant protein kinase enzymes. Specific inhibitors of the epidermal growth fac tor receptor (EGFR) tyrosine kinase have received the most attention, and s everal elaborations of the fundamental 4-(phenylamino)pyrimidine pharmacoph ore have now been reported as potent and selective inhibitors of this class of enzyme. Three separate pharmaceutical companies have now entered quinaz oline EGFR inhibitors into clinical trials for the treatment of cancer, dem onstrating the competitive nature of this area. Recent work with vascular e ndothelial growth factor (VEGF) and cyclin-dependent kinase (CDK) inhibitor s has shown that the field is still expanding, and will undoubtably continu e to show potential for some time to come. This review article concentrates on the synthetic approaches and chemical procedures that have been used fo r the production of these novel pharmaceutical agents.