Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4‑d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family

Jeff B. Smaill, Andrea J. Gonzales, Julie A. Spicer, Helen Lee, Jessica E. Reed, Karen Sexton, Irene W. Althaus, Tong Zhu, Shannon L. Black, Adrian Blaser, William A. Denny, Paul A. Ellis, Stephen Fakhoury, Patricia J. Harvey, Ken Hook, Florence O. J. McCarthy, Brian D. Palmer, Freddy Rivault, Kevin Schlosser, Teresa Ellis, Andrew M. Thompson, Erin Trachet, R. Thomas Winters, Haile Tecle, Alexander Bridges

Structure-activity relationships for inhibition of erbB1, erbB2 and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.