Pyrido[2,3-d]pyrimidine derivatives exhibit potent EGFR inhibitory and anticancer activities. In this study, a series of novel pyrido[2,3-d]pyrimidine derivatives 10a–10f were synthesized via a multi-step procedure with high yields (80–90%) under relatively mild conditions and simple recrystallization-based purification. In silico investigations, including molecular docking and ADMET predictions, were performed to assess their potential as EGFR inhibitors. Docking results revealed that compounds 10a–10f exhibited favorable binding energies (− 9.01 to − 10.40 kcal/mol) at the EGFR active site, surpassing the reference drug erlotinib (− 8.06 kcal/mol) and indicating enhanced binding affinity. ADMET analysis confirmed compliance with Lipinski\\\\\\\'s rule of five, absence of PAINS/Brenk alerts (unlike erlotinib), and favorable pharmacokinetic properties, including high gastroin­ testinal absorption and Caco-2/MDCK permeability values similar to those of erlotinib. These findings suggest that the synthesized pyrido[2,3-d]pyrimidine derivatives are promising lead candidates for targeting EGFRoverexpressing cancer cells, such as lung, colorectal, and breast malignancies.

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