A series of 4-aminoquinazoline linked to cyanopyrimidine derivatives (6a-c and 7a-f) was designed, synthesized with good yields and screened at National Cancer Institute (NCI)-disease oriented anticancer screen protocol against nine panel of cancer cell lines. Comprehensively, the structures of the synthesized compounds were confirmed by different spectroscopic methods like melting points, H1- NMR, 13C- NMR and HRMS, Moreover, the most active compound 7a was selected for in vitro enzyme inhibitory activities against epidermal growth factor receptor and cyclin dependent kinase-2 enzymes. Cell cycle analysis and apoptosis were evaluated on three different cancerous cells; UO-31, MCF-7 and IGROV-1. Finally, the molecular modelling for compound 7a inside the ATP binding site of epidermal growth factor receptor and cyclin dependent kinase-2 enzymes was performed to predict the binding mode to the active site of these enzymes using lapatinib and ribociclib as standards respectively. Our research found that quinazoline-containing cyano pyrimidine derivatives were promising cytotoxic agents for further study.