A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized and evaluated for their in vitro cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds, 11_a, 11_b, 12_b, 15_b and 16_a, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound 11_b showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC₅₀ values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC₅₀ values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFR^WT and EGFR^T790M using homogeneous time resolved fluorescence (HTRF) assay. Compound 11_b was also found to be the most active compound against both EGFR^WT and mutant EGFR^T790M, exhibiting IC₅₀ values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound 11_b can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound 11_b upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFR^WT and EGFR^T790M. Additional in silico ADMET studies were performed to explore drug-likeness properties.