Focal adhesion kinase (FAK) is a kind of tyrosine kinase that modulates integrin and growth factor signaling pathways. FAK is a promising therapeutic target, involving in cancer cell migration, proliferation and survival. In order to design highly active FAK inhibitors, a three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics simulation were combined to study the interaction between pyrimidine derivatives and FAK. Both the comparative molecular field analysis (CoMFA) model (q² = 0.664, r² = 0.973) and comparative molecular similarity index analysis (CoMSIA) model (q² = 0.755, r² = 0.999) indicated that the constructed QSAR models are stable and reliable. Based on the model, several new compounds were designed and their inhibitory activities were validated by molecular docking and molecular dynamics simulation. The results show that the complex of FAK with new designed compounds is stable during the simulation, which supports the fact that the new compounds are potential FAK inhibitors.