c-Met has been considered as an attractive target for developing antitumor agents. The highly selective c-Met inhibitors provide invaluable opportunities for the combination with other therapies safely to achieve the optimal efficacy. In this work, a series of triazolopyrazine c-Met inhibitors with exquisitely selectivity were investigated using a combination of molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular dynamics simulation. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models were developed to reveal the structural determinants for c-Met inhibition. Both models were validated to have high reliability and predictability, and contour map analysis suggested feature requirements for different substituents on the scaffold. It is worth noting that an important hydrogen bond rich region was identified in the unique narrow channel, which is distinct from other kinases. Molecular dynamics simulations and binding free energy calculations provided further support that suitable groups in this hydrogen bond rich region made great contributions to the binding of ligands. Moreover, hydrogen bonds with residues of the narrow channel were also indicated to be essential to improve the activity and selectivity. This study will facilitate the discovery and optimization of novel c-Met inhibitors with higher activity and selectivity.