Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

•New pyrazol-4-ylpyrimidine derivatives were designed as ROS1 kinase inhibitors.•Compound 7c was the most potent derivative against ROS1 kinase (IC50 = 24 nM).•Compound 7c showed high selectivity for ROS1 ∼170-fold, relative to the closely related kinase ALK.•A hypothetical model predicting the required essential features for ROS1 inhibitory activity was made.

With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a–e and 7a–e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.

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