Based on the cabozantinib scaffold, novel c‐Met inhibitors were rationalized from the limited knowledge of structure‐activity relationships for the quinoline 6‐position. Emphasis was given to modifications capable of engaging in additional polar interactions with the c‐Met active site. In addition, ortho‐fluorinations of the terminal benzene ring were explored. Fifteen new molecules were synthesized and evaluated in a c‐Met enzymatic binding assay. A wide range of substituents were tolerated in the quinoline 6‐position, while the ortho‐fluorinations performed were shown to give considerable reductions in the c‐Met binding affinity. The antiproliferative effects of the compounds were evaluated in the NCI60 cancer cell line panel. Most notably, compounds 15b and 18b were able to inhibit cell proliferation more efficiently than cabozantinib in leukemia, CNS, and breast cancer cell lines. The in vitro data agreed well with the in silico docking results, where additional hydrogen bonding was identified in the enzymatic pocket for the para‐amino substituted 15b and 18b.
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