Design, synthesis, and biological evaluation of novel 2-substituted aniline pyrimidine derivatives as potential and orally bioavailable Mer inhibitors with antitumor activities.

The constitutive overexpression of Mer tyrosine kinase (MerTK), strongly associated with tumorigenesis and progression across multiple malignancies, establishes it as a promising therapeutic target for oncology discovery. In this study, we systematically designed and synthesized a series of 2-substituted aniline pyrimidine derivatives as potent MerTK inhibitors. The lead compound 15f demonstrated excellent inhibitory activity against Mer kinase with an IC50 value of 37.5 ± 2.7 nM, coupled with broad-spectrum antiproliferative activities against A2780, MDA-MB-231, and HCT116 cancer cell lines. Notably, 15f exhibited minimal hERG liability, addressing critical safety concerns. Mechanistic studies revealed dose-dependent inhibition of cancer cell migration and induction of apoptosis, while pharmacokinetic evaluation demonstrated favorable drug-like properties including high AUC, prolonged half-life, and good oral bioavailability (F: 32.4 %). The bioavailability of 15f was significantly higher than that of compound UNC2250 (F: 23 %). These integrated findings position 15f as a structurally novel and multi-faceted MerTK inhibitor for therapeutic application in cancer patients.