Platelet-derived growth factor receptors (PDGFRs) are now considered promising targets for the treatment of osteosarcoma. Herein, the design, synthesis, and structure-activity relationships (SAR) of novel pyrimidine-2,4-diamine derivatives that selectively inhibit PDGFRα/β kinases have been studied. The screening cascades revealed that 7m was the preferred compound among these derivatives, with IC50 values of 2.4 and 0.9 nM for PDGFRα and PDGFRβ, respectively. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) experiment revealed that 7m has a substantial cytotoxic effect against all osteosarcoma cancer cell lines; 7m also displayed robust antitumor effects and low toxicity in a xenograft model. Additionally, 7m showed excellent bioavailability (F = 62.9%), suitable half-life (T1/2 = 2.12 h), satisfactory metabolic stability, and weak CYP isoform inhibitory activity, suggesting that 7m is a potential drug candidate for PDGFR-driven osteosarcoma.