In order to explore novel TRK and ALK dual inhibitors, a series of 2-phenylamino-4-prolylpyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxicity and enzymatic activities. Delightfully, most compounds were detected moderated to excellent activities in cellular assay. Among them, compound 21 exhibited encouraging cytotoxicity on KM12, H2228 and KARPAS299 cells with IC₅₀ values of 0.86, 0.141 and 0.072 μM. Meanwhile, the performances of 21 in the enzymatic assays were in good accordance with anti-proliferative activity with IC₅₀ values of 2.2, 9.3 and 38 nM towards TRKA, ALK^WT and ALK^L1196M, respectively. Compared with Entrectinib, compound 21 not only ensured the inhibitory activity on TRKA, but also improved the affinity with ALK and ALK^L1196M to a certain extent. Ultimately, the binding model of 21 with TRKA and ALK were ideally established through molecular docking, which further confirmed the SARs analysis.

为了探索新型TRK和ALK双重抑制剂，设计、合成了一系列2-苯基氨基-4-脯氨酰嘧啶衍生物，并对其体外细胞毒性和酶活性进行了评估。令人高兴的是，大多数化合物在细胞测定中都被检测到具有出色的活性。其中，化合物21对KM12、H2228和KARPAS299细胞表现出令人鼓舞的细胞毒性，IC ₅₀值为0.86、0.141和0.072 μM。同时，21个酶促检测的表现与抗增殖活性良好一致，对TRKA、ALK ^WT和ALK ^L1196M的IC _{50值分别为2.2、9.3和38 nM。}， 分别。与Entrectinib相比，化合物21不仅保证了对TRKA的抑制活性，而且在一定程度上提高了与ALK和ALK ^{L1196M的亲和力。}最终通过分子对接理想地建立了21与TRKA和ALK的结合模型，进一步证实了SARs分析。