Design and Synthesis of 2‐Aminopyrazolpyrimidopyridone Derivatives as <scp> RET ^V </scp> ^{804 <scp>M</scp>} and <scp> RET ^G </scp> ^{810 <scp>C</scp>} Kinase Inhibitors

Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. The clinical therapeutic benefits of the second-generation RET inhibitor pralsetinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RET^G810R/S/C). Herein, a class of 2-aminopyrazolpyrimidopyridone derivatives as RET^V804M and RET^G810C solvent-front mutant inhibitors were designed and synthesized for overcoming pralsetinib resistance. One of the optimal compounds, 7la, exhibited inhibitory potency against the proliferation of BaF3 cells harboring CCDC6-RET^V804M mutation with IC50 values of 0.271 μM. Interestingly, another one of these series compounds, 7qe, suppressed BaF3 cells harboring CCDC6-RET^V804M and CCDC6-RET^G810C mutations with IC₅₀ values of 0.841 and 0.272 μM, respectively. The compound also dose-dependently suppressed the activation of RET and downstream signals. However, the relatively poor pharmacokinetic properties of these compounds will limit their further development. Therefore, compound 7qe might be a promising lead compound for the development of novel RET^V804M and RET^G810C inhibitors overcoming the clinical acquired resistance.