Design and Synthesis of 2-Aminopyrazolpyrimidopyridone Derivatives as RETV 804M and RETG 810C 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., RETG810R/S/C). Herein, a class of 2-aminopyrazolpyrimidopyridone derivatives as RETV804M and RETG810C 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-RETV804M mutation with IC50 values of 0.271 μM. Interestingly, another one of these series compounds, 7qe, suppressed BaF3 cells harboring CCDC6-RETV804M and CCDC6-RETG810C 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 RETV804M and RETG810C inhibitors overcoming the clinical acquired resistance.