A novel c-Met inhibitor containing chiral pyrrolidine side chain and its application as anti-tumor agents

c-Met inhibitors have demonstrated encouraging efficacy in the treatment of non-small cell lung cancer. However, some of these drugs are conditionally approved and still face certain limitations and challenges, primarily manifested as poor blood-brain barrier penetration, off-target toxicity, drug resistance, and low oral bioavailability. These factors restrict their clinical efficacy and widespread application. To discover novel c-Met inhibitors with high potency, minimal toxic side effects, and the ability to penetrate the blood-brain barrier, we designed and synthesized 33 new pyrimidine derivatives using Tepotinib as the lead, employing bioisosterism and conformational restriction strategies. Their anti-tumor activities were evaluated in vitro and in vivo. Among these derivatives, the optimal compound 11g exhibited IC₅₀ values of 4.01 nM and 3.50 nM against MHCC97H and EBC-1 cells, respectively. In the EBC-1 xenograft mouse model, at a dose of 4 mg/kg, 11g achieved a tumor growth inhibition (TGI) rate of 64.9%, which was significantly higher than that of Tepotinib (33.5%) at the same dose. Pathological evaluation further confirmed that 11g possessed improved safety and reduced toxic side effects. In addition, 11g displayed superior blood-brain barrier permeability and metabolic stability compared with the lead compound. Mechanistic studies demonstrated that 11g effectively inhibits tumor cell proliferation and migration by binding to the c-Met protein and induces cell apoptosis. In summary, as a novel and highly potent c-Met inhibitor, 11g shows promising potential for the treatment of NSCLC, particularly in the prevention and treatment of tumor brain metastasis.