Design, synthesis, and biological activity evaluation of Pyrimido[4,5-b]pyridine-based derivatives as SOS1 inhibitors

SOS1 represents a promising therapeutic target for pan-RAS inhibition. In this study, we designed and synthesized a series of pyrimido[4,5-b]pyridine derivatives using commercially available (R)-1-phenylethan-1-amine and pyrido[2,3-d]pyrimidine as starting matrials. After chlorination, subsequent chloro substitution, and palladium-catalyzed cross coupling reaction, total 21 target compounds were obtained and their structures were characterized by HR-MS, ¹H NMR, and ¹³C NMR. Then the SOS1 inhibition and antitumor activity were systematically evaluated in vitro and in vivo. Among the candidates, seven compounds exhibited potent inhibitory effects in enzyme as well as cellular assays with IC₅₀ values ranging from 56 to 207 nM. Particularly, in the pharmacokinetic studies compound 6f demonstrated superior systemic exposure in mice and rats. In the NCI-H358 (NSCLC, KRAS G12C) subcutaneous xenograft model, compound 6f exhibited significant antitumor efficacy, achieving a tumor growth inhibition (TGI) rate of 118.95%. Furthermore, 6f displayed a favorable safety profile, highlighting its potential as a drug candidate. These findings support the continued development of 6f as a novel SOS1 inhibitor for anticancer therapy.