Design and Optimization of a Series of 1‑Sulfonyl­pyrazolo[4,3‑<i>b</i>]pyridines as Selective c‑Met Inhibitors

c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit <b>7</b>. By rational design, a novel sulfonyl­pyrazolo­[4,3-<i>b</i>]­pyridine <b>9</b> with improved DMPK properties was discovered. Further elaboration of π–π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound <b>46</b> was selected as a preclinical candidate for further anticancer drug development.