[摘要]：C-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. The current studies began with the design and synthesis of novel pyrimidone I (R = Me), which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified I [R = 3-(4-morpholinyl)propyl] as a bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compds. that were more potent both in vitro and in vivo than I [R = 3-(4-morpholinyl)propyl] and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.
