Design,Synthesis And The SAR Study Of Pyrido[2,3-b] Pyrazine-based C-Met Kinase Inhibitors

The hepatocyte growth factor receptor(HGFR)family is an important lineage of the receptor tyrosine kinase superfamily.The c-Met/HGF signaling pathway is closely related to tumor development and metastasis.C-Met small molecule inhibitors can block the signal pathway,thereby reaching the goal of target therapy for cancer.The c-Met small molecule inhibitors Crizotinib and Cabozantinib have came into the market,but the Crizotinib has been found the side effects and drug resistance.Notably,a study in 2007 showed that the amplification of the MET gene is one of the key reasons for the drug resistance of EGFR inhibitors.So it is urgent to develop a new type of c-Met kinase small molecule inhibitors.We have identified a small molecule c-Met kinase inhibitor 2-4(IC50=0.24?M)with 1H-imidazo[4,5-b]pyridine scaffold.Starting from the c-Met inhibitor 2-4,based on the binding modes,we design two classes of pyrido[2,3-b]pyrazine-based c-Met inhibitors.On the one hand,baesd on the compound 1-1a we designed Type ? c-Met small molecule inhibitors with different substituents at positions C-2/C-8 or C-3/C-8.We synthesized 14 compunds which almost have good acitivity.The highest activity of compound to c-Met is nearly an order of magnitude higher than the 1H-imidazo[4,5-b]pyridine scaffold.On another hand,we want to discover a new type of c-Met selective inhibitors,evaluate its antitumor activity.Based on the U binding mode,we designed Type ? c-Met small molecule inhibitors with different substituents at positions C-2/C-8 or C-3/C-8.We synthesized 21 compunds,and part of them showed inhibitory activity.In all,we design two classes of pyrido[2,3-b]pyrazine-based c-Met inhibitors by introducing different substituents at positions C-2/C-8 or C-3/C-8 as Type ? and Type ?c-Met small molecule inhibitors.Among the series of Type ? small molecule inhibitors we designed to synthesize,the highest activity of compound to c-Met is nearly an order of magnitude higher than the 1H-imidazo[4,5-b]pyridine scaffold.We succeed in providing the powerful support for the further development of novel pyrido[2,3-b]pyrazine-baesd c-Met kinase inhibitors.