LY2874455 Synthetic Process And Its Analogues Design, Synthesis And Activity Screening

Cancer is a common disease which is seriously harmful for human health. Date shows the occurrence and development of many cancers are closely related to tyrosine protein kinase(PTK). Fibroblast growth factor receptor(FGFR), a class of tyrosine protein kinase, is a research focus over the past decade. FGFRs play an important role in regulating tumor cell differentiation, proliferation, infiltration, migration, angiogenesis and survival. However, the activating mutation and over-expression of FGFRs have an impact on the occurrence and development of many cancers, such as breast carcinoma, bladder carcinoma, lung cancer, cervical cancer, multiple myeloma, liver cancer and renalcarcinoma. Thus, FGFR tyrosine protein kinase inhibitors have great values in cancer treatment.The inhibitors include selective inhibitors and non-selective inhibitors, now there are dozens of inhibitors in clinical and pre-clinical stage. Herein, we focused on the research of FGFR. In the research, we chose the small molecule compound LY2874455(Eli Lilly) as a lead compound, which is belong to Indazole vinyl compounds and specifically inhibits FGFR. To Study its synthesis technology, we considered some conditions which may affect the yield, these conditions include the reaction solvent, the reaction temperature, the equivalent ratio and the selection of intermediate. Ultimately, we explored three improved routes to provide the important intermediates and a simple, convenient and economical synthetic route for the follow-up synthesis of designed compounds.Considering the structure-activity relationship of LY2874455,we designed a series of LY2874455 analogs,totally 36 new compounds,then we tested the activity of these compounds in vitro and analyzed their structure-activity relationships.We have found that most compounds could cause the inhibition of FGFR to a certain degree,and nine of these compounds exhibited similar inhibitory activity compared with LY2874455.We chose five compounds to test the inhibition of KATO-3 gastric cancer cells in which FGFR is highly expressed,and the result was also good.Among them,the activity of A12 and A14 compounds were similar to that of positive control,further pharmacological screening test is still in progress.