Design, Synthesis And Preliminary Antitumor Activities Of Novel Pyrimidine Derivatives As ALK Kinase Inhibitors

According to the data of IARC, about 800 million people died of cancer in the worldwide every year, of which there are about 1.5 million people died of lung cancer.Lung cancer is the most deadly of all cancers, cancer is a serious threat to human health. In China, lung cancer is also a serious threat to the health of our residents, is the first cause of cancer death, accounting for 22.7% of all cancer deaths. At the same time, due to environmental pollution, poor eating habits and population ageing in china, the incidence of cancer is increasing in China, which is a serious threat to human life and health,the work of prevention and treatment for cancer will be a long way to go.Lung cancer includes the following two types:small cell lung cancer(SLCL),which is accounting for 10~15% of all lung cancer;Non-small cell lung cancer(NSCLC),which is compared with 85~90%.Relative to small cell lung cancer, however, the traditional surgery and chemotherapy for non-small cell lung cancer, the success rate is not high, and 5 years survival rate is only 15% or so, so the demand of molecular targeted therapy drugs for NSCLC is very urgent.So-called targeted therapy, which generally refers to the cell and molecular level,treats related diseasesmainly by targeting drug targets, such as through targeting positioning lung cancer treatment drug targets and making its specific binding to tumor cells, and to kill tumor cells, and to avoid damage to the body’s normal cells.Compared with traditional drugs, targeted drugs have the characteristics of high efficacy and low toxicity, which also provides a new way for NSCLC treatment.Anaplastic lymphoma kinase(ALK) is a kind of receptor tyrosine kinases(RTKs), its activation can promote tumor cell proliferation and differentiation, and promotes the development of drug resistance of tumor cells.Studies have been reported that the ratio of ALK gene rearrangement in NSCLC patients was 3% ~ 6%, the number of patients with NSCLC is very huge,in addition, the form of ALK fusion protein is found in inflammatory muscle fiber mother cell tumor(IMT), neuroblastoma and breast cancer.So from what has been discussed above,ALK kinase is a potential antitumor medicine target.ALK kinase inhibitors currently listed mostly exist resistance, side effects and high price and other shortcomings, and all of which are foreign products, therefore, there is an urgent needing to develop ALK kinase inhibitor drugs with strong anti-cancer effects, small side effects and our own intellectual property,to benefit the masses of cancer patients.This paper depthly analyzes the characteristics of NVP-TAE684 conjunction with ALK kinase complex crystalline and structure-activity relationships.Taking NVP-TAE684 as the lead compound,we design and synthesis twelve new compounds,all target compounds are not reported,the structure of them were identified by nuclear magnetic resonance.All twelve new target compounds were determined with T cell lymphoma cell line Karpas-299 cell by MTT method to measure the inhibitory activity of them,taking the Ceritinib(LDK378)as the positive control, preliminary results showed that there are four target compounds(I-4, I-6, I-8 and II-2) showing good inhibitory activity in vitro, compared with the positive control,the active approachs to it or is slightly better than it, they can be used as candidates for emerging compounds for further modification of structure and biological activity evaluation, providing a possibility for us to look for new lead compounds with higher activity.