Design, Synthesis And Biological Activity Evaluation Of EGFR Inhibitors In Non-small Cell Lung Cancer

In the past 30 years, the death of lung cancer has increased about 465% and the incidence grows by 26.9% annually. Non-small cell lung cancer (NSCLC) is the largest subgroup of lung cancer, occurring at the frequency of about 80%. The current standard of care for NSCLC is far from satisfactory, with 5 year survival rate below 20%. According to literature, almost 50%～80% NSCLC patients showed over-expression of EGFR, therefore the development of small-molecule tyrosine kinase inhibitors (TKIs) that target EGFR has revolutionised the management of NSCLC.The first-generation EGFR-TKIs such as gefitinib and erlotinib have achieved great success for the treatment of NSCLC. Progression-free survival and the quality-of-life have been significantly improved. Meanwhile, compared with chemotherapy, they did not cause side effects such as myelosuppression, nausea and neurotoxicity. However, EGFR mutation-positive patients eventually develop resistance to erlotinib or gefitinib after 9-12 months of treatment. The second-generation EGFR-TKIs, including afatinib, dacomitinib and neratinib, can better differentiate the cancer cell and normal cell, which reduce the side effect. However, they showed low selectivity of T790M mutations. The third-generation EGFR-TKIs irreversibly inhibit activating EGFR mutations including the most common T790M mutation.The third generation EGFR-TKIs not only demonstrated significantly improved safety by sparing EGFRWT, but also exhibited better potency and drug resistancy profile. In order to obtain the third-generation EGFR-TKIs inhibitors with independent intellectual property rights, a series of novel compounds were designed and synthesized, based on the lead compound of CO-1686 by principle of bioisosterism and hybride. All the compounds have a meta- acrylamide derived from the 4- or 2- position of the core pyrimidine, which targets the cys 797 in the EGFR catalytic domain. In the EGFRT790 kinase, the smaller threonine residue is replaced by the bulkier methionine, which affford a higher affinity with 5-CF3 substitution in the diaminopyrimidine ring, so it is not changed. The linker at 4-position can be either an -O- or -NH-, and the length of it is changed to explore space to ensure a comformation in which the electrophile reaches the targeted cys797. Ortho-methoxyaniline was replaced by pyridones to improve solubility with reduced cLogP. Piperazine which is easily oxidized was substituted by spiro or bicyclic group to inprove stability.In this thesis,14 compounds were designed and synthesized while their structures were confirmed by’HNMR and ESI-MS. Biological activity screening of all these compound were tested by MTT colorimetry in vitro tumor cell paoliferation inhibitory activity, while CO-1686 were used as control. The preliminary activity test results showed that half of the compounds showed high activity against EGFRT790M mutations, some of them have better stability than that of CO-1686. These compounds could be used as a promising leads for further optimization.