Design And Synthesis Of1,5-bicyclic Pyrazolones As Selective Axl And Mer Receptor Tyrosine Kinase Inhibitors

This work focused on the design and synthesis of1,5-bicyclic pyrazolones as selectiveAxl and Mer receptor tyrosine kinase inhibitors. The synthetic methodology to constructvarious fused1,5-bicyclic pyrazolone derivatives was also investigated.In Chapter One, the development of Axl and Mer inhibitors as anti-cancer drugs isreviewed. Receptor tyrosine kinases (RTK) regulate cellular processes including survival,growth, differentiation, adhesion, proliferation, and motility. RTKs have been shown to playan important role in signal transduction in both normal and malignant cells. Overexpressionor ectopic expression of the TAM receptors, a RTK subfamily (Tyro-3, Axl, and Mer), hasbeen detected in a wide array of human cancers and is associated with poor prognosis.Furthermore, activation of Axl and Mer are associated with chemoresistance and targeteddrug resistance, as well as tumor metastasis. As drug resistance and metastasis are majorproblems in cancer treatment, development of Mer and Axl inhibitors constitutes a noveltherapeutic strategy to treat cancer patients.In Chapter Two, a series of Axl and Mer inhibitors was designed and synthesized. Basedon the structures of known, non-selective Axl inhibitors BMS777607and Ningetinib, weprepared37bicyclic pyrazolone derivatives by a convergent synthetic strategy. Thestructures and conformation of the pyrazolones were unambiguously confirmed by thecrystal structure of two exemplary compounds.In Chapter Three, we described our discovery of selective Axl and Mer kinase inhibitorsand evaluated37compounds for their activities against Axl, Mer and c-Met. Since the leadcompounds BMS777607and Ningetinib are multi-kinase inhibitors, we initially tested ourcompounds against c-Met and VEGFR-2to assess the selectivity of bicyclic pyrazolonederivatives. To this end, the bicyclic pyrazolone compounds showed potent inhibitoryactivity against Axl and Mer and much improved selectivity against c-Met. Among37 compounds tested, we identified compound2-11g as the most potent kinase activity againstAxl and Mer, and the best selectivity over c-Met. Compound2-20e was also unique in termof its Axl selectivity over Mer and c-Met. Based on the results from these kinase assays, wegained better understanding on the structure-activity relationship (SAR) for the bicyclicpyrazolone-derived kinase inhibitors.In Chapter Four, we designed a synthetic methodology to construct structural diversifiedbicyclic pyrazolones compounds from readily available starting material. Accordingly, thescope of the synthesis was explored and the reaction was optimized, as demonstrated in thepreparation of23exemplary compounds. Our synthetic approach to these bicyclicpyrazolones constitutes a novel, facile method to access these therapeutically importantcompounds.In conclusion, we designed and synthesized a series of novel bicyclicpyrazolone-derived Axl and Mer inhibitors. Based on the structure-activity relationshipstudies, we identified two promising compounds with potent kinase activities and significantselectivity among kinases we tested. Further, we designed and explored a facile syntheticmethod to access structurally diversified bicyclic pyrazolone derivatives, which willfacilitate our investigation on novel kinase inhibitors.