Synthesis Of Small Molecule Kinase Inhibitors Containing Four-membered Heterocycles And Iridium Catalyzed Reaction

This thesis is mainly focused on the syntheses of four-membered heterocycles and their applications in the modification of small molecule kinase inhibitors. Microwave-assisted solventless reaction of iridium-catalyzed alkylation of amines with alcohols in the absense of base was another focus as well.In recent years, much attention had been drawn on the discovery and development of four-membered heterocycles (oxetanes, azetidines, thietanes) and their applications in drug discovery. Because of their unique structure characteristics, grafting these small four-membered heterocycles unit into a drug molecular scaffold can create new patent space, enhance water solubility, reduce lipophilicity and improve metabolic stability of target parent compounds. The targeted tumor therapy is a great achievement for cancer therapy. Small molecule kinase inhibitors are important therapeutic areas for cancer research. Small molecule kinase inhibitors were selected as our targets for the study the four-membered heterocyclic modification. All of the selected kinase inhibitors consist of a water soluble group in the solvent region. Four-membered heterocycles can replace these soluble groups to achieve novel small molecule kinase inhibitors. The syntheses of Imatinib derivatives (Imatinib is a BCR-ABL kinase inhibitor for the treatment of the chronic myeloid leukemia marketed in 2001), Erlotinib derivatives (Erlotinib is an EGFR kinase inhibitor for the treatment of metastatic NSCLC marketed in 2004) and Lapatinib derivatives (Lapatinib is an EGFR/Her2 dual kinase inhibitor for the treatment of breast cancer marketed in 2007) containing contained four-membered heterocycles were the main efforts. Five chapters are included in the thesis.Chapter 1 Synthesis and scale-up of four-membered heterocyclesAlthough the structures of four-membered heterocycles are very simple, it is difficult to synthesize and scale up these small molecules. Herein two important spirocycles, namely 2-oxa-6-aza-spiro[3.3]heptane and 2-thia-6-aza-spiro[3.3]heptane were scaled up to about 5-10g scale. Two novel fluorinated spirocyclic compounds 1-trifluoromethyl-2-oxa-6-aza-spiro[3.3]heptane and 1-trifluoromethyl-2-thia-6-aza-spiro[3.3]heptane were synthesized.Chapter 2 Synthesis of Imatinib derivatives containing four-membered heterocyclesIn this chapter, the structure modification of Imatinib was focused on piperazine replacement with different four-membered heterocycles. Herein 8 Imatinib derivatives were synthesized. These compounds were evaluated for cytotoxic properties in K562 (Human leukemic cell line) and MKN-45 (Gastric cancer cell line). Most compounds (10smol/l) showed more than 50% inhibition rates in MKN-45 cell line, but failed to exhibit efficacy in K562 cell line. Excellent potency of compound B08 on the MKN-45 cell line (ICso:8.3 nM) was discovered. Compound B08 was also found to be selective when measured against other cancer cell lines.Chapter 3 Synthesis of Erlotinib derivatives containing four-membered heterocyclesIln the third chapter,12 of Erlotinib derivatives with four-membered heterocycles on solvent region were synthesized. All the compounds were evaluated for cytotoxic properties in nonsmall cell lung cancer cell line (HCC827) and EGFR kinase inhibitory assay. The most potent compound, compound C14. had ICso values of 15.5 nM on HCC827 cell line and 2.2 nM on EGFR kinase inhibitory activity. Most of these compounds showed good potency on the EGFR inhibitory assay. These data confirmed that these compounds can block the signal transfer of EGFR and thus exhibitored good anti-cancer activity.Chapter 4 Synthesis of Lapatinib derivatives containing four-membered heterocyclesFrom the structure modification of Lapatinib, we mainly focused on the six position of Lapatinib where 2-methanesulfonyl-ethylamine group was replaced by many different four-membered heterocycles. Herein 12 of Lapatinib derivatives containing four-membered heterocycles were synthesized. The kinase enzyme assay indicated that the compounds prepared are EGFR/Her2 kinase inhibitors. The most potent compound, compound D09, has IC50 values of 20/8.6 nM on EGFR/Her2 kinase inhibitory activity. Chapter 5 Microwave-assisted solventless reaction of iridium-catalyzed alkylation of amines with alcohols in the absense of baseRecently it is a hot topic for the iridium catalyzed alkylation of amines with alcohols in the organic synthesis methodology. One green and atom-economic alkylation reaction conditions was found which are all effective for monoalkylation, dialkylation, as well as triaklyation of amines. In the presence of 1 mol%[Cp*IrCl2]2, microwave-assisted iridium catalyzed alkylation of amines with alcohols was undertaken under solvent free and base free conditions. The reaction is easily worked up and the yield is generally good.