C-5 Aryl Substituted Azaspirooxindolinones Derivatives: Synthesis and Biological Evaluation as Potential Inhibitors of Tec Family Kinases

The interleukin-2-inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in human. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure-activity relationship study of a new series of 5'-(benzo[d][1,3]dioxol-5-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one linked with N-acyl and C-5 aryl-substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds 11, 12, 14 and 15 showed high antiproliferative activity against ITK and BTK cell lines. Compounds 11 and 12 with a C-5 benzodioxole group and gem-dialkyl group attached to carbonyl on piperidine were highly effective in ITK-high Jurkat and CEM cell lines, and compound 14, a biotin analogue, was identified as a good inhibitor of BTK-high RAMOS cells. Compound 15 with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines.