Herein, we report an efficient synthetic approach towards trisubstituted imidazo [4,5-c]pyridines designed as inhibitors of Bruton's tyrosine kinase (BTK). Two alternative synthetic routes for the simple preparation of desired compounds with variable substitutions at the N1, C4, C6 positions were introduced with readily available building blocks. Further, the developed synthetic approach was feasible for isomeric compounds bearing imidazo [4,5-b]pyridine scaffolds. In contrast to expectations based on previous studies, the imidazo [4,5-c]pyridine inhibitor exhibited a significantly higher activity against BTK compared to its imidazo [4,5-b]pyridine isomer. An inherent SAR study in the series of imidazo [4,5-c]pyridine compounds revealed a remarkably high tolerance of C6 substitutions for both hydrophobic and hydrophilic substituents. Preliminary cellular experiments indicated selective BTK targeting in Burkitt lymphoma and mantle cell lymphoma cell lines. The inhibitors could thus serve as starting points for further development, eventually leading to BTK inhibitors that could be used after ibrutinib failure.

Department of Organic Chemistry Faculty of Science Palacký University 17 Listopadu 12 77146 Olomouc Czech Republic

Department of Organic Chemistry Faculty of Science Palacký University 17 Listopadu 12 77146 Olomouc Czech Republic; Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 5 77900 Olomouc Czech Republic

Laboratory of Growth Regulators Palacký University and Institute of Experimental Botany The Czech Academy of Sciences Šlechtitelů 27 78371 Olomouc Czech Republic

Laboratory of Growth Regulators Palacký University and Institute of Experimental Botany The Czech Academy of Sciences Šlechtitelů 27 78371 Olomouc Czech Republic; Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 5 77900 Olomouc Czech Republic

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Novel 5-Substituted Oxindole Derivatives as Bruton's Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation