Our research group focuses on the synthesis of thiazolo[5,4-f]quinazolin-9(8H)-one derivatives as potential kinase inhibitors involved in Alzheimer's disease.[1] Previous in vitro results led us to intensively study the backbone for further SAR investigations. In order to establish SAR studies, C-H arylation methods were investigated. [2] The regioselective C-H bond activation of the thiazole moieties was developed to furnish the corresponding valuable C2-arylated compounds.

Herein, we report an extension of this methodology to thiazolo[5,4-f]quinazolin-9(8H)-ones in order to functionalize regioselectively at C2 and C7 positions.[3] A metal-free synthesis of the tricyclic starting material was also described giving access to these compounds in a facile manner.[4] Two monoarylated compounds show high inhibition values for kinases of the DYRK's family,  involved in Alzheimer's disease.

[1]    (a) Chaikuad, A.; Diharce, J.; Schröder, M.. Foucourt, A.; Leblond, B.; Casagrande, A.-S.; Désiré, L.; Bonnet, P.; Knapp, S.; Besson, T. J. Med. Chem. 2016, 59, 10315; (b) Hédou, D.; Dubouilh-Benard, C.; Loaëc, N.; Meijer, L.; Fruit, C.; Besson, T. Molecules 2016, 21, 794; (c) Courtadeur, S.; Benyamine, H.; Delalonde, L.; de Oliveira, C.; Leblond, B.; Foucourt, A.; Besson, T.; Casagrande, A.-S.; Taverne, T.; Girard, A.; Pando, M.P.; Désiré, L. J. Neurochem. 2015, 133, 440; (d) Thompson, B.; Bhansali, R.; Diebold, L.; Cook, D. E.; Stolzenburg, L.;Casagrande, A. –S.; Besson, T.; Leblond, B.; Desire, L.; Malinge, S.; Crispino, J. D. J. Exp. Med. 2015, 212, 723.

[2]    (a) Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.; Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T. Org. Lett. 2015, 17, 1700 ; (b) Godeau, J.; Harari, M.; Laclef, S.; Deau, E.; Fruit, C.; Besson, T. Eur. J. Org. Chem. 2015, 7705.

[3]    Harari, M.; Couly, F.; Fruit, C.; Besson, T. Org. Lett. 2016, 18, 3282.

[4]    Couly, F.; Dubouilh-Benard, C.; Besson, T.; Fruit, C. Synthesis 2017, in press, DOI: 10.1055/s-0036-1588434.