New biologically active compounds based on pyrazolo[1,5-a]pyrimidine and its isosteres

                                 Michaela Hylsová and Kamil Paruch

  Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech
                                             Republic.

Since protein kinases play dominant roles in regulation of a wide range of cellular functions
including initiation of cancer cells, tumor progression, and the development of metastatic
diseases, many of them represent attractive targets for modern medicine. Some of these kinases have
been targeted by modern oncology therapeutics (protein kinase inhibitors) for treatment of cancer
(e.g. Gefitinib and Imatinib), and many other inhibitors are under clinical trials (e.g.
Dinaciclib).^1

Because the majority of developed kinase inhibitors bind the kinase active site in the same manner
as ATP, their scaffolds are often based on heterocycles (in many cases 5,6- and 6,6-condensed
heterocycles) that imitate the adenine moiety and form highly analogous interactions with the
kinase active site.^2

Among a number of 5,6-condensed heterocyclic systems the pyrazolo[1,5-a]pyrimidine  scaffold proved
to be particularly suitable for development of protein kinase inhibitors. Numerous small organic
molecules with pyrazolo[1,5-a]pyrimidine  scaffold (depicted below) were designed and developed
targeting different protein kinases.^3

We have developed small libraries of kinase inhibitors with two different central pharmacophores:
pyrazolo[1,5-a]pyrimidines and furo[3,2-b]pyridines.

[1] Thurston, D. E. Chemistry and pharmacology of anticancer drugs; CRC Press/Taylor & Francis:
Boca Raton, 2007.

[2] (a) Roskoski, R. Pharmacol. Res. 2016, 103, 26. (b) Maddox, S. et al. Future Med. Chem. 2016, 8
(3), 241.

[3] (a) Dwyer, M. P. et al. Bioorg. Med. Chem. Lett. 2011, 21 (1), 467. (b) Le Roux, J. et al.
Bioorg. Med. Chem. Lett. 2016, 26 (2), 454.