Synthesis and biological evaluation of 7-(aminoalkyl)pyrazolo[1,5-a] pyrimidine derivatives as cathepsin K inhibitors

A series of novel 7-aminoalkyl substituted pyrazolo [1,5-a]pyrimidine derivatives were synthesized and tested for inhibition of cathepsin K. The synthetic methodology comprises cyclization of 5-aminopyrazoles with N-Boc-alpha-amino acid-derived ynones followed by transformation of the ester and the Boc-amino functions. It allows for easy diversification of the pyrazolo [1,5-a]pyrimidine scaffold at various positions. Molecular docking studies with pyrazolo [1,5-a]pyrimidine derivatives were also performed to elucidate the binding mode in the active site of cathepsin K. The synthesized compounds exhibited moderate inhibition activity (K-i >= 77 mu M).