Introduction of pyrrolidineoxy or piperidineamino group at the 4-position of quinazoline leading to novel quinazoline-based phosphoinositide 3-kinase delta (PI3Kδ) inhibitors

Abstract

Phosphoinositide 3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ was confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Herein, we reported a novel series of 4-pyrrolidineoxy or 4-piperidineamino substituted quinazolines, showing potent PI3Kδ inhibitory activities. Among these compounds, 12d, 14b and 14c demonstrated higher potency against PI3Kδ with the half maximal inhibitory concentration (IC50) values of 4.5, 3.0, and 3.9 nM, respectively, which were comparable to idelalisib (IC50 = 2.7 nM). The further PI3K isoforms selectivity evaluation showed that compounds 12d, 14b and 14c have excellent PI3Kδ selectivity over PI3Kα, PI3Kβ, and PI3Kγ. Moreover, compounds 12d, 14b and 14c also displayed different anti-proliferative profiles against a panel of four human B cell lines including Ramos, Raji, RPMI-8226, and SU-DHL-6. The molecular docking simulation indicated several key hydrogen bonding interactions were formed. This study suggests the introduction of pyrrolidineoxy or piperidineamino groups into the 4-position of quinazoline leads to new potent and selective PI3Kδ inhibitors.

Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases

“…A group from Xi’an Jiaotong University has published a patent and three papers on quinazoline based inhibitors − with good potency but only modest selectivity against PI3Kα; two representative examples ( 84 , 85 ) are shown.…”

Synthesis and biological activity of new 2,4,6-trisubstituted triazines as potential phosphoinositide 3-kinase inhibitors

“…12,13 For example, several 6-aryl substituted quinazoline derivatives were synthesized and some showed promising potency against PI3Kδ in vitro. 14,15 The other strategy was to develop pan-PI3K or PI3K/mTOR inhibitors, exemplified by the preparation of several series of derivatives such as quinazolin-4( 3H )-ones, 16,17 [1,2,4]triazolo[1,5-a]pyridines, 18 benzo[d]thiazoles, 19,20 4-morpholinoquinazolines, 21 and 4-(morpholin-4-yl)-1,3,5-triazines. 22 In particular, in the series of 4-(morpholin-4-yl)-1,3,5-triazines, representative derivatives displayed potent antitumor effects in vitro and in vivo.…”