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.

Keywords: 4-piperidineamino; 4-pyrrolidineoxy; PI3Kδ inhibitors; anti-proliferation; selectivity.

Graphical abstract

Scheme 1.

Reagents and conditions: (a) (S)-1-Boc-3-hydroxypyrrolidine, anhydrous THF, NaH, rt, overnight, 70%; (b) 6-methoxy-3-pyridinylboronic acid, Na₂CO₃, PdCl₂ (dppf), DME/H₂O, reflux, 4 h, 65–81%; (c) (i)TFA, CH₂Cl₂, rt, 2 h, 23–91%; (ii) diverse acids, DMF, HATU, DIPEA, rt, 12 h, 23–91%; (d) (S)-1-Boc-3-aminopiperidine, DMF, DIPEA, 90 °C, 6 h, 90%; (e) 1-Boc-4-aminopiperidine, DMF, DIPEA, 90 °C, 6 h, 52%.

Figure 1.

Representative structures for previously reported potent PI3Kδ inhibitors.

Figure 2.

Design of the 4-pyrrolidineoxy and 4-piperidineamino substituted quinazolines as PI3Kδ inhibitors.

Figure 3.

Molecular docking studies of Compounds 12d (a), 14b (b) as well as 14c (c) into the site of PI3Kδ (PDB code: 2WXP). Compound is shown as sticks. Hydrogen bonds within 2.5 Å are shown as yellow dashed lines.