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

Figures & data

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%.

Table 1. PI3Kδ inhibitory activity of 4-pyrrolidineoxy substituted quinazolines^a.

Compounds	R	PI3Kδ Inhibition (%)^b	PI3Kδ IC50 (nM)^c
12a		79	ND
12b		90	9.3
12c		96	6.1
12d		98	4.9
12e		53	ND
1	–	96	2.7

^aAll the data are shown as the mean for at least two experiments.

^bPI3Kδ inhibition at the concentration of 100 nM.

^cThe IC₅₀ values for PI3Kδ inhibition.

ND: not detected.

Table 2. PI3Kδ inhibitory activity of 4-piperidineamino substituted quinazolines^a.

Compounds	R	PI3Kδ Inhibition (%)^b	PI3Kδ IC50 (nM)^c
14a		51	ND
14b		94	3.0
14c		91	3.9
14d		91	8.7
14e		88	5.2
14f		54	ND
16a		72	ND
16b		70	ND
16c		48	ND
1	–	96	2.7

^aAll the data are shown as the mean for at least two experiments.

^bPI3Kδ inhibition at the concentration of 100 nM.

^cThe IC₅₀ values for PI3Kδ inhibition.

ND: not detected.

Table 3. Isoform selectivity of compounds against PI3K (p110α, p110β, p110γ, and p110δ)

	IC50 (nM)^a
Compounds	p110α	p110β	p110γ	p110δ
12d	50.4	592.5	467.6	4.9
14b	36.6	317.2	104.0	3.0
14c	58.9	375.9	121.1	3.9
1	306.4	120.1	139.4	2.7

^aThe IC₅₀ values are shown as the mean for at least two experiments.

Table 4. Anti-proliferative activities of new compounds in vitro

	IC50 (μM)^a
Compounds	Ramos^b	Raji^b	RPMI-8226^b	SU-DHL-6^c
12d	1.34	9.81	0.44	3.23
14b	1.34	0.81	8.66	1.04
14c	ND	ND	ND	1.49
1	>10	9.95	5.49	0.65
SAHA	0.52	0.97	0.66	ND

^aThe IC₅₀ values are shown as the mean for at least two experiments.

^bAnti-proliferative activities were determined by(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) reduction method.

^cAnti-proliferative activities were determined by CCK-8 method.

ND: not detected.

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.