Z. Wang, D. Kang, D. Feng et al.
European Journal of Medicinal Chemistry 206 (2020) 112811
119.08, 108.60, 66.86, 66.71, 61.04, 52.52, 46.29, 42.13, 31.65, 16.29.
piperidine-H). 13C NMR (100 MHz, DMSOd6)
d 164.31,156.47,154.13,
ESI-MS: m/z 451.18 [MþH]þ. C24H30N6O3 (450.24).
151.05, 146.47, 133.17, 132.93, 119.11, 108.73, 105.22, 102.32, 94.78,
66.50, 56.30, 56.21, 53.77, 52.42, 52.08, 40.44, 29.51, 16.36. ESI-MS:
m/z 547.22 [MþH]þ. C30H38N6O4 (546.30).
4.1.3.3. 3,5-dimethyl-4-((2-((1-(2-morpholinoethyl)piperidin-4-yl)
amino)quinazolin-4-yl)oxy)benzonitrile (14b1). White solid, yield:
44.5%, mp: 116ꢃ118 ꢀC. 1H NMR (400 MHz, DMSOd6)
d
8.13 (d, J ¼
4.1.3.8. 4-((6,7-dimethoxy-2-((1-(2-morpholino-2-oxoethyl)piper-
idin-4-yl)amino)quinazolin-4-yl)oxy)-3,5-dimethylbenzonitrile
(14d2). White solid, yield: 43.6%, mp: 127ꢃ129 ꢀC. 1H NMR
8.1 Hz, 1H, C8-quinazoline-H), 7.75 (d, J ¼ 7.1 Hz, 3H, C3,C5-Ph-H, C5-
quinazoline-H), 7.47 (d, J ¼ 8.5 Hz,1H, C7-quinazoline-H), 7.27 (t, J ¼
7.5 Hz,1H, C6-quinazoline-H), 7.08 (s,1H, NH), 3.57 (t, J ¼ 4.6 Hz, 6H,
morpholine-H), 3.14 (s, 3H, piperidine-H), 2.48e2.26 (m, 6H,
morpholine-H, NeCH2 ꢄ 2), 2.13 (s, 6H, CH3 ꢄ 2), 1.95 (d, J ¼
12.1 Hz, 2H, piperidine-H), 1.64 (s, 2H, piperidine-H), 1.23 (s, 2H,
(400 MHz, DMSOd6)
d 7.71 (s, 2H, C3,C5-Ph-H), 7.38 (s, 1H, C8-
dimethoxyquinazoline-H), 6.89 (s, 1H, C5-dimethoxyquinazoline-
H), 6.65 (s,1H, NH), 3.91 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.64e3.50
(m, 6H, morpholine-H), 3.44 (p, J ¼ 4.4 Hz, 2H, morpholine-H), 3.19
(d, J ¼ 16.2 Hz, 2H, NeCH2), 3.01e2.67 (m, 3H, piperidine-H), 2.12 (s,
6H, CH3 ꢄ 2), 1.97e1.16 (m, 6H, piperidine-H). 13C NMR (100 MHz,
piperidine-H). 13C NMR (100 MHz, DMSOd6)
d 165.32, 154.28,
135.01, 133.07, 129.23, 125.21, 123.97, 122.52, 119.05, 110.63, 108.97,
66.50, 53.79, 52.15, 29.91, 16.30. ESI-MS: m/z 487.21 [MþH]þ.
DMSOd6) d 156.45, 154.89, 150.19, 147.79, 146.38, 133.19, 132.90,
C
28H34N6O2 (486.27).
108.71,107.26,107.01,102.84, 66.94, 66.81, 66.67, 56.70, 56.31, 56.21,
52.67, 46.27, 42.15, 39.67, 31.87, 16.36. ESI-MS: m/z 561.18 [MþH]þ.
4.1.3.4. 3,5-dimethyl-4-((2-((1-(2-morpholino-2-oxoethyl)piperidin-
C30H36N6O5 (560.27).
4-yl)amino)quinazolin-4-yl)oxy)benzonitrile (14b2). White solid,
yield: 40.8%, mp: 165ꢃ167 ꢀC. 1H NMR (400 MHz, DMSOd6)
d
8.11
4.1.3.9. 3,5-dimethyl-4-((2-((1-(2-morpholinoethyl)piperidin-4-yl)
(d, J ¼ 8.1 Hz, 1H, C8-quinazoline-H), 7.74 (s, 2H, C3,C5-Ph-H),
7.68e7.62 (m, 1H, C5-quinazoline-H), 7.47 (d, J ¼ 8.6 Hz, 1H, C7-
quinazoline-H), 7.25 (t, J ¼ 7.5 Hz,1H, C6-quinazoline-H), 6.96 (s,1H,
NH), 3.59e3.50 (m, 6H, morpholine-H), 3.43 (q, J ¼ 5.5, 4.6 Hz, 2H,
morpholine-H), 3.14 (d, J ¼ 5.8 Hz, 2H, NeCH2), 2.99e2.59 (m, 3H,
piperidine-H), 2.12 (d, J ¼ 8.4 Hz, 6H, CH3 ꢄ 2), 2.01e1.26 (m, 6H,
amino)thieno[3,2-d]pyrimidin-4-yl)oxy)benzonitrile
(14e1).
White solid, yield: 61.7%, mp: 170ꢃ172 ꢀC. 1H NMR (400 MHz,
DMSOd6)
d
8.20 (d, J ¼ 5.5 Hz, 1H, C6-thienopyrimidine-H), 7.72 (s,
2H, C3,C5-Ph-H), 7.29 (dd, J ¼ 26.8, 5.1 Hz, 1H, C7-thienopyrimidine-
H), 6.88 (s, 1H, NH), 3.55 (t, J ¼ 4.6 Hz, 6H, morpholine-H), 2.84 (s,
3H, piperidine-H), 2.44e2.34 (m, 6H, morpholine-H, NeCH2 ꢄ 2),
2.12 (s, 6H, CH3 ꢄ 2), 1.97e1.10 (m, 6H, piperidine-H). 13C NMR
piperidine-H). 13C NMR (100 MHz, DMSOd6)
d 168.17,161.94, 154.67,
134.92, 133.58, 133.16, 133.07, 132.63, 126.60, 123.93, 123.73, 122.32,
119.05, 113.05, 108.94, 107.91, 66.86, 66.72, 61.00, 52.58, 48.70,
46.30, 42.14, 31.69, 31.25, 16.37, 16.31. ESI-MS: m/z 501.14 [MþH]þ.
(100 MHz, DMSOd6) d 162.49, 160.53, 156.96, 153.45, 136.73, 133.22,
132.96, 123.99, 119.00, 109.06, 66.63, 56.29, 55.35, 54.14, 54.09,
53.03, 48.30, 31.51, 16.25. ESI-MS: m/z 493.15 [MþH]þ.
C
28H32N6O3 (500.25).
C26H32N6O2S (492.23).
4.1.3.5. 4-((7-fluoro-2-((1-(2-morpholinoethyl)piperidin-4-yl)
4.1.3.10. 3,5-dimethyl-4-((2-((1-(2-morpholino-2-oxoethyl)piper-
idin-4-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)benzonitrile (14e2).
White solid, yield: 65.2%, mp: 174ꢃ176 ꢀC. 1H NMR (400 MHz,
amino)quinazolin-4-yl)oxy)-3,5-dimethylbenzonitrile
(14c1).
White solid, yield: 30.9%, mp: 169ꢃ171 ꢀC. 1H NMR (400 MHz,
DMSOd6)
d
8.22 (dd, J ¼ 8.8, 6.4 Hz, 1H, C5-fluoroquinazoline-H),
DMSOd6)
d
8.13 (d, J ¼ 5.5 Hz, 1H, C6-thienopyrimidine-H), 7.65 (s,
7.74 (s, 2H, C3,C5-Ph-H), 7.67 (s, 1H, NH), 7.17 (td, J ¼ 9.5, 3.4 Hz, 2H,
2H, C3,C5-Ph-H), 7.29e7.08 (m, 1H, C7-thienopyrimidine-H), 6.81 (s,
1H, NH), 3.47 (dd, J ¼ 10.9, 4.9 Hz, 6H, morpholine-H), 3.36 (d, J ¼
4.9 Hz, 2H, morpholine-H), 3.07 (d, J ¼ 28.7 Hz, 2H, NeCH2), 2.75 (d,
J ¼ 50.6 Hz, 3H, piperidine-H), 2.05 (s, 6H, CH3 ꢄ 2), 1.86e1.14 (m,
C6,C8-fluoroquinazoline-H), 3.60 (dt, 9.4, 4.5 Hz, 6H,
J
¼
morpholine-H), 3.06 (d, J ¼ 7.5 Hz, 3H, piperidine-H), 2.45 (s, 6H,
morpholine-H, NeCH2 ꢄ 2), 2.13 (s, 6H, CH3 ꢄ 2), 2.05e1.33 (m, 6H,
piperidine-H). ESI-MS: m/z 505.18 [MþH]þ. C28H33FN6O2 (504.26).
6H, piperidine-H). 13C NMR (100 MHz, DMSOd6)
d 168.21, 162.47,
160.55, 156.97, 153.43, 136.80, 133.23, 132.96, 124.00, 119.01, 109.05,
66.86, 66.72, 61.05, 52.57, 46.30, 42.13, 31.73, 16.26. ESI-MS: m/z
507.12 [MþH]þ. C26H30N6O3S (506.21).
4.1.3.6. 4-((7-fluoro-2-((1-(2-morpholino-2-oxoethyl)piperidin-4-yl)
amino)quinazolin-4-yl)oxy)-3,5-dimethylbenzonitrile
(14c2).
White solid, yield: 34.1%, mp: 185ꢃ187 ꢀC. 1H NMR (400 MHz,
DMSOd6)
d
8.18 (t, J ¼ 7.6 Hz, 1H, C5-fluoroquinazoline-H), 7.73 (s,
4.1.3.11. 3,5-dimethyl-4-((2-((1-(2-morpholinoethyl)piperidin-4-yl)
2H, C3,C5-Ph-H), 7.66 (s, 1H, NH), 7.21e7.06 (m, 2H, C6,C8-fluo-
roquinazoline-H), 3.54 (dt, J ¼ 9.8, 5.0 Hz, 6H, morpholine-H), 3.42
(t, J ¼ 4.7 Hz, 2H, morpholine-H), 3.14 (s, 2H, NeCH2), 2.96e2.58 (m,
3H, piperidine-H), 2.12 (s, 6H, CH3 ꢄ 2), 1.98e1.22 (m, 6H,
amino)furo[3,2-d]pyrimidin-4-yl)oxy)benzonitrile
(14f1). White
solid, yield: 60.6%, mp: 231ꢃ233 ꢀC. 1H NMR (400 MHz, DMSOd6)
d
8.26 (d, J ¼ 2.2 Hz, 1H, C6-furopyrimidine-H), 7.72 (s, 2H, C3,C5-Ph-
H), 6.89 (s, 2H, C7-furopyrimidine-H, NH), 3.58 (t, J ¼ 4.6 Hz, 6H,
morpholine-H), 2.58 (s, 3H, piperidine-H), 2.43 (d, J ¼ 5.2 Hz, 6H,
morpholine-H, NeCH2 ꢄ 2), 2.13 (s, 6H, CH3 ꢄ 2), 2.03e1.22 (m, 6H,
piperidine-H). 13C NMR (100 MHz, DMSOd6)
d
168.05 (JCF
¼
37.9 Hz), 165.18 (JCF ¼ 39.9 Hz), 158.72, 153.60, 133.06, 133.06,
132.66, 127.09 (JCF ¼ 10.9 Hz), 119.03, 111.66 (JCF ¼ 23.1 Hz), 109.39,
109.04, 107.89 (JCF ¼ 28.1 Hz), 66.85, 66.71, 60.95, 53.93, 52.56,
48.02, 46.30, 42.12, 31.62, 16.33. ESI-MS: m/z 519.21 [MþH]þ.
piperidine-H). 13C NMR (100 MHz, DMSOd6)
d 158.86, 153.25,
152.86, 152.06, 133.22, 132.97, 127.76, 119.00, 109.05, 107.27, 66.46,
53.68, 51.79, 29.16, 16.33. ESI-MS: m/z 477.28 [MþH]þ. C26H32N6O3
(476.25).
C
28H31FN6O3 (518.24).
4.1.3.7. 4-((6,7-dimethoxy-2-((1-(2-morpholinoethyl)piperidin-4-yl)
4.1.3.12. 3,5-dimethyl-4-((2-((1-(2-morpholino-2-oxoethyl)piper-
idin-4-yl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)benzonitrile (14f2).
White solid, yield: 57.2%, mp: 177ꢃ179 ꢀC. 1H NMR (400 MHz,
amino)quinazolin-4-yl)oxy)-3,5-dimethylbenzonitrile
(14d1).
White solid, yield: 40.5%, mp: 168ꢃ170 ꢀC. 1H NMR (400 MHz,
DMSOd6)
d
7.72 (s, 2H, C3,C5-Ph-H), 7.39 (s, 1H, C8-dimethox-
DMSOd6)
d
8.23 (d, J ¼ 2.2 Hz,1H, C6-furopyrimidine-H), 7.72 (s, 2H,
yquinazoline-H), 6.89 (s, 1H, C5-dimethoxyquinazoline-H), 6.79 (s,
1H, NH), 3.91 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.57 (t, J ¼ 4.7 Hz, 6H,
morpholine-H), 2.78 (s, 3H, piperidine-H), 2.48e2.36 (m, 6H,
morpholine-H, NeCH2 ꢄ 2), 2.13 (s, 6H, CH3 ꢄ 2), 2.02e1.18 (m, 6H,
C3,C5-Ph-H), 6.88 (s,1H, C7-furopyrimidine-H), 6.74 (s,1H, NH), 3.54
(p, J ¼ 5.0, 4.4 Hz, 6H, morpholine-H), 3.42 (t, J ¼ 4.7 Hz, 2H,
morpholine-H), 3.09 (s, 2H, NeCH2), 2.92e2.62 (m, 3H, piperidine-
H), 2.13 (s, 6H, CH3 ꢄ 2), 1.93e1.21 (m, 6H, piperidine-H). 13C NMR
13