10
Y. Chen et al. / European Journal of Medicinal Chemistry 199 (2020) 112388
163.54, 161.94, 157.34, 153.33, 139.99, 139.88, 137.22, 135.69, 129.59,
123.22, 121.37, 118.79, 117.30, 116.35, 114.54, 108.16, 106.67, 54.61,
50.20, 45.60. HRMS (ESI): m/z calcd for C26H23FN6O2S, [MþH]þ:
503.1665; found: 503.1663.
155.67, 153.32, 153.26, 140.00, 139.89, 137.25, 135.80, 135.69, 133.54,
133.45, 129.58, 123.21, 121.36, 119.11, 117.30, 116.34, 114.53, 108.16,
107.55, 106.87, 106.61, 61.91, 50.13, 49.32, 26.86, 24.33, 23.06, 21.04.
HRMS (ESI): m/z calcd for C31H31FN6O2S, [MþH]þ: 571.2291; found:
571.2290.
4.2.4.8. 7-((2-((4-(1,1-dioxidothiomorpholino)phenyl)amino)thieno
[3,2-d]pyrimidin-4-yl)oxy)quinolin-2(1H)-one
(6h). Pink
solid,
11.87 (s,
4.2.4.13. 7-(2-(4-((4-methylpiperazin-1-yl)methyl)phenylamino)
yield: 43%, Mp > 300 ꢁC. 1H NMR (400 MHz, DMSO‑d6)
d
thieno[3,2-d]pyrimidin-4-yloxy)quinolin-2(1H)-one
Yellow solid, yield: 59%, Mp 235e237 ꢁC. 1H NMR (400 MHz,
DMSO‑d6)
(6m).
1H), 9.27 (s, 1H), 8.28 (d, J ¼ 5.4 Hz, 1H), 7.99 (d, J ¼ 9.6 Hz, 1H), 7.81
(d, J ¼ 8.5 Hz, 1H), 7.41 (s, 2H), 7.33 (d, J ¼ 5.4 Hz, 1H), 7.23e7.15 (m,
2H), 6.72 (d, J ¼ 7.5 Hz, 2H), 6.55 (d, J ¼ 9.6 Hz, 1H), 3.61 (s, 4H),
d
11.85 (s, 1H), 9.45 (s, 1H), 8.31 (d, J ¼ 5.4 Hz,1H), 7.99 (d,
J ¼ 9.6 Hz,1H), 7.80 (d, J ¼ 8.5 Hz,1H), 7.47 (d, J ¼ 7.8 Hz, 2H), 7.37 (d,
J ¼ 5.4 Hz, 1H), 7.22 (d, J ¼ 2.1 Hz, 1H), 7.19 (dd, J ¼ 8.4, 2.3 Hz, 1H),
6.94 (d, J ¼ 8.1 Hz, 2H), 6.53 (d, J ¼ 9.6 Hz, 1H), 3.29 (s, 2H), 2.28 (s,
3.13e3.03 (m, 4H). 13C NMR (100 MHz, DMSO‑d6)
d 164.97, 163.48,
161.96, 157.74, 153.43, 142.40, 139.93, 136.94, 133.12, 129.53, 123.17,
121.36, 120.31, 117.18, 116.50, 116.15, 108.33, 49.75, 47.49. HRMS
(ESI): m/z calcd for C25H21N5O4S2, [MþH]þ: 520.1113; found:
520.1112.
8H), 2.14 (s, 3H). 13C NMR (100 MHz, DMSO‑d6)
d 164.87, 163.50,
161.87, 157.58, 153.42, 140.00, 139.80, 139.15, 137.09, 130.73, 129.47,
128.73, 123.22, 121.44, 118.50, 117.17, 116.43, 108.19, 107.45, 61.58,
54.61, 52.24, 45.61. HRMS (ESI): m/z calcd for C27H26N6O2S,
[MþH]þ: 499.1916; found: 499.1917.
4.2.4.9. 7-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyr-
imidin-4-yloxy)quinolin-2(1H)-one (6i). White solid, yield: 52%, Mp
269e271 ꢁC. 1H NMR (400 MHz, DMSO‑d6)
d
11.86 (s, 1H), 9.47 (s,
4.2.4.14. 7-(2-(4-((4-ethylpiperazin-1-yl)methyl)phenylamino)
1H), 8.31 (d, J ¼ 5.4 Hz, 1H), 8.00 (d, J ¼ 9.6 Hz, 1H), 7.81 (d,
J ¼ 8.4 Hz, 1H), 7.47 (d, J ¼ 7.5 Hz, 2H), 7.38 (d, J ¼ 5.4 Hz, 1H), 7.20
(dt, J ¼ 8.3, 2.2 Hz, 2H), 6.95 (d, J ¼ 8.1 Hz, 2H), 6.54 (d, J ¼ 9.6 Hz,
1H), 3.58e3.50 (m, 4H), 3.29 (s, 2H), 2.26 (s, 4H). 13C NMR
thieno[3,2-d]pyrimidin-4-yloxy)quinolin-2(1H)-one
Yellow solid, yield: 59%, Mp 247e248 ꢁC. 1H NMR (400 MHz,
DMSO‑d6)
(6n).
d
11.87 (s, 1H), 9.45 (s,1H), 8.30 (d, J ¼ 5.4 Hz,1H), 7.99 (d,
J ¼ 9.6 Hz,1H), 7.81 (d, J ¼ 8.5 Hz,1H), 7.46 (d, J ¼ 7.6 Hz, 2H), 7.37 (d,
J ¼ 5.4 Hz, 1H), 7.23 (d, J ¼ 2.2 Hz, 1H), 7.19 (dd, J ¼ 8.5, 2.3 Hz, 1H),
6.94 (d, J ¼ 8.1 Hz, 2H), 6.53 (d, J ¼ 9.6 Hz, 1H), 3.31 (s, 2H),
2.47e2.08 (m, 10H), 1.00 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz,
(100 MHz, DMSO‑d6) d 164.87, 163.52, 161.90, 157.55, 153.41, 139.98,
139.84, 139.23, 137.12, 130.19, 129.50, 128.84, 123.22, 121.41, 118.49,
117.19, 116.45, 108.24, 107.44, 66.13, 61.98, 52.96. HRMS (ESI): m/z
calcd for C26H23N5O3S, [MþH]þ: 486.1600; found: 486.1601.
DMSO‑d6)
d 164.87, 163.52, 161.94, 157.55, 153.42, 139.95, 139.88,
139.20, 137.12, 130.36, 129.50, 128.81, 123.21, 121.38, 118.50, 117.20,
116.48, 108.24, 107.44, 61.37, 51.92, 51.76, 51.38, 11.41. HRMS (ESI):
m/z calcd for C28H28N6O2S, [MþH]þ: 513.2073; found: 513.2075.
4.2.4.10. 7-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)
thieno[3,2-d]pyrimidin-4-yloxy)quinolin-2(1H)-one
(6j). White
solid, yield: 44%, Mp 265e266 ꢁC. 1H NMR (400 MHz, DMSO‑d6)
d
11.87 (s, 1H), 8.27 (d, J ¼ 5.4 Hz, 1H), 7.99 (d, J ¼ 9.6 Hz, 1H),
4. 2 . 4 .15 . 7- ( 2 - ( 4 - ( 2- ( d i m e t hyla m i n o ) e t hyl a mi n o) - 3-
fluorophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)quinolin-2(1H)-
one (6o). Yellow solid, yield: 49%, Mp 257e259 ꢁC. 1H NMR
7.85e7.70 (m, 2H), 7.57e7.36 (m, 1H), 7.31 (d, J ¼ 5.4 Hz,1H), 7.21 (d,
J ¼ 2.2 Hz, 1H), 7.17 (dd, J ¼ 8.5, 2.3 Hz, 1H), 6.54 (dd, J ¼ 5.9, 3.5 Hz,
2H), 6.15 (s, 1H), 3.75 (s, 3H), 3.10e2.91 (m, 4H), 2.48e2.36 (m, 4H),
(400 MHz, DMSO‑d6)
d
11.85 (s, 1H), 9.28 (s, 1H), 8.29 (d, J ¼ 5.4 Hz,
2.23 (s, 3H). 13C NMR (100 MHz, DMSO‑d6)
d
165.07, 163.42, 161.97,
1H), 7.97 (d, J ¼ 9.6 Hz, 1H), 7.79 (d, J ¼ 8.5 Hz, 1H), 7.36 (t,
J ¼ 10.4 Hz, 2H), 7.22 (d, J ¼ 2.1 Hz, 1H), 7.18 (dd, J ¼ 8.5, 2.3 Hz, 1H),
7.10 (s, 1H), 6.49 (dd, J ¼ 20.5, 9.6 Hz, 2H), 4.62 (s, 1H), 3.02 (dd,
J ¼ 11.8, 5.9 Hz, 2H), 2.41 (t, J ¼ 6.4 Hz, 2H), 2.15 (s, 6H). 13C NMR
158.19, 153.28, 150.66, 147.74, 139.85, 136.94, 129.43, 123.15, 121.28,
120.37, 117.12, 116.40, 108.19, 106.34, 99.94, 55.50, 54.53, 48.57,
45.62. HRMS (ESI): m/z calcd for C27H26N6O3S, [MþH]þ: 515.1865;
found: 515.1866.
(100 MHz, DMSO‑d6) d 164.93, 163.46, 161.90, 157.64, 153.37, 151.35,
149.01, 140.02, 139.84, 136.97, 131.33, 131.21, 130.12, 130.02, 129.52,
123.17, 121.39, 117.19, 116.33, 115.32, 111.86, 108.04, 106.53, 106.28,
57.62, 45.07, 40.76. HRMS (ESI): m/z calcd for C25H23FN6O2S,
[MþH]þ: 491.1665; found: 491.1663.
4.2.4.11. 7-(2-(4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino)
thieno[3,2-d]pyrimidin-4-yloxy)quinolin-2(1H)-one
Yellow solid, yield: 51%, Mp 271e273 ꢁC. 1H NMR (400 MHz,
DMSO‑d6)
(6k).
d
11.85 (s, 1H), 8.26 (d, J ¼ 5.4 Hz, 1H), 7.97 (d, J ¼ 9.6 Hz,
1H), 7.81e7.74 (m, 2H), 7.54e7.41 (m, 1H), 7.30 (d, J ¼ 5.4 Hz, 1H),
7.21 (d, J ¼ 2.2 Hz, 1H), 7.16 (dd, J ¼ 8.5, 2.3 Hz, 1H), 6.53 (dd, J ¼ 6.0,
3.5 Hz, 2H), 6.14 (d, J ¼ 6.9 Hz, 1H), 3.74 (s, 3H), 3.06e2.96 (m, 4H),
4.2.4.16. 7-(2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)thieno
[3,2-d]pyrimidin-4-yloxy)quinolin-2(1H)-one (6p). White solid,
yield: 40%, Mp > 300 ꢁC. 1H NMR (400 MHz, DMSO‑d6)
d 11.84 (s,
2.48e2.41 (m, 4H), 2.35 (q, J ¼ 7.2 Hz, 2H), 1.02 (t, J ¼ 7.2 Hz, 3H). 13
C
1H), 9.36 (s, 1H), 8.32 (d, J ¼ 5.4 Hz, 1H), 8.00 (d, J ¼ 9.6 Hz, 1H), 7.89
(d, J ¼ 2.9 Hz,1H), 7.81 (d, J ¼ 8.6 Hz,1H), 7.59 (d, J ¼ 9.1 Hz,1H), 7.38
(d, J ¼ 5.4 Hz, 1H), 7.26 (d, J ¼ 2.2 Hz, 1H), 7.20 (dd, J ¼ 8.5, 2.3 Hz,
1H), 6.91 (dd, J ¼ 9.1, 2.8 Hz, 1H), 6.53 (d, J ¼ 9.5 Hz, 1H), 3.06e2.93
(m, 4H), 2.47e2.38 (m, 4H), 2.21 (s, 3H). 13C NMR (100 MHz,
NMR (100 MHz, DMSO‑d6)
d 165.08, 163.42, 161.95, 158.18, 153.29,
150.61, 147.80, 139.89, 136.89, 129.40, 123.16, 122.31, 121.31, 120.37,
117.11,116.36,108.17,106.98,106.32, 99.90, 55.51, 52.31, 51.58, 48.76,
11.92. HRMS (ESI): m/z calcd for C28H28N6O3S, [MþH]þ: 529.2022;
found: 529.2021.
DMSO‑d6)
d 164.90, 163.43, 161.94, 156.85, 153.35, 145.35, 142.37,
139.89, 137.27, 135.23, 129.48, 124.29, 123.24, 121.32, 117.15, 116.40,
4.2.4.12. 7-(2-(4-(1,40-bipiperidin-10-yl)-3-fluorophenylamino)thieno
[3,2-d]pyrimidin-4-yloxy)quinolin-2(1H)-one (6l). Yellow solid,
113.62, 108.30, 107.76, 54.31, 48.34, 45.65. HRMS (ESI): m/z calcd for
C
25H23N7O2S, [MþH]þ: 486.1712; found: 486.1712.
yield: 40%, Mp 245e246 ꢁC. 1H NMR (400 MHz, DMSO‑d6)
d 11.85 (s,
1H), 9.50 (s, 1H), 8.32 (d, J ¼ 5.4 Hz, 1H), 7.98 (d, J ¼ 9.6 Hz, 1H), 7.80
(d, J ¼ 8.5 Hz, 1H), 7.50e7.35 (m, 2H), 7.23 (d, J ¼ 2.2 Hz, 1H), 7.18
(dd, J ¼ 8.5, 2.3 Hz, 2H), 6.74 (t, J ¼ 9.1 Hz, 1H), 6.53 (d, J ¼ 9.6 Hz,
1H), 3.23 (d, J ¼ 11.7 Hz, 3H), 2.80 (s, 4H), 2.55 (d, J ¼ 11.5 Hz, 2H),
1.92 (d, J ¼ 11.5 Hz, 2H), 1.72e1.57 (m, 6H), 1.46 (d, J ¼ 4.7 Hz, 2H).
4.2.4.17. 7-(2-(4-fluorophenylamino)thieno[3,2-d]pyrimidin-4-
yloxy)quinolin-2(1H)-one (6q). White solid, yield: 49%,
Mp > 300 ꢁC. 1H NMR (400 MHz, DMSO‑d6)
11.87 (s, 1H), 9.49 (s,
1H), 8.31 (d, J ¼ 5.4 Hz, 1H), 8.00 (d, J ¼ 9.6 Hz, 1H), 7.81 (d,
J ¼ 8.4 Hz, 1H), 7.57 (dd, J ¼ 7.6, 4.9 Hz, 2H), 7.38 (d, J ¼ 5.4 Hz, 1H),
7.20 (dt, J ¼ 8.4, 2.2 Hz, 2H), 6.88 (t, J ¼ 8.7 Hz, 2H), 6.54 (d,
d
13C NMR (100 MHz, DMSO‑d6)
d
¼ 164.78, 163.54, 161.95, 157.33,