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J.-N. Chen et al. / European Journal of Medicinal Chemistry 107 (2016) 12e25
4.2.6.3. N-(3-methylphenyl)-N'-(3-(((quinazolin-4-yl)amino)methyl)
phenyl)urea (7c). White powder, yield: 55.87%, m.p.
227.1e228.8 ꢂC. 1H NMR (500 MHz, DMSO-d6)
(ppm): 8.87 (t,
243.5e245.2 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 8.87 (t,
J ¼ 5.8 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J ¼ 8.0 Hz,1H), 8.14 (t, J ¼ 8.3 Hz,
1H), 7.80 (t, J ¼ 7.0 Hz, 1H), 7.72 (dd, J ¼ 8.3, 1.0 Hz, 1H), 7.55 (t,
J ¼ 7.0 Hz,1H), 7.44 (dd, J ¼ 8.1, 1.1 Hz, 1H), 7.28e7.19 (m, 2H), 7.13 (t,
J ¼ 7.8 Hz, 1H), 7.04e6.95 (m, 2H), 4.80 (d, J ¼ 5.9 Hz, 2H). 13C NMR
d
J ¼ 5.9 Hz,1H), 8.47 (s, 1H), 8.34 (d, J ¼ 8.3 Hz,1H), 7.79 (t, J ¼ 7.6 Hz,
1H), 7.72 (d, J ¼ 8.3 Hz, 1H), 7.55 (t, J ¼ 7.6 Hz, 1H), 7.42 (d, J ¼ 7.9 Hz,
1H), 7.27 (s, 1H), 7.22 (dd, J ¼ 17.6, 9.5 Hz, 2H), 7.14 (t, J ¼ 7.7 Hz, 1H),
6.98 (d, J ¼ 7.7 Hz, 1H), 6.78 (d, J ¼ 7.6 Hz, 1H), 4.79 (d, J ¼ 5.9 Hz,
(125 MHz, DMSO-d6) d (ppm): 159.87,155.59,153.36,152.58,149.71,
140.76,139.99,133.09,129.33, 128.05,126.20,124.98,124.96, 123.13,
122.87, 121.42, 120.91, 116.97, 115.46, 115.40, 115.31, 43.95. ESI-
HRMS (m/z): calcd. for C22H18FN5O [MþH]þ: 388.15736; found:
388.15584.
2H), 2.27 (s, 3H). 13C NMR (125 MHz, DMSO-d6)
d (ppm): 159.87,
155.59, 152.91, 149.68, 140.63, 140.27, 140.04, 138.40, 133.09, 129.23,
129.07, 128.03, 126.20, 123.14, 123.02, 121.12, 119.13, 117.07, 117.01,
115.80, 115.40, 43.97, 21.68. ESI-HRMS (m/z): calcd. for C23H21N5O
[MþH]þ: 384.18244; found: 384.18077.
4.2.6.9. N-(4-fluorophenyl)-N'-(3-(((quinazolin-4-yl)amino)methyl)
phenyl)urea
(7i). White
powder,
yield:
40.56%,
d (ppm): 8.87 (t,
m.p.
4.2.6.4. N-(4-methylphenyl)-N'-(3-(((quinazolin-4-yl)amino)methyl)
281.3e282.9 ꢂC. 1H NMR (500 MHz, DMSO-d6)
phenyl)urea
(7d). White
powder,
yield:
26.10%,
(ppm): 8.89 (t,
m.p.
J ¼ 5.9 Hz,1H), 8.47 (s, 1H), 8.33 (d, J ¼ 8.3 Hz, 1H), 7.79 (t, J ¼ 7.6 Hz,
1H), 7.72 (d, J ¼ 8.3 Hz, 1H), 7.55 (t, J ¼ 7.6 Hz, 1H), 7.47e7.38 (m,
3H), 7.23 (t, J ¼ 7.8 Hz, 1H), 7.10 (t, J ¼ 8.9 Hz, 2H), 6.99 (d, J ¼ 7.6 Hz,
266.1e267.4 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d
J ¼ 5.7 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J ¼ 8.1 Hz, 1H), 7.80 (t, J ¼ 7.6 Hz,
1H), 7.72 (d, J ¼ 8.2 Hz,1H), 7.56 (t, J ¼ 7.5 Hz,1H), 7.42 (d, J ¼ 8.0 Hz,
1H), 7.31 (d, J ¼ 8.3 Hz, 2H), 7.23 (t, J ¼ 7.8 Hz,1H), 7.07 (d, J ¼ 8.2 Hz,
1H), 4.79 (d, J ¼ 5.9 Hz, 2H). 13C NMR (125 MHz, DMSO-d6)
d (ppm):
159.87,158.73,156.84,155.59,153.04,149.69,140.63,140.23,136.48,
136.46, 133.08, 129.21, 128.03, 126.19, 123.14, 121.18, 120.41, 117.15,
115.80, 115.62, 115.40, 43.96. ESI-HRMS (m/z): calcd. for C22H18FN5O
[MþH]þ: 388.15736; found: 388.15573.
2H), 6.98 (d, J ¼ 7.5 Hz, 1H), 4.79 (d, J ¼ 5.7 Hz, 2H), 2.24 (s, 3H). 13
C
NMR (125 MHz, DMSO-d6)
d (ppm): 159.31, 154.91, 152.39, 148.99,
139.96, 139.75, 136.96, 132.46, 130.51, 128.98, 128.56, 127.32, 125.56,
122.55, 120.52, 118.19, 116.60, 116.48, 114.81, 43.46, 20.17. ESI-HRMS
(m/z): calcd. for C23H21N5O [MþH]þ: 384.18244; found: 384.18319.
4.2.6.10. N-(2-chlorophenyl)-N'-(3-(((quinazolin-4-yl)amino)
methyl)phenyl)urea (7j). White powder, yield: 44.91%, m.p.
4.2.6.5. N-(2-methoxyphenyl)-N'-(3-(((quinazolin-4-yl)amino)
233.7e235.4 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 8.89 (t,
methyl)phenyl)urea (7e). White powder, yield: 38.59%, m.p.
J ¼ 5.9 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J ¼ 8.1 Hz, 1H), 8.15 (dd, J ¼ 8.3,
1.3 Hz, 1H), 7.83e7.77 (m, 1H), 7.72 (d, J ¼ 8.0 Hz, 1H), 7.55 (t,
J ¼ 7.6 Hz, 1H), 7.47e7.42 (m, 2H), 7.32e7.22 (m, 2H), 7.07e6.95 (m,
229.5e232.4 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 8.87 (t,
J ¼ 5.8 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J ¼ 7.7 Hz, 1H), 8.12 (dd, J ¼ 7.9,
1.7 Hz,1H), 7.85e7.75 (m, 1H), 7.75e7.69 (m, 1H), 7.58e7.52 (m, 1H),
7.46 (d, J ¼ 1.1 Hz, 1H), 7.24 (t, J ¼ 7.8 Hz, 1H), 7.02e6.97 (m, 2H),
6.96e6.91 (m, 1H), 6.91e6.86 (m, 1H), 4.80 (d, J ¼ 5.9 Hz, 2H), 3.86
2H), 4.81 (d, J ¼ 5.9 Hz, 2H). 13C NMR (125 MHz, DMSO-d6)
d (ppm):
159.87, 155.59, 152.53, 149.69, 140.75, 140.00, 136.41, 133.11, 129.65,
129.35, 128.04, 128.02, 126.22, 123.70, 123.13, 122.31, 121.68, 121.49,
117.06, 117.01,115.39, 43.95. ESI-HRMS (m/z): calcd. for C22H18ClN5O
[MþH]þ: 404.12781; found: 404.12638.
(s, 3H). 13C NMR (125 MHz, DMSO-d6)
d (ppm): 159.87, 155.60,
152.80, 149.71, 148.07, 140.65, 140.41, 133.09, 129.27, 129.15, 128.05,
126.20, 123.14, 122.21, 121.08, 121.01, 118.68, 116.78, 115.40, 111.18,
56.22, 43.97. ESI-HRMS (m/z): calcd. for C23H21N5O2 [MþH]þ:
400.17735; found: 400.17596.
4.2.6.11. N-(3-chlorophenyl)-N'-(3-(((quinazolin-4-yl)amino)methyl)
phenyl)urea
(7k). White
powder,
yield:
43.67%,
(ppm): 8.83 (t,
m.p.
235.7e236.9 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d
4.2.6.6. N-(4-methoxyphenyl)-N'-(3-(((quinazolin-4-yl)amino)
J ¼ 5.7 Hz, 1H), 8.42 (s, 1H), 8.28 (d, J ¼ 8.2 Hz, 1H), 7.74 (t, J ¼ 7.6 Hz,
1H), 7.70e7.59 (m, 2H), 7.50 (t, J ¼ 7.5 Hz, 1H), 7.37 (d, J ¼ 8.0 Hz,
1H), 7.23 (t, J ¼ 8.0 Hz, 1H), 7.19 (t, J ¼ 7.8 Hz, 2H), 6.95 (d, J ¼ 7.7 Hz,
methyl)phenyl)urea (7f). White powder, yield: 27.56%, m.p.
272.1e273.7 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 8.87 (t,
J ¼ 5.9 Hz, 1H), 8.47 (s, 1H), 8.36e8.31 (m, 1H), 7.79 (t, J ¼ 7.6 Hz,
1H), 7.74e7.70 (m,1H), 7.55 (t, J ¼ 7.0 Hz,1H), 7.40 (d, J ¼ 8.0 Hz,1H),
7.34e7.31 (m, 2H), 7.22 (t, J ¼ 7.8 Hz, 1H), 6.97 (d, J ¼ 8.0 Hz, 1H),
6.88e6.83 (m, 2H), 4.78 (d, J ¼ 5.9 Hz, 2H), 3.71 (s, 3H). 13C NMR
2H), 4.74 (d, J ¼ 5.8 Hz, 2H). 13C NMR (125 MHz, DMSO-d6)
d (ppm):
159.31, 154.95, 152.19, 149.11, 141.12, 140.07, 139.34, 133.07, 132.43,
130.18, 128.61, 127.41, 125.54, 122.54, 121.29, 120.92, 117.47, 116.88,
116.75, 116.50, 114.84, 43.43. ESI-HRMS (m/z): calcd. for
(125 MHz, DMSO-d6)
d
(ppm): 159.86, 155.59, 154.93, 153.13,
C
22H18ClN5O [MþH]þ: 404.12781; found: 404.12635.
149.68, 140.58, 140.44, 133.14, 133.08, 129.19, 128.02, 126.19, 123.14,
120.95, 120.45, 117.00, 116.96, 115.40, 114.45, 55.64, 43.97. ESI-
HRMS (m/z): calcd. for C23H21N5O2 [MþH]þ: 400.17735; found:
400.17573.
4.2.6.12. N-(4-chlorophenyl)-N'-(3-(((quinazolin-4-yl)amino)
methyl)phenyl)urea (7l). White powder, yield: 60.79%, m.p.
283.4e284.5 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 8.88 (t,
J ¼ 6.0 Hz, 1H), 8.47 (s, 1H), 8.33 (d, J ¼ 7.7 Hz, 1H), 7.85e7.76 (m,
1H), 7.72 (dd, J ¼ 8.3, 0.8 Hz, 1H), 7.58e7.52 (m, 1H), 7.48e7.44 (m,
2H), 7.42 (d, J ¼ 8.1 Hz, 1H), 7.33e7.29 (m, 2H), 7.24 (t, J ¼ 7.8 Hz,
1H), 7.00 (d, J ¼ 7.6 Hz, 1H), 4.79 (d, J ¼ 5.9 Hz, 2H). 13C NMR
4.2.6.7. N-((4-tert-butyl)phenyl)-N'-(3-(((quinazolin-4-yl)amino)
methyl)phenyl)urea (7g). White powder, yield: 28.23%, m.p.
218.2e220.6 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 8.81 (t,
J ¼ 5.8 Hz, 1H), 8.42 (s, 1H), 8.28 (d, J ¼ 8.1 Hz, 1H), 7.74 (t, J ¼ 7.2 Hz,
1H), 7.66 (d, J ¼ 8.2 Hz, 1H), 7.50 (t, J ¼ 7.6 Hz,1H), 7.36 (d, J ¼ 8.1 Hz,
1H), 7.30e7.20 (m, 4H), 7.17 (t, J ¼ 7.8 Hz,1H), 6.92 (d, J ¼ 7.5 Hz,1H),
4.74 (d, J ¼ 5.8 Hz, 2H), 1.20 (s, 9H). 13C NMR (125 MHz, DMSO-d6)
(125 MHz, DMSO-d6) d (ppm): 159.87, 155.58, 152.84, 149.66,
140.66, 140.06, 139.15, 133.09, 129.24, 129.07, 128.01, 126.20, 125.78,
123.14, 121.33, 120.14, 117.22, 117.17, 115.40, 43.96. ESI-HRMS (m/z):
calcd. for C22H18ClN5O [MþH]þ: 404.12781; found: 404.12645.
d
(ppm): 159.30, 154.96, 152.39, 149.13, 144.05, 140.00, 139.74,
136.88, 132.42, 128.56, 127.42, 125.53, 125.18, 122.53, 120.51, 117.95,
4.2.6.13. N-(4-nitrophenyl)-N'-(3-(((quinazolin-4-yl)amino)methyl)
116.57, 116.46, 114.84, 43.44, 33.72, 31.12. ESI-HRMS (m/z): calcd. for
C
phenyl)urea 12.07%,
(7m). White
powder,
yield:
m.p.
26H27N5O [MþH]þ: 426.22939; found: 426.22784.
243.8e245.1 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 8.88 (t,
J ¼ 6.0 Hz,1H), 8.47 (s, 1H), 8.33 (d, J ¼ 7.6 Hz,1H), 8.18 (d, J ¼ 9.3 Hz,
2H), 7.82e7.77 (m, 1H), 7.72 (dd, J ¼ 8.3, 0.9 Hz, 1H), 7.67 (d,
J ¼ 9.3 Hz, 2H), 7.55 (t, J ¼ 7.6 Hz, 1H), 7.42 (d, J ¼ 8.1 Hz, 1H), 7.26 (t,
4.2.6.8. N-(2-fluorophenyl)-N'-(3-(((quinazolin-4-yl)amino)methyl)
phenyl)urea (7h). White powder, yield: 49.35%, m.p.