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M. Liu et al. / European Journal of Medicinal Chemistry 119 (2016) 96e108
66.87; H, 5.78; N, 13.76. Found (%): C, 66.90; H, 5.72; N, 13.80.
d
9.19 (s, 1H), 8.52 (d, J ¼ 5.2 Hz, 1H), 8.41 (s, 1H), 7.98 (dd, J ¼ 11.9,
2.4 Hz, 1H), 7.59 (d, J ¼ 7.8 Hz, 2H), 7.56e7.51 (m, 1H), 7.46 (d,
J ¼ 5.7 Hz, 2H), 7.32 (d, J ¼ 8.6 Hz, 1H), 7.28 (s, 1H), 6.46 (d,
J ¼ 5.2 Hz, 1H), 4.27 (t, J ¼ 6.7 Hz, 2H), 4.06 (s, 3H), 2.95 (t,
J ¼ 11.8 Hz, 2H), 2.62e2.46 (m, 2H), 2.15 (dd, J ¼ 14.1, 7.1 Hz, 2H),
1.97 (t, J ¼ 11.5 Hz, 2H), 1.64 (d, J ¼ 12.6 Hz, 2H), 1.28 (t, J ¼ 10.4 Hz,
3H), 0.94 (d, J ¼ 6.3 Hz, 3H); MS (ESI) m/z (%): 679.1 [MþH]þ; Anal.
calcd. for C34H33Cl2FN6O4 (%): C, 60.09; H, 4.89; N, 12.37. Found (%):
C, 60.13; H, 4.93; N, 12.39.
5.7.20. 1-(2-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy) quinolin- 4-yl)oxy)phenyl)-1H-
1,2,3-triazole-4-carboxamide (45)
Yield: 75.8%; M.p.: 177.9e178.7 ꢁC; 1H NMR (400 MHz, CDCl3)
d
9.14 (s, 1H), 8.63 (s, 1H), 8.52 (d, J ¼ 5.3 Hz, 1H), 7.98 (dd, J ¼ 11.9,
2.4 Hz, 1H), 7.70e7.65 (m, 2H), 7.59 (s, 1H), 7.55 (td, J ¼ 7.1, 1.8 Hz,
2H), 7.31 (d, J ¼ 8.6 Hz,1H), 6.46 (d, J ¼ 4.8 Hz,1H), 4.27 (t, J ¼ 6.7 Hz,
2H), 4.06 (s, 3H), 2.95 (d, J ¼ 11.3 Hz, 2H), 2.58 (t, J ¼ 7.1 Hz, 2H), 2.18
(dd, J ¼ 14.3, 6.9 Hz, 2H), 1.99 (t, J ¼ 10.6 Hz, 2H), 1.65 (d, J ¼ 13.1 Hz,
2H), 1.41e1.34 (m, 1H), 1.28 (d, J ¼ 8.9 Hz, 2H), 0.94 (d, J ¼ 6.2 Hz,
5.7.25. 1-(3,4-difluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy) quinolin-4-yl)oxy)phenyl)-1H-1,2,3-
triazole-4-carboxamide (50)
3H); 13C NMR (600 MHz, CDCl3)
d 159.96, 157.63, 153.27, 152.33,
149.90, 148.76, 146.96, 142.78, 137.70, 137.58, 136.06, 135.96, 131.60,
131.03, 128.83, 128.18, 127.67, 123.95, 116.08, 115.43, 109.63, 109.40,
108.79, 102.23, 67.64, 56.17, 55.42, 54.01 (2C), 34.29 (2C), 30.81,
26.49, 21.90; MS (ESI) m/z (%): 645.1 [MþH]þ; Anal. calcd. for
Yield: 78.3%; M.p.: 179.6e180.9 ꢁC; 1H NMR (400 MHz, CDCl3)
d
9.10 (s, 1H), 8.61 (s, 1H), 8.51 (d, J ¼ 5.3 Hz, 1H), 7.97 (dd, J ¼ 11.9,
2.5 Hz, 1H), 7.79e7.73 (m, 1H), 7.59 (s, 1H), 7.56 (dd, J ¼ 9.1, 3.5 Hz,
1H), 7.45 (s, 1H), 7.44e7.38 (m, 2H), 7.31 (t, J ¼ 8.6 Hz, 1H), 6.44 (d,
J ¼ 4.6 Hz, 1H), 4.27 (t, J ¼ 6.7 Hz, 2H), 4.06 (s, 3H), 2.93 (d,
J ¼ 11.4 Hz, 2H), 2.59e2.53 (m, 2H), 2.19e2.11 (m, 2H), 1.96 (t,
J ¼ 10.5 Hz, 2H), 1.64 (d, J ¼ 12.9 Hz, 2H),1.40e1.32 (m, 1H), 1.26 (dd,
J ¼ 11.9, 3.3 Hz, 2H), 0.94 (d, J ¼ 6.3 Hz, 3H); MS (ESI) m/z (%): 647.2
[MþH]þ; Anal. calcd. for C34H33F3N6O4 (%): C, 63.15; H, 5.14; N,
13.00. Found (%): C, 63.19; H, 5.17; N, 13.06.
C
34H34ClFN6O4 (%): C, 63.30; H, 5.31; N, 13.03. Found (%): C, 63.37;
H, 5.37; N, 13.06.
5.7.21. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy) phenyl)-1-(2-fluorophenyl)-1H-1,2,3-
triazole-4-carboxamide (46)
Yield: 73.6%; M.p.: 178.2e180.1 ꢁC; 1H NMR (400 MHz, CDCl3)
d
9.14 (s, 1H), 8.63 (s, 1H), 8.52 (d, J ¼ 5.3 Hz, 1H), 7.98 (dd, J ¼ 11.9,
5.7.26. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)
propoxy)quinolin-4-yl)oxy) phenyl)-1-phenyl-1H-1,2,3-triazole-4-
carboxamide (51)
2.4 Hz, 1H), 7.70e7.65 (m, 2H), 7.59 (s, 1H), 7.55 (td, J ¼ 7.1, 1.8 Hz,
2H), 7.31 (d, J ¼ 8.6 Hz,1H), 6.46 (d, J ¼ 4.8 Hz,1H), 4.27 (t, J ¼ 6.7 Hz,
2H), 4.06 (s, 3H), 2.95 (d, J ¼ 11.3 Hz, 2H), 2.58 (t, J ¼ 7.1 Hz, 2H), 2.18
(dd, J ¼ 14.3, 6.9 Hz, 2H), 1.99 (t, J ¼ 10.6 Hz, 2H), 1.65 (d, J ¼ 13.1 Hz,
2H), 1.41e1.34 (m, 1H), 1.28 (d, J ¼ 8.9 Hz, 2H), 0.94 (d, J ¼ 6.2 Hz,
3H); MS (ESI) m/z (%): 663.4 [MþCl]-; Anal. calcd. for C34H34F2N6O4
(%): C, 64.96; H, 5.45; N, 13.37. Found (%): C, 64.93; H, 5.37; N, 13.41.
Yield: 73.4%; M.p.: 160.2e162.1 ꢁC; 1H NMR (400 MHz, CDCl3)
d
9.16 (s, 1H), 8.67 (s, 1H), 8.53 (d, J ¼ 5.2 Hz, 1H), 8.00 (dd, J ¼ 11.9,
2.1 Hz, 1H), 7.83 (d, J ¼ 7.7 Hz, 2H), 7.65 (d, J ¼ 7.2 Hz, 3H), 7.57 (t,
J ¼ 7.3 Hz,1H), 7.47 (d, J ¼ 3.1 Hz, 2H), 7.33 (d, J ¼ 8.6 Hz,1H), 6.48 (d,
J ¼ 5.1 Hz, 1H), 4.31 (t, J ¼ 6.5 Hz, 2H), 4.08 (s, 3H), 3.01e2.52 (m,
10H), 2.44 (s, 3H), 2.24e2.11 (m, 2H); MS (ESI) m/z (%): 611.9
[MþH]þ; Anal. calcd. for C35H34FN7O4 (%): C, 64.80; H, 5.60; N,
16.03. Found (%): C, 64.84; H, 5.67; N, 16.06.
5.7.22. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy) phenyl)-1-(o-tolyl)-1H-1,2,3-triazole-4-
carboxamide (47)
Yield: 77.2%; M.p.: 177.7e178.2 ꢁC; 1H NMR (400 MHz, CDCl3)
9.17 (s, 1H), 8.51 (d, J ¼ 5.3 Hz, 1H), 8.39 (s, 1H), 7.97 (dd, J ¼ 11.9,
5.7.27. 1-(2-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperazin-1-yl)propoxy) quinolin-4-yl)oxy)phenyl)-1H-1,2,3-
triazole-4-carboxamide (52)
d
2.5 Hz, 1H), 7.59 (s, 1H), 7.51 (ddd, J ¼ 8.2, 5.6, 2.8 Hz, 1H), 7.46e7.45
(m, 1H), 7.45 (s, 1H), 7.44e7.43 (m, 1H), 7.42e7.38 (m, 2H), 7.30 (t,
J ¼ 8.0 Hz,1H), 6.45 (d, J ¼ 5.2 Hz,1H), 4.27 (t, J ¼ 6.7 Hz, 2H), 4.06 (s,
3H), 2.95 (d, J ¼ 11.4 Hz, 2H), 2.62e2.54 (m, 2H), 2.28 (s, 3H),
2.20e2.12 (m, 2H), 1.98 (t, J ¼ 10.9 Hz, 2H), 1.64 (d, J ¼ 12.8 Hz, 2H),
1.41e1.33 (m, 1H), 1.30e1.24 (m, 2H), 0.93 (d, J ¼ 8.0 Hz, 3H); MS
(ESI) m/z (%): 625.2 [MþH]þ; Anal. calcd. for C35H37FN6O4 (%): C,
67.29; H, 5.97; N, 13.45. Found (%): C, 67.33; H, 5.93; N, 13.46.
Yield: 75.1%; M.p.: 161.1e163.8 ꢁC; 1H NMR (400 MHz, CDCl3)
d
9.13 (s, 1H), 8.73 (s, J ¼ 2.4 Hz, 1H), 8.51 (d, J ¼ 5.2 Hz, 1H),
8.02e7.95 (m, 2H), 7.59 (s, 1H), 7.58e7.51 (m, 1H), 7.47 (s, 1H), 7.45
(s, 1H), 7.41 (t, J ¼ 7.7 Hz, 2H), 7.31 (d, J ¼ 8.6 Hz, 1H), 6.45 (d,
J ¼ 5.2 Hz, 1H), 4.28 (t, J ¼ 6.6 Hz, 2H), 4.06 (s, 3H), 2.73e2.44 (m,
10H), 2.38 (s, 3H), 2.19e2.11 (m, 2H); MS (ESI) m/z (%): 644.2
[MꢀH]ꢀ; Anal. calcd. for C33H33ClFN7O4 (%): C, 61.34; H, 5.15; N,
15.17. Found (%): C, 61.38; H, 5.17; N, 15.16.
5.7.23. 1-(2,6-dimethylphenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(4-methylpiperidin-1-yl)propoxy) quinolin-4-yl)oxy)phenyl)-1H-
1,2,3-triazole-4-carboxamide (48)
5.7.28. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)
propoxy)quinolin-4-yl)oxy) phenyl)-1-(2-fluorophenyl)-1H-1,2,3-
triazole-4-carboxamide (53)
Yield: 76.8%; M.p.: 178.3e180.2 ꢁC; 1H NMR (400 MHz, CDCl3)
d
9.17 (s, 1H), 8.51 (d, J ¼ 5.3 Hz, 1H), 8.39 (s, 1H), 7.97 (dd, J ¼ 11.9,
Yield: 76.2%; M.p.: 162.4e164.1 ꢁC; 1H NMR (400 MHz, CDCl3)
2.5 Hz, 1H), 7.59 (s, 1H), 7.51 (dd, J ¼ 8.2, 5.6 Hz, 1H), 7.46e7.45 (m,
1H), 7.45 (s, 1H), 7.44e7.43 (m, 1H), 7.42e7.38 (m, 1H), 7.30 (t,
J ¼ 8.0 Hz,1H), 6.45 (d, J ¼ 5.2 Hz,1H), 4.27 (t, J ¼ 6.7 Hz, 2H), 4.06 (s,
3H), 2.95 (d, J ¼ 11.4 Hz, 2H), 2.62e2.54 (m, 2H), 2.20e2.12 (m, 2H),
2.04 (s, 6H), 1.98 (t, J ¼ 10.9 Hz, 2H), 1.64 (d, J ¼ 12.8 Hz, 2H),
1.41e1.33 (m, 1H), 1.30e1.24 (m, 2H), 0.93 (d, J ¼ 8.0 Hz, 3H); MS
(ESI) m/z (%): 639.3 [MþH]þ; Anal. calcd. for C36H39FN6O4 (%): C,
67.69; H, 6.15; N, 13.16. Found (%): C, 67.73; H, 6.17; N, 13.21.
d
9.13 (s, 1H), 8.73 (s, J ¼ 2.4 Hz, 1H), 8.51 (d, J ¼ 5.2 Hz, 1H),
8.02e7.95 (m, 2H), 7.59 (s, 1H), 7.58e7.51 (m, 1H), 7.47 (s, 1H), 7.45
(s, 1H), 7.41 (t, J ¼ 7.7 Hz, 2H), 7.31 (d, J ¼ 8.6 Hz, 1H), 6.45 (d,
J ¼ 5.2 Hz, 1H), 4.28 (t, J ¼ 6.6 Hz, 2H), 4.06 (s, 3H), 2.73e2.44 (m,
10H), 2.38 (s, 3H), 2.19e2.11 (m, 2H); MS (ESI) m/z (%): 664.4
[MþCl]ꢀ; Anal. calcd. for C35H34F2N7O4 (%): C, 62.95; H, 5.28; N,
15.57. Found (%): C, 62.93; H, 5.37; N, 15.56.
5.7.29. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)
propoxy)quinolin-4-yl)oxy) phenyl)-1-(o-tolyl)-1H-1,2,3-triazole-4-
carboxamide (54)
5.7.24. 1-(2,6-dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy) quinolin-4-yl)oxy)phenyl)-1H-1,2,3-
triazole-4-carboxamide (49)
Yield: 75.4%; M.p.: 161.7e163.4 ꢁC; 1H NMR (400 MHz, CDCl3)
Yield: 77.4%; M.p.: 179.1e180.5 ꢁC; 1H NMR (400 MHz, CDCl3)
d
9.24 (s, 1H), 8.52 (d, J ¼ 5.2 Hz, 1H), 8.32 (s, 1H), 8.01 (dd, J ¼ 11.8,