J. Liu et al. / European Journal of Medicinal Chemistry 123 (2016) 431e446
443
(m, 6H), 2.27 (m, 2H), 1.75 (m, 4H), 1.52 (br, 2H); MS (ESI) m/z(%):
6.7.25. 1-(2-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-
methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (50)
645.4 [MþH]þ; Anal. calcd. for C34H34F2N6O5 (%): C, 63.34; H, 5.32;
N, 13.04. Found (%): C, 63.36; H, 5.35; N, 13.03.
Yield: 83.5%; M.p.: 115.7e118 ꢀC; 1H NMR (400 MHz, CDCl3)
8.73 (s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.82 (dd, J ¼ 11.6, 2.4 Hz, 1H),
d
6.7.21. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-1-(2-fluorophenyl)-4-methyl-5-
oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (46)
7.60e7.55 (m, 2H), 7.49 (m, 1H), 7.45e7.39 (m, 3H), 7.35 (m, 1H),
7.26 (t, 1H), 6.40 (d, J ¼ 5.2 Hz, 1H), 4.25 (t, J ¼ 6.4 Hz, 2H), 4.03 (s,
3H), 3.76 (s, 3H), 2.98e2.37 (m, 10H), 2.33 (s, 3H), 2.13 (m, 2H); MS
(ESI) m/z(%): 676.4 [M]þ; Anal. calcd. for C34H35ClFN7O5 (%): C,
60.40; H, 5.22; N, 14.50; Found (%): C, 60.34; H, 5.23; N, 14.55.
Yield: 80.6%; M.p.: 113.4e115.3 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.74 (s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.83 (dd, J ¼ 11.6, 2.4 Hz, 1H),
7.55 (m, 2H), 7.43 (m, 2H), 7.36 (m, 1H), 7.28 (m, 3H), 6.41 (d,
J ¼ 5.2 Hz, 1H), 4.25 (t, J ¼ 6.4 Hz, 2H), 4.02 (s, 3H), 3.75 (s, 3H), 3.08
(br, 2H), 2.72 (br, 2H), 2.19 (m, 4H), 1.68 (m, 2H), 1.42 (br, 3H), 0.95
6.7.26. N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)
quinolin-4-yl)oxy)phenyl)-4-methyl-5-oxo-1-(2-(trifluoromethoxy)
phenyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (51)
(d, J ¼ 5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 159.85, 157.89,
155.36, 154.37, 152.98, 152.22, 149.91, 148.69, 146.87, 139.07, 138.20,
135.07, 130.70, 127.46, 124.69, 124.00, 117.20, 117.00, 116.30, 115.54,
109.82, 108.86, 102.30, 99.53, 67.25, 56.12, 55.25, 53.70 (2C), 33.36,
30.37, 30.04, 29.68, 25.83, 21.58; MS (ESI) m/z(%): 659.4 [MþH]þ;
Anal. calcd. for C35H36F2N6O5 (%): C, 63.82; H, 5.77; N, 12.76. Found
(%): C, 63.81; H, 5.79; N, 12.79.
Yield: 82.2%; M.p.: 102e104 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.72
(s, 1H), 8.49 (d, J ¼ 5.2 Hz,1H), 7.82 (dd, J ¼ 11.6, 2.4 Hz, 1H), 7.63 (m,
1H), 7.55 (s, 1H), 7.54e7.48 (m, 1H), 7.48e7.38 (m, 3H), 7.35 (m, 1H),
7.26 (t, J ¼ 8.4 Hz, 1H), 6.41 (d, J ¼ 5.2 Hz, 1H), 4.25 (t, J ¼ 6.4 Hz, 2H),
4.02 (s, 3H), 3.75 (s, 3H), 3.01e2.55 (m, 6H), 2.33 (t, J ¼ 7.2 Hz, 2H),
1.82 (br, 4H), 1.55 (br, 2H); MS (ESI) m/z(%): 711.3 [MþH]þ; Anal.
calcd. for C35H34F4N6O6 (%): C, 59.15; H, 4.82; N, 11.83; Found (%): C,
59.18; H, 4.83; N, 11.91.
6.7.22. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-1-(2-fluorophenyl)-4-methyl-5-
oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (47)
6.7.27. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-5-oxo-1-(2-
(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazole-3-
carboxamide (52)
Yield: 78.4%; M.p.: 115.8e117.7 ꢀC; IR (KBr) cmꢁ1: 3421.3, 2941.4,
2801.8, 1731.7, 1619.6, 1542.1, 1508.4, 1480.1, 1431.3, 1349.5, 1305.8,
1249.2, 1211.5, 1167.9, 1105.1, 1013.1, 896.7, 855.1, 765.8, 733.6; 1H
NMR (400 MHz, CDCl3)
d
8.74 (s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.83
Yield: 82.3%; M.p.: 106e108 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.70
(dd, J ¼ 11.6, 2.4 Hz, 1H), 7.55 (m, 2H), 7.43 (m, 2H), 7.36 (m, 1H),
7.28 (m, 3H), 6.41 (d, J ¼ 5.2 Hz, 1H), 4.26 (t, J ¼ 6.4 Hz, 2H), 4.03 (s,
(s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.82 (dd, J ¼ 11.6, 2.4 Hz,1H), 7.64 (m,
1H), 7.56 (s, 1H), 7.54e7.42 (m, 3H), 7.40 (s, 1H), 7.35 (m, 1H), 7.27 (t,
J ¼ 8.4 Hz,1H), 6.41 (d, J ¼ 5.2 Hz,1H), 4.26 (t, J ¼ 6.4 Hz, 2H), 4.02 (s,
3H), 3.76 (s, 3H), 3.32 (br, 2H), 2.99 (br, 2H), 2.40 (br, 4H), 1.70 (m,
3H), 3.75 (s, 3H), 2.80e2.40 (m, 10H), 2.32 (s, 3H), 2.13 (m, 2H); 13
C
NMR (100 MHz, CDCl3)
d 159.85, 157.90, 155.37, 154.36, 152.99,
152.38, 149.96, 148.66, 146.94, 139.06, 138.12, 135.03,130.63, 127.46,
124.69, 124.66, 124.01, 117.21, 116.28, 115.45, 109.82, 108.76, 102.26,
99.47, 67.33, 56.14, 54.98 (2C), 54.85, 52.88 (2C), 45.81, 30.05, 26.31;
MS (ESI) m/z(%): 660.3 [MþH]þ; Anal. calcd. for C34H35F2N7O5 (%):
C, 61.90; H, 5.35; N, 14.86. Found (%): C, 61.94; H, 5.39; N, 14.89.
5H), 1.00 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 159.87,
155.72, 154.33, 153.23, 153.00, 151.92, 149.80, 148.77, 146.75, 143.79,
138.92, 138.15, 135.18, 130.43, 128.36, 128.03, 127.48, 124.05, 121.91,
116.25, 115.70, 109.74, 109.03, 102.39, 99.65, 66.66, 56.09 (2 C),
55.09, 53.32, 32.00, 30.03, 29.74, 29.68, 24.85, 21.16; MS (ESI) m/
z(%): 725.4 [MþH]þ; Anal. calcd. for C36H36F4N6O6 (%): C, 59.66; H,
5.01; N, 11.60; Found (%): C, 59.73; H, 5.05; N, 11.65.
6.7.23. 1-(2-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-5-
oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (48)
6.7.28. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-5-oxo-1-(2-
(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazole-3-
carboxamide (53)
Yield: 82.6%; M.p.: 135e137 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.73
(s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.83 (dd, J ¼ 11.6, 2.4 Hz, 1H),
7.59e7.50 (m, 2H), 7.49 (m, 1H), 7.40e7.46 (m, 3H), 7.35 (m, 1H),
7.26 (t, 1H), 6.41 (d, J ¼ 5.2 Hz, 1H), 4.25 (t, J ¼ 6.4 Hz, 2H), 4.02 (s,
3H), 3.76 (s, 3H), 2.82e2.70 (m, 6H), 2.30 (t, J ¼ 7.2 Hz, 2H), 1.78 (br,
4H), 1.53 (br, 2H); MS (ESI) m/z(%): 661.3 [M]þ; Anal. calcd. for
Yield: 80.1%; M.p.: 105e107 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.69
(s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.82 (dd, J ¼ 11.6, 2.4 Hz,1H), 7.64 (m,
1H), 7.55 (s, 1H), 7.54e7.49 (m, 1H), 7.49e7.42 (m, 3H), 7.34 (m, 1H),
7.27 (t, J ¼ 8.4 Hz,1H), 6.41 (d, J ¼ 5.2 Hz, 1H), 4.26 (t, J ¼ 6.4 Hz, 2H),
4.03 (s, 3H), 3.76 (s, 3H), 2.85e2.40 (m, 10H), 2.33 (s, 3H), 2.13 (m,
2H); MS (ESI) m/z(%): 726.4 [MþH]þ; Anal. calcd. for C35H35F4N7O6
(%): C, 57.93; H, 4.86; N, 13.51; Found (%): C, 57.85; H, 4.82; N, 13.55.
C
34H34ClFN6O5 (%): C, 61.77; H, 5.18; N,12.71; Found (%): C, 61.85; H,
5.13; N, 12.73.
6.7.24. 1-(2-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-
5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (49)
6.7.29. 1-(2,4-dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-5-
oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (54)
Yield: 80.6%; M.p.: 136.3e139 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.73 (s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.83 (dd, J ¼ 11.6, 2.4 Hz, 1H),
7.60e7.50 (m, 2H), 7.49 (m, 1H), 7.45e7.35 (m, 3H), 7.35 (m, 1H),
7.26 (t, 1H), 6.41 (d, J ¼ 5.2 Hz, 1H), 4.25 (t, J ¼ 6.4 Hz, 2H), 4.02 (s,
3H), 3.76 (s, 3H), 3.19 (br, 2H), 2.84 (br, 2H), 2.31 (br, 4H), 1.71 (m,
2H),1.51 (m, 3H), 0.97 (d, J ¼ 5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
Yield: 83.4%; M.p.: 116e118 ꢀC; IR (KBr) cmꢁ1: 3448.3, 2940.3,
2777.3, 1731.4, 1691.9, 1620.9, 1542.0, 1508.4, 1480.2, 1431.3, 1349.8,
1305.8, 1250.0, 1211.5, 1171.2, 1103.3, 995.2, 853.9, 733.7; 1H NMR
(400 MHz, CDCl3)
d
8.72 (s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.83 (dd,
d
159.86, 155.70, 154.41, 153.05, 152.07, 149.83, 148.72, 146.79,
J ¼ 12.0 Hz, 2.4 Hz, 1H), 7.58 (d, J ¼ 2.0 Hz, 1H), 7.55 (s, 1H), 7.42 (m,
3H), 7.35 (m, 1H), 7.27 (t, J ¼ 8.4 Hz, 1H), 6.41 (d, J ¼ 5.2 Hz, 1H), 4.25
(t, J ¼ 6.4 Hz, 2H), 4.02 (s, 3 H), 3.75 (s, 3H), 2.75 (m, 6H), 2.83 (br,
138.91, 137.99, 135.21, 133.36, 132.04, 130.96, 130.79, 129.17, 127.77,
124.01, 116.28, 115.59, 109.56, 108.90, 102.32, 99.56, 66.97, 56.10
(2C), 55.18, 53.53, 32.74, 30.08 (2C), 29.69, 25.38, 21.41; MS (ESI) m/
z(%): 675.4 [M]þ; Anal. calcd. for C35H36ClFN6O5 (%): C, 62.26; H,
5.37; N, 12.45; Found (%): C, 62.34; H, 5.33; N, 12.51.
2H), 1.77 (br, 4H), 1.53 (br, 2H); 13C NMR (101 MHz, CDCl3)
d 159.84,
155.71, 154.27, 152.91, 152.10, 149.85, 148.72, 146.81, 139.14, 136.31,
135.02, 132.84, 132.02, 130.67, 129.84, 128.11, 124.04, 116.30, 115.57,