S. Zhou et al. / European Journal of Medicinal Chemistry 83 (2014) 581e593
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5.6.24. 1-(2,4-Dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-6-
5.6.28. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-6-oxo-1-(2-
(trifluoromethoxy)phenyl)-1,6-dihydropyridazine-3-carboxamide
(16d)
oxo-1,6-dihydropyridazine-3-carboxamide (20c)
Yield: 79.6%; M.p.: 146e147 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.98
(s, 1H), 8.48 (d, J ¼ 5.2 Hz, 1H), 7.84 (dd, 1H), 7.63 (s, 1H), 7.56 (s, 1H),
7.49e7.39 (m, 3H), 7.34 (d, J ¼ 8.9 Hz, 1H), 7.25 (t, J ¼ 8.7 Hz, 1H),
6.96 (s, 1H), 6.39 (d, J ¼ 5.2 Hz, 1H), 4.26 (t, J ¼ 6.5 Hz, 2H), 4.04 (s,
3H), 2.71 (s, 3H), 2.62 (t, 2H), 2.56e2.30 (m, 4H), 2.27e2.09 (m, 2H),
1.75e1.55 (m, 4H), 1.53e1.41 (m, 2H). 13C NMR (600 MHz, CDCl3)
Yield: 82.0%; M.p.: 138e139 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.98
(s, 1H), 8.44 (d, J ¼ 5.2 Hz, 1H), 7.81 (dd, J ¼ 11.9, 2.2 Hz, 1H), 7.64 (d,
J ¼ 8.9 Hz, 2H), 7.52 (s,1H), 7.35 (dd, J ¼ 16.1, 7.4 Hz, 3H), 7.30 (s, 1H),
7.21 (d, J ¼ 8.6 Hz, 1H), 6.90 (s, 1H), 6.35 (d, J ¼ 5.2 Hz, 1H), 4.21 (t,
J ¼ 6.7 Hz, 2H), 4.00 (s, 3H), 2.91 (d, J ¼ 9.5 Hz, 2H), 2.65 (s, 3H),
2.60e2.46 (m, 2H), 2.19e2.03 (m, J ¼ 13.6, 6.8 Hz, 2H), 1.94 (t,
J ¼ 9.7 Hz, 2H), 1.60 (d, J ¼ 12.4 Hz, 2H), 1.40e1.30 (m, 1H), 1.23 (t,
J ¼ 7.6 Hz, 2H), 0.90 (d, J ¼ 6.2 Hz, 3H); MS (ESI) m/z (%): 736.6
[MþH]þ; Anal. calcd. for C38H37F4N5O6 (%): C, 62.04; H, 5.07; N,
9.52; Found (%): C, 62.03; H, 5.07; N, 9.56.
d
160.27, 159.93, 158.85, 155.26, 153.61, 152.28, 149.86, 148.57,
146.82, 145.23, 138.53, 136.53, 136.35, 132.44, 130.77, 130.51, 129.70,
128.20, 123.87, 116.38, 115.38, 109.72, 109.56, 108.61, 102.10, 99.43,
67.48, 56.13, 55.71, 54.48 (2C), 26.13, 25.70 (2C), 24.25, 20.68; MS
(ESI) m/z (%): 706.4 [MþH]þ; Anal. calcd. for C36H34Cl2FN5O5 (%): C,
61.19; H, 4.85; N, 9.91; Found (%): C, 61.20; H, 4.87; N, 9.96.
5.6.29. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-1-(3-fluorophenyl)-4-methyl-6-
oxo-1,6-dihydropyridazine-3-carboxamide (17d)
5.6.25. N-(3-fluoro-4-((6-methoxy-7-(4-methylpiperidin-1-yl))
propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-6-oxo-1-phenyl-1,6-
dihydropyridazine-3-carboxamide (13d)
Yield: 82.2%; M.p.: 142e144 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.96
(s, 1H), 8.48 (d, J ¼ 5.2 Hz, 1H), 7.93 (s, 1H), 7.86 (t, J ¼ 8.4 Hz, 2H),
7.76 (d, J ¼ 7.7 Hz, 1H), 7.70 (t, J ¼ 7.9 Hz, 1H), 7.57 (s, 1H), 7.42 (s,
1H), 7.37e7.30 (m, 1H), 7.27e7.21 (m, 1H), 6.97 (d, J ¼ 0.9 Hz, 1H),
6.40 (d, J ¼ 5.1 Hz, 1H), 4.26 (t, J ¼ 6.6 Hz, 2H), 4.04 (s, 3H), 2.99 (t,
J ¼ 6.1 Hz, 2H), 2.70 (s, 3H), 2.61 (t, J ¼ 6.2 Hz, 2H), 2.18 (t, J ¼ 6.0 Hz,
2H), 2.01 (t, J ¼ 6.2 Hz, 2H),1.65 (t, J ¼ 6.1 Hz, 2H),1.48e1.33 (m, 2H),
1.29e1.23 (m, 1H), 0.94 (d, J ¼ 6.0 Hz, 3H); MS (ESI) m/z (%): 670.2
[MþH]þ; Anal. calcd. for C37H37F2N5O5 (%): C, 66.36; H, 5.57; N,
10.46; Found (%): C, 66.37; H, 5.58; N, 10.47.
Yield: 80.5%; M.p.: 135e136 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.03
(s, 1H), 8.44 (d, J ¼ 5.2 Hz, 1H), 7.81 (d, J ¼ 11.8 Hz, 1H), 7.58 (d,
J ¼ 7.4 Hz, 2H), 7.54e7.49 (m, J ¼ 10.2 Hz, 3H), 7.48e7.43 (m, 1H),
7.39 (s, 1H), 7.31 (d, J ¼ 8.9 Hz, 1H), 7.20 (d, J ¼ 8.7 Hz, 1H), 6.90 (s,
1H), 6.36 (d, J ¼ 5.1 Hz, 1H), 4.21 (t, J ¼ 6.6 Hz, 2H), 4.00 (s, 3H), 2.89
(d, J ¼ 11.0 Hz, 2H), 2.65 (s, 3H), 2.51 (t, J ¼ 7.2 Hz, 2H), 2.19e2.02 (m,
2H), 1.92 (t, J ¼ 11.3 Hz, 2H), 1.60 (d, J ¼ 12.2 Hz, 2H), 1.38e1.29 (m,
1H), 1.23 (t, J ¼ 12.1 Hz, 2H), 0.89 (d, J ¼ 6.2 Hz, 3H); MS (ESI) m/z
(%): 652.6 [MþH]þ; Anal. calcd. for C37H38FN5O5 (%): C, 68.19; H,
5.88; N, 10.75; Found (%): C, 68.20; H, 5.87; N, 10.76.
5.6.30. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-1-(4-methoxyphenyl)-4-
methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (18d)
5.6.26. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-4–methyl-6-oxo-1-(2-
methylphenyl)-1,6-dihydropyridazine-3-carboxamide (14d)
Yield: 82.3%; M.p.: 146e148 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.06
(s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.84 (dd, J ¼ 11.9, 2.2 Hz, 1H), 7.57 (s,
1H), 7.54 (d, J ¼ 8.9 Hz, 2H), 7.44 (s, 1H), 7.35 (d, J ¼ 8.8 Hz, 1H), 7.24
(d, J ¼ 8.6 Hz, 1H), 7.05 (d, J ¼ 8.9 Hz, 2H), 6.93 (s, 1H), 6.41 (d,
J ¼ 5.2 Hz, 1H), 4.26 (t, J ¼ 6.6 Hz, 2H), 4.05 (s, 3H), 3.89 (s, 3H), 2.95
(d, J ¼ 11.1 Hz, 2H), 2.69 (s, 3H), 2.58 (t, J ¼ 7.2 Hz, 2H), 2.16 (dt,
J ¼ 13.7, 6.7 Hz, 2H), 1.99 (t, J ¼ 11.2 Hz, 2H), 1.65 (d, J ¼ 12.2 Hz, 2H),
1.45e1.34 (m, 1H), 1.27 (dd, J ¼ 14.7, 8.1 Hz, 2H), 0.94 (d, J ¼ 6.3 Hz,
3H); MS (ESI) m/z (%): 682.5 [MþH]þ; Anal. calcd. for C38H40FN5O6
(%): C, 66.95; H, 5.91; N, 10.27; Found (%): C, 66.96; H, 5.92; N, 10.28.
Yield: 82.1%; M.p.: 137e138 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.92
(s, 1H), 8.49 (d, J ¼ 5.2 Hz, 1H), 7.85 (dd, J ¼ 11.8, 2.4 Hz, 1H), 7.55 (s,
1H), 7.47 (d, J ¼ 7.8 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J ¼ 5.3 Hz, 1H), 7.32
(t, J ¼ 5.6 Hz, 2H), 7.25 (t, J ¼ 8.7 Hz, 2H), 6.98 (d, J ¼ 1.1 Hz,1H), 6.39
(d, J ¼ 5.2 Hz, 1H), 4.25 (t, J ¼ 6.7 Hz, 2H), 4.05 (s, 3H), 3.01 (t, 2H),
2.74 (s, 3H), 2.63 (t, J ¼ 4.2 Hz, 2H), 2.25 (s, 3H), 2.17 (t, J ¼ 6.0 Hz,
2H), 2.03 (t, 2H), 1.67 (t, J ¼ 12.5 Hz, 2H), 1.37e1.22 (m, 3H), 0.98 (d,
J ¼ 6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3)
d 160.58, 160.08, 158.96,
155.81, 153.33, 152.42, 150.03, 148.77, 147.03, 145.24, 138.78, 137.83,
137.22, 136.04, 132.16, 131.05, 130.70, 129.65, 128.11, 123.94, 116.60,
115.56, 109.74, 108.89, 102.28, 99.63, 67.61, 56.26, 55.43, 54.00 (2C),
34.11 (2C), 30.78, 26.37, 21.94, 20.79, 18.09; MS (ESI) m/z (%): 666.4
[MþH]þ; Anal. calcd. for C38H40FN5O5 (%): C, 68.55; H, 6.06; N,
10.52; Found (%): C, 68.56; H, 6.07; N, 10.53.
5.6.31. 1-(4-Chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-
6-oxo-1,6-dihydropyridazine-3-carboxamide (19d)
Yield: 80.1%; M.p.: 152e153 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.92
(s, 1H), 8.47 (d, J ¼ 5.1 Hz, 1H), 7.92 (s, 1H), 7.87 (t, J ¼ 8.4 Hz, 2H),
7.78 (d, J ¼ 7.7 Hz, 1H), 7.70 (t, J ¼ 7.9 Hz, 1H), 7.58 (s, 1H), 7.43 (s,
1H), 7.37e7.31 (m, 1H), 7.27e7.22 (m, 1H), 6.96 (d, J ¼ 0.9 Hz, 1H),
6.40 (d, J ¼ 5.1 Hz, 1H), 4.25 (t, J ¼ 6.6 Hz, 2H), 4.05 (s, 3H), 2.98 (t,
J ¼ 6.2 Hz, 2H), 2.70 (s, 3H), 2.60 (t, J ¼ 6.2 Hz, 2H), 2.18 (t, J ¼ 6.0 Hz,
2H), 2.01 (t, J ¼ 6.2 Hz, 2H), 1.66 (t, J ¼ 6.2 Hz, 2H), 1.48e1.32 (m,
2H), 1.29e1.24 (m, 1H), 0.96 (d, J ¼ 6.1 Hz, 3H); MS (ESI) m/z (%):
686.3 [MþH]þ; Anal. calcd. for C37H37ClFN5O5 (%): C, 64.76; H, 5.44;
N, 10.21; Found (%): C, 64.77; H, 5.45; N, 10.22.
5.6.27. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-4-methyl-6-oxo-1-(2-
(trifluoromethyl)phenyl)-1,6-dihydropyridazine-3-carboxamide
(15d)
Yield: 80.9%; M.p.: 132e133 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.87
(s, 1H), 8.44 (d, J ¼ 5.3 Hz, 1H), 7.88 (d, J ¼ 7.6 Hz, 1H), 7.81e7.70 (m,
2H), 7.66 (t, J ¼ 7.6 Hz, 1H), 7.53 (d, J ¼ 7.4 Hz, 2H), 7.39 (s, 1H),
7.29e7.24 (m, 1H), 7.19 (t, J ¼ 8.5 Hz, 1H), 6.91 (s, 1H), 6.34 (d,
J ¼ 5.2 Hz, 1H), 4.21 (t, J ¼ 6.7 Hz, 2H), 4.00 (s, 3H), 2.92 (d,
J ¼ 9.9 Hz, 2H), 2.68 (s, 3H), 2.55 (t, 2H), 2.17e2.07 (m, J ¼ 13.9,
6.8 Hz, 2H), 1.95 (t, J ¼ 10.7 Hz, 2H), 1.61 (d, J ¼ 12.8 Hz, 2H),
1.41e1.31 (m, 1H), 1.29e1.19 (m, 2H), 0.90 (d, J ¼ 6.2 Hz, 3H); MS
(ESI) m/z (%): 720.5 [MþH]þ; Anal. calcd. for C38H37F4N5O5 (%): C,
63.41; H, 5.18; N, 9.73; Found (%): C, 63.42; H, 5.17; N, 9.74.
5.6.32. 1-(2,4-Dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-
methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (20d)
Yield: 78.6%; M.p.: 145e146 ꢀC; IR (KBr) cmꢁ1: 2948.1, 2769.9,
1689.6, 1620.5, 1597.8, 1581.7, 1508.3, 1479.3, 1430.4, 1377.1, 1348.8,
1305.2, 1250.1, 1211.2, 1170.4, 1149.8, 1101.0, 854.7; 1H NMR
(400 MHz, CDCl3)
d
8.93 (s, 1H), 8.48 (d, J ¼ 5.3 Hz, 1H), 7.84 (dd,
J ¼ 11.9, 2.3 Hz,1H), 7.55 (d, J ¼ 3.1 Hz, 2H), 7.53 (s,1H), 7.49e7.40 (m,