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(s, 1H), 8.19 (m, 1H), 8.08 (m, 1H), 7.90 (m, 1H), 7.74 (m, 2H), 7.55 (s,
1H), 7.49 (d, J ¼ 9.0 Hz, 1H), 7.42 (s, 1H), 7.11 (d, J ¼ 8.9 Hz, 2H), 6.47
(d, J ¼ 4.8 Hz, 1H), 4.23 (t, J ¼ 6.1 Hz, 2H), 3.95 (s, 3H), 3.84 (s, 3H),
3.03 (m, 6H), 2.22 (s, 2H), 1.72 (s, 4H), 1.50 (s, 2H); MS (ESI) m/z (%):
705.5 [M þ H]þ; Anal. calcd. for C41H38F2N4O5 (%): C, 69.87; H, 5.43;
N, 7.95; Found (%): C, 69.83; H, 5.44; N, 7.95.
5.13.29. 6-Fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiper-
idin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-2-(3-methoxyphenyl)
quinoline-4-carboxamide (16j)
Yield:54%;M.p.:175e177 ꢁC;1HNMR(300 MHz,DMSO-d6)
d11.28
(s, 1H), 8.46 (s, 2H), 8.22 (m, 1H), 8.08 (m, 1H), 7.92 (m, 3H), 7.77 (dd,
J ¼ 11.5, 4.0 Hz,1H), 7.70 (m,1H), 7.52 (s,1H), 7.47 (m, 2H), 7.37 (s,1H),
7.09 (m, 1H), 6.45 (d, J ¼ 4.7 Hz,1H), 4.17 (t, J ¼ 4.7 Hz, 2H), 3.93 (s, 3H),
3.86 (s, 3H), 3.13 (s, 2H), 2.93 (d, J ¼ 10.6 Hz, 2H), 2.56 (s, 2H), 2.01 (m,
2H),1.58 (d, J ¼ 10.6 Hz, 2H),1.34 (s,1H),1.19 (s, 2H), 0.85 (d, J ¼ 6.5 Hz,
3H); MS (ESI) m/z (%): 719.3 [M þ H]þ; Anal. calcd. for C42H40F2N4O5
(%): C, 70.18; H, 5.61; N, 7.79. Found (%): C, 70.11; H, 5.62; N, 7.82.
5.13.24. 2-(2,4-Dichlorophenyl)-6-fluoro-N-(3-fluoro-4-(6-methoxy-
7-(3-(piperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)quinoline-4-
carboxamide (16e)
Yield: 56%; M.p.: 196e198 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
11.18 (s, 1H), 8.45 (d, J ¼ 5.2 Hz, 1H), 8.22 (dd, J ¼ 9.3, 5.6 Hz, 1H),
8.00 (m, 3H), 7.81 (m, 3H), 7.61 (m, 2H), 7.50 (d, J ¼ 5.6 Hz, 1H), 7.45
(d, J ¼ 9.0 Hz, 1H), 7.38 (s, 1H), 6.44 (d, J ¼ 5.2 Hz, 1H), 4.18 (t,
J ¼ 6.2 Hz, 2H), 3.91 (d, J ¼ 7.2 Hz, 3H), 2.76 (m, 6H), 2.10 (s, 2H), 1.61
(d, J ¼ 5.2 Hz, 4H), 1.42 (s, 2H); MS (ESI) m/z (%): 743.0 [M þ H]þ;
Anal. calcd. for C40H34Cl2F2N4O4 (%): C, 64.61; H, 4.61; N, 7.53.
Found (%): C, 64.62; H, 4.58; N, 7.55.
5.13.30. 6-Fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperi-
din-1-yl)propoxy)quinolin-4-yloxy)phenyl)-2-p-tolylquinoline-4-
carboxamide (16k)
Yield: 57%; M.p.: 183e184 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
11.40 (s,1H), 8.51 (m, 2H), 8.32 (s,1H), 8.29 (s,1H), 8.23 (d, J ¼ 7.3 Hz,
1H), 8.11 (s, 1H), 7.97 (dd, J ¼ 10.2, 3.0 Hz, 1H), 7.79 (m, 2H), 7.58 (s,
1H), 7.53 (d, J ¼ 9.2 Hz,1H), 7.43 (s,1H), 7.40 (s,1H), 7.36 (d, J ¼ 8.1 Hz,
1H), 6.51 (d, J ¼ 4.7 Hz,1H), 4.23 (t, J ¼ 6.4 Hz, 2H), 3.98 (s, 3H), 3.05 (s,
2H), 2.73 (d, J ¼ 6.9 Hz, 2H), 2.42 (s, 3H), 2.25 (s, 2H), 2.10 (s, 2H),1.66
(d, J ¼ 11.0 Hz, 2H), 1.45 (s, 1H), 1.30 (m, 2H), 0.92 (d, J ¼ 6.3 Hz, 3H);
MS (ESI) m/z (%): 703.4 [M þ H]þ; Anal. calcd. for C42H40F2N4O4 (%):
C, 71.78; H, 5.74; N, 7.97. Found (%): C, 71.75; H, 5.77; N, 7.98.
5.13.25. 6-Fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-morpholinopro
poxy)quinolin-4-yloxy)phenyl)-2-(4-fluorophenyl)quinoline-4-
carboxamide (16f)
Yield: 54%; M.p.: 147e148 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
11.19 (s, 1H), 8.51 (s, 2H), 8.45 (m, 2H), 8.26 (m, 1H), 8.09 (d,
J ¼ 12.6 Hz, 1H), 7.97 (d, J ¼ 9.8 Hz, 1H), 7.82 (m, 1H), 7.71 (d,
J ¼ 7.6 Hz, 1H), 7.54 (m, 2H), 7.44 (m, 3H), 6.49 (d, J ¼ 5.0 Hz, 1H),
4.22 (s, 2H), 3.97 (s, 3H), 3.61 (s, 4H), 2.44 (s, 6H), 2.00 (s, 2H); MS
(ESI) m/z (%): 695.8 [M þ H]þ; Anal. calcd. for C39H33F3N4O5 (%): C,
67.43; H, 4.79; N, 8.06. Found (%): C, 67.39; H, 4.81; N, 8.10.
5.13.31. 6-Fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yloxy)phenyl)-2-phenylquinoline-4-carboxam-
ide (16l)
Yield: 67%; M.p.: 134e135 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
11.34 (s, 1H), 8.48 (m, 2H), 8.35 (d, J ¼ 6.9 Hz, 2H), 8.23 (q,1H), 8.10
5.13.26. 2-(3-Chlorophenyl)-6-fluoro-N-(3-fluoro-4-(6-methoxy-7-
(3-morpholinopropoxy)quinolin-4-yloxy)phenyl)quinoline-4-
carboxamide (16g)
(d, J ¼ 13.0 Hz, 1H), 7.95 (dd, J ¼ 10.1, 2.7 Hz, 1H), 7.77 (m, 2H), 7.54
(m, 5H), 7.43 (s, 1H), 6.48 (d, J ¼ 5.1 Hz, 1H), 4.26 (t, J ¼ 6.1 Hz, 2H),
3.95 (s, 3H), 3.54 (s, 2H), 3.01 (d, J ¼ 6.1 Hz, 4H), 2.27 (m, 2H), 1.96 (s,
4H); MS (ESI) m/z (%): 661.6 [M þ H]þ; Anal. calcd. for C39H34F2N4O4
(%): C, 70.90; H, 5.19; N, 8.48. Found (%): C, 70.83; H, 5.61; N, 8.50.
Yield: 65%; M.p.: 175e176 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
11.28 (s, 1H), 8.58 (s, 1H), 8.52 (d, J ¼ 5.2 Hz, 1H), 8.45 (s, 1H), 8.37
(m, 1H), 8.29 (m, 1H), 8.12 (m, 1H), 8.01 (dd, J ¼ 10.2, 2.8 Hz, 1H),
7.83 (m, 1H), 7.75 (d, J ¼ 10.1 Hz, 1H), 7.63 (m, 2H), 7.55 (m, 2H), 7.41
(d, J ¼ 14.7 Hz, 1H), 6.49 (t, J ¼ 4.4 Hz, 1H), 4.23 (t, J ¼ 6.6 Hz, 2H),
3.97 (s, 3H), 3.62 (m, 4H), 2.48 (d, J ¼ 17.0 Hz, 6H), 2.01 (m, 2H); MS
(ESI) m/z (%): 711.2 [M þ H]þ; Anal. calcd. for C39H33ClF2N4O5 (%): C,
65.87; H, 4.68; N, 7.88. Found (%): C, 65.82; H, 4.69; N, 7.86.
5.13.32. 2-(3-Chlorophenyl)-6-fluoro-N-(3-fluoro-4-(6-methoxy-7-
(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)quinoline-4-
carboxamide (16m)
Yield: 71%; M.p.: 166e167 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
11.30 (s, 1H), 8.59 (s, 1H), 8.53 (d, J ¼ 5.4 Hz, 1H), 8.47 (s, 1H), 8.38
(d, J ¼ 5.2 Hz, 1H), 8.31 (q, 1H), 8.13 (d, J ¼ 15.4 Hz, 1H), 8.01 (dd,
J ¼ 10.2, 2.8 Hz, 1H), 7.85 (m, 1H), 7.75 (d, J ¼ 9.7 Hz, 2H), 7.65 (d,
J ¼ 5.3 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J ¼ 9.0 Hz, 1H), 7.46 (s, 1H), 6.51
(d, J ¼ 5.2 Hz, 1H), 4.28 (t, J ¼ 5.9 Hz, 2H), 4.00 (s, 3H), 3.07 (s, 6H),
5.13.27. 6-Fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenyl)-2-p-tolylquinoline-4-carboxamide (16h)
Yield: 69%; M.p.: 173e174 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d 11.18
(s, 1H), 8.52 (d, J ¼ 5.2 Hz, 1H), 8.48 (s, 1H), 8.27 (m, 3H), 8.10 (dd,
J ¼ 13.0, 2.3 Hz, 1H), 7.97 (dd, J ¼ 10.2, 2.8 Hz,1H), 7.81 (m,1H), 7.72 (d,
J ¼ 8.0Hz,1H), 7.55 (m, 2H), 7.41 (m, 3H), 6.51 (d, J¼ 4.4 Hz,1H), 4.23 (t,
J ¼ 6.5 Hz,2H), 3.99(s, 3H), 3.62(m, 4H), 2.47 (m, 9H), 2.01 (m, 2H); MS
(ESI) m/z (%): 691.2 [M þ H]þ; Anal. calcd. for C40H36F2N4O5 (%): C,
69.55; H, 5.25; N, 8.11. Found (%): C, 69.53; H, 5.27; N, 8.13.
2.20 (s, 2H), 1.89 (s, 4H); 13C NMR (CDCl3)
d 170.94, 160.03, 159.47,
155.17, 153.52, 152.03, 149.73, 148.81, 146.79, 142.37, 138.52, 137.21,
136.88, 134.72, 133.86, 131.22, 130.04, 128.28, 127.29, 125.99, 125.62,
123.65, 123.43, 117.44, 116.61, 115.52, 109.99, 109.83, 108.83, 102.28,
99.55, 67.06, 56.10, 54.07 (2C), 52.97, 27.73, 23.44 (2C); MS (ESI) m/z
(%): 695.6 [M þ H]þ; Anal. calcd. for C39H33ClF2N4O4 (%): C, 67.38; H,
4.78; N, 8.06. Found (%): C, 67.42; H, 4.80; N, 8.07.
5.13.28. 2-(3-Chlorophenyl)-6-fluoro-N-(3-fluoro-4-(6-methoxy-7-
(3-(4-methylpiperdin-1-yl)propoxy)quinolin-4-yloxy)phenyl)
quinoline-4-carboxamide (16i)
5.13.33. 6-Fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yloxy)phenyl)-2-(4-methoxyphenyl)quinoline-
4-carboxamide (16n)
Yield: 49%; M.p.: 181e182 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
11.36 (s, 1H), 8.55 (s, 1H), 8.48 (d, J ¼ 5.2 Hz, 1H), 8.42 (s, 1H),
Yield: 60%; M.p.: 158e159 ꢁC; 1H NMR (300 MHz, DMSO-d6)
8.33 (m, 1H), 8.26 (dd, J ¼ 9.2, 5.6 Hz, 1H), 8.09 (m, 1H), 7.97 (dd,
J ¼ 10.2, 2.8 Hz, 1H), 7.79 (d, J ¼ 2.5 Hz, 1H), 7.74 (d, J ¼ 8.4 Hz, 1H),
7.59 (m, 2H), 7.55 (s, 1H), 7.49 (m, 1H), 7.42 (s, 1H), 6.47 (d,
J ¼ 5.0 Hz, 1H), 4.24 (t, J ¼ 6.3 Hz, 2H), 3.93 (s, 3H), 3.10 (s, 4H),
2.80 (s, 2H), 2.25 (s, 2H), 1.74 (d, J ¼ 12.5 Hz, 2H), 1.45 (m, 3H), 0.90
(d, J ¼ 6.0 Hz, 3H); MS (ESI) m/z (%): 723.6 [M þ H]þ; Anal. calcd.
for C41H37ClF2N4O4 (%): C, 68.09; H, 5.16; N, 7.75. Found (%): C,
68.10; H, 5.17; N, 7.77.
d
11.31 (s, 1H), 8.49 (d, J ¼ 5.3 Hz,1H), 8.42 (s,1H), 8.33 (d, J ¼ 8.7 Hz,
2H), 8.18 (q, 1H), 8.09 (d, J ¼ 13.3 Hz, 1H), 7.91 (dd, J ¼ 10.1, 2.8 Hz,
1H), 7.74 (m, 2H), 7.55 (s, 1H), 7.50 (t, J ¼ 9.1 Hz,1H), 7.43 (s,1H), 7.11
(d, J ¼ 8.8 Hz, 2H), 6.48 (d, J ¼ 5.3 Hz, 1H), 4.26 (t, J ¼ 6.0 Hz, 2H),
3.95 (s, 3H), 3.83 (s, 3H), 3.21 (s, 4H), 3.01 (m, 2H), 2.24 (s, 2H), 1.93
(s, 4H); MS(ESI) m/z (%): 691.3 [M þ H]þ; Anal. calcd. for
C
40H36F2N4O5 (%): C, 69.55; H, 5.25; N, 8.11. Found (%): C, 69.49; H,
5.27; N, 8.12.