Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
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1676.5, 1620.6, 1605.7, 1579.5, 1509.2, 1479.3, 1430.3, 1384.1,
1348.8, 1304.8, 1251.0, 1211.0, 1168.4, 1139.5, 1021.3, 853.7,
832.5, 728.7, 686.3, 618.1, 555.7; 1H NMR (400 MHz, CDCl3) d
9.42–9.30 (m, 1H), 9.30–9.14 (m, 1H), 8.52 (dd, J = 7.9, 1.6 Hz,
1H), 8.48 (d, J = 5.2 Hz, 1H), 8.02–7.91 (m, 2H), 7.91–7.82 (m,
1H), 7.68–7.63 (m, 1H), 7.60–7.54 (m, 2H), 7.54 (s, 1H), 7.47–
7.39 (m, 2H), 7.31–7.28 (m, 1H), 7.06–6.98 (m, 1H), 6.42 (d,
J = 5.2 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.99–3.84 (m,
3H), 2.62 (s, 2H), 2.71–2.48 (m, 8H), 2.37 (s, 3H), 2.18–2.10 (m,
2H); 13C NMR (400 MHz, CDCl3) d 161.12, 159.97, 158.99, 155.72,
154.97, 153.23, 152.28, 149.87, 148.69, 146.88, 135.96, 134.09,
132.43, 128.16, 127.74, 127.55 (2C), 127.02, 126.36, 125.27,
123.88, 122.65, 116.40, 115.42, 114.19, 111.62, 109.36, 108.71,
102.18, 99.50, 67.24, 56.15, 55.60, 54.90 (2C), 54.78, 52.67 (2C),
45.69, 26.26. Anal. Calcd for C40H39FN6O6: C, 66.84; H, 5.47; N,
11.69. Found: C, 66.85; H, 5.46; N, 11.67.
J = 15.4, 6.6 Hz, 2H), 7.37–7.29 (m, 2H), 7.25 (s, 1H), 6.42 (d,
J = 5.2 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 2.54 (t,
J = 7.3 Hz, 2H), 2.43 (s, 4H), 2.20–2.11 (m, 2H), 1.60 (dd, J = 10.8,
5.3 Hz, 4H), 1.45 (s, 2H); 13C NMR (400 MHz, CDCl3) d 160.89,
159.94, 158.86, 158.62, 156.10, 155.76, 153.27, 152.38, 149.93,
148.71, 146.99, 137.72, 136.75, 135.84, 134.41, 132.61, 131.00,
128.79, 128.24, 127.84, 127.56, 124.78, 123.89, 116.91, 116.43,
115.39, 109.71, 108.79, 102.16, 99.45, 67.69, 56.17, 55.81, 54.63
(2C), 26.42, 26.05 (2C), 24.48. Anal. Calcd for C39H35F2N5O5: C,
67.72; H, 5.10; N, 10.12. Found: C, 67.74; H, 5.11; N, 10.09.
7.4.26. 3-(4-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl) -4-oxo-3,4-
dihydrophthalazine-1-carboxamide (50)
Yellow solid; yield: 56%; mp: 178–180 °C; MS (ESI) m/z (%):
752.5 [M+H]+; IR (KBr) cmÀ1: 3379.4, 2931.8, 2851.1, 1677.0,
1620.4, 1597.5, 1578.5, 1508.2, 1479.3, 1430.2, 1384.1, 1348.7,
1326.0, 1305.7, 1249.8, 1210.6, 1171.4, 1138.9, 1078.6, 1011.5,
852.2, 828.4, 788.8, 751.6, 686.4, 616.3, 513.9; 1H NMR
(400 MHz, CDCl3) d 9.28 (s, 1H), 9.24 (d, J = 8.1 Hz, 1H), 8.59–8.52
(m, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.01–7.86 (m, 3H), 7.70–7.64 (m,
2H), 7.58 (dt, J = 6.7, 2.3 Hz, 3H), 7.42 (d, J = 7.2 Hz, 2H), 7.29 (d,
J = 9.5 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.4 Hz, 2H), 4.04
(s, 3H), 2.72 (s, 2H), 2.62 (s, 4H), 2.32–2.18 (m, 2H), 1.72 (s, 4H),
1.51 (s, 2H); 13C NMR (400 MHz, CDCl3) d 161.05, 159.94, 158.91,
155.69, 153.21, 152.17, 149.84, 148.65, 146.81, 140.03, 137.62,
137.02, 136.07, 134.32, 132.56, 132.06 (2C), 128.34, 127.57,
127.47, 127.28 (2C), 123.88, 122.15, 116.46, 115.49, 109.70,
108.78, 102.20, 99.55, 67.21, 56.12, 55.59, 54.27 (2C), 25.68,
25.15 (2C), 23.86. Anal. Calcd for C39H35BrFN5O5: C, 62.24; H,
4.69; N, 9.31. Found: C, 62.22; H, 4.70; N, 9.33.
7.4.23. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-3-phenyl-3,4-
dihydrophthalazine-1-carboxamide (47)
Yellow solid; yield: 61%; mp: 183–185 °C; MS (ESI) m/z (%):
674.1 [M+H]+; IR (KBr) cmÀ1: 3384.5, 3060.4, 2941.1, 2638.0,
2537.1, 1671.7, 1597.0, 1507.4, 1478.7, 1431.2, 1384.6, 1350.3,
1329.9, 1306.0, 1282.6, 1252.5, 1210.5, 1173.0, 1140.0, 1113.0,
1078.6, 1020.4, 971.8, 938.5, 852.8, 756.3, 687.6, 568.6; 1H NMR
(400 MHz, DMSO)
d 11.21 (s, 1H), 10.51 (s, 1H), 8.61 (d,
J = 5.1 Hz, 1H), 8.44 (d, J = 6.9 Hz, 2H), 8.18–7.95 (m, 3H), 7.83 (d,
J = 7.5 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.56 (d,
J = 8.2 Hz, 3H), 7.48 (d, J = 7.1 Hz, 1H), 6.67 (d, J = 4.0 Hz, 1H),
4.30 (s, 2H), 4.00 (s, 3H), 3.49 (d, J = 10.6 Hz, 2H), 2.92 (s, 2H),
2.50 (s, 2H), 2.34 (s, 2H), 1.81 (s, 4H), 1.76–1.31 (m, 2H); 13C
NMR (400 MHz, DMSO) d 162.47, 161.88–160.56 (m, 1H), 158.64,
155.05–154.78 (m, 0H), 153.29–152.82 (m, 1H), 152.60–152.36
(m, 0H), 150.51, 147.72–147.27 (m, 1H), 141.71, 140.25, 138.48–
137.97 (m, 1H), 136.52–136.07 (m, 1H), 134.76, 133.23, 129.17,
129.09 (s, 2H), 128.44, 127.41, 127.29, 126.68 (s, 3H), 124.62,
117.71, 115.27, 109.95–109.58 (m, 0H), 109.58–109.20 (m, 0H),
102.90, 99.95, 66.84, 56.57, 53.89, 52.52 (s, 2H), 23.54, 22.85 (s,
3H), 21.85. Anal. Calcd for C39H36FN5O5: C, 69.53; H, 5.39; N,
10.39. Found: C, 69.50; H, 5.40; N, 10.40.
7.4.27. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-nitrophenyl)-4-oxo-
3,4-dihydrophthalazine-1-carboxamide (51)
Yellow solid; yield: 51%; mp: 187–190 °C; MS (ESI) m/z (%):
718.4 [M+H]+; IR (KBr) cmÀ1: 3418.4, 2935.3, 1679.9, 1621.1,
1596.0, 1509.7, 1432.2, 1384.4, 1349.2, 1323.8, 1307.1, 1252.3,
1211.4, 1172.6, 1139.5, 1114.8, 1022.0, 972.4, 941.0, 845.4, 750.7,
686.7, 617.9; 1H NMR (400 MHz, CDCl3) d 9.34 (s, 1H), 9.20 (d,
J = 8.1 Hz, 1H), 8.58 (d, J = 7.2 Hz, 1H), 8.49 (d, J = 4.6 Hz, 1H),
8.39 (t, J = 10.4 Hz, 2H), 8.05–7.97 (m, 4H), 7.94 (dd, J = 11.2,
4.0 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.31
(t, J = 7.1 Hz, 1H), 6.43 (d, J = 5.1 Hz, 1H), 4.26 (t, J = 5.6 Hz, 2H),
4.03 (s, 3H), 3.42–2.82 (m, 6H), 2.53 (d, J = 4.6 Hz, 2H), 2.03 (s,
4H), 1.69 (s, 2H); 13C NMR (400 MHz, CDCl3) d 160.77, 160.02,
158.92, 155.72, 153.24, 151.66, 149.71, 148.74, 146.64, 146.03,
137.99, 137.72, 135.96, 134.75, 133.01, 128.36, 127.82, 127.46,
126.31 (2C), 124.37 (2C), 123.97, 116.54, 115.84, 109.84, 109.05,
102.41, 99.76, 66.12, 56.09, 55.30, 53.58 (2C), 23.85, 22.93 (2C),
22.32. Anal. Calcd for C39H35FN6O7: C, 65.17; H, 4.91; N, 11.69.
Found: C, 65.19; H, 4.90; N, 11.67.
7.4.24. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-4-oxo-
3,4-dihydrophthalazine-1-carboxamide (48)
Yellow solid; yield: 59%; mp: 187–190 °C; MS (ESI) m/z (%):
692.3 [M+H]+; 1H NMR (400 MHz, DMSO) d 10.47 (s, 1H), 8.71 (d,
J = 5.4 Hz, 1H), 8.44 (d, J = 7.8 Hz, 2H), 8.17–7.97 (m, 3H), 7.91
(dd, J = 19.2, 11.2 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.69 (d,
J = 16.4 Hz, 2H), 7.61 (t, J = 8.8 Hz, 1H), 7.41 (t, J = 8.5 Hz, 2H),
6.81 (d, J = 4.9 Hz, 1H), 4.32 (s, 2H), 4.03 (s, 3H), 3.49 (d,
J = 11.1 Hz, 2H), 3.22 (s, 2H), 2.92 (s, 2H), 2.36 (s, 2H), 1.82 (s,
4H), 1.76–1.33 (m, 2H); 13C NMR (400 MHz, DMSO) d 164.83,
162.46, 160.42, 158.74, 154.77, 154.00, 152.32, 150.98, 145.86,
140.19, 138.56, 138.06, 136.00, 134.68, 133.19, 132.79, 128.95
(2C), 128.37, 127.34, 126.73, 124.52, 117.79, 115.90, 116.01 (2C),
115.38, 109.60, 103.09, 100.23, 67.11, 56.75, 53.79, 52.49 (2C),
23.46, 22.79 (2C), 21.88. Anal. Calcd for C39H35F2N5O5: C, 67.72;
H, 5.10; N, 10.12. Found: C, 67.75; H, 5.12; N, 10.09.
7.4.28. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-methoxy phenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (52)
Yellow solid; yield: 54%; mp: 183–185 °C; MS (ESI) m/z (%):
703.3 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.25 (dt, J = 22.0,
11.7 Hz, 2H), 8.56 (d, J = 7.8 Hz, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.03–
7.84 (m, 3H), 7.74–7.66 (m, 1H), 7.57 (dt, J = 8.8, 3.1 Hz, 2H), 7.44
(s, 1H), 7.41 (d, J = 6.8 Hz, 1H), 7.33–7.25 (m, 2H), 7.07 (dd,
J = 9.0, 2.6 Hz, 1H), 6.43 (d, J = 5.3 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H),
4.06 (s, 3H), 4.03–3.86 (m, 3H), 2.57 (t, J = 7.1 Hz, 2H), 2.46 (s,
4H), 2.25–2.10 (m, 2H), 1.68–1.55 (m, 4H), 1.46 (s, 2H). Anal. Calcd
for C40H38FN5O6: C, 68.27; H, 5.44; N, 9.95. Found: C, 68.24; H,
5.46; N, 9.97.
7.4.25. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(2-fluorophenyl)-4-oxo-
3,4-dihydrophthalazine-1-carboxamide (49)
Yellow solid; yield: 63%; mp: 181–183 °C; MS (ESI) m/z (%):
692.3 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.29 (d, J = 8.2 Hz,
1H), 9.18 (s, 1H), 8.56 (t, J = 8.5 Hz, 1H), 8.53–8.44 (m, 1H), 7.99
(t, J = 7.8 Hz, 1H), 7.96–7.87 (m, 2H), 7.62–7.49 (m, 3H), 7.41 (dd,