F. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3149e3157
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5.1.3.8. 2-Amino-6-(5-fluoro-1H-indol-3-yl)-4-(2,3,4-trimethoxyphenyl)
nicotinonitrile (17). Yield: 23%. m.p. 245e247 ꢁC. ESI-MS m/z: 419.0
[M þ H]þ. IR (KBr) cmꢂ1: 3418.7, 3158.6, 2939.8, 2220.1, 1645.1,
1594.8, 1506.7, 1485.3, 1463.6, 1410.0, 1296.4, 1236.8, 1178.8, 1100.0,
3.91 (s, 3H), 3.94 (s, 3H), 6.97 (s, 2H), 7.19 (s, 1H), 7.31e7.26 (m, 1H),
7.52e7.45 (m, 1H), 7.66e7.58 (m, 1H), 7.97 (s, 1H), 8.16 (d, J ¼ 3.0 Hz,
1H), 11.70 (s, 1H). 13C NMR (DMSO-d6)
d: 161.43, 161.26, 159.34,
158.13, 150.21, 147.42, 139.39, 138.70, 133.10, 129.25, 125.91, 122.73,
122.34, 118.05, 115.51, 112.76, 109.90, 105.26, 101.04, 84.24, 61.78,
61.65, 57.16. Anal. Calcd. For C23H18F2N4O3: C, 63.30; H, 4.16; F, 8.71;
N, 12.84; O, 11.00. Found: C, 63.28; H, 4.19; N, 12.79.
806.4. 1H NMR (300 MHz, DMSO-d6)
d: 3.75 (s, 3H), 3.81 (s, 3H),
3.88 (s, 3H), 6.46 (s, 2H), 6.96 (d, J ¼ 8.7 Hz, 1H), 7.10e7.03 (m, 1H),
7.14e7.10 (m, 2H), 7.50e7.45 (m, 1H), 8.28 (d, J ¼ 10.5 Hz, 1H), 8.49
(d, J ¼ 3.0 Hz, 1H), 12.10 (s, 1H). 13C NMR (DMSO-d6)
d: 161.36,
159.02, 158.63, 155.74, 152.18, 151.45, 142.34, 134.54, 132.45, 125.75,
125.38, 123.90, 116.56, 114.34, 111.73, 111.40, 110.44, 108.60, 107.18,
88.42, 62.08, 61.35, 56.78. Anal. Calcd. For C23H19FN4O3: C, 66.02; H,
4.58; F, 4.54; N, 13.39; O, 11.47. Found: C, 66.07; H, 4.55; N, 13.31.
5.1.3.14. 2-Amino-4-(3,4-difluorophenyl)-6-(5,6,7-trimethoxy-1H-
indol-3-yl)nicotinonitrile (23). Yield: 39%. m.p. 230e231 ꢁC. ESI-
MS m/z: 436.7 [M þ H]þ. IR (KBr) cmꢂ1: 3448.6, 3368.0, 3253.5,
2999.1, 2953.4, 2836.5, 2208.1,1656.0,1580.7,1535.3,1518.3,1466.6,
1431.7, 1409.9, 1289.7, 1266.9, 1200.5, 1128.5, 1054.9, 959.0, 873.8,
5.1.3.9. 2-Amino-6-(6-fluoro-1H-indol-3-yl)-4-(3,4,5-trimethoxyphenyl)
nicotinonitrile (18). Yield: 32%. m.p. 237e238 ꢁC. ESI-MS m/z: 419.1
[M þ H]þ. IR (KBr) cmꢂ1: 3445.0, 3287.7, 3167.6, 2933.7, 2835.4,
2215.1, 1625.6, 1578.5, 1529.0, 1497.0, 1451.4, 1407.2, 1382.0, 1296.9,
1267.2, 1236.4, 1220.4, 1141.2, 1097.7, 1011.9, 832.8, 812.1. 1H NMR
767.8. 1H NMR (300 MHz, DMSO-d6)
d: 3.79 (s, 3H), 3.91 (s, 3H), 3.95
(s, 3H), 6.96 (s, 2H), 7.24 (s, 1H), 7.65e7.52 (m, 2H), 7.83e7.75 (m,
1H), 7.98 (s,1H), 8.22 (d, J ¼ 3.0 Hz,1H),11.70 (s,1H). Anal. Calcd. For
C23H18F2N4O3: C, 63.30; H, 4.16; F, 8.71; N, 12.84; O, 11.00. Found: C,
63.33; H, 4.12; N, 12.75.
(300 MHz, DMSO-d6)
7.01e6.87 (m, 3H), 7.24e7.20 (m, 1H), 7.27 (s,1H), 8.34 (d, J ¼ 3.0 Hz,
1H), 8.77e8.72 (m, 1H), 11.80 (s, 1H). 13C NMR (DMSO-d6)
: 161.91,
159.87, 158.47, 153.82, 153.58 (2C), 139.02, 137.74, 133.47, 130.01,
124.96, 123.08, 118.77, 115.43, 109.38, 108.96, 106.66 (2C), 98.50,
83.43, 60.85, 56.80 (2C). Anal. Calcd. For C23H19FN4O3: C, 66.02; H,
4.58; F, 4.54; N, 13.39; O, 11.47. Found: C, 66.01; H, 4.63; N, 13.35.
d: 3.74 (s, 3H), 3.88 (s, 6H), 6.83 (s, 2H),
5.1.3.15. 2-Amino-4-(2-chloro-4-fluorophenyl)-6-(5,6,7-trimethoxy-
1H-indol-3-yl)nicotinonitrile (24). Yield: 45%. m.p. 230e233 ꢁC.
ESI-MS m/z: 452.1 (Cl ¼ 35), 454.2 (Cl ¼ 37) [M þ H]þ. IR (KBr)
cmꢂ1: 3449.1, 3363.0, 3247.8, 2942.8, 2204.6, 1649.5,1605.8,1580.5,
1531.3, 1497.4, 1466.2, 1433.9, 1289.5, 1206.1, 1119.0, 1046.6, 877.0.
d
1H NMR (300 MHz, DMSO-d6)
d
: 3.78 (s, 3H), 3.90 (s, 3H), 3.94 (s,
3H), 6.98 (s, 2H), 7.13 (s, 1H), 7.43e7.36 (m, 1H), 7.59e7.54 (m, 1H),
7.69e7.65 (m, 1H), 7.98 (s, 1H), 8.14 (s, 1H). 13C NMR (DMSO-d6)
5.1.3.10. 2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-6-(6-fluoro-1H-
indol-3-yl)nicotinonitrile (19). Yield: 36%. m.p. 263e265 ꢁC. ESI-MS
d:
164.45, 161.07, 159.25, 150.85, 150.20, 139.37, 138.70, 134.10, 133.38,
133.02, 129.23, 125.92, 122.33, 117.84, 117.54, 115.53, 115.47, 109.69,
101.04, 84.56, 61.78, 61.65, 57.18. Anal. Calcd. For C23H18ClFN4O3: C,
61.00; H, 4.01; Cl, 7.83; F, 4.20; N, 12.37; O, 10.60. Found: C, 61.08; H,
4.00; N, 12.34.
m/z: 467.3 (Br ¼ 79), 469.2 (Br ¼ 81) [M þ H]þ. IR (KBr) cmꢂ1
:
3339.0, 2201.6, 1633.7, 1580.0, 1537.7, 1491.8, 1425.5, 1262.2, 1237.9,
1141.1, 1109.5, 1046.7, 980.3, 822.7. 1H NMR (300 MHz, DMSO-d6)
d:
3.81 (s, 3H), 3.93 (s, 3H), 6.90 (s, 2H), 7.00e6.92 (m, 1H), 7.25-7.22
(m, 2H), 7.34 (d, J ¼ 1.8 Hz, 1H), 7.44 (d, J ¼ 1.8 Hz, 1H), 8.36 (s, 1H),
8.74e8.69 (m, 1H). 13C NMR (DMSO-d6)
d
: 161.84, 159.80, 158.76,
5.1.3.16. 2-Amino-4-(2,3-dichlorophenyl)-6-(5,6,7-trimethoxy-1H-
indol-3-yl)nicotinonitrile (25). Yield: 44%. m.p. 216e218 ꢁC. ESI-
MS m/z: 470.7 [M þ H]þ. IR (KBr) cmꢂ1: 3473.6, 3451.1, 3340.9,
2969.6, 2939.2, 2833.0, 2200.8,1623.1,1571.9,1535.7,1464.1,1425.6,
1388.1, 1319.1, 1291.1, 1264.8, 1206.2, 1145.7, 1109.1, 1041.6, 889.5,
153.94, 152.00, 147.10, 137.87, 135.32, 130.38, 124.85, 124.55, 123.06,
118.53, 117.47, 115.20, 113.67, 109.32, 108.93, 98.63, 83.04, 60.95,
57.08. Anal. Calcd. For C22H16BrFN4O2: C, 56.55; H, 3.45; Br, 17.10; F,
4.07; N, 11.99; O, 6.85. Found: C, 56.43; H, 3.46; N, 11.95.
794.2, 727.7. 1H NMR (300 MHz, DMSO-d6)
d: 3.79 (s, 3H), 3.92 (s,
5.1.3.11. 2-Amino-6-(6-fluoro-1H-indol-3-yl)-4-(2,3,4-trimethoxy-
phenyl)nicotinonitrile (20). Yield: 28%. m.p. 238e239 ꢁC. ESI-MS
m/z: 419.3 [M þ H]þ. IR (KBr) cmꢂ1: 3472.6, 3378.6, 3297.3, 2930.1,
2836.3, 2211.7, 1608.0, 1581.8, 1533.7, 1498.4, 1445.9, 1410.3, 1384.9,
1294.8, 1258.1, 1216.2, 1144.9, 1098.0, 1011.0, 949.7, 837.2, 815.1. 1H
3H), 3.94 (s, 3H), 7.01 (s, 2H), 7.16 (s, 1H), 7.52e7.48 (m, 2H),
7.80e7.77 (m, 1H), 7.99 (s, 1H), 8.15 (d, J ¼ 2.7 Hz, 1H), 11.70 (d,
J ¼ 2.4 Hz, 1H). 13C NMR (DMSO-d6)
d: 161.07, 159.41, 151.30, 150.22,
139.87, 139.38, 138.71, 132.92, 131.68, 130.53, 130.09, 129.31 (2C),
125.93, 122.34, 117.74, 115.53, 109.24, 101.07, 83.98, 61.78, 61.66,
57.18. Anal. Calcd. For C23H18Cl2N4O3: C, 58.86; H, 3.87; Cl, 15.11; N,
11.94; O, 10.23. Found: C, 58.85; H, 3.86; N, 12.01.
NMR (300 MHz, DMSO-d6) d: 3.72 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H),
6.77 (s, 2H), 7.08e6.93 (m, 4H), 7.20-7.17 (m, 1H), 8.24 (s, 1H), 8.71
(s, 1H), 11.72 (s, 1H). Anal. Calcd. For C23H19FN4O3: C, 66.02; H, 4.58;
F, 4.54; N, 13.39; O, 11.47. Found: C, 66.04; H, 4.53; N, 13.35.
5.1.3.17. 2-Amino-6-(1-methyl-1H-indol-3-yl)-4-(3,4,5-trimethoxy-
phenyl)nicotinonitrile (26). Yield: 22%. m.p. 197e200 ꢁC. ESI-MS
5.1.3.12. 2-Amino-6-(5,6,7-trimethoxy-1H-indol-3-yl)-4-(2,3,4-trime-
thoxyphenyl)nicotinonitrile (21). Yield: 41%. m.p. 197e200 ꢁC. ESI-
MS m/z: 491.7 [M þ H]þ. IR (KBr) cmꢂ1: 3315.7, 3171.4, 2939.4,
2219.8, 1648.6, 1599.5, 1507.3, 1464.1, 1419.5, 1278.9, 1235.4, 1204.2,
m/z: 415.1 [M þ H]þ. IR (KBr) cmꢂ1
: 3476.5, 3361.3, 3148.6,
2935.6, 2835.0, 2200.9,1641.1,1580.1,1530.3,1506.6,1466.4,1399.4,
1253.4,1128.4, 1000.7, 812.7, 729.3. 1H NMR (300 MHz, DMSO-d6)
d:
3.74 (s, 3H), 3.86 (s, 3H), 3.87 (s, 6H), 6.85 (s, 2H), 6.95 (s, 2H),
1160.9,1122.1,1097.2, 817.9. 1H NMR (300 MHz, DMSO-d6)
d
: 3.75 (s,
7.28e7.16 (m, 3H), 7.50 (d, J ¼ 8.4 Hz, 1H), 8.32 (s, 1H), 8.72 (d,
3H), 3.79 (s, 3H), 3.81 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H),
6.89 (s, 2H), 6.96 (d, J ¼ 8.7 Hz, 1H), 7.12 (d, J ¼ 7.5 Hz, 2H), 7.73 (s,
1H), 8.24 (d, J ¼ 2.7 Hz, 1H), 11.90 (s, 1H). Anal. Calcd. For
C26H26N4O6: C, 63.66; H, 5.34; N, 11.42; O, 19.57. Found: C, 63.69; H,
5.33; N, 11.47.
J ¼ 7.5 Hz, 1H). 13C NMR (DMSO-d6)
d: 161.92, 158.46, 153.77, 153.60
(2C), 139.06, 138.29, 133.53, 133.37, 126.65, 123.79, 122.92, 121.44,
118.79, 114.33, 110.88, 108.92, 106.64 (2C), 83.27, 60.87, 56.84 (2C),
33.73. Anal. Calcd. For C24H22N4O3: C, 69.55; H, 5.35; N, 13.52; O,
11.58. Found: C, 69.49; H, 5.37; N, 13.56.
5.1.3.13. 2-Amino-4-(2,4-difluorophenyl)-6-(5,6,7-trimethoxy-1H-
indol-3-yl)nicotinonitrile (22). Yield: 47%. m.p. 230e231 ꢁC. ESI-
MS m/z: 437.7 [M þ H]þ. IR (KBr) cmꢂ1: 3454.8, 3371.8, 3251.3,
2953.9, 2835.1, 2205.6, 1653.3, 1584.8, 1535.6, 1508.1, 1467.1, 1290.8,
5.1.3.18. 2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-6-(1-methyl-
1H-indol-3-yl)nicotinonitrile (27). Yield: 29%. m.p. 235 ꢁC. ESI-MS
m/z: 462.5 (Br ¼ 79), 464.6 (Br ¼ 81) [M þ H]þ. IR (KBr) cmꢂ1
:
3451.2, 3345.2, 2943.3, 2198.3, 1628.6, 1579.3, 1533.7, 1493.8,
1127.1, 1055.5, 972.2. 1H NMR (300 MHz, DMSO-d6)
d: 3.78 (s, 3H),
1470.5, 1265.1, 1222.4, 1132.4, 1113.4, 1045.2, 999.2, 823.2, 745.4. 1H