Journal of Medicinal Chemistry
ARTICLE
105.9, 112.9, 117.2, 120.3, 120.9, 122.9, 123.1, 123.9, 124.5, 125.0, 129.6,
133.4, 137.0, 138.7, 139.6, 153.6, 158.7, 162.6, 171.7, 172.0. IR (KBr)
commercially available (7-chloro-1H-indol-3-yl)oxoacetic acid methyl
ester. ES-MS: 473 [M + H]+. HRMS: calcd for C25H22ClN6O2 [M +
H]+ 473.148 73, found 473.148 95. 1H NMR (DMSO-d6, 600 MHz): δ
2.79 (s, 3H), 3.10ꢀ3.35 (br, 2H), 3.35ꢀ3.65 (br, 4H), 4.65ꢀ4.80 (br,
2H), 6.36 (d, J = 8.4 Hz, 1H), 6.70 (dd, J = 8.4, 7.8 Hz, 1H), 7.13 (d, J =
7.8 Hz, 1H), 7.17 (dd, J = 8.4, 6.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H),
7.72ꢀ7.74 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 3.3 Hz, 1H),
10.30ꢀ10.45 (br, 1H), 11.46 (s, 1H), 12.51 (s, 1H). 13C NMR (DMSO-
d6, 150.9 MHz): δ 41.0, 42.4, 52.2, 105.9, 116.9, 118.8, 119.1, 121.6,
122.2, 123.7, 125.9, 126.0, 126.8, 127.2, 133.3, 133.5, 135.3, 137.8, 152.2,
157.6, 162.4, 171.3, 171.6. IR (FTIR, transmission) νmax 3062, 2871,
νmax 3200, 1761, 1692, 1606, 1544, 752 cmꢀ1
.
3-(1H-Indol-3-yl)-4-[8-methyl-2-(4-methylpiperazin-1-
yl)quinazolin-4-yl]pyrrole-2,5-dione (22). 22 was synthesized as
described for 1 but starting from commercially available 8-methyl-1H-
quinazoline-2,4-dione. ES-MS: 451 [M ꢀ H]ꢀ. HRMS: calcd for C26H24-
N6O2 [M + H]+ 453.2039, found 453.2041. 1H NMR (DMSO-
d6, 400 MHz): δ 2.15 (s, 3H), 2.16ꢀ2.26 (br, 4H), 2.53 (s, 3H),
3.67ꢀ3.78 (br, 4H), 6.47 (d, J = 8.2 Hz, 1H), 6.66 (dd, J = 8.2, 6.9 Hz,
1H), 6.97ꢀ7.05 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.52ꢀ7.54 (m, 2H),
8.08 (s, 1H), 11.25 (br s, 1H), 11.99 (br s, 1H). 13C NMR (DMSO-d6,
100.6 MHz): δ 17.2, 44.0, 46.1, 54.5, 105.3, 112.7, 118.3, 120.5, 120.8,
122.3, 122.8, 124.9, 125.2, 125.3, 132.8, 133.5, 134.3, 136.9, 138.1, 151.6,
157.9, 162.8, 171.8, 172.1. IR (KBr) νmax 3142, 1688, 1617, 1553, 1428,
2730, 2489, 1761, 1716, 1621, 1551, 1485, 1433, 1343, 784 cmꢀ1
.
3-(7-Methyl-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-
quinazolin-4-yl]pyrrole-2,5-dione (27). 27 was synthesized as
described for 1, but the final cyclocondensation was conducted with
commercially available (7-methyl-1H-indol-3-yl)oxoacetic acid methyl
ester. ES-MS: 453 [M + H]+. HRMS: calcd for C26H25N6O2 [M + H]+
453.203 35, found 453.203 43. 1H NMR (DMSO-d6, 600 MHz): δ 2.42
(s, 3H), 2.60ꢀ2.90 (br, 2H), 2.75 (s, 3H), 3.10ꢀ3.25 (br, 2H),
3.25ꢀ3.50 (br, 2H), 4.60ꢀ4.80 (br, 2H), 6.04 (d, J = 8.1 Hz, 1H),
6.54 (dd, J = 8.1, 7.0 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H), 7.20 (dd, J = 8.0,
7.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 7.4 Hz, 1H), 7.81 (d,
J = 8.0 Hz, 1H), 8.14 (d, J = 3.0 Hz, 1H), 10.18ꢀ10.28 (br, 1H), 11.36
(br s, 1H), 12.21 (br s, 1H). 13C NMR (DMSO-d6, 150.9 MHz): δ 16.6,
40.9, 42.3, 52.0, 105.4, 117.5, 118.9, 120.7, 122.0, 123.2, 123.5, 123.8,
124.5, 125.8, 127.3, 132.8, 135.0, 136.1, 138.2, 152.1, 157.4, 162.7, 171.4,
171.8. IR (FTIR, transmission) νmax 2956, 2730, 2485, 1760, 1714,
760 cmꢀ1
.
3-(4-Chloro-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-
quinazolin-4-yl]pyrrole-2,5-dione (23). 23 was synthesized as
described for 1, but the final cyclocondensation was conducted with
commercially available (4-chloro-1H-indol-3-yl)oxoacetic acid methyl
ester. ES-MS: 473 [M + H]+. HRMS: calcd for C25H22ClN6O2 [M +
H]+ 473.148 73, found 473.148 99. 1H NMR (DMSO-d6, 600 MHz): δ
2.82 (s, 3H), 2.90ꢀ3.10 (br, 2H), 3.25ꢀ3.35 (br, 2H), 3.45ꢀ3.55 (br,
2H), 4.70ꢀ4.85 (br, 2H), 7.06 (d, J = 7.7 Hz, 1H), 7.12 (dd, J = 8.1, 7.7
Hz, 1H), 7.19ꢀ7.22 (m, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.52 (br s, 1H),
7.56 (d, J = 8.4 Hz, 1H), 7.70ꢀ7.73 (m, 2H), 10.30ꢀ10.45 (br, 1H),
11.53 (s, 1H), 12.03 (s, 1H). 13C NMR (DMSO-d6, 150.9 MHz): δ 40.9,
42.3, 52.0, 102.4, 111.4, 118.1, 120.8, 123.2, 123.5, 123.7, 124.7, 125.8,
126.6, 129.9, 133.3, 135.0, 137.7, 141.0, 151.9, 157.2, 160.9, 170.7, 171.6.
IR (FTIR, transmission) νmax 3202, 3041, 2730, 2486, 1766, 1720, 1618,
1619, 1551, 1485, 1345, 784, 757 cmꢀ1
.
3-(1-Methyl-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-
quinazolin-4-yl]pyrrole-2,5-dione (28). 28 was synthesized as
described for 1, but the final cyclocondensation was conducted with
commercially available (1-methyl-1H-indol-3-yl)oxoacetic acid methyl
ester. ESI-MS: 453 [M + H]+. HRMS: calcd for C26H24N6O2 [M + H]+
453.2039, found 453.2045. 1H NMR (DMSO-d6, 400 MHz): δ 2.14 (s,
3H), 2.14ꢀ2.22 (br, 4H), 3.64ꢀ3.76 (br, 4H), 3.88 (s, 3H), 6.28 (d, J =
8.0 Hz, 1H), 6.68 (dd, J = 8.0, 7.0 Hz, 1H), 7.08ꢀ7.12 (m, 2H), 7.45 (d,
J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.65ꢀ7.71 (m, 2H), 8.24
(s, 1H), 11.29 (br, 1H). 13C NMR (DMSO-d6, 125.8 MHz): δ 33.2,
43.6, 45.8, 54.2, 104.0, 110.9, 118.4, 120.1, 120.8, 122.5, 122.6, 123.9,
125.2, 125.6, 127.0, 134.8, 136.4, 137.2, 137.4, 152.4, 158.0, 162.2, 171.5,
1571, 1553, 1485, 1455, 756 cmꢀ1
.
3-(5-Chloro-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-
quinazolin-4-yl]pyrrole-2,5-dione (24). 24 was synthesized as
described for 1, but the final cyclocondensation was conducted with
commercially available (5-chloro-1H-indol-3-yl)oxoacetic acid methyl
ester. ES-MS: 473 [M + H]+. HRMS: calcd for C25H22ClN6O2 [M +
H]+ 473.148 73, found 473.148 92. 1H NMR (DMSO-d6, 600 MHz): δ
2.70ꢀ3.00 (br, 2H), 2.79 (s, 3H), 3.15ꢀ3.35 (br, 2H), 3.40ꢀ3.55 (br,
2H), 4.70ꢀ4.80 (br, 2H), 6.31 (br s, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H),
7.19 (dd, J = 8.1, 7.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz,
1H), 7.74 (dd, J = 8.4, 7.0 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 8.16 (d, J =
2.9 Hz, 1H), 10.30ꢀ10.45 (br, 1H), 11.41 (s, 1H), 12.34 (s, 1H). 13C
NMR (DMSO-d6, 150.9 MHz): δ 41.0, 42.4, 52.2, 104.4, 114.1, 118.9,
119.7, 122.4, 123.7, 124.8, 125.0, 125.9, 127.0, 134.1, 135.0, 135.2, 137.7,
152.1, 157.5, 162.7, 171.3, 171.6. IR (FTIR, transmission) νmax 3166,
171.8. IR (KBr) νmax 2960, 1707, 1548, 1333, 1005, 749 cmꢀ1
.
3-(1-Isopropyl-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-
quinazolin-4-yl]pyrrole-2,5-dione (29). 29 was synthesized as
described for 1, but the final cyclocondensation was conducted with
(1-isopropyl-1H-indol-3-yl)oxoacetic acid methyl ester, which was synthe-
sized from 1-isopropyl-1H-indole26 as described.27 ES-MS: 481 [M +
H]+. HRMS: calcd for C28H28N6O2 [M + H]+ 481.2352, found
3037, 2730, 1760, 1716, 1620, 1570, 1551, 1484, 1456, 1429, 757 cmꢀ1
.
3-(6-Chloro-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-
quinazolin-4-yl]pyrrole-2,5-dione (25). 25 was synthesized as
described for 1, but the final cyclocondensation was conducted with
commercially available (6-chloro-1H-indol-3-yl)oxoacetic acid methyl
ester. ES-MS: 473 [M + H]+. HRMS: calcd for C25H22ClN6O2 [M +
H]+ 473.148 73, found 473.148 83. 1H NMR (DMSO-d6, 600 MHz): δ
2.05ꢀ2.25 (br, 4H), 2.12 (s, 3H), 3.60ꢀ3.80 (br, 4H), 6.35 (d, J = 8.1
Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 7.10 (dd, J = 8.1, 6.9 Hz, 1H), 7.45 (s,
1H), 7.54 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 8.5, 6.9 Hz, 1H), 7.72 (d, J =
8.1 Hz, 1H), 8.11 (s, 1H), 11.25ꢀ11.50 (br, 1H), 11.95ꢀ12.20 (br, 1H).
13C NMR (DMSO-d6, 150.9 MHz): δ 43.6, 45.8, 54.2, 105.0, 112.2,
118.1, 120.6, 121.4, 122.5, 123.5, 125.5, 125.7, 127.1, 133.5, 134.7, 137.1,
137.7, 152.5, 157.9, 161.8, 171.4, 171.6. IR (FTIR, transmission) νmax
3190, 2946, 2805, 1769, 1757, 1696, 1619, 1568, 1550, 1505, 1485, 1342,
1
481.2358. H NMR (DMSO-d6, 400 MHz): δ 1.48 (d, J = 6.6 Hz,
6H), 2.05ꢀ2.15 (br, 4H), 2.13 (s, 3H), 3.60ꢀ3.70 (br, 4H), 4.83 (h, J =
6.6 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H), 6.68ꢀ6.72 (m, 1H), 7.08ꢀ7.16
(m, 2H), 7.54ꢀ7.58 (m, 2H), 7.68ꢀ7.72 (m, 1H), 7.74 (d, J = 8.3, 1H),
8.20 (s, 1H), 11.28ꢀ11.34 (br s, 1H). 13C NMR (DMSO-d6, 100.7
MHz): δ 22.4, 43.9, 46.1, 47.8, 54.5, 105.0, 111.4, 118.6, 120.7, 121.1,
122.7, 122.8, 124.9, 125.7, 125.9, 127.4, 131.7, 134.9, 136.3, 138.2, 152.9,
158.3, 162.3, 171.7, 172.1. IR (KBr) νmax 1717, 1547, 1300, 1234, 1214,
1002, 738 cmꢀ1
.
3-(2-Methyl-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-
quinazolin-4-yl]pyrrole-2,5-dione (30). 30 was synthesized as
described for 1, but the final cyclocondensation was conducted with
commercially available (2-methyl-1H-indol-3-yl)oxoacetic acid methyl
ester. ES-MS: 453 [M + H]+. HRMS: calcd for C26H24N6O2 [M + H]+
453.2039, found 453.2044. 1H NMR (DMSO-d6, 400 MHz): δ 2.20 (s,
3H), 2.21 (s, 3H), 2.27ꢀ2.33 (br, 4H), 3.75ꢀ3.82 (br, 4H), 6.76ꢀ6.80
(m, 1H), 6.95ꢀ6.99 (m, 1H), 7.00ꢀ7.03 (m, 1H), 7.11 (d, J = 7.9 Hz,
759 cmꢀ1
.
3-(7-Chloro-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-
quinazolin-4-yl]pyrrole-2,5-dione (26). 26 was synthesized as
described for 1, but the final cyclocondensation was conducted with
6037
dx.doi.org/10.1021/jm200469u |J. Med. Chem. 2011, 54, 6028–6039