A.D. Jagtap et al. / European Journal of Medicinal Chemistry 85 (2014) 268e288
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4.1.12.23. 3-(5-((6-(3-(2-Fluoro-4-methoxybenzoyl)ureido)-2-
oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrol-3-yl)prop-
anoic acid (43). Condensation of 28k (0.085 g, 0.25 mmol) with 3-
(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propanoic acid (0.054 g,
0.28 mmol) afforded 43 (0.063 g, 49%). mp: 255e260 ꢂC (dec.). IR
(J ¼ 251.0 Hz), 163.7 (J ¼ 11.7 Hz), 164.3, 165.7 (J ¼ 1.8 Hz), 169.8.
Anal. (C27H25FN4O6) C, H, N. MS (ESI) m/z 501.1 [MꢁH]ꢁ.
4.1.12.27. Ethyl 3-(5-((6-(3-(2-fluoro-4-methoxybenzoyl)ureido)-2-
oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrol-3-yl)prop-
anoate (47). Condensation of 28k (0.085 g, 0.25 mmol) with 8
(0.062 g, 0.28 mmol) afforded 47 (0.061 g, 45%). mp: 250e255 ꢂC
(ATR): 3456, 3341, 1716, 1687, 1472, 844, 758 cmꢁ1
.
1H NMR
(400 MHz, DMSO-d6):
d
2.24 (s, 3H), 2.28 (s, 3H), 2.34 (t, J ¼ 7.6 Hz,
2H), 2.63 (t, J ¼ 7.6 Hz, 2H), 3.84 (s, 3H), 6.90 (dd, J ¼ 2.0, 8.6 Hz,1H),
6.95e6.98 (m, 2H), 7.40 (d, J ¼ 1.6 Hz,1H), 7.48 (s,1H), 7.64e7.71 (m,
2H), 10.63 (s, 1H), 10.76 (s, 1H), 13.26 (s, 1H). 13C NMR (100 MHz,
(dec.). IR (ATR): 3449, 3342, 1712, 1670, 1466, 838, 751 cmꢁ1
.
1H
NMR (400 MHz, DMSO-d6):
d
1.15 (t, J ¼ 7.0 Hz, 3H), 2.23 (s, 3H),
2.27 (s, 3H), 2.42 (t, J ¼ 7.6 Hz, 2H), 2.66 (t, J ¼ 7.4 Hz, 2H), 3.84 (s,
3H), 4.03 (q, J ¼ 7.2 Hz, 2H), 6.90 (dd, J ¼ 2.0, 8.4 Hz, 1H), 6.95e6.98
(m, 2H), 7.39 (brs, 1H), 7.48 (s, 1H), 7.65e7.71 (m, 2H), 10.62 (s, 1H),
10.73 (s, 1H), 10.76 (s, 1H), 13.26 (s, 1H). 13C NMR (100 MHz, DMSO-
DMSO-d6):
d
9.3,11.8,19.4, 34.6, 56.0,101.2,102.0 (J ¼ 25.6 Hz),110.6
(J ¼ 2.6 Hz), 112.2, 114.0 (J ¼ 12.5 Hz), 118.4, 121.7, 122.3, 125.7, 129.1,
131.5 (J ¼ 3.6 Hz), 133.4, 135.3, 138.4, 150.4, 160.9 (J ¼ 250.7 Hz),
163.7 (J ¼ 11.6 Hz), 165.7 (J ¼ 1.8 Hz), 169.6, 173.9. Anal.
(C27H25FN4O6 $1/2H2O) C, H, N. MS (ESI) m/z 519.0 [MꢁH]ꢁ.
d6):
d
8.9, 11.3, 13.6, 18.9, 33.9, 55.6, 59.3, 100.7, 101.5 (J ¼ 25.6 Hz),
110.2 (J ¼ 2.7 Hz), 111.8, 111.9, 113.6 (J ¼ 12.7 Hz), 118.0, 120.9, 121.2,
121.9, 125.3, 128.6, 131.1 (J ¼ 3.7 Hz), 132.9, 134.9, 138.0, 149.9, 160.5
(J ¼ 250.6 Hz), 163.2 (J ¼ 11.6 Hz), 165.3 (J ¼ 2.0 Hz), 169.1, 171.8.
Anal. (C29H29FN4O6) C, H, N. MS (ESI) m/z 547.0 [MꢁH]ꢁ.
4.1.12.24. 5-((5-Fluoro-6-(3-(2-fluoro-4-methoxybenzoyl)ureido)-2-
oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic
acid (44). Condensation of 28m (0.090 g, 0.25 mmol) with 5-
formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.046 g,
0.28 mmol) afforded 44 (0.096 g, 76%). mp: 297 to >300 ꢂC. IR
4.1.12.28. (5-((6-(3-(2-Fluoro-4-methoxybenzoyl)ureido)-2-
oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrol-3-yl) 4-
methylpiperazin-1-yl ketone (48). Condensation of 28k (0.085 g,
0.25 mmol) with (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl) 4-
methylpiperazin-1-yl ketone 9 (0.069 g, 0.28 mmol) afforded 48
(0.049 g, 35%). mp: 250e255 ꢂC (dec.). IR (ATR): 3449, 3329, 1706,
(ATR): 3460, 3348, 1709, 1670, 1465, 864, 770 cmꢁ1
.
1H NMR
2.50 (s, 3H), 2.52 (s, 3H), 3.85 (s, 3H), 6.90
(400 MHz, DMSO-d6):
d
(dd, J ¼ 2.4, 8.8 Hz, 1H), 6.97 (dd, J ¼ 2.4, 12.8 Hz, 1H), 7.66 (s, 1H),
7.66 (dd, J ¼ 8.8, 8.8 Hz, 1H), 7.84 (d, J ¼ 6.4 Hz, 1H), 7.91 (d,
J ¼ 11.2 Hz, 1H), 10.93 (s, 1H), 11.03 (s, 1H), 11.04 (s, 1H), 13.73 (s, 1H).
1670, 1462, 841, 752 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d 2.17 (s,
13C NMR (100 MHz, DMSO-d6):
d 12.0, 15.0, 56.7, 102.5, 102.6, 102.7,
3H), 2.22 (brs, 4H), 2.26 (s, 6H), 3.44 (brs, 4H), 3.83 (s, 3H), 6.89 (dd,
J ¼ 2.4, 8.8 Hz, 1H), 6.94e6.99 (m, 2H), 7.41 (d, J ¼ 2.0 Hz, 1H), 7.52
(s, 1H), 7.68 (dd, J ¼ 8.4, 8.8 Hz, 1H), 7.70 (d, J ¼ 8.0 Hz, 1H), 10.64 (s,
1H), 10.72 (s, 1H), 10.88 (s, 1H), 13.43 (s, 1H). 13C NMR (100 MHz,
111.2 (J ¼ 2.3 Hz), 114.3 (J ¼ 12.3 Hz), 114.7, 116.3 (J ¼ 3.1 Hz), 121.2
(J ¼ 9.2 Hz),124.2,124.6 (J ¼ 12.5 Hz),126.7, 132.3 (J ¼ 3.7 Hz), 133.3,
135.4 (J ¼ 1.4 Hz), 141.1, 148.8 (J ¼ 232.8 Hz), 150.9, 161.6
(J ¼ 251.1 Hz), 164.4 (J ¼ 11.5 Hz), 166.5, 166.7 (J ¼ 2.0 Hz), 170.3.
Anal. (C25H20F2N4O6 $1/2H2O) C, H, N. MS (ESI) m/z 509.1 [MꢁH]ꢁ.
DMSO-d6):
d
10.0, 12.3, 45.6, 56.0, 101.3, 102.0 (J ¼ 25.7 Hz), 110.6
(J ¼ 2.6 Hz), 112.5, 114.0 (J ¼ 12.6 Hz), 114.9, 119.1, 119.7, 121.1, 122.2,
125.9, 127.4, 131.5 (J ¼ 3.7 Hz), 132.9, 136.1, 138.9, 150.4, 160.9
(J ¼ 250.7 Hz), 163.7 (J ¼ 11.8 Hz), 165.3, 165.7 (J ¼ 1.9 Hz), 169.7.
Anal. (C30H31FN6O5$3/2H2O) C, H, N. MS (ESI) m/z 573.1 [MꢁH]ꢁ.
4.1.12.25. 3-(5-((5-Fluoro-6-(3-(2-fluoro-4-methoxybenzoyl)ure-
ido)-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrol-3-yl)
propanoic acid (45). Condensation of 28m (0.090 g, 0.25 mmol)
with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propanoic acid
(0.054 g, 0.28 mmol) afforded 45 (0.072 g, 54%). mp: 275e280 ꢂC
4.1.12.29. 2-(5-((6-(3-(2-Fluoro-4-methoxybenzoyl)ureido)-2-
oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrol-3-yl)ethyl 4-
methylpiperazin-1-yl ketone (49). Condensation of 28k (0.085 g,
0.25 mmol) with 2-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)ethyl 4-
methylpiperazin-1-yl ketone 10 (0.077 g, 0.28 mmol) afforded 49
(0.054 g, 37%). mp: 229e234 ꢂC (dec.). IR (ATR): 3451, 3340, 1700,
(dec.). IR (ATR): 3451, 3343, 1714, 1682, 1469, 849, 760 cmꢁ1
.
1H
NMR (400 MHz, DMSO-d6):
d 2.25 (s, 3H), 2.28 (s, 3H), 2.34 (t,
J ¼ 7.6 Hz, 2H), 2.63 (t, J ¼ 7.6 Hz, 2H), 3.84 (s, 3H), 6.90 (d, J ¼ 2.0 Hz,
8.8 Hz, 1H), 6.97 (dd, J ¼ 2.4, 13.2 Hz, 1H), 7.56 (s, 1H), 7.70 (dd,
J ¼ 8.8, 8.4 Hz, 1H), 7.80 (d, J ¼ 6.8 Hz, 1H), 7.81 (d, J ¼ 11.2 Hz, 1H),
10.74 (s, 1H), 10.98 (s, 1H), 10.99 (s, 1H), 13.32 (s, 1H). 13C NMR
1679, 1457, 842, 751 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d 2.11 (s,
3H), 2.12e2.14 (m, 2H), 2.19e2.20 (m, 2H), 2.23 (s, 3H), 2.27 (s, 3H),
2.41 (t, J ¼ 7.6 Hz, 2H), 2.62 (t, J ¼ 7.6 Hz, 2H), 3.42 (brs, 4H), 3.84 (s,
3H), 6.90 (dd, J ¼ 2.4, 8.4 Hz, 1H), 6.95e6.99 (m, 2H), 7.41 (brs, 1H),
7.48 (s, 1H), 7.65e7.71 (m, 2H), 10.63 (s, 1H), 10.76 (s, 2H), 13.27 (s,
(100 MHz, DMSO-d6):
d 8.9, 11.4, 19.0, 34.0, 55.6, 101.4, 101.7, 104.8
(J ¼ 23.1 Hz), 110.2 (J ¼ 2.4 Hz), 111.3 (J ¼ 2.9 Hz), 113.4 (J ¼ 12.3 Hz),
121.0 (J ¼ 9.2 Hz), 121.7, 122.4 (J ¼ 12.4 Hz), 123.2, 125.4, 129.8, 131.2
(J ¼ 3.6 Hz), 133. 6, 134.0, 147.8 (J ¼ 232.0 Hz), 149.9, 160.5
(J ¼ 251.0 Hz), 163.4 (J ¼ 11.7 Hz), 165.7 (J ¼ 1.9 Hz), 169.0, 173.5.
Anal. (C27H24F2N4O6$2/3H2O) C, H, N. MS (ESI) m/z 537.0 [MꢁH]ꢁ.
1H). 13C NMR (100 MHz, DMSO-d6):
d 9.3, 11.8, 19.9, 32.7, 40.8, 44.8,
45.5, 54.2, 54.5, 56.0, 101.2 (J ¼ 2.2 Hz), 102.0 (J ¼ 25.8 Hz), 110.6
(J ¼ 2.5 Hz), 112.1, 112.3, 114.0 (J ¼ 12.6 Hz), 118.4, 120.8, 121.9
(J ¼ 31.8 Hz), 124.5, 125.7, 129.2, 131.5 (J ¼ 3.7 Hz), 133.4, 135.3,
136.9, 138.3, 144.1, 150.4, 160.9 (J ¼ 250.6 Hz), 163.7 (J ¼ 11.7 Hz),
165.7, 169.6, 170.1, 176.6. Anal. (C32H35FN6O5$5/4H2O) C, H, N. MS
(ESI) m/z 601.1 [MꢁH]ꢁ.
4.1.12.26. Ethyl 3-(5-((6-(3-(2-fluoro-4-methoxybenzoyl)ureido)-2-
oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-
carboxylate (46). Condensation of 28k (0.085 g, 0.25 mmol) with 7
(0.054 g, 0.28 mmol) afforded 46 (0.081 g, 63%). mp: 278e283 ꢂC
4.1.12.30. (5-((6-(3-(2-Fluoro-4-methoxybenzoyl)ureido)-2-
oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrol-3-yl) morpho-
lin-4-yl ketone (50). Condensation of 28k (0.085 g, 0.25 mmol) with
(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl) morpholin-4-yl ketone 11
(0.066 g, 0.28 mmol) afforded 50 (0.053 g, 39%). mp: 273e278 ꢂC
(dec.). IR (ATR): 3455, 3330, 1716, 1663, 1470, 835, 745 cmꢁ1
.
1H
NMR (400 MHz, DMSO-d6):
d
1.29 (t, J ¼ 7.0 Hz, 3H), 2.48 (s, 3H),
2.52 (s, 3H), 3.84 (s, 3H), 4.20 (q, J ¼ 7.2 Hz, 2H), 6.90 (dd, J ¼ 2.2,
8.4 Hz, 1H), 6.95e7.00 (m, 2H), 7.43 (d, J ¼ 1.6 Hz, 1H), 7.58 (s, 1H),
7.67 (dd, J ¼ 8.4, 8.8 Hz, 1H), 7.75 (d, J ¼ 8.4 Hz, 1H), 10.66 (s, 1H),
10.73 (s, 1H), 10.97 (s, 1H), 13.75 (s, 1H). 13C NMR (100 MHz, DMSO-
(dec.). IR (ATR): 3455, 3330, 1716, 1660, 1460, 835, 745 cmꢁ1
.
1H
NMR (400 MHz, DMSO-d6):
d 2.25 (s, 3H), 2.28 (s, 3H), 3.46 (brs,
d6):
d
11.3, 14.2, 14.4, 56.0, 59.0, 101.3, 102.0 (J ¼ 25.6 Hz), 110.6
4H), 3.57 (brs, 4H), 3.84 (s, 3H), 6.90 (dd, J ¼ 2.4, 8.4 Hz, 1H),
6.95e7.00 (m, 2H), 7.42 (d, J ¼ 1.6 Hz, 1H), 7.53 (s, 1H), 7.67e7.73 (m,
2H), 10.65 (s, 2H), 10.90 (s, 1H), 13.45 (s, 1H). 13C NMR (100 MHz,
(J ¼ 2.4 Hz), 112.6, 113.1, 114.0 (J ¼ 12.4 Hz), 116.5, 119.5, 120.8, 122.0,
126.0, 131.1, 131.5 (J ¼ 3.4 Hz), 136.5, 139.2, 139.7, 150.4, 160.9