540
N. Jiang et al. / European Journal of Medicinal Chemistry 54 (2012) 534e541
benzene (5 mL) was stirred under reflux for 2e3 h. Then the solvent
was removed under reduced pressure. Ether (5 mL) was added to
reaction mixture at room temperature and stirred for 30 min. The
precipitate was collected by filtration and purified by silica gel
chromatography (MeOH:CH2Cl2 ¼ 12:1) to afford title compounds
9ae9p (58e76%) as yellow solids.
J ¼ 8.1 Hz), 7.29 (1H, s), 7.22e7.14 (3H, m, J ¼ 8.1, 7.8 Hz), 7.10 (1H, s),
5.77 (2H, s), 3.51 (2H, q), 2.19 (2H, t), 2.11 (6H, s), 1.77e1.65 (2H, p).
MS (ESI) m/z: 447.1, 448.1 (Mþ).
4.1.8.8. (E)-N1-(2-(2-((1-(2,3-Dichlorobenzyl)-1H-imidazol-2-yl)meth-
ylene)hydrazinyl)quinazolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine
1
(9h). Yellow solid, 65% yield. mp 128e132 ꢀC. H NMR (300 MHz,
4.1.8.1. (E)-N1-(2-(2-((1-Benzyl-1H-imidazol-2-yl)methylene)hydra-
zinyl)quinazolin-4-yl)-N2,N2-dimethylethane-1,2-diamine (9a). Yel
low solid, 56% yield. mp 102e105 ꢀC. 1H NMR (300 MHz, DMSO-d6)
DMSO-d6) d: 10.89 (1H, s), 8.22 (1H, t), 8.16 (1H, s), 8.05 (1H, d,
J ¼ 8.1 Hz), 7.56 (2H, q, J ¼ 7.8, 5.1 Hz), 7.34 (2H, q, J ¼ 7.8, 7.2 Hz), 7.28
(1H, s), 7.15 (1H, t, J ¼ 7.8 Hz), 7.08 (1H, s), 6.87 (1H, d, J ¼ 6.3 Hz), 5.99
(2H, s), 3.45 (2H, q), 2.18 (2H, t), 2.09 (6H, s), 1.77e1.63 (2H, p). 13C
d
: 10.91 (1H, s), 8.13 (2H, d), 8.07 (1H, d, J ¼ 8.4 Hz), 7.62e7.52 (3H,
m), 7.43 (1H, s), 7.38 (1H, d, J ¼ 8.2 Hz), 7.32e7.24 (3H, m), 7.18 (1H,
t, J ¼ 8.1 Hz), 7.02 (1H, s), 5.78 (2H, s), 3.62 (2H, q), 2.63 (2H,t), 2.29
(6H, s). MS (ESI) m/z: 415.1, 416.1 (Mþ).
NMR (151 MHz, DMSO-d6) d: 211.94, 161.09, 157.35, 143.35, 139.11,
133.16, 132.67, 130.72, 130.29, 129.90, 129.20, 126.22, 124.12, 123.54,
122.29, 112.96, 57.69, 49.15, 45.86, 27.08. MS (ESI) m/z: 497.6, 499.6
(Mþ).
4.1.8.2. (E)-N1-(2-(2-((1-(4-Methylbenzyl)-1H-imidazol-2-yl)methy-
lene)hydrazinyl)quinazolin-4-yl)-N2,N2-dimethylethane-1,2-diamine
(9b). Yellow solid, 65% yield. mp 101e104 ꢀC. 1H NMR (300 MHz,
4.1.8.9. (E)-2-(2-((1-Benzyl-1H-imidazol-2-yl)methylene)hydrazinyl)-
N-(3-morpholinopropyl)quinazolin-4-amine (9i). Yellow solid, 71%
DMSO-d6)
d
: 10.89 (1H, s), 8.09 (3H, t, J ¼ 8.4 Hz), 7.59 (1H, t,
yield. mp 123e125 ꢀC. 1H NMR (300 MHz, DMSO-d6)
d: 10.94 (1H, s),
J ¼ 7.2 Hz), 7.48 (2H, d, J ¼ 7.8 Hz), 7.41 (1H, s), 7.38 (1H, d,
J ¼ 8.1 Hz), 7.17 (1H, t, J ¼ 7.5 Hz), 7.08 (2H, d, J ¼ 7.8 Hz), 6.99 (1H, s),
5.75 (2H, s), 3.59 (2H, q), 2.47 (2H, t), 2.22 (3H, s), 2.14 (6H, s). MS
(ESI) m/z: 427.6, 428.6 (Mþ).
8.17 (1H, t), 8.09 (2H, d), 7.65e7.55 (3H, m), 7.44 (1H, s), 7.38 (1H, d,
J ¼ 8.1 Hz), 7.33e7.23 (3H, m), 7.18 (1H, t, J ¼ 7.8 Hz), 7.00 (1H, s), 5.83
(2H, s), 3.62e3.50 (6H, m), 2.35e2.17 (6H, m), 1.81e1.68 (2H, p). MS
(ESI) m/z: 471.2, 472.2 (Mþ).
4.1.8.3. (E)-N1-(2-(2-((1-(4-Fluorobenzyl)-1H-imidazol-2-yl)methy-
lene)hydrazinyl)quinazolin-4-yl)-N2,N2-dimethylethane-1,2-diamine
(9c). Yellow solid, 61% yield. mp 107e1110 ꢀC. 1H NMR (300 MHz,
4.1.8.10. (E)-2-(2-((1-(4-Methylbenzyl)-1H-imidazol-2-yl)methylene)
hydrazinyl)-N-(3-morpholinopropyl)quinazolin-4-amine (9j). Yellow
solid, 68% yield. mp 133e135 ꢀC. 1H NMR (300 MHz, DMSO-d6)
d:
DMSO-d6)
d
: 10.99 (1H, s), 8.31 (1H, t), 8.17 (2H, d, J ¼ 8.4 Hz), 7.77
10.94 (1H, s), 8.23 (1H, t), 8.12 (2H, d, J ¼ 7.8 Hz), 7.59 (1H, t,
J ¼ 7.2 Hz), 7.50 (2H, t), 7.39 (2H, d), 7.17 (1H, t, J ¼ 8.4 Hz), 7.09
(2H, d, J ¼ 7.8 Hz), 6.99 (1H, s), 5.76 (s, 2H), 3.60e3.50 (6H, m),
2.27 (4H, s), 2.23 (5H, s), 1.80e1.68 (2H, p). 13C NMR (151 MHz,
(2H, dd, J ¼ 8.1, 6.0 Hz), 7.61 (1H, t, J ¼ 8.1 Hz), 7.51 (1H, s), 7.41 (1H,
d, J ¼ 7.8 Hz), 7.20e7.12 (3H, m, J ¼ 8.7, 7.8 Hz), 7.03 (1H, s), 5.77 (2H,
s), 3.61 (2H, q), 2.50 (2H, t), 2.16 (6H, s). MS (ESI) m/z: 433.0, 434.0
(Mþ).
DMSO-d6) d: 211.95, 161.23, 157.64, 151.89, 142.68, 137.48, 135.93,
134.16, 133.08, 129.59, 129.11, 125.99, 124.70, 123.90, 122.23,
112.94, 66.90, 56.88, 54.08, 49.90, 26.16, 21.41. MS (ESI) m/z: 485.1,
486.0 (Mþ).
4.1.8.4. (E)-N1-(2-(2-((1-(2,3-Dichlorobenzyl)-1H-imidazol-2-yl)meth-
ylene)hydrazinyl)quinazolin-4-yl)-N2,N2-dimethylethane-1,2-diamine
(9d). Yellow solid, 72% yield. mp 116e118 ꢀC. 1H NMR (300 MHz,
DMSO-d6)
d
: 10.84 (1H, s), 8.15 (1H, s), 8.03 (1H, d, J ¼ 8.1 Hz), 7.96
4.1.8.11. (E)-2-(2-((1-(4-Fluorobenzyl)-1H-imidazol-2-yl)methylene)
hydrazinyl)-N-(3-morpholinopropyl)quinazolin-4-amine (9k). Yell
ow solid, 64% yield. mp 110e114 ꢀC. 1H NMR (300 MHz, DMSO-d6)
(1H, t), 7.56 (2H, t, J ¼ 7.8 Hz), 7.33 (2H, q, J ¼ 8.4, 7.8, 3.3 Hz), 7.26 (1H,
s), 7.15 (1H, t, J ¼ 7.5 Hz), 7.08 (1H, s), 6.83 (1H, d, J ¼ 7.2 Hz), 6.00 (2H,
s), 3.53 (2H, q), 2.41 (2H, t), 2.10 (6H, s). MS (ESI) m/z: 482.9, 484.7
(Mþ).
d
: 10.96 (1H, s), 8.29 (1H, t), 8.15 (2H, d), 7.75 (2H, t, J ¼ 7.8, 6.0 Hz),
7.59 (1H, t, J ¼ 7.5 Hz), 7.49 (1H, s), 7.39 (1H, d, J ¼ 8.4 Hz), 7.19 (1H, t,
J ¼ 7.8 Hz), 7.13 (2H, t, J ¼ 8.7 Hz), 7.01 (1H, s), 5.79 (2H, s), 3.59 (2H,
q), 3.54 (4H, t), 2.28 (4H, s), 2.22 (2H, t), 1.75 (2H, p). 13C NMR
4.1.8.5. (E)-N1-(2-(2-((1-Benzyl-1H-imidazol-2-yl)methylene)hydra-
zinyl)quinazolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine (9e). Yell
ow solid, 73% yield. mp 105e107 ꢀC. 1H NMR (300 MHz, DMSO-d6)
(151 MHz, DMSO-d6) d: 212.09, 161.26, 157.63, 151.87, 142.62, 135.21,
133.34, 132.78, 131.54, 131.43, 129.64, 125.99, 124.04, 123.84, 122.27,
116.03, 115.75, 113.00, 66.89, 56.87, 54.08, 49.27, 26.15. MS (ESI)
m/z: 489.0, 490.0 (Mþ).
d
: 10.89 (1H, s), 8.18 (1H, t), 8.10 (1H, s), 8.04 (1H, d, J ¼ 8.1 Hz), 7.59
(3H, q, J ¼ 8.1, 6.6 Hz), 7.44 (1H, s), 7.38 (1H, d, J ¼ 8.1 Hz), 7.32e7.23
(3H, m, J ¼ 7.2, 6.6 Hz), 7.17 (1H, t, J ¼ 8.1 Hz), 7.00 (1H, s), 5.83 (2H,
s), 3.49 (2H, q), 2.17 (2H, t), 2.10 (6H, s), 1.76e1.66 (2H, p). MS (ESI)
m/z: 428.8, 429.8 (Mþ).
4.1.8.12. (E)-2-(2-((1-(2,3-Dichlorobenzyl)-1H-imidazol-2-yl)methy-
lene)hydrazinyl)-N-(3-morpholinopropyl)quinazolin-4-amine (9l).
Yellow solid, 76% yield. mp 160e164 ꢀC. 1H NMR (300 MHz, DMSO-
4.1.8.6. (E)-N1-(2-(2-((1-(4-Methylbenzyl)-1H-imidazol-2-yl)methy-
lene)hydrazinyl)quinazolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine
(9f). Yellow solid, 69% yield. mp 159e162 ꢀC. 1H NMR (300 MHz,
d6)
d
: 10.85 (1H, s), 8.15 (1H, s), 8.11 (1H, t), 8.05 (1H, d, J ¼ 7.8 Hz),
7.56 (2H, t, J ¼ 7.8, 6.3 Hz), 7.35 (1H, d, J ¼ 9.0 Hz), 7.29 (1H, t,
J ¼ 8.4 Hz), 7.25 (1H, s), 7.15 (1H, t, J ¼ 7.8 Hz), 7.07 (1H, s), 6.87 (1H,
d, J ¼ 6.6 Hz), 6.00 (2H, s), 3.53 (4H, t), 3.45 (2H, q), 2.27 (4H, s), 2.21
(2H, t), 1.77e1.64 (2H, p). MS (ESI) m/z: 539.0, 541.9 (Mþ).
DMSO-d6) d: 10.90 (1H, s), 8.22 (1H, t), 8.10 (1H, s), 8.07 (1H, d,
J ¼ 8.1 Hz), 7.59 (1H, t, J ¼ 7.8 Hz), 7.50 (2H, d, J ¼ 7.8 Hz), 7.41 (1H, s),
7.38 (1H, d, J ¼ 8.1 Hz), 7.17 (1H, t, J ¼ 7.8 Hz), 7.09 (2H, d, J ¼ 7.8 Hz),
6.99 (1H, s), 5.76 (2H, s), 3.51 (2H, q), 2.21 (5H, t), 2.13 (6H, s),
1.79e1.66 (2H, p). MS (ESI) m/z: 443.2, 444.2 (Mþ).
4.1.8.13. (E)-2-(2-((1-Benzyl-1H-imidazol-2-yl)methylene)hydrazinyl)-
N-(1-methylpiperidin-4-yl)quinazolin-4-amine (9m). Yellow solid,
69% yield. mp 172e175 ꢀC.1H NMR (300 MHz, DMSO-d6)
d: 10.95 (1H,
4.1.8.7. (E)-N1-(2-(2-((1-(4-Fluorobenzyl)-1H-imidazol-2-yl)methy-
lene)hydrazinyl)quinazolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine
(9g). Yellow solid, 58% yield. mp 118e121 ꢀC. 1H NMR (300 MHz,
s), 8.18 (1H, d, J ¼ 8.4 Hz), 8.09 (1H, s), 7.81 (1H, d, J ¼ 7.8 Hz), 7.67 (2H,
d, J ¼ 6.6 Hz), 7.59 (1H, t, J ¼ 8.1 Hz), 7.46 (1H, s), 7.37 (1H, d,
J ¼ 7.8 Hz), 7.27 (3H, t, J ¼ 7.8, 7.5 Hz), 7.16 (1H, t, J ¼ 8.1 Hz), 6.98
(s, 1H), 5.84 (s, 2H), 4.22 (1H, s), 2.66 (2H, s), 2.07 (3H, s), 1.78 (2H, s),
1.63 (4H, s). MS (ESI) m/z: 441.2, 442.1 (Mþ).
DMSO-d6)
d: 10.90 (1H, s), 8.51 (1H, s), 8.17 (1H, s), 8.07 (1H, d,
J ¼ 8.4 Hz), 7.60e7.56 (2H, dd, J ¼ 7.8 Hz), 7.38e7.32 (2H, m,