S.-L. Cao et al. / European Journal of Medicinal Chemistry 64 (2013) 401e409
407
NMR (600 MHz, DMSO-d6)
d
: 2.27 (s, 3H, CH3), 2.91 (br s, 4H,
6.1.7.14. (2,4-Diaminoquinazolin-6-yl)methyl
4-(2-fluorophenyl)
piperazine-H), 4.03 (br s, 2H, piperazine-H), 4.37 (br s, 2H,
piperazine-H), 4.57 (s, 2H, CH2S), 6.97 (t, J ¼ 7.2 Hz, 1H, Ph 40-H),
7.0 (d, J ¼ 7.2 Hz, 1H, Ph 60-H), 7.13 (t, J ¼ 7.2 Hz, 1H, Ph 50-H), 7.16
(d, J ¼ 7.2 Hz, 1H, Ph 30-H), 7.33 (d, J ¼ 8.4 Hz, 1H, quinazoline 8-H),
7.73 (d, J ¼ 8.4 Hz, 1H, quinazoline 7-H), 8.22 (s, 1H, quinazoline 5-
H), 8.43 (br s, 2H, NH2). ESI-MS m/z: 425 [M þ H]þ. ESI-HRMS m/z:
calcd for C21H25N6S2 ([M þ H]þ): 425.1582, found: 425.1567.
piperazine-1-carbodithioate (8n). Yield 73%, white solid, mp
232.3e234.3 ꢀC (CC, eluent:dichloromethane/methanol ¼ 90:10).
1H NMR (600 MHz, DMSO-d6)
d: 3.10 (br s, 4H, piperazine-H), 4.05
(br s, 2H, piperazine-H), 4.39 (br s, 2H, piperazine-H), 4.51 (s, 2H,
CH2S), 6.27 (br s, 2H, NH2), 6.99 (m, 1H, Ph 40-H), 7.04 (t, J ¼ 8.4 Hz,
1H, Ph 60-H), 7.10 (t, J ¼ 8.4 Hz, 1H, Ph 50-H), 7.46 (m, 1H, Ph 30-H),
7.35 (d, J ¼ 8.4 Hz, 1H, quinazoline 8-H), 7.49 (br s, 2H, NH2), 7.56
(d, J ¼ 8.4 Hz, quinazoline 7-H), 8.03 (s, 1H, quinazoline 5-H). ESI-
MS m/z: 429 [M þ H]þ. ESI-HRMS m/z: calcd for C20H22FN6S2
([M þ H]þ): 429.1331, found: 429.1325.
6.1.7.9. (2,4-Diaminoquinazolin-6-yl)methyl 4-(2,4-dimethylphenyl)
piperazine-1-carbodithioate (8i). Yield 54%, white solid, mp 211.2e
212.8 ꢀC (CC, eluent:dichloromethane/methanol ¼ 90:10). 1H NMR
(600 MHz, DMSO-d6)
d: 2.20 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.87 (br
6.1.7.15. (2,4-Diaminoquinazolin-6-yl)methyl 4-(2,4-difluorophenyl)
s, 4H, piperazine-H), 4.03 (br s, 2H, piperazine-H), 4.38 (br s, 2H,
piperazine-H), 4.53 (s, 2H, CH2S), 6.42 (br s, 2H, NH2), 6.91 (d,
J ¼ 8.4 Hz, 1H, Ph 60-H), 6.94 (d, J ¼ 8.4 Hz, 1H, Ph 50-H), 6.99 (s, 1H,
Ph 30-H), 7.21 (d, J ¼ 8.4 Hz, 1H, quinazoline 8-H), 7.58 (d, J ¼ 8.4 Hz,
1H, quinazoline 7-H), 7.62 (br s, 2H, NH2), 8.06 (s,1H, quinazoline 5-
H). ESI-MS m/z: 439 [M þ H]þ. ESI-HRMS m/z: calcd for C22H27N6S2
([M þ H]þ): 439.1739, found: 439.1728.
piperazine-1-carbodithioate
(8o). Yield
44%,
white
solid,
mp > 300 ꢀC (CC, eluent:dichloromethane/methanol ¼ 90:10). 1H
NMR (300 MHz, DMSO-d6) d: 3.06 (br s, 4H, piperazine-H), 4.05 (br
s, 2H, piperazine-H), 4.39 (br s, 2H, piperazine-H), 4.54 (s, 2H,
CH2S), 6.80 (br s, 2H, NH2), 7.02 (td, J ¼ 8.4, 1.2 Hz, 1H, Ph 30-H), 7.10
(m, 1H, Ph 60-H), 7.22 (m, 2H, Ph 50-H and quinazoline 8-H), 7.63
(dd, J ¼ 8.4, 2.4 Hz, 1H, quinazoline 7-H), 7.90 (m, 2H, NH2), 8.12 (d,
J ¼ 2.4 Hz, 1H, quinazoline 5-H). ESI-MS m/z: 447 [M þ H]þ. ESI-
HRMS m/z: calcd for C20H21F2N6S2 ([M þ H]þ): 447.1237, found:
447.1235.
6.1.7.10. (2,4-Diaminoquinazolin-6-yl)methyl 4-(4-chlorophenyl)
piperazine-1-carbodithioate (8j). Yield 35%, white solid, mp
206.6e208.0 ꢀC (CC, eluent:dichloromethane/methanol ¼ 90:10).
1H NMR (300 MHz, DMSO-d6)
d
: 3.43 (br s, 4H, piperazine-H), 4.07
6.1.7.16. (2,4-Diaminoquinazolin-6-yl)methyl 4-(4-acetylphenyl)piper-
(br s, 2H, piperazine-H), 4.41 (br s, 2H, piperazine-H), 4.56 (s, 2H,
CH2S), 6.98 (d, J ¼ 9.0 Hz, 2H, Ph 20 and 60-H), 7.23 (d, J ¼ 8.7 Hz,
1H, quinazoline 8-H), 7.29 (d, J ¼ 9.0 Hz, 2H, Ph 30 and 50-H), 7.60
(dd, J ¼ 8.7, 1.5 Hz, 1H, quinazoline 7-H), 8.09 (d, J ¼ 1.5 Hz, 1H,
quinazoline 5-H). ESI-MS m/z: 445 [M þ H]þ. ESI-HRMS m/z: calcd
for C20H22ClN6S2 ([M þ H]þ): 445.1036, found: 445.1028.
azine-1-carbodithioate (8p). Yield 33%, yellow solid, mp > 300 ꢀC
(from DMF/acetone). 1H NMR (300 MHz, DMSO-d6)
d: 2.46 (s, 3H,
COCH3), 3.56 (br s, 4H, piperazine-H), 4.06 (br s, 2H, piperazine-H),
4.38 (br s, 2H, piperazine-H), 4.52 (s, 2H, CH2S), 6.01 (br s, 2H,
NH2), 6.93 (d, J ¼ 9.0 Hz, 2H, Ph 20 and 60-H), 7.14 (d, J ¼ 8.4 Hz, 1H,
quinazoline 8-H), 7.26 (br s, 2H, NH2), 7.51 (d, J ¼ 8.4 Hz, 1H, qui-
nazoline 7-H), 7.83 (d, J ¼ 9.0 Hz, 2H, Ph 30 and 50-H), 7.96 (s, 1H,
quinazoline 5-H). ESI-MS m/z: 453 [M þ H]þ. ESI-HRMS m/z: calcd
for C22H25N6OS2 ([M þ H]þ): 453.1531, found: 453.1533.
6.1.7.11. (2,4-Diaminoquinazolin-6-yl)methyl
4-(2-chlorophenyl)
piperazine-1-carbodithioate (8k). Yield 41%, white solid, mp
245.1e246.1 ꢀC (CC, eluent:dichloromethane/methanol ¼ 90:10).
1H NMR (300 MHz, DMSO-d6)
d
: 3.09 (br s, 4H, piperazine-H), 4.07
6.1.7.17. (2,4-Diaminoquinazolin-6-yl)methyl 4-(4-nitrophenyl)piper-
(br s, 2H, piperazine-H), 4.40 (br s, 2H, piperazine-H), 4.59 (s, 2H,
CH2S), 7.10 (td, J ¼ 7.8, 1.2 Hz, 1H, Ph 40-H), 7.20 (dd, J ¼ 7.8, 1.2 Hz,
1H, Ph 60-H), 7.33 (td, J ¼ 7.8, 1.2 Hz, 1H, Ph 50-H), 7.35 (d, J ¼ 8.4 Hz,
1H, quinazoline 8-H), 7.46 (dd, J ¼ 7.8, 1.2 Hz, 1H, Ph 30-H), 7.75 (d,
J ¼ 8.4 Hz, 1H, quinazoline 7-H), 8.22 (s, 1H, quinazoline 5-H), 8.39
(br s, 2H, NH2). ESI-MS m/z: 445 [M þ H]þ. ESI-HRMS m/z: calcd
for C20H22ClN6S2 ([M þ H]þ): 445.1036, found: 445.1032.
azine-1-carbodithioate (8q). Yield 28%, yellow solid, mp > 300 ꢀC
(from DMF/acetone). 1H NMR (300 MHz, DMSO-d6)
d: 3.69 (br s, 4H,
piperazine-H), 4.08 (br s, 2H, piperazine-H), 4.37 (br s, 2H,
piperazine-H), 4.51 (s, 2H, CH2S), 5.99 (br s, 2H, NH2), 6.93 (d,
J ¼ 9.6 Hz, 2H, Ph 20 and 60-H), 7.13 (d, J ¼ 8.4 Hz, 1H, quinazoline 8-
H), 7.24 (br s, 2H, NH2), 7.50 (dd, J ¼ 8.4, 1.8 Hz, 1H, quinazoline 7-H),
7.99 (d, J ¼ 1.8 Hz, 1H, quinazoline 5-H), 8.09 (d, J ¼ 9.6 Hz, 2H, Ph 30
and 50-H). ESI-MS m/z: 456 [M þ H]þ. ESI-HRMS m/z: calcd for
C20H22N7O2S2 ([M þ H]þ): 456.1276, found: 456.1273.
6.1.7.12. (2,4-Diaminoquinazolin-6-yl)methyl 4-(3,4-dichlorophenyl)
piperazine-1-carbodithioate (8l). Yield 27%, grey solid, mp 233.6e
236.4 ꢀC (CC, eluent:dichloromethane/methanol ¼ 90:10). 1H NMR
6.1.7.18. (2,4-Diaminoquinazolin-6-yl)methyl 4-(2-nitrophenyl)piper-
azine-1-carbodithioate(8r). Yield 24%, yellow solid, mp > 300 ꢀC (CC,
eluent:dichloromethane/methanol ¼ 90:10). 1H NMR (600 MHz,
(300 MHz, DMSO-d6) d: 3.18 (br s, 4H, piperazine-H), 4.07 (br s, 2H,
piperazine-H), 4.36 (br s, 2H, piperazine-H), 4.56 (s, 2H, CH2S), 6.80
(br s, 2H, NH2), 6.93 (dd, J ¼ 9.0, 3.0 Hz, 1H, Ph 60-H), 7.15 (d,
J ¼ 3.0 Hz,1H, Ph 20-H), 7.27 (d, J ¼ 8.4 Hz,1H, quinazoline 8-H), 7.44
(d, J ¼ 9.0 Hz, 1H, Ph 50-H), 7.65 (d, J ¼ 8.4 Hz, 1H, quinazoline 7-H),
7.97 (br s, 2H, NH2), 8.13 (s, 1H, quinazoline 5-H). ESI-MS m/z: 479
[M þ H]þ. ESI-HRMS m/z: calcd for C20H21Cl2N6S2 ([M þ H]þ):
479.0646, found: 479.0638.
DMSO-d6) d: 3.15 (br s, 4H, piperazine-H), 4.02 (br s, 2H, piperazine-
H), 4.32 (br s, 2H, piperazine-H), 4.57 (s, 2H, CH2S), 6.65 (br s, 2H,
NH2), 7.15 (t, J ¼ 7.8 Hz, 1H, Ph 40-H), 7.23 (d, J ¼ 8.4 Hz, 1H, quina-
zoline 8-H), 7.33 (m, 2H, NH2), 7.59 (t, J ¼ 7.8 Hz, 1H, Ph 50-H), 7.71 (d,
J ¼ 8.4 Hz, 1H, quinazoline 7-H), 7.84 (d, J ¼ 7.8 Hz, 1H, Ph 60-H), 7.89
(d, J ¼ 7.8 Hz, 1H, Ph 30-H), 8.18 (s, 1H, quinazoline 5-H). ESI-MS m/z:
456 [M þ H]þ. ESI-HRMS m/z: calcd for C20H22N7O2S2 ([M þ H]þ):
456.1276, found: 456.1272.
6.1.7.13. (2,4-Diaminoquinazolin-6-yl)methyl
4-(4-fluorophenyl)
piperazine-1-carbodithioate (8m). Yield 87%, white solid, mp 249.0e
349.8 ꢀC (CC, eluent:dichloromethane/methanol ¼ 80:20). 1H NMR
6.1.7.19. (2,4-Diaminoquinazolin-6-yl)methyl 4-(4-(trifluoromethyl)
phenyl)piperazine-1-carbodithioate (8s). Yield 43%, mp 263.0e
264.0 ꢀC (CC, eluent:dichloromethane/methanol ¼ 90:10). 1H NMR
(200 MHz, DMSO-d6) d: 3.21 (br s, 4H, piperazine-H), 4.06 (br s, 2H,
piperazine-H), 4.37 (br s, 2H, piperazine-H), 4.58 (s, 2H, CH2S),
6.94e7.13 (m, 4H, Ph-H), 7.32 (d, J ¼ 8.4 Hz, 1H, quinazoline 8-H),
7.72 (d, J ¼ 8.4 Hz,1H, quinazoline 7-H), 8.16 (s,1H, quinazoline 5-H).
ESI-MS m/z: 429 [M þ H]þ. Anal. calcd. for C20H21FN6S2$1/2H2O: C,
54.90; H, 5.07; N, 19.21. Found: C, 54.90; H, 5.03; N, 18.95.
(600 MHz, DMSO-d6) d: 3.47 (br s, 4H, piperazine-H), 4.04 (br s, 2H,
piperazine-H), 4.36 (br s, 2H, piperazine-H), 4.56 (s, 2H, CH2S), 7.01
(d, J ¼ 8.4 Hz, 2H, Ph 20 and 60-H), 7.11 (m, 2H, NH2), 7.29 (d,
J ¼ 8.4 Hz, 1H, quinazoline 8-H), 7.51 (d, J ¼ 8.4 Hz, 2H, Ph 30 and