E. Casale et al. / Bioorg. Med. Chem. 22 (2014) 4135–4150
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5.1.37. 5-Benzo[1,3]dioxol-5-ylmethyl-N-8-(2-dimethylamino-
ethyl)-[1,2,4]triazolo[1,5-c]quinazoline-2,8-diamine 12d
Yield 33% as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d
7.86 (d, J = 8.8 Hz, 1H), 7.03 (dd, J = 8.8, 2.3 Hz, 1H), 6.98 (s, 1H),
6.84 (d, J = 1.0 Hz, 2H), 6.77 (d, J = 2.1 Hz, 1H), 6.37 (t, J = 5.2 Hz,
1H), 6.23 (s, 2H), 5.97 (s, 2H), 4.32 (s, 2H), 3.25 (q J = 4.9 Hz, 2H),
2.57 (t, J = 4.9 Hz, 2H), 2.28 (s, 6H). LCMS: m/z 406 [M+H]+ at rt
3.79 min; HRMS (ESI) calcd for C21H24N7O2 [M+H]+ 406.1986 found
406.1992.
2H), 6.54 (s, 2H), 5.98 (s, 2H), 4.45 (s, 2H), 4.47 (m, 1H), 3.49 (m,
2H), 3.36 (m, 2H), 1.71 (m, 2H). LCMS: m/z 421 [M+H]+ at rt
4.4 min; HRMS (ESI) calcd for C21H21N6O4 [M+H]+ 421.1619 found
421.1613.
5.1.43. 2-{[2-Amino-5-(1,3-benzodioxol-5-
ylmethyl)[1,2,4]triazolo[1,5-c]quinazolin-10-yl]amino}ethanol
14
To 5-benzo[1,3]dioxol-5-ylmethyl-10-fluoro-[1,2,4]triazolo[1,5-
c]quinazolin-2-ylamine 7o (0.05 g, 0.15 mmol), 2-aminoethanol
(0.7 mL) was added and the mixture was heated at 140 °C for 2–8 h.
The reaction was cooled at room temperature, the solid precipitated
was filtered and washed with a mixture MeOH/H2O 9:1, to provide
the desired compounds. Yield 60% as a off-white solid. 1H NMR
(400 MHz, DMSO-d6) d 7.74 (t, J = 5.7 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H),
6.99 (dd, J = 8.2, 0.6 Hz, 1H), 6.97 (t, J = 1.0 Hz, 1H), 6.82 (d,
J = 1.0 Hz, 2H), 6.73 (d, J = 8.2 Hz, 1H), 6.43 (s, 2H), 5.96 (s, 2H), 4.82
(t, J = 5.6 Hz, 1H), 4.37 (s, 2H), 3.66 (q, J = 5.6 Hz, 2H), 3.40 (q,
J = 5.9 Hz,2H). LCMS:m/z379[M+H]+ atrt5.36 min;HRMS(ESI)calcd
for C19H19N6O2 [M+H]+ 379.1513 found 379.1529.
5.1.38. 5-Benzo[1,3]dioxol-5-ylmethyl-N-8-(2-pyrrolidin-1-yl-
ethyl)-[1,2,4]triazolo[1,5-c]quinazoline-2,8-diamine 12e
Yield 30% as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d
7.86 (d, J = 8.7 Hz, 1H), 7.02 (dd, J = 8.8, 2.3 Hz, 1H), 6.98 (s, 1H),
6.84 (d, J = 1.1 Hz, 2H), 6.77 (d, J = 2.0 Hz, 1H), 6.45 (t, J = 5.5 Hz,
1H), 6.23 (s, 2H), 5.97 (s, 2H), 4.32 (s, 2H), 3.25–3.29 (m, 2H),
2.55–2.70 (br m, 6H) 1.74 (br s, 4H). LCMS: m/z 432 [M+H]+ at rt
3.91 min; HRMS (ESI) calcd for C23H26N7O2 [M+H]+ 432.2143 found
432.2151.
5.1.39. 5-Benzo[1,3]dioxol-5-ylmethyl-8-(4-methyl-piperazin-
1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine 12f
5.1.44. 5-(1,3-Benzodioxol-5-ylmethyl)-10-fluoro-8-(4-
Yield 50% as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d
7.98 (d, J = 9.0 Hz, 1H), 7.39 (dd, J = 9.0, 2.4 Hz, 1H), 7.13 (d,
J = 2.4 Hz, 1H), 6.98 (t, J = 1.0 Hz, 1H), 6.83 (d, J = 1.0 Hz, 2H), 6.30
(s, 2H), 5.96 (s, 2H), 4.35 (s, 2H), 3.35 (m, 4H), 2.46 (m, 4H), 2.23
(s, 3H). LCMS: m/z 418 [M+H]+ at rt 3.98 min; HRMS (ESI) calcd
for C22H24N7O2 [M+H]+ 418.1986 found 418.1987.
methylpiperazin-1-yl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine.
17
To a 0–5 °C cooled suspension of 5p (0.50 g, 1.49 mmol) in
dichloromethane (20 mL) was added 2 M (trimethylsilyl)diazo-
methane diethyl ether solution (0.82 mL, 1.64 mmol). The mixture
was stirred at room temperature for 1 h, then the solvent was evap-
orated, to provide the desired methyl ester (0.52 g, 98% yield). 1H
NMR (400 MHz, DMSO-d6) d 10.28 (s, 1H), 7.54 (ddd, J = 11.0, 2.4,
1.6 Hz, 1H), 7.15 (ddd, J = 11.1, 8.8, 2.6 Hz, 1H), 6.85–6.93 (m, 2H),
6.68–6.82 (m, 1H), 5.99 (s, 2H), 3.72 (s, 3H), 3.60 (s, 2H). To a
solution of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-4,6-difluoro-
benzoic acid methyl ester (0.50 g, 1.43 mmol) in dimethylsulfoxide
(8 mL) was added N-methylpiperazine (0.20 mL, 2.86 mmol). The
reaction was stirred at 80 °C for 3 h then cooled at room tempera-
ture. The precipitated solid was filtered and washed with a mixture
H2O/EtOH 1:1, to provide 15 (0.15 g, 25% yield). 1H NMR (400 MHz,
DMSO-d6) d 10.52 (s, 1H), 7.58 (d, J = 2.3 Hz, 1H), 6.89 (d, J = 1.6 Hz,
1H), 6.87 (d, J = 7.9 Hz, 1H), 6.78 (dd, J = 7.9, 1.7 Hz, 1H), 6.56
(dd, J = 15.5, 2.4 Hz, 1H), 5.99 (s, 2H), 3.71 (s, 3H), 3.60 (s, 2H),
3.28 (m, 4H), 2.41 (br s, 4H), 2.22 (s, 3H). To a suspension of 2-(2-
benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-
1-yl)-benzoic acid methyl ester 15 (0.15 g, 0.35 mmol) in a mixture
of tetrahydrofuran (10 mL), methanol (1 mL) and water (2 mL), was
added lithium hydroxide (0.15 g, 3.49 mmol). The reaction was stir-
red at room temperature overnight then the solvent was evapo-
rated. The residue was diluted with water and 2 N HCl solution
was added until pH 7. The solid precipitated was filtered and
washed with water to obtain crude 2-(2-benzo[1,3]dioxol-5-yl-ace-
tylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid. The
acid was suspended in acetic anhydride (3 mL) and the reaction
mixture was heated under microwave condition at 130 °C for
10 min. The solvent was evaporated to obtain the 2-benzo[1,3]diox-
ol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]
oxazin-4-one 16 as crude that was dissolved in dry pyridine (3 mL)
then, aminoguanidine hydrogencarbonate (0.05 g, 0.39 mmol) was
added and the resulting mixture was heated under microwave
condition at 180 °C for 15 min. The reaction was cooled at room
temperature and diluted with water to induce the precipitation of
a brown solid, which was washed with a mixture MeOH/H2O 8:2,
to afford the title compound (0.07 g, 46% yield). 1H NMR
(400 MHz, DMSO-d6) d 9.69 (br s, 1H), 7.33 (dd, J = 13.7, 2.2 Hz,
1H), 7.12 (d, J = 2.2 Hz, 1H), 6.97 (m, 1H), 6.81–6.86 (m, 2H), 6.45
(br s, 2H), 5.97 (s, 2H), 4.37 (s, 2H), 4.17 (m, 2H), 3.51 (m, 2H),
3.05–3.23 (m, 4H), 2.86 (s, 3H). LCMS: m/z 436 [M+H]+ at rt
5.1.40. 5-Benzo[1,3]dioxol-5-ylmethyl-N-8-(2-methoxy-ethyl)-
[1,2,4]triazolo[1,5-c]quinazoline-2,8-diamine 12g
Yield 37% as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d
7.85 (d, J = 8.9 Hz, 1H), 7.03 (dd, J = 8.8, 2.3 Hz, 1H), 6.98 (s, 1H),
6.84 (d, J = 1.1 Hz, 2H), 6.77 (d, J = 2.2 Hz, 1H), 6.55 (br s, 1H), 6.23
(br s, 2H), 5.97 (s, 2H), 4.32 (s, 2H), 3.55 (t, J = 5.5 Hz, 2H), 3.33
(m, 2H), 3.30 (s, 3H). LCMS: m/z 393 [M+H]+ at rt 5.2 min; HRMS
(ESI) calcd for C20H21N6O3 [M+H]+ 418.1986 found 418.1987.
5.1.41. 2-Amino-5-(1,3-benzodioxol-5-ylmethyl)-N-(2-
hydroxyethyl)[1,2,4]triazolo[1,5-c]quinazoline-8-carboxamide
13a
To a solution of 7v (0.05 g, 0.14 mmol), and 2-aminoethanol
(0.017 mL, 0.28 mmol) in anhydrous dichloromethane (5 mL),
TBTU (0.05 g, 0.17 mmol) was added. The reaction was stirred at
room temperature for 30 min, then 2-aminoethanol (0.02 mL,
0.28 mmol) was added. After stirring for 1 h, the solution was
washed with NaHCO3 saturated solution, then with water and
brine. The organic phase was dried over Na2SO4 and evaporated
to give a crude that was purified by flash column chromatography
on silica gel eluting with DCM/EtOH/NH4OH 8:1.9:0.1, to provide
the title compound (22 mg, 40% yield). 1H NMR (400 MHz,
DMSO-d6) d 8.74 (t, J = 5.6 Hz, 1H), 8.36 (d, J = 1.4 Hz, 1H), 8.26
(d, J = 8.3 Hz, 1H), 8.16 (br s, 1H), 8.07 (dd, J = 8.3, 1.4 Hz, 1H),
7.01 (d, J = 1.0 Hz, 1H), 6.82–6.92 (m, 2H), 6.54 (s, 2H), 5.98 (s,
2H), 4.73 (t, J = 5.7 Hz, 1H), 4.45 (s, 2H), 3.54 (q, J = 6.1 Hz, 2H),
3.34–3.42 (m, 1H), 1.26 (d, 1H). LCMS: m/z 407 [M+H]+ at rt
4.29 min; HRMS (ESI) calcd for C20H19N6O4 [M+H]+ 407.1463 found
407.146. The following compound 13b was prepared according to
the method described above.
5.1.42. 2-Amino-5-(1,3-benzodioxol-5-ylmethyl)-N-(3-
hydroxypropyl)[1,2,4]triazolo[1,5-c]quinazoline-8-
carboxamide 13b
Yield 30% as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d
8.74 (t, J = 5.4 Hz, 1H), 8.34 (d, J = 1.2 Hz, 1H), 8.26 (d, J = 8.4 Hz,
1H), 8.07 (dd, J = 8.4, 1.6 Hz, 1H), 7.01 (d, J = 1.0 Hz, 1H), 6.86 (m,