Heteroaryl compounds, compositions thereof, and use thereof as protein kinase inhibitors
A kind of compound, the technology of heteroaryl, be used in heteroaryl compound, its composition and its use field as protein kinase inhibitor
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Embodiment 2
[0281] 5.1.2 Example 2: Synthesis of 2-(4-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide
[0282]A. (Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-methoxyphenyl)urea. In a round bottom flask, 2,3-diaminomalenitrile (3.41 g, 31.62 mmol) was dissolved in acetonitrile (60 mL) and stirred at room temperature. 2-Methoxyphenylisocyanate (5.0 g, 33.5 mmol) was added and the solution was stirred at room temperature for 16 hours. The resulting urea product was collected by filtration, washed with a small portion of acetonitrile and then with diethyl ether. The filtrate was dried under high vacuum at 60°C overnight to give the title compound (4.10 g, 51%). MS(ESI)m / z258.0[M+1] + .
[0283] B. 2-(4-Hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide. (Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-methoxyphenyl)urea (0.200g, 0.778mmol) was dissolved in methanol (15ml) in Stir at room temperature until homogeneous. Triethylamine (0.15 mL) and 4-h...
Embodiment 3
[0284] 5.1.3 Example 3: Synthesis of 2-(3-hydroxyphenyl)-8-oxo-9-o-tolyl-8,9-dihydro-7H-purine-6-carboxamide
[0285] A. (Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-methoxyphenyl)urea. Diaminomalenitrile (600 mg, 5.55 mmol) and o-tolyl isocyanate (0.729 mL, 5.88 mmol) were reacted in acetonitrile according to General Procedure A to afford the title compound (604.8 mg, 42%). MS(ESI)m / z242.2[M+1] + .
[0286] B. 2-(3-Hydroxyphenyl)-8-oxo-9-o-tolyl-8,9-dihydro-7H-purine-6-carboxamide. (Z)-1-(2-amino-1,2-dicyanovinyl)-3-(2-methoxyphenyl)urea (0.2g, 0.83mmol), 3-hydroxybenzaldehyde (0.221g , 1.81 mmol) and triethylamine (0.1 mL) were reacted according to general procedure B. The resulting precipitate was dissolved in DMF and water was added to induce precipitation. The precipitate was filtered off and dried in vacuo to afford the title compound in 95% purity (0.188 g, 63%). 1 H NMR (400MHz, DMSO-d 6 )δ11.79(s, 1H), 9.47(s, 1H), 8.40(s, 1H), 7.98(s, 1H), 7.89(d, J=8.00, 1H), 7.67(s...
Embodiment 7
[0294] 5.1.7 Example 7: Synthesis of 2-(2-hydroxypyridin-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6 -Formamide
[0295] A. 2-(2-Hydroxypyridin-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide. (Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-methoxyphenyl)urea (see Example 2.A) (0.2 g, 0.78 mmol), 2-Hydroxypyridine-3-carbaldehyde (0.209 g, 1.7 mmol) and triethylamine (0.1 mL) were reacted according to General Procedure B. The resulting precipitate was dissolved in DMF and water was added to induce precipitation. The precipitate was filtered off and dried in vacuo to afford the title compound in 97.6% purity (0.2 g, 68%). 1 H NMR (400MHz, DMSO-d 6 )δ11.91(s, 1H), 11.64(s, 1H), 8.57(s, 1H), 7.98(s, 1H), 7.55(t, J=7.9, 1H), 7.49(d, J=7.8, 1H), 7.40(d, J=6.4, 1H), 7.29(m, 2H), 7.14(m, 2H), 3.74(s, 3H); MS(ESI) m / z 379.4[M+1] + ; mp 360-362°C.
[0296] 5.1.8 Example 8: Synthesis of 9-(2-chlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carb...
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