Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
a technology of kinase inhibitors and proliferative diseases, applied in the field of kinase inhibitors and modulator compounds, can solve the problems of molecularly targeted small therapies that target c-kit mutations that remain elusiv
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example a1
[0137]A suspension of 3-fluoro-4-aminophenol (8.0 g, 63.0 mmol) in dimethylacetamide (80 mL) was de-gassed in vacuo and treated with potassium tert-butoxide (7.3 g, 65 mmol). The resultant mixture was stirred at RT for 30 min. 2,4-Dichloropyridine (8 g, 54 mmol) was added and the mixture was heated to 80° C. for 12 h. The solvent was removed under reduced pressure to give a residue which was partitioned between water and EtOAc (3×100 mL). The organic layers were washed with saturated brine, dried (MgSO4), concentrated in vacuo and purified by silica gel column chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-phenylamine (11 g, 86% yield). 1H NMR (300 MHz, DMSO-d6), δ 8.24 (d, J=5.7 Hz, 1 H), 7.00 (dd, J=9.0, 2.7 Hz, 1 H), 6.89-6.73 (m, 4 H), 5.21 (br s, 2 H); MS (ESI) m / z: 239.2 (M+H+).
[0138]To a degassed solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (0.801 g, 3.36 mmol) in DMF (2 mL) and TEA (2 mL) was added ethynyltrimethylsilane (0.929 ml, 6.71 mmol), tr...
example a2
[0141]To a solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine from Example A1 (1.0 g, 4.2 mmol) in NMP (10 ml) was added DBU (0.94 mL, 6.3 mmol) and 1,2,4-triazol sodium salt (0.57 g, 6.3 mmol) and the mixture was heated overnight under argon atmosphere at 160° C. The reaction mixture cooled to RT, diluted with water (100 mL) and the solution was extracted with EtOAc (3×). The organics were combined and washed with LiCl solution and brine (2×), dried (Na2SO4) and concentrated in vacuo. The residue was slurried in EtOAc (5 mL), the solid was filtered and washed with EtOAc to obtain a mixture of product and SM. The filtrate was concentrated in vacuo, the residue was slurried in CH2Cl2, filtered and washed with CH2Cl2 to obtain 4-(2-(1H-1,2,4-triazol-1-yl)pyridin-4-yloxy)-2-fluorobenzenamine (0.35 g). MS (ESI) m / z: 272.2 (M+H+).
example a3
[0142]4-(2-Chloropyridin-4-yloxy)-2-fluorobenzenamine from Example A1 (150 mg, 0.629 mmol), 2-(tri-n-butylstannyl)oxazole (0.132 ml, 0.629 mmol) and PdCl2(dppf)-CH2Cl2 (51.3 mg, 0.063 mmol) were combined in DMF (3 ml) under Ar and stirred with heating at 90° C. After 3 h, the completed reaction was cooled to RT and treated with satd. aq. KF (5 ml; prepared from equal portions of KF.H2O and H2O) and stirred at RT for 1 h. The suspension was diluted with EtOAc and filtered through Celite®, rinsing forward with EtOAc. The filtrate was diluted with H2O and the layers were separated. The aqueous was extracted with EtOAc (2×). The combined organics were washed with brine (2×), dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (EtOAc / hexanes) to afford 80 mg of 2-fluoro-4-(2-(oxazol-2-yl)pyridin-4-yloxy)benzenamine (0.295 mmol, 47% yield) as an oil that solidified on standing. 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J=5.8 Hz, 1H), 8.26 (s, 1H), 7.40 (d, J=2.3 H...
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