Anthranilamide pyridinureas as vegf receptor kinase inhibitors
A kind of pyridine, alkyl technology, applied in the application field of medicine
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Embodiment 10
[0315] 2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzene Preparation of formamide
[0316]
[0317] 2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (110 mg, 0.25 mmol, prepared as detailed in Example 4A below) and 1,1-dimethylurea (114 mg, 1.3 mmol) were suspended in dioxane (3 mL) and washed successively with DMF (1 mL), cesium carbonate (98mg, 0.3mmol), Pd 2 dba 3 (5mg, 0.005mmol) and Xantphos (9mg, 0.015mmol) treatment. The reaction mixture was purged with nitrogen and heated at 110°C for 5 hours (bath temperature). On cooling the reaction was concentrated in vacuo. Make the residue in CH 2 Cl 2 and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. use The residue was purified by flash chromatography on silica gel (Separtis) (gradient elution: 100% CH 2 Cl 2 ~CH 2 Cl 2 / EtOH95:5) gave solid 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-...
Embodiment 20
[0325] 6-(2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole- Preparation of 3-carboxylate methyl ester
[0326]
[0327] 2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoic acid (112 mg, 0.35 mmol), 6-amino-2-methyl- 2H-Indazole-3-carboxylic acid methyl ester (62mg, 0.3mmol), N-methylmorpholine (0.09mL, 0.82mmol) and HATU (152mg, 0.4mmol) were suspended in anhydrous DMF (3mL), and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between dichloromethane. The organic phase was washed sequentially with saturated aqueous sodium bicarbonate, water, and brine, dried, and concentrated in vacuo. use The residue was purified by flash chromatography on silica gel (Separtis) (gradient elution: 100% CH 2 Cl 2 ~CH 2 Cl 2 / EtOH9:1) to give solid 6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methanol Base-2H-indazole-3-carboxylic ac...
Embodiment 30
[0333] N-(2,3-Dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino Preparation of}-benzamide
[0334]
[0335] To a stirred solution of 2,3-dimethyl-2H-indazol-6-ylamine (60 mg, 0.34 mmol) in DCE (1.5 mL) was added trimethylaluminum (2M in solution in toluene, 0.35 mL, 0.7 mmol), then 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoic acid methyl ester (111 mg, 0.34 mmol) in DCE (1.5 mL). The reaction was heated (bath temperature) at 100°C for 5 hours. Upon cooling, the reaction was poured into saturated aqueous sodium bicarbonate and diluted with dichloromethane. The mixture was stirred for 15 minutes, then passed through filter. The organic phase was washed with water and brine, dried and concentrated in vacuo. reuse The residue was purified by flash chromatography on silica gel (Separtis) (gradient elution: 100% CH 2 Cl 2 ~CH 2 Cl 2 / EtOH 95:5) gave solid N-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyrid...
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