N-{3-[(2-amino-3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide | 1365647-50-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-{3-[(2-amino-3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide
• 英文别名: N-[3-(2-amino-3-tert-butylimidazo[4,5-b]pyridin-5-yl)oxyphenyl]-3-(2-cyanopropan-2-yl)benzamide
• CAS: 1365647-50-2
• 化学式: C₂₇H₂₈N₆O₂
• 分子量: 468.558
• InChiKey: YOPRQHYBWPEGGF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-{3-[(2-amino-3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide 在 吡啶 、 4-二甲氨基吡啶 、 三氟乙酸 作用下， 反应 20.0h， 生成 3-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]-3H-imidazo[4,5-b]pyridin-5-yl}oxy)phenyl]benzamide
  参考文献：
  名称：

  Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

  摘要：

  To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.

  DOI：

  10.1021/jm300126x
• 作为产物：
  描述：

  3-(2-氰基丙烷-2-基)苯甲酸甲酯 在 草酰氯 、 lithium hydroxide monohydrate 、 palladium 10% on activated carbon 、 水 、 氢气 、 碳酸氢钠 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 57.5h， 生成 N-{3-[(2-amino-3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide
  参考文献：
  名称：

  Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

  摘要：

  To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.

  DOI：

  10.1021/jm300126x