(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(6-chloropyrazin-2-yl)methanone | 1350821-30-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(6-chloropyrazin-2-yl)methanone
• CAS: 1350821-30-5
• 化学式: C₁₄H₁₃ClN₆O
• 分子量: 316.75
• InChiKey: XZGPTVZZMRIEIY-UHFFFAOYSA-N

物化性质

• 沸点：
  558.8±50.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.27
• 重原子数：
  22.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  99.58
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(6-chloropyrazin-2-yl)methanone 在 盐酸 、 水 、 N,N-二异丙基乙胺 、 cesium fluoride 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 生成 (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl){6-[(2R,3R)-2-(4-fluorophenyl)pyrrolidin-3-ylamino]pyrazin-2-yl}methanone formate
  参考文献：
  名称：

  Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1)

  摘要：

  Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3K alpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 K-i of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.

  DOI：

  10.1021/jm201019k
• 作为产物：
  描述：

  (6-chloropyrazin-2-yl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone 在 氨 、 caesium carbonate 作用下， 以 甲醇 、 异丁酰胺 为溶剂， 反应 40.0h， 生成 (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(6-chloropyrazin-2-yl)methanone
  参考文献：
  名称：

  Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1)

  摘要：

  Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3K alpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 K-i of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.

  DOI：

  10.1021/jm201019k