N-cyclopropyl-4-(8-(propylamino)imidazo[1,2-a]pyrazin-3-yl)benzamide | 1263420-91-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-cyclopropyl-4-(8-(propylamino)imidazo[1,2-a]pyrazin-3-yl)benzamide
• 英文别名: N-cyclopropyl-4-[8-(propylamino)imidazo[1,2-a]pyrazin-3-yl]benzamide
• CAS: 1263420-91-2
• 化学式: C₁₉H₂₁N₅O
• 分子量: 335.409
• InChiKey: MBMZRMHNZZULBD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  71.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-甲氧甲酰苯硼酸频哪醇酯 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 sodium carbonate 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 22.0h， 生成 N-cyclopropyl-4-(8-(propylamino)imidazo[1,2-a]pyrazin-3-yl)benzamide
  参考文献：
  名称：

  Discovery of Imidazo[1,2-b]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity

  摘要：

  Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.

  DOI：

  10.1021/jm501599u