4-(6-bromo-8-((tetrahydro-2H-pyran-4-yl)methylamino)-imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropylbenzamide | 1263422-34-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(6-bromo-8-((tetrahydro-2H-pyran-4-yl)methylamino)-imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropylbenzamide
• CAS: 1263422-34-9
• 化学式: C₂₂H₂₄BrN₅O₂
• 分子量: 470.369
• InChiKey: JWQXVNZZTZYAOS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.89
• 重原子数：
  30.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  80.55
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  4-(6-bromo-8-((tetrahydro-2H-pyran-4-yl)methylamino)-imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropylbenzamide 、 4-氰基苯硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 作用下， 以 水 为溶剂， 反应 0.17h， 以54%的产率得到4-(6-(4-cyanophenyl)-8-((tetrahydro-2H-pyran-4-yl)methylamino)imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropylbenzamide
  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
• 作为产物：
  描述：

  6,8-dibromo-3-iodoimidazo[1,2-a]pyrazine 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 N,N-二甲基乙酰胺 、 水 为溶剂， 反应 0.66h， 生成 4-(6-bromo-8-((tetrahydro-2H-pyran-4-yl)methylamino)-imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropylbenzamide
  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