7-{2-[4-(2-dimethylaminoethoxy)-phenyl]-1-methoxymethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl}-2,4,4a,5-tetrahydroindeno[1,2-c]pyridazin-3-one | 1251931-58-4

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: 7-{2-[4-(2-dimethylaminoethoxy)-phenyl]-1-methoxymethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl}-2,4,4a,5-tetrahydroindeno[1,2-c]pyridazin-3-one
• CAS: 1251931-58-4
• 化学式: C₃₁H₃₂N₆O₃
• 分子量: 536.633
• InChiKey: VSDPOYUGLHARLB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.22
• 重原子数：
  40.0
• 可旋转键数：
  9.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  93.87
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  7-{2-[4-(2-dimethylaminoethoxy)-phenyl]-1-methoxymethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl}-2,4,4a,5-tetrahydroindeno[1,2-c]pyridazin-3-one 在 三氟乙酸 作用下， 以 苯甲醚 为溶剂， 反应 24.0h， 以47%的产率得到7-{2-[4-(2-dimethylaminoethoxy)-phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl}-2,4,4a,5-tetrahydroindeno[1,2-c]pyridazin-3-one
  参考文献：
  名称：

  Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

  摘要：

  V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin- 4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methylpiperazin- 1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.031
• 作为产物：
  描述：

  7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,4,4a,5-tetrahydroindeno[1,2-c]pyridazin-3-one 、 {2-[4-(4-bromo-1-methoxymethyl-5-pyridin-4-yl-1H-imidazol-2-yl)-phenoxy]-ethyl}-dimethyl-amine 在 palladium diacetate 、 potassium carbonate 、 三苯基膦 作用下， 以 乙二醇二甲醚 、 水 为溶剂， 以63%的产率得到7-{2-[4-(2-dimethylaminoethoxy)-phenyl]-1-methoxymethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl}-2,4,4a,5-tetrahydroindeno[1,2-c]pyridazin-3-one
  参考文献：
  名称：

  Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

  摘要：

  V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin- 4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methylpiperazin- 1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.031