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 | 1251931-64-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 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
• 英文别名: 7-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl]-2,4,4a,5-tetrahydroindeno[1,2-c]pyridazin-3-one
• CAS: 1251931-64-2
• 化学式: C₂₉H₂₈N₆O₂
• 分子量: 492.58
• InChiKey: QMNCJZJFNLUSIZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  95.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  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

文献信息

• Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds
  作者：Dan Niculescu-Duvaz、Ion Niculescu-Duvaz、Bart M.J.M. Suijkerbuijk、Delphine Ménard、Alfonso Zambon、Arnaud Nourry、Lawrence Davies、Helen A. Manne、Frank Friedlos、Lesley Ogilvie、Douglas Hedley、Andrew K. Takle、David M. Wilson、Jean-Francois Pons、Tom Coulter、Ruth Kirk、Neus Cantarino、Steven Whittaker、Richard Marais、Caroline J. Springer

  DOI：10.1016/j.bmc.2010.06.031

  日期：2010.9

  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.