(E)-tert-butyl 4-(4-(1-(methoxyimino)-2,3-dihydro-1H-inden-5-yl)-5-(pyridin-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate | 1251931-50-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: (E)-tert-butyl 4-(4-(1-(methoxyimino)-2,3-dihydro-1H-inden-5-yl)-5-(pyridin-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate
• CAS: 1251931-50-6
• 化学式: C₂₈H₃₃N₅O₃
• 分子量: 487.602
• InChiKey: VNWIGGFRGGOBHZ-AWSUPERCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.55
• 重原子数：
  36.0
• 可旋转键数：
  4.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  92.7
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  二碳酸二叔丁酯 、 (E)-tert-butyl 4-(4-(1-(methoxyimino)-2,3-dihydro-1H-inden-5-yl)-5-(pyridin-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate 在 盐酸 、 水 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 四氢呋喃 、 水 为溶剂， 以57%的产率得到tert-butyl 4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-5-(pyridin-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate
  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：

  1-(1-methoxyiminoindan-5-yl)-2-(pyridin-4-yl)-ethane-1,2-dione 、 1-叔丁氧羰基哌啶-4-甲醛 在 ammonium acetate 、 溶剂黄146 作用下， 以92%的产率得到(E)-tert-butyl 4-(4-(1-(methoxyimino)-2,3-dihydro-1H-inden-5-yl)-5-(pyridin-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate
  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

• Imidazole derivatives as raf kinase inhibitors
  申请人：——

  公开号：US20040038964A1

  公开（公告）日：2004-02-26

  Novel compounds (I) and their use as pharmaceuticals particularly as Raf kinase inhibitors for the treatment of neurotraumatic diseases, cancer, chronic neurodegeneration, pain, migraine and cardiac hypertrophy wherein Ar is a group of formula a) or b).

  小说化合物（I）及其作为药物的用途，特别是作为Raf激酶抑制剂用于治疗神经创伤性疾病，癌症，慢性神经退行性疾病，疼痛，偏头痛和心脏肥大，其中Ar是a）或b）公式的一组。
• IMIDAZOLE DERIVATIVES AS RAF KINASE INHIBITORS
  申请人：DEAN Kenneth David

  公开号：US20070135433A1

  公开（公告）日：2007-06-14

  Novel compounds and their use as pharmaceuticals particularly as Raf kinase inhibitors for the treatment of neurotraumatic diseases, cancer, chronic neurodegeneration, pain, migraine and cardiac hypertrophy.

  小说化合物及其作为药物的使用，特别是作为Raf激酶抑制剂，用于治疗神经创伤性疾病、癌症、慢性神经退化、疼痛、偏头痛和心脏肥大。
• US7199137B2
  申请人：——

  公开号：US7199137B2

  公开（公告）日：2007-04-03
• [EN] IMIDAZOLE DERIVATIVES AS RAF KINASE INHIBITORS<br/>[FR] DERIVES D'IMIDAZOLE EN TANT QU'INHIBITEURS DE LA RAF KINASE
  申请人：SMITHKLINE BEECHAM PLC

  公开号：WO2002024680A1

  公开（公告）日：2002-03-28

  Novel compounds (I) and their use as pharmaceuticals particularly as Raf kinase inhibitors for the treatment of neurotraumatic diseases, cancer, chronic neurodegeneration, pain, migraine and cardiac hypertrophy wherein Ar is a group of formula a) or b).
• 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.