4-(6-(2-(3-fluorophenyl)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile | 1196547-03-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-(6-(2-(3-fluorophenyl)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile
• 英文别名: 4-[6-[2-(3-fluorophenyl)piperidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]benzonitrile
• CAS: 1196547-03-1
• 化学式: C₂₄H₂₀FN₅
• 分子量: 397.455
• InChiKey: WJSPZKYFHWWSDK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  57.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-溴-6-氯咪唑并[1,2-b]哒嗪 在 potassium fluoride 、 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 乙二醇二甲醚 、 二甲基亚砜 为溶剂， 反应 13.33h， 生成 4-(6-(2-(3-fluorophenyl)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile
  参考文献：
  名称：

  (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

  摘要：

  Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.

  DOI：

  10.1021/acsmedchemlett.5b00050

文献信息

• FUSED NITROGEN CONTAINING HETEROCYCLES AND COMPOSITIONS THEREOF AS KINASE INHIBITORS
  申请人：Albaugh Pamela A.

  公开号：US20110166133A1

  公开（公告）日：2011-07-07

  The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly Ros, KDR, FMS, C-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, IGF-IR, ALK4, ALK5 and ALK or combinations thereof.

  该发明提供了化合物、包含这些化合物的药物组成物以及使用这些化合物治疗或预防与异常或非规则激酶活性相关的疾病或障碍的方法，特别是Ros、KDR、FMS、C-FMS、FLT3、c-Kit、JAK2、JAK3、Aurora、PDGFR、Lck、TrkA、TrkB、TrkC、IGF-IR、ALK4、ALK5和ALK或它们的组合。
• FUSED NITROGEN CONTAINING HETEROCYCLES AND COMPOSITIONS THEREOF AS KINASE INHIBITORS
  申请人：Novartis AG

  公开号：EP2300469B1

  公开（公告）日：2015-06-24
• US8507488B2
  申请人：——

  公开号：US8507488B2

  公开（公告）日：2013-08-13
• [EN] COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS<br/>[FR] COMPOSÉS ET COMPOSITIONS SERVANT D'INHIBITEURS DE KINASES
  申请人：IRM LLC

  公开号：WO2009140128A2

  公开（公告）日：2009-11-19

  The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly Ros, KDR, FMS, c-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, IGF-1R, ALK4, ALK5 and ALK or combinations thereof.
• (<i>R</i>)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors
  作者：Ha-Soon Choi、Paul V. Rucker、Zhicheng Wang、Yi Fan、Pamela Albaugh、Greg Chopiuk、Francois Gessier、Fangxian Sun、Francisco Adrian、Guoxun Liu、Tami Hood、Nanxin Li、Yong Jia、Jianwei Che、Susan McCormack、Allen Li、Jie Li、Auzon Steffy、AnneMarie Culazzo、Celine Tompkins、Van Phung、Andreas Kreusch、Min Lu、Bin Hu、Apurva Chaudhary、Mahavir Prashad、Tove Tuntland、Bo Liu、Jennifer Harris、H. Martin Seidel、Jon Loren、Valentina Molteni

  DOI：10.1021/acsmedchemlett.5b00050

  日期：2015.5.14

  Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.