(S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide | 1052709-81-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide
• 英文别名: 6-(2,6-difluorophenyl)-5-fluoro-pyridine-2-carboxylic acid ((S)-3-amino-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-3'-yl)-amide；N-[4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide
• CAS: 1052709-81-5
• 化学式: C₂₂H₂₀F₃N₅O
• 分子量: 427.429
• InChiKey: VQHMANLEKXLTRQ-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  84.1
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 生成 (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide
  参考文献：
  名称：

  Identification of N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies

  摘要：

  Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.

  DOI：

  10.1021/acs.jmedchem.5b01275

文献信息

• PIM KINASE INHIBITORS AND METHODS OF THEIR USE
  申请人：Burger Matthew

  公开号：US20120208815A1

  公开（公告）日：2012-08-16

  New compounds, compositions and methods of inhibition of kinase activity associated with tumorigenesis in a human or animal subject are provided. In certain embodiments, the compounds and compositions are effective to inhibit the activity of at least one serine/threonine kinase or receptor tyrosine kinase. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a serine/threonine kinase- or receptor tyrosine kinase-mediated disorder, such as cancer.

  提供了一种用于抑制人或动物主体中与肿瘤发生相关的激酶活性的新化合物、组合物和方法。在某些实施例中，这些化合物和组合物能够有效地抑制至少一种丝氨酸/苏氨酸激酶或受体酪氨酸激酶的活性。这些新的化合物和组合物可以单独使用或与至少一种额外的药物联合使用，用于治疗丝氨酸/苏氨酸激酶或受体酪氨酸激酶介导的疾病，如癌症。
• US8822497B2
  申请人：——

  公开号：US8822497B2

  公开（公告）日：2014-09-02
• Identification of <i>N</i>-(4-((1<i>R</i>,3<i>S</i>,5<i>S</i>)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies
  作者：Matthew T. Burger、Gisele Nishiguchi、Wooseok Han、Jiong Lan、Robert Simmons、Gordana Atallah、Yu Ding、Victoriano Tamez、Yanchen Zhang、Michelle Mathur、Kristine Muller、Cornelia Bellamacina、Mika K. Lindvall、Richard Zang、Kay Huh、Paul Feucht、Tatiana Zavorotinskaya、Yumin Dai、Steve Basham、Julie Chan、Elaine Ginn、Alex Aycinena、Jocelyn Holash、Joseph Castillo、John L. Langowski、Yingyun Wang、Min Y. Chen、Amy Lambert、Christine Fritsch、Audry Kauffmann、Estelle Pfister、K. Gary Vanasse、Pablo D. Garcia

  DOI：10.1021/acs.jmedchem.5b01275

  日期：2015.11.12

  Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.