tert-butyl 4-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate | 1620576-74-0

• 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: tert-butyl 4-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate
• 英文别名: tert-butyl 4-(5-bromo-1-methyl-1,2,4-triazol-3-yl)piperidine-1-carboxylate
• CAS: 1620576-74-0
• 化学式: C₁₃H₂₁BrN₄O₂
• 分子量: 345.239
• InChiKey: KWHXQNGQCGCYTC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  60.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate 、 在 4-甲基-2-戊醇 、 bis-triphenylphosphine-palladium(II) chloride 、 lithium chloride 作用下， 反应 5.0h， 以91%的产率得到tert-butyl 4-(5-(5-amino-6-(benzotriazol-1-yl)pyrazin-2-yl)-1-methyl-1,2,4-triazol-3-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  Design of selective PI3Kα inhibitors starting from a promiscuous pan kinase scaffold

  摘要：

  Starting from compound 1, a potent PI3K alpha inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3K alpha and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Ka, with excellent kinase selectivity. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.04.084
• 作为产物：
  描述：

  tert-butyl 4-(5-bromo-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate 、 三甲基硅烷化重氮甲烷 以 甲醇 、 正己烷 、 甲苯 为溶剂， 反应 1.0h， 以55.3%的产率得到tert-butyl 4-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  CHEMICAL COMPOUNDS

  摘要：

  这项发明涉及公式(I)的化合物或其药用盐，其中R1和R2具有在描述中定义的任何含义；它们的制备方法，含有它们的药物组合物以及它们在治疗细胞增殖性疾病中的用途。

  公开号：

  US20140206700A1

文献信息

• [EN] CHEMICAL COMPOUNDS<br/>[FR] COMPOSÉS CHIMIQUES
  申请人：ASTRAZENECA AB

  公开号：WO2014114928A1

  公开（公告）日：2014-07-31

  The invention concerns compounds of Formula (I) (Formula (I)) or pharmaceutically-acceptable salts thereof, wherein R1 and R2 have any of the meanings defined herein before in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.

  该发明涉及Formula (I)的化合物（Formula (I)）或其药用盐，其中R1和R2具有在描述中定义的任何含义；它们的制备方法，含有它们的药物组合物以及它们在治疗细胞增殖性疾病中的用途。
• Discovery of a novel aminopyrazine series as selective PI3Kα inhibitors
  作者：Bernard Barlaam、Sabina Cosulich、Martina Fitzek、Hervé Germain、Stephen Green、Lyndsey L. Hanson、Craig S. Harris、Urs Hancox、Kevin Hudson、Christine Lambert-van der Brempt、Maryannick Lamorlette、Françoise Magnien、Gilles Ouvry、Ken Page、Linette Ruston、Lara Ward、Bénédicte Delouvrié

  DOI：10.1016/j.bmcl.2017.05.028

  日期：2017.7

  We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kβ and excellent general kinase selectivity. This effort culminated with the identification of compound

  我们报告发现了一种新型的氨基吡嗪类PI3Kα抑制剂的发现，该抑制剂是通过杂交两个已知的PI3K抑制剂支架而设计的。我们描述了从第一个化合物受到普遍激酶选择性差困扰的进展，到显示对PI3Kα的选择性高于对PI3Kβ的化合物以及优异的一般激酶选择性的化合物。这项努力最终以鉴定具有高效力和选择性以及适合口服给药的理化和药代动力学特性的化合物5得以鉴定。在体内，化合物5在小鼠的MCF7异种移植模型中显示出对肿瘤生长的良好抑制作用（每天两次口服50 mg / kg，对肿瘤生长的抑制率为86％）。
• Chemical compounds
  申请人：ASTRAZENECA AB

  公开号：US09156831B2

  公开（公告）日：2015-10-13

  The invention concerns compounds of Formula (I) or pharmaceutically-acceptable salts thereof, wherein R1 and R2 have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.

  本发明涉及式（I）的化合物或其药学上可接受的盐，其中R1和R2具有上述描述中定义的任何含义；其制备方法，含有它们的制药组合物以及它们在治疗细胞增殖性疾病中的应用。
• Chemical Compounds
  申请人：AstraZeneca AB

  公开号：US20160137634A1

  公开（公告）日：2016-05-19

  The invention concerns compounds of Formula (I) or pharmaceutically-acceptable salts thereof, wherein R 1 and R 2 have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.

  本发明涉及公式(I)的化合物或其药学上可接受的盐，其中R1和R2具有本说明书中定义的任何含义；它们的制备过程，包含它们的制药组合物以及它们在治疗细胞增殖性疾病方面的用途。
• Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers
  作者：Bernard Barlaam、Sabina Cosulich、Bénédicte Delouvrié、Rebecca Ellston、Martina Fitzek、Hervé Germain、Stephen Green、Urs Hancox、Craig S. Harris、Kevin Hudson、Christine Lambert-van der Brempt、Honorine Lebraud、Françoise Magnien、Maryannick Lamorlette、Antoine Le Griffon、Rémy Morgentin、Gilles Ouvry、Ken Page、Georges Pasquet、Urszula Polanska、Linette Ruston、Twana Saleh、Michel Vautier、Lara Ward

  DOI：10.1016/j.bmcl.2015.10.002

  日期：2015.11

  Starting from potent inhibitors of PI3K alpha having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3K alpha (wild type, E545K and H1047R mutations) and PI3K delta, selective versus PI3K beta and PI3K gamma, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3K alpha mutated SKOV-3 xenograft tumour model after chronic oral administration at 25 mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials. (C) 2015 Elsevier Ltd. All rights reserved.