1-(difluoromethyl)-4-ethynyl-1H-pyrazole | 1400287-71-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(difluoromethyl)-4-ethynyl-1H-pyrazole
• 英文别名: 1-(Difluoromethyl)-4-ethynyl-1H-pyrazole；1-(difluoromethyl)-4-ethynylpyrazole
• CAS: 1400287-71-9
• 化学式: C₆H₄F₂N₂
• 分子量: 142.108
• InChiKey: YBGLDCDLIRGZOE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  10
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  17.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(difluoromethyl)-4-ethynyl-1H-pyrazole 在 4-二甲氨基吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 水 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.25h， 生成 tert-butyl 6-bromo-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate
  参考文献：
  名称：

  [EN] PYRROLOPYRIDINEAMINO DERIVATIVES AS MPS1 INHIBITORS
  [FR] DÉRIVÉS PYRROLOPYRIDINEAMINO EN TANT QU'INHIBITEURS DE MPS1

  摘要：

  本发明涉及使用特定的吡咯吡啶氨基衍生物（以下简称为“PPA衍生物”），特别是1H-吡咯[3,2-c]吡啶-6-氨基衍生物，直接或间接地通过与Mps激酶本身的相互作用来抑制单丝粒体1（Mps1 - 也称为TTK）激酶的纺锤体检查点功能。具体而言，本发明涉及将PPA衍生物用作治疗和/或预防增生性疾病，如癌症的治疗剂。本发明还涉及制备PPA衍生物的方法，以及包含它们的药物组合物。公式（I）

  公开号：

  WO2012123745A1
• 作为产物：
  描述：

  1-(difluoromethyl)-4-((trimethylsilyl)ethynyl)-1H-pyrazole 在 甲醇 、 potassium carbonate 作用下， 反应 0.83h， 以72%的产率得到1-(difluoromethyl)-4-ethynyl-1H-pyrazole
  参考文献：
  名称：

  [EN] PYRROLOPYRIDINEAMINO DERIVATIVES AS MPS1 INHIBITORS
  [FR] DÉRIVÉS PYRROLOPYRIDINEAMINO EN TANT QU'INHIBITEURS DE MPS1

  摘要：

  本发明涉及使用特定的吡咯吡啶氨基衍生物（以下简称为“PPA衍生物”），特别是1H-吡咯[3,2-c]吡啶-6-氨基衍生物，直接或间接地通过与Mps激酶本身的相互作用来抑制单丝粒体1（Mps1 - 也称为TTK）激酶的纺锤体检查点功能。具体而言，本发明涉及将PPA衍生物用作治疗和/或预防增生性疾病，如癌症的治疗剂。本发明还涉及制备PPA衍生物的方法，以及包含它们的药物组合物。公式（I）

  公开号：

  WO2012123745A1

文献信息

• PYRROLOPYRIDINEAMINO DERIVATIVES AS MPS1 INHIBITORS
  申请人：Bavetsias Vassilios

  公开号：US20130345181A1

  公开（公告）日：2013-12-26

  The present invention relates to the use of certain pyrrolopyridineamino derivatives (hereinafter referred to as “PPA derivatives”), particularly 1H-pyrrolo[3,2-c]pyridine-6-amino derivatives, to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps kinase itself. In particular, the present invention relates to PPA derivatives for use as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of the PPA derivatives, and pharmaceutical compositions comprising them. Formula (I)

  本发明涉及使用特定的吡咯吡啶氨基衍生物（以下简称为“PPA衍生物”），特别是1H-吡咯[3,2-c]吡啶-6-氨基衍生物，直接或间接地通过与Mps激酶本身的相互作用来抑制单丝粒体1（Mps1，也称为TTK）激酶的纺锤体检查点功能。具体而言，本发明涉及将PPA衍生物用作治疗和/或预防增生性疾病，如癌症的治疗剂。本发明还涉及制备PPA衍生物的方法，以及包含它们的药物组合物。公式（I）
• Pyrrolopyridineamino derivatives as MPS1 inhibitors
  申请人：Bavetsias Vassilios

  公开号：US09371319B2

  公开（公告）日：2016-06-21

  The present invention relates to the use of certain pyrrolopyridineamino derivatives (hereinafter referred to as “PPA derivatives”), particularly 1H-pyrrolo[3,2-c]pyridine-6-amino derivatives, to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps kinase itself. In particular, the present invention relates to PPA derivatives for use as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of the PPA derivatives, and pharmaceutical compositions comprising them. Formula (I)

  本发明涉及使用某些吡咯吡啶氨基衍生物（以下简称“PPA衍生物”），尤其是1H-吡咯[3,2-c]吡啶-6-氨基衍生物，直接或间接地通过与Mps激酶本身的相互作用来抑制单纺锤体1（Mps1 - 也称为TTK）激酶的纺锤体检查点功能。特别地，本发明涉及使用PPA衍生物作为治疗和/或预防增生性疾病（如癌症）的治疗剂。本发明还涉及制备PPA衍生物的方法以及包含它们的药物组合物。式（I）
• Structure-Based Design of Orally Bioavailable 1<i>H</i>-Pyrrolo[3,2-<i>c</i>]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
  作者：Sébastien Naud、Isaac M. Westwood、Amir Faisal、Peter Sheldrake、Vassilios Bavetsias、Butrus Atrash、Kwai-Ming J. Cheung、Manjuan Liu、Angela Hayes、Jessica Schmitt、Amy Wood、Vanessa Choi、Kathy Boxall、Grace Mak、Mark Gurden、Melanie Valenti、Alexis de Haven Brandon、Alan Henley、Ross Baker、Craig McAndrew、Berry Matijssen、Rosemary Burke、Swen Hoelder、Suzanne A. Eccles、Florence I. Raynaud、Spiros Linardopoulos、Rob L. M. van Montfort、Julian Blagg

  DOI：10.1021/jm401395s

  日期：2013.12.27

  The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly over-expressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.
• Orally bioavailable Syk inhibitors with activity in a rat PK/PD model
  作者：Gebhard Thoma、Siem Veenstra、Ross Strang、Joachim Blanz、Eric Vangrevelinghe、Jörg Berghausen、Christian C. Lee、Hans-Günter Zerwes

  DOI：10.1016/j.bmcl.2015.08.037

  日期：2015.10

  Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued. (C) 2015 Elsevier Ltd. All rights reserved.