(S)-tert-butyl 3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate | 1630086-25-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (S)-tert-butyl 3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate
• 英文别名: tert-butyl (3S)-3-[[4-(2-fluoro-3-pyridyl)pyrimidin-2-yl]amino]piperidine-1-carboxylate；tert-butyl (S)-3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)-piperidine-1-carboxylate；tert-butyl (3S)-3-[[4-(2-fluoropyridin-3-yl)pyrimidin-2-yl]amino]piperidine-1-carboxylate
• CAS: 1630086-25-7
• 化学式: C₁₉H₂₄FN₅O₂
• 分子量: 373.43
• InChiKey: KGHAWASGVLTUSG-ZDUSSCGKSA-N

物化性质

• 沸点：
  545.6±60.0 °C(Predicted)
• 密度：
  1.249±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  80.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl 3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate 在 吡啶 、 4-二甲氨基吡啶 、 caesium carbonate 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 32.0h， 生成 (S)-tert-butyl 3-(4-(2-(2,3,5-trifluoro-4-(phenylmethylsulfonamido)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate
  参考文献：
  名称：

  发现有效的、选择性的、口服的 IRE1α 抑制剂，在多发性骨髓瘤模型中展示出与 IRE1 敲低相当的 PD 调节作用

  摘要：

  由于缺乏选择性和安全的体内 IRE1α 工具分子，限制了 IRE1α 作为治疗多发性骨髓瘤的可行靶点的评估。专注于通过降低亲脂性、分子量和碱度来改善文献化合物的理化性质，从而发现了具有良好体外安全性和良好口服暴露性的新系列。这些努力最终鉴定出一种有效且选择性的体内工具化合物G-5758 ，在多日口服剂量高达 500 mg/kg 后具有良好的耐受性。在多发性骨髓瘤模型 (KMS-11) 中通过 XBP1s 水平测量， G-5758表现出与诱导 IRE1 敲低相当的药效学效果。

  DOI：

  10.1021/acs.jmedchem.3c02425
• 作为产物：
  描述：

  2-氟-3-吡啶硼酸 在 四(三苯基膦)钯 、 potassium carbonate 、 N,N-二异丙基乙胺 、 cesium fluoride 作用下， 以 1,4-二氧六环 、 水 、 二甲基亚砜 为溶剂， 反应 21.0h， 生成 (S)-tert-butyl 3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate
  参考文献：
  名称：

  [EN] PHENOXY-PYRIDYL-PYRIMIDINE COMPOUNDS AND METHODS OF USE
  [FR] COMPOSÉS PHÉNOXY-PYRIDYL-PYRIMIDINE ET MÉTHODES D'UTILISATION ASSOCIÉES

  摘要：

  本文描述了具有肌醇需要酶1（IRE1）调节活性或功能的苯氧基吡啶基嘧啶化合物，其具有Formula I结构或立体异构体、互变异构体或其药用可接受的盐，并具有所述的取代基和结构特征。还描述了包括Formula I化合物的药物组合物和药物，以及使用这种IRE1调节剂的方法，单独或与其他治疗剂联合使用，用于治疗通过雌激素受体介导或依赖的疾病或症状。

  公开号：

  WO2020056089A1

文献信息

• [EN] PYRIMIDINYL-PYRIDYLOXY-NAPHTHYL COMPOUNDS AND METHODS OF TREATING IRE1-RELATED DISEASES AND DISORDERS<br/>[FR] COMPOSÉS PYRIMIDINYL-PYRIDYLOXY-NAPHTYLE ET PROCÉDÉS DE TRAITEMENT DE MALADIES ET DE TROUBLES LIÉS À IRE1
  申请人：GENENTECH INC

  公开号：WO2018166528A1

  公开（公告）日：2018-09-20

  Described herein are pyrimidinyl-pyridyloxy-naphthyl compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula (I) or (I') structure : or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula (I) or (I') compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

  本文描述了具有肌醇需要酶1（IRE1）调节活性或功能的嘧啶基-吡啶氧基-萘基化合物，其具有公式（I）或（I'）结构：或其立体异构体，互变异构体或药学上可接受的盐，并具有所述的取代基和结构特征。还描述了包括公式（I）或（I'）化合物的制药组合物和药物，以及使用这种IRE1调节剂的方法，单独或与其他治疗剂联合治疗介导或依赖于雌激素受体的疾病或病况。
• [EN] IRE1ALPHA INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE IRE1ALPHA ET UTILISATIONS ASSOCIÉES
  申请人：UNIV CALIFORNIA

  公开号：WO2022104151A1

  公开（公告）日：2022-05-19

  Disclosed herein,inter alia, are compounds for inhibiting IRE1α and uses thereof.

  本文中披露了用于抑制IRE1α的化合物及其用途。
• Pyrimidinyl-pyridyloxy-naphthyl compounds and methods of treating IRE1-related diseases and disorders
  申请人：Genentech, Inc.

  公开号：US10968203B2

  公开（公告）日：2021-04-06

  Described herein are pyrimidinyl-pyridyloxy-naphthyl compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula I or I′ structure: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I or I′ compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

  这里描述的是具有式 I 或 I′结构的嘧啶基吡啶氧基萘化合物，它们具有调节肌醇需要酶 1（IRE1）的活性或功能： 或其立体异构体、同系物或药学上可接受的盐，并具有本文所述的取代基和结构特征。还描述了包括式Ⅰ或Ⅰ′化合物的药物组合物和药物，以及单独或与其它治疗剂联合使用这种IRE1调节剂治疗由雌激素受体介导或依赖于雌激素受体的疾病或病症的方法。
• Development of a Chemical Toolset for Studying the Paralog-Specific Function of IRE1
  作者：Hannah C. Feldman、Venkata Narayana Vidadala、Zachary E. Potter、Feroz R. Papa、Bradley J. Backes、Dustin J. Maly

  DOI：10.1021/acschembio.9b00482

  日期：2019.12.20

  The dual kinase endoribonuclease IRE1 is a master regulator of cell fate decisions in cells experiencing endoplasmic reticulum (ER) stress. In mammalian cells, there are two paralogs of IRE1: IRE1 alpha and IRE1 beta. While IRE1 alpha has been extensively studied, much less is understood about IRE1 beta and its role in signaling. In addition, whether the regulation of IRE1 beta's enzymatic activities varies compared to IRE1 alpha is not known. Here, we show that the RNase domain of IRE1 beta is enzymatically active and capable of cleaving an XBP1 RNA mini-substrate in vitro. Using ATP-competitive inhibitors, we find that, like IRE1 alpha, there is an allosteric relationship between the kinase and RNase domains of IRE1 beta. This allowed us to develop a novel toolset of both paralog specific and dual-IRE1 alpha/beta kinase inhibitors that attenuate RNase activity (KIRAs). Using sequence alignments of IRE1 alpha and IRE1 beta, we propose a model for paralog-selective inhibition through interactions with nonconserved residues that differentiate the ATP-binding pockets of IRE1 alpha and IRE1 beta.
• Unfolded Protein Response in Cancer: IRE1α Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability
  作者：Paul E. Harrington、Kaustav Biswas、David Malwitz、Andrew S. Tasker、Christopher Mohr、Kristin L. Andrews、Ken Dellamaggiore、Richard Kendall、Holger Beckmann、Peter Jaeckel、Silvia Materna-Reichelt、Jennifer R. Allen、J. Russell Lipford

  DOI：10.1021/ml500315b

  日期：2015.1.8

  The kinase/endonuclease inositol requiring enzyme 1 (IRE1 alpha), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1 alpha endonuclease activity that bound to the kinase site on the enzyme. Structure-activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1 alpha endonuclease as well as cellular IRE1 alpha. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1 alpha was obtained. Screening of native tumor cell lines (>300) against selective IRE1 alpha inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1 alpha activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis.