2-chloro-4-(2-fluoropyridin-3-yl)pyrimidine

• 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: 2-chloro-4-(2-fluoropyridin-3-yl)pyrimidine
• 化学式: C₉H₅ClFN₃
• 分子量: 209.61
• InChiKey: AFUWPPDPTXFWAT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  38.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-chloro-4-(2-fluoropyridin-3-yl)pyrimidine 在 potassium carbonate 、 三乙胺 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.13h， 生成
  参考文献：
  名称：

  [EN] IRE1ALPHA INHIBITORS AND USES THEREOF
  [FR] INHIBITEURS DE IRE1ALPHA ET UTILISATIONS ASSOCIÉES

  摘要：

  本文中披露了用于抑制IRE1α的化合物及其用途。

  公开号：

  WO2022104151A1
• 作为产物：
  描述：

  2,4-二氯嘧啶 、 2-氟-3-吡啶硼酸 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 16.0h， 以60.7%的产率得到2-chloro-4-(2-fluoropyridin-3-yl)pyrimidine
  参考文献：
  名称：

  [EN] IRE1ALPHA INHIBITORS AND USES THEREOF
  [FR] INHIBITEURS DE IRE1ALPHA ET UTILISATIONS ASSOCIÉES

  摘要：

  本文中披露了用于抑制IRE1α的化合物及其用途。

  公开号：

  WO2022104151A1

文献信息

• [EN] PHENOXY-PYRIDYL-PYRIMIDINE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS PHÉNOXY-PYRIDYL-PYRIMIDINE ET MÉTHODES D'UTILISATION ASSOCIÉES
  申请人：GENENTECH INC

  公开号：WO2020056089A1

  公开（公告）日：2020-03-19

  Described herein are phenoxy-pyridyl -pyrimidine compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula 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 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。
• [EN] HETEROARYL-HETEROARYL-O-PHENYL COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING CANCER DISORDERS<br/>[FR] COMPOSÉS HÉTÉROARYLE-HÉTÉROARYL-O-PHÉNYLE, COMPOSITIONS ET MÉTHODES DE TRAITEMENT DE TROUBLES CANCÉREUX
  申请人：CHENGDU ANTICANCER BIOSCIENCE LTD

  公开号：WO2022199654A1

  公开（公告）日：2022-09-29

  The present disclose includes, among other things, compounds that treat or lessen the severity of cancer, pharmaceutical compositions and methods of making and using the same.

  本披露涵盖了治疗或减轻癌症严重程度的化合物，制药组合物以及制备和使用它们的方法。
• Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model
  作者：Marie-Gabrielle Braun、Avi Ashkenazi、Ramsay E. Beveridge、Georgette Castanedo、Heidi Ackerly Wallweber、Maureen H. Beresini、Kevin R. Clark、Tom De Bruyn、Liqiang Fu、Paul Gibbons、Fan Jiang、Susan Kaufman、David Kan、James R. Kiefer、Jean-Philippe Leclerc、Alexandre Lemire、Cuong Ly、Ehud Segal、Jessica Sims、Weiru Wang、Wentao Wei、Liang Zhao、Jacob B. Schwarz、Joachim Rudolph

  DOI：10.1021/acs.jmedchem.3c02425

  日期：2024.6.13

  culminated in the identification of a potent and selective in vivo tool compound, G-5758, that was well tolerated following multiday oral administration of doses up to 500 mg/kg. G-5758 demonstrated comparable pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s levels in a multiple myeloma model (KMS-11).

  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。
• 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.