1-[(1R)-1-[4-[3-(cyclopropoxy)azetidin-1-yl]cyclohexyl]ethyl]-2-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid | 2702269-35-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: 1-[(1R)-1-[4-[3-(cyclopropoxy)azetidin-1-yl]cyclohexyl]ethyl]-2-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid
• CAS: 2702269-35-8
• 化学式: C₂₃H₃₁N₃O₃
• 分子量: 397.517
• InChiKey: UGTQHAAOGHDJOF-DJIMGWMZSA-N

物化性质

• 沸点：
  576.8±50.0 °C (Predicted,Press: 760 Torr)
• 密度：
  1.39±0.1 g/cm³ (Predicted,Temp: 20 °C; Press: 760 Torr)
• pKa：
  1.45±0.10 (Predicted,Most Acidic Temp: 25 °C)

计算性质

• 辛醇/水分配系数(LogP)：
  4.03
• 重原子数：
  29.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  67.59
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride 、 1-[(1R)-1-[4-[3-(cyclopropoxy)azetidin-1-yl]cyclohexyl]ethyl]-2-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 以53.3 mg的产率得到1-((R)-1-((1r,4R)-4-(3-cyclopropoxyazetidin-1-yl)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time

  摘要：

  Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27-a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic malignancies and frequently overexpressed in solid tumors, where its expression level often correlates with poor prognosis. First generation EZH2 inhibitors are beginning to show clinical benefit, and we believe that a second generation EZH2 inhibitor could further build upon this foundation to fully realize the therapeutic potential of EZH2 inhibition. During our medicinal chemistry campaign, we identified 4-thiomethyl pyridone as a key modification that led to significantly increased potency and prolonged residence time. Leveraging this finding, we optimized a series of EZH2 inhibitors, with enhanced antitumor activity and improved physiochemical properties, which have the potential to expand the clinical use of EZH2 inhibition.

  DOI：

  10.1021/acsmedchemlett.0c00045
• 作为产物：
  描述：

  4-[(1R)-1-[(3-bromo-2-pyridyl)amino]ethyl]cyclohexanol 在 2-吡啶甲酸 、 copper(l) iodide 、 lithium hydroxide monohydrate 、 水 、 caesium carbonate 、 戴斯-马丁氧化剂 、 N,N-二异丙基乙胺 、 potassium iodide 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.34h， 生成 1-[(1R)-1-[4-[3-(cyclopropoxy)azetidin-1-yl]cyclohexyl]ethyl]-2-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time

  摘要：

  Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27-a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic malignancies and frequently overexpressed in solid tumors, where its expression level often correlates with poor prognosis. First generation EZH2 inhibitors are beginning to show clinical benefit, and we believe that a second generation EZH2 inhibitor could further build upon this foundation to fully realize the therapeutic potential of EZH2 inhibition. During our medicinal chemistry campaign, we identified 4-thiomethyl pyridone as a key modification that led to significantly increased potency and prolonged residence time. Leveraging this finding, we optimized a series of EZH2 inhibitors, with enhanced antitumor activity and improved physiochemical properties, which have the potential to expand the clinical use of EZH2 inhibition.

  DOI：

  10.1021/acsmedchemlett.0c00045

文献信息

• Modulators of methyl modifying enzymes, compositions and uses thereof
  申请人：Constellation Pharmaceuticals, Inc.

  公开号：US11459315B2

  公开（公告）日：2022-10-04

  Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compostions thereof, which are useful for treating a variety of conditions associated with methyl modifying enzymes.

  所提供的是式（I）化合物：及其药学上可接受的盐和混合物，可用于治疗与甲基修饰酶有关的各种病症。
• MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF
  申请人：Constellation Pharmaceuticals, Inc.

  公开号：US20210230148A1

  公开（公告）日：2021-07-29

  Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compostions thereof, which are useful for treating a variety of conditions associated with methyl modifying enzymes.