N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide | 1260162-58-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
• 英文别名: N-{3-[5-chloro-2-(difluoromethoxy)phenyl]-1-methyl-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide；N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-methylpyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
• CAS: 1260162-58-0
• 化学式: C₁₈H₁₃ClF₂N₆O₂
• 分子量: 418.79
• InChiKey: CJXPNZXEEPSZHK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  86.3
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-溴-4-氯苯酚 在 盐酸 、 4-二甲氨基吡啶 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 N,N-二异丙基乙胺 、 三甲基丙酮酸 、 ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) 、 正丁基二(1-金刚烷基)膦 作用下， 以 乙醇 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 59.5h， 生成 N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  参考文献：
  名称：

  Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling

  摘要：

  Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).

  DOI：

  10.1016/j.bmcl.2019.04.008

文献信息

• Regioselective Synthesis of C3-Hydroxyarylated Pyrazoles
  作者：Leonie O’Sullivan、Ketul V. Patel、Ben C. Rowley、Duncan K. Brownsey、Evgueni Gorobets、Benjamin S. Gelfand、Jeffrey F. Van Humbeck、Darren J. Derksen

  DOI：10.1021/acs.joc.1c02518

  日期：2022.1.7

  report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole N-oxides with arynes using mild conditions. Importantly, this method does not require the C4 and C5 positions of the pyrazole to be functionalized to observe regioselectivity. Using this method, we completed the synthesis of a recently reported JAK 1/2 inhibitor. Our synthesis produces the desired

  吡唑是药物化学中普遍存在的结构。我们报告了通过吡唑N-氧化物与芳烃在温和条件下反应获得的 C3-羟基芳基化吡唑的第一个区域选择性途径。重要的是，该方法不需要对吡唑的 C4 和 C5 位置进行功能化以观察区域选择性。使用这种方法，我们完成了最近报道的 JAK 1/2 抑制剂的合成。我们的合成从市售的起始材料分 4 个步骤生产所需的产品。
• PYRAZOLOPYRIMIDINE JAK INHIBITOR COMPOUNDS AND METHODS
  申请人：Gibbons Paul

  公开号：US20120190665A1

  公开（公告）日：2012-07-26

  A compound of Formula I, enantiomers, diasteriomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 and R 3 are defined herein, are useful as inhibitors of one or more Janus kinases. A pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient are disclosed.

  公式I的化合物、对映异构体、顺反异构体、互变异构体或其药学上可接受的盐，其中R1、R2和R3的定义如本文所述，可用作一种或多种Janus激酶的抑制剂。本文还揭示了一种包括公式I的化合物和药学上可接受的载体、辅料或载体的药物组合物，以及治疗或减轻患者对Janus激酶活性抑制响应的疾病或状况的方法。
• 5-CHLORO-2-DIFLUOROMETHOXYPHENYL PYRAZOLOPYRIMIDINE COMPOUNDS WHICH ARE JAK INHIBITORS
  申请人：F. Hoffmann-La Roche AG

  公开号：EP3145929B1

  公开（公告）日：2021-01-13
• JANUS KINASES INHIBITORS, COMPOSITIONS THEREOF AND USE THEREOF
  申请人：F. Hoffmann-La Roche AG

  公开号：EP3380474B1

  公开（公告）日：2019-08-21
• INHALED POWDER FORMULATIONS
  申请人：Genentech, Inc.

  公开号：US20200165260A1

  公开（公告）日：2020-05-28

  Compounds of Formula (00A) and salts thereof, wherein R 1 , R 2 R 3 , R 4 and n are defined herein, are useful as inhibitors of one or more Janus kinases. Also provided are pharmaceutical compositions that include a compound of Formula (00A) and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.