(3R,8aR)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6(7H)-one | 1620676-53-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并[1,5-a]吡嗪
• 英文名称: (3R,8aR)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6(7H)-one
• 英文别名: (3R,8aR)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1,3,4,7,8,8a-hexahydropyrrolo[2,1-c][1,4]oxazin-6-one
• CAS: 1620676-53-0
• 化学式: C₁₃H₁₄BrN₅O₂
• 分子量: 352.19
• InChiKey: RALUMOOKYBYVRU-HTQZYQBOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  85.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3R,8aR)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6(7H)-one 、 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide 在 氮气 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 乙酸乙酯 、 钯 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 1.0h， 以to give 4-(8-amino-3-((3R,8aR)-6-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (13.96 mg, yield 20.8%) as a white solid的产率得到4-(8-amino-3-((3R,8aR)-6-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide
  参考文献：
  名称：

  BTK INHIBITORS

  摘要：

  本发明提供了符合公式I或其药学上可接受的盐的布鲁顿酪氨酸激酶(Btk)抑制剂化合物，以及包含这些化合物的药物组合物，以及它们在治疗中的用途。特别是，本发明涉及使用Btk抑制剂化合物治疗Btk介导的疾病。

  公开号：

  US20150353570A1
• 作为产物：
  描述：

  3-氯吡嗪-2甲胺 在 N-溴代丁二酰亚胺(NBS) 、 氯甲酸异丙酯 、 三乙胺 、 三氯氧磷 作用下， 以 N,N-二甲基甲酰胺 、 异丙醇 、 乙腈 为溶剂， 反应 26.0h， 生成 (3R,8aR)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6(7H)-one
  参考文献：
  名称：

  Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes

  摘要：

  Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.

  DOI：

  10.1016/j.bmcl.2020.127390

文献信息

• [EN] BTK INHIBITORS<br/>[FR] INHIBITEURS DE BTK
  申请人：MERCK SHARP & DOHME

  公开号：WO2016109221A1

  公开（公告）日：2016-07-07

  The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I, or pharmaceutically acceptable salts thereof, Formula I or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds of Formula I in the treatment of Btk mediated disorders.

  本发明提供布鲁顿酪氨酸激酶（Btk）抑制剂化合物，根据公式I，或其药用可接受的盐，公式I，或包含这些化合物的药物组合物，以及它们在治疗中的用途。特别是，本发明涉及在治疗Btk介导的疾病中使用公式I的Btk抑制剂化合物。
• US9481682B2
  申请人：——

  公开号：US9481682B2

  公开（公告）日：2016-11-01
• BTK INHIBITORS
  申请人：KIM RONALD M.

  公开号：US20140206681A1

  公开（公告）日：2014-07-24

  The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds in the treatment of Btk mediated disorders.

  本发明提供了根据式I提供的Bruton's酪氨酸激酶（Btk）抑制剂化合物，或其药学上可接受的盐，或包含这些化合物的药物组合物，并且用于治疗的使用。具体地，本发明涉及在治疗Btk介导的疾病中使用Btk抑制剂化合物。
• Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes
  作者：Jian Liu、Deodial Guiadeen、Arto Krikorian、Xiaolei Gao、James Wang、Sobhana Babu Boga、Abdul-Basit Alhassan、Wensheng Yu、Oleg Selyutin、Younong Yu、Rajan Anand、Jiayi Xu、Joseph Kelly、Joseph L. Duffy、Shilan Liu、Chundao Yang、Hao Wu、Jiaqiang Cai、Chad Bennett、Kevin M. Maloney、Sriram Tyagarajan、Ying-Duo Gao、Thierry O. Fischmann、Jeremy Presland、My Mansueto、Zangwei Xu、Erica Leccese、Jie Zhang-Hoover、Ian Knemeyer、Charles G. Garlisi、Peter Stivers、Philip E. Brandish、Alexandra Hicks、Ronald Kim、Joseph A. Kozlowski

  DOI：10.1016/j.bmcl.2020.127390

  日期：2020.9

  Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.