(S)-methyl 3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-methyl 3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate
• 英文别名: methyl (3S)-3-[(5-benzyl-1,2-oxazole-3-carbonyl)amino]-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepine-7-carboxylate
• 化学式: C₂₃H₂₁N₃O₆
• 分子量: 435.436
• InChiKey: UUYBWDFXXOQFLF-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  111
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-methyl 3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate 在 三乙胺 、 N,N'-羰基二咪唑 、 lithium hydroxide 、 肼 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 (S)-5-benzyl-N-(5-methyl-4-oxo-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide
  参考文献：
  名称：

  Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases

  摘要：

  RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting, its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.

  DOI：

  10.1021/acs.jmedchem.6b01751
• 作为产物：
  描述：

  methyl (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepine-7-carboxylate 在 N-甲基吗啉 、 盐酸 、 potassium carbonate 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 6.5h， 生成 (S)-methyl 3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate
  参考文献：
  名称：

  Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases

  摘要：

  RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting, its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.

  DOI：

  10.1021/acs.jmedchem.6b01751

文献信息

• [EN] HETEROCYCLIC AMIDES AS KINASE INHIBITORS<br/>[FR] AMIDES HÉTÉROCYCLIQUES À UTILISER EN TANT QU'INHIBITEURS DE KINASE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2014125444A1

  公开（公告）日：2014-08-21

  Disclosed are compounds having the formula (I) wherein X, Y, Z1, Z2, Z3, Z4, R5, RA, m, A. L, and B are as defined herein, and methods of making and using the same.

  揭示了具有式（I）的化合物，其中X、Y、Z1、Z2、Z3、Z4、R5、RA、m、A、L和B如本文所定义，并公开了制备和使用这些化合物的方法。
• HETEROCYCLIC AMIDES AS KINASE INHIBITORS
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：US20170183332A1

  公开（公告）日：2017-06-29

  Disclosed are compounds having the formula: wherein X, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 5 , R A , m, A. L, and B are as defined herein, and methods of making and using the same.

  本发明涉及具有以下结构式的化合物：其中X、Y、Z1、Z2、Z3、Z4、R5、RA、m、A、L和B如本文所定义，以及制备和使用它们的方法。
• Heterocyclic amides as kinase inhibitors
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：US10292987B2

  公开（公告）日：2019-05-21

  Disclosed are compounds having the formula: wherein X, Y, Z1, Z2, Z3, Z4, R5, RA, m, A. L, and B are as defined herein, and methods of making and using the same.

  所公开的是具有以下式子的化合物 其中 X、Y、Z1、Z2、Z3、Z4、R5、RA、m、A. L 和 B 如本文所定义，以及制造和使用它们的方法。
• HETEROCYCLIC AMIDES AS RIP1 KINASE INHIBITORS AS MEDICAMENTS
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：EP3182974A1

  公开（公告）日：2017-06-28
• US9624202B2
  申请人：——

  公开号：US9624202B2

  公开（公告）日：2017-04-18