3-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one | 1293344-24-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 3-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one
• 英文别名: 3-(5-(4-Ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one；3-[[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino]-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one
• CAS: 1293344-24-7
• 化学式: C₂₃H₃₄BN₅O₃
• 分子量: 439.366
• InChiKey: YCXFOCJBBSAXPO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.97
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  70.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-tert-butyl-2-(3-chloro-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one 、 3-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 在 potassium carbonate 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 、 三环己基膦 作用下， 以 1,4-二氧六环 、 水 为溶剂， 生成 6-tert-Butyl-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one
  参考文献：
  名称：

  Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s Tyrosine Kinase (BTK) inhibitor scaffold

  摘要：

  A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.11.030
• 作为产物：
  描述：

  5-bromo-1-methyl-3-[5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino]-1H-pyridin-2-one 、 联硼酸频那醇酯 、 2-二环己基磷-2,4,6-三异丙基联苯 、 potassium acetate 在 (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium 乙酸乙酯 、 水 、 magnesium sulfate 作用下， 以 1,4-二氧六环 为溶剂， 反应 4.0h， 以to yield the crude product 190a which的产率得到3-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one
  参考文献：
  名称：

  PYRIDONE AND AZA-PYRIDONE COMPOUNDS AND METHODS OF USE

  摘要：

  本发明提供公式I的吡啶酮和氮杂吡啶酮化合物，包括立体异构体、互变异构体和其医药上可接受的盐，用于抑制Btk激酶并治疗由Btk激酶介导的免疫紊乱，例如炎症。本发明还公开了使用公式I化合物在哺乳动物细胞中进行体外、原位和体内诊断和治疗此类疾病或相关病理条件的方法。

  公开号：

  US20120010191A1

文献信息

• Inhibitors of Bruton's Tyrosine Kinase
  申请人：Berthel Steven

  公开号：US20100222325A1

  公开（公告）日：2010-09-02

  This application discloses 5-phenyl-1H-pyridin-2-one, 6-phenyl-2H-pyridazin-3-one, and 5-Phenyl-1H-pyrazin-2-one derivatives according to generic Formulae I-III: wherein, variables Q, R, X, X′, Y 1 , Y 2 , Y 2′ , Y 3 , Y 4 , Y 5 , m, and n are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formulae I-III and at least one carrier, diluent or excipient.

  该应用程序根据通用公式I-III披露了5-苯基-1H-吡啶-2-酮，6-苯基-2H-吡啶-3-酮和5-苯基-1H-吡嗪-2-酮衍生物： 其中，变量Q、R、X、X'、Y1、Y2、Y2'、Y3、Y4、Y5、m和n的定义如本文所述，这些化合物抑制Btk。本文披露的化合物对调节Btk的活性并治疗与过度Btk活性相关的疾病有用。这些化合物进一步有助于治疗与异常B细胞增殖相关的炎症和自身免疫疾病，如类风湿性关节炎。还披露了含有公式I-III化合物和至少一种载体、稀释剂或赋形剂的组合物。
• Pyridone and aza-pyridone compounds and methods of use
  申请人：Barbosa Antonio J. M.

  公开号：US08618107B2

  公开（公告）日：2013-12-31

  Pyridone and aza-pyridone compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  本发明提供了公式I的吡啶酮和氮杂吡啶酮化合物，包括立体异构体、互变异构体和其药学上可接受的盐，用于抑制Btk激酶和治疗由Btk激酶介导的免疫紊乱，如炎症。本发明还揭示了使用公式I化合物进行哺乳动物细胞中的体外、原位和体内诊断和治疗这种疾病或相关病理情况的方法。
• Structure-Based Drug Design of RN486, a Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis
  作者：Yan Lou、Xiaochun Han、Andreas Kuglstatter、Rama K. Kondru、Zachary K. Sweeney、Michael Soth、Joel McIntosh、Renee Litman、Judy Suh、Buelent Kocer、Dana Davis、Jaehyeon Park、Sandra Frauchiger、Nolan Dewdney、Hasim Zecic、Joshua P. Taygerly、Keshab Sarma、Junbae Hong、Ronald J. Hill、Tobias Gabriel、David M. Goldstein、Timothy D. Owens

  DOI：10.1021/jm500305p

  日期：2015.1.8

  Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclinical characterization based on its favorable properties.
• Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s Tyrosine Kinase (BTK) inhibitor scaffold
  作者：Yan Lou、Zachary K. Sweeney、Andreas Kuglstatter、Dana Davis、David M. Goldstein、Xiaochun Han、Junbae Hong、Buelent Kocer、Rama K. Kondru、Renee Litman、Joel McIntosh、Keshab Sarma、Judy Suh、Joshua Taygerly、Timothy D. Owens

  DOI：10.1016/j.bmcl.2014.11.030

  日期：2015.1

  A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains. (C) 2014 Elsevier Ltd. All rights reserved.
• PYRIDONE AND AZA-PYRIDONE COMPOUNDS AND METHODS OF USE
  申请人：BARBOSA Antonio J.M.

  公开号：US20120010191A1

  公开（公告）日：2012-01-12

  Pyridone and aza-pyridone compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  本发明提供公式I的吡啶酮和氮杂吡啶酮化合物，包括立体异构体、互变异构体和其医药上可接受的盐，用于抑制Btk激酶并治疗由Btk激酶介导的免疫紊乱，例如炎症。本发明还公开了使用公式I化合物在哺乳动物细胞中进行体外、原位和体内诊断和治疗此类疾病或相关病理条件的方法。