(±)-10-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

• 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: (±)-10-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide
• 英文别名: 10-Bromo-6-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide；10-bromo-6-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide
• 化学式: C₁₃H₁₂BrN₃O₂
• 分子量: 322.161
• InChiKey: ANVSYFGBGFEHGN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  70.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (±)-10-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 、 2-甲基-3-丁炔-2-醇 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 以64%的产率得到10-(3-hydroxy-3-methylbut-1-yn-1-yl)-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide
  参考文献：
  名称：

  Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

  摘要：

  We report here structure-guided optimization of a novel series of NF-kappa B inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-kappa B2 (p52/REL-B) but not canonical NF-kappa B1 (REL-A/p50).

  DOI：

  10.1021/acs.jmedchem.6b01363
• 作为产物：
  描述：

  5-溴-2-氟苯甲醛 在 bis-triphenylphosphine-palladium(II) chloride 、 N-碘代丁二酰亚胺 、 乙基溴化镁 、 ammonium acetate 、 sodium hydride 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 41.34h， 生成 (±)-10-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide
  参考文献：
  名称：

  Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

  摘要：

  We report here structure-guided optimization of a novel series of NF-kappa B inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-kappa B2 (p52/REL-B) but not canonical NF-kappa B1 (REL-A/p50).

  DOI：

  10.1021/acs.jmedchem.6b01363

文献信息

• TRICYCLIC COMPOUNDS AND METHODS OF USE THEREFOR
  申请人：Genentech, Inc.

  公开号：US20130217666A1

  公开（公告）日：2013-08-22

  The invention relates to novel compounds of Formula I: wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and subscripts m and n each has the meaning as described herein. Compounds of Formula I and pharmaceutical compositions thereof are useful in the treatment of disease and disorders in which undesired or over-activation of NF-kB signaling is observed.

  本发明涉及公式I的新化合物：其中A1，A2，A3，A4，A5，A6，R2，R4，R5，R6，R7，R8和下标m和n的含义如此处所述。公式I的化合物及其制药组合物在治疗观察到NF-kB信号不良或过度激活的疾病和障碍方面是有用的。
• US9034866B2
  申请人：——

  公开号：US9034866B2

  公开（公告）日：2015-05-19
• [EN] TRICYCLIC COMPOUNDS AND METHODS OF USE THEREFOR<br/>[FR] COMPOSÉS TRICYCLIQUES ET MÉTHODES D'UTILISATION CORRESPONDANTES
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013120980A1

  公开（公告）日：2013-08-22

  The invention relates to novel compounds of Formula I: wherein A1, A2, A3, A4, A5, A6, R2, R4, R5, R6, R7, R8 and subscripts m and n each has the meaning as described herein. Compounds of Formula I and pharmaceutical compositions thereof are useful in the treatment of disease and disorders in which undesired or over-activation of NF-kB signaling is observed.
• Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)
  作者：Georgette M. Castanedo、Nicole Blaquiere、Maureen Beresini、Brandon Bravo、Hans Brightbill、Jacob Chen、Hai-Feng Cui、Charles Eigenbrot、Christine Everett、Jianwen Feng、Robert Godemann、Emily Gogol、Sarah Hymowitz、Adam Johnson、Nobuhiko Kayagaki、Pawan Bir Kohli、Kathleen Knüppel、Joachim Kraemer、Susan Krüger、Pui Loke、Paul McEwan、Christian Montalbetti、David A. Roberts、Myron Smith、Stefan Steinbacher、Swathi Sujatha-Bhaskar、Ryan Takahashi、Xiaolu Wang、Lawren C. Wu、Yamin Zhang、Steven T. Staben

  DOI：10.1021/acs.jmedchem.6b01363

  日期：2017.1.26

  We report here structure-guided optimization of a novel series of NF-kappa B inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-kappa B2 (p52/REL-B) but not canonical NF-kappa B1 (REL-A/p50).