6-bromo-7-fluoro-2,3-dihydro-1H-1,3-methanonaphthalen-4-one oxime | 1451085-13-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: 6-bromo-7-fluoro-2,3-dihydro-1H-1,3-methanonaphthalen-4-one oxime
• 英文别名: 6-Bromo-7-fluoro-2,3-dihydro-1H-1,3-methano-naphthalen-4-one oxime；N-(5-bromo-4-fluoro-8-tricyclo[7.1.1.02,7]undeca-2,4,6-trienylidene)hydroxylamine
• CAS: 1451085-13-4
• 化学式: C₁₁H₉BrFNO
• 分子量: 270.101
• InChiKey: TWLRMKRVDRLSRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  32.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-bromo-7-fluoro-2,3-dihydro-1H-1,3-methanonaphthalen-4-one oxime 在 盐酸 、 bis-triphenylphosphine-palladium(II) chloride 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 N-碘代丁二酰亚胺 、 copper(l) iodide 、 氯化亚砜 、 五氯化磷 、 乙基溴化镁 、 水 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 、 正丁醇 为溶剂， 反应 29.0h， 生成 10-fluoro-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,5-diazatetracyclo[11.1.1.0^2,6.0^7,12]pentadeca-3,5,7(12),8,10-pentaene-4-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：

  3-氧代环丁烷基羧酸 在 三乙基硅烷 、 4-二甲氨基吡啶 、 盐酸羟胺 、 异丙基氯化镁 、 sodium carbonate 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 18.0h， 生成 6-bromo-7-fluoro-2,3-dihydro-1H-1,3-methanonaphthalen-4-one oxime
  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。
• Tricyclic compounds and methods of use therefor
  申请人：Genentech, Inc.

  公开号：US09034866B2

  公开（公告）日：2015-05-19

  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.

  本发明涉及式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。式I的化合物及其制备的药物组合物在治疗疾病和障碍方面是有用的，其中观察到NF-kB信号的不良或过度激活。
• 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).