tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate | 1360056-47-8

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 英文名称: tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
• CAS: 1360056-47-8
• 化学式: C₁₅H₂₀N₄O₄
• 分子量: 320.348
• InChiKey: NFJUBVXSLUCLKY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  91.5
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 tris-(dibenzylideneacetone)dipalladium(0) 、 palladium 10% on activated carbon 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 氢气 、 caesium carbonate 、 三氟乙酸 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 108.0h， 生成 6-tert-butyl-2-(3-{5-[5-(2,6-diaza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one
  参考文献：
  名称：

  Inhibitors of Bruton's Tyrosine Kinase

  摘要：

  该应用程序根据通用公式I揭示了6-(2-羟甲基苯基)-2-甲基-2H-吡啶并-3-酮衍生物： 其中，变量X、R和Y4如本文所述定义，这些衍生物抑制Btk。本文披露的化合物可用于调节Btk的活性并治疗与过度Btk活性相关的疾病。这些化合物进一步可用于治疗与异常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化合物和至少一种载体、稀释剂或赋形剂的组合物。

  公开号：

  US20120040949A1
• 作为产物：
  描述：

  5-溴-2-硝基吡啶 、 2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 1,4-二氧六环 为溶剂， 生成 tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
  参考文献：
  名称：

  [EN] NITROGEN-CONTAINING TRICYCLIC BIFUNCTIONAL COMPOUND, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF
  [FR] COMPOSÉ BIFONCTIONNEL TRICYCLIQUE CONTENANT DE L'AZOTE, SON PROCÉDÉ DE PRÉPARATION ET SON APPLICATION
  [ZH] 含氮三并环双功能化合物及其制备方法和应用

  摘要：

  提供了一类含氮三并环双功能化合物及其制备方法和应用，具体为式(Ⅳ)所示化合物及其药学上可接受的盐。

  公开号：

  WO2022206924A1

文献信息

• [EN] CDK INHIBITORS AND THEIR USE AS PHARMACEUTICALS<br/>[FR] INHIBITEURS DE CDK ET LEUR UTILISATION EN TANT QUE PRODUITS PHARMACEUTIQUES
  申请人：PRELUDE THERAPEUTICS INC

  公开号：WO2022061273A1

  公开（公告）日：2022-03-24

  The disclosure is directed to compounds of Formula (I) Pharmaceutical compositions comprising compounds of Formula (I), as well as methods of their use and preparation, are also described.

  该披露涉及到化合物的公式（I），还描述了包括该公式（I）化合物的药物组合物，以及它们的使用和制备方法。
• Inhibitors of bruton's tyrosine kinase
  申请人：Berthel Steven Joseph

  公开号：US08481540B2

  公开（公告）日：2013-07-09

  This application discloses 6-(2-Hydroxymethyl-phenyl)-2-methyl-2H-pyridazin-3-one derivatives according to generic Formula I: wherein, variables X, R, and Y4, 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 Formula I and at least one carrier, diluent or excipient.

  本申请公开了根据通用式I定义的6-(2-羟甲基-苯基)-2-甲基-2H-吡嗪-3-酮衍生物，其中变量X、R和Y4如本文所述，这些衍生物能够抑制Btk。本文所披露的化合物对调节Btk的活性和治疗与过度Btk活性相关的疾病有用。这些化合物还有助于治疗与异常B细胞增殖相关的炎症和自身免疫性疾病，如类风湿性关节炎。还公开了含有通用式I化合物和至少一种载体、稀释剂或赋形剂的组合物。
• INHIBITORS OF BRUTON'S TYROSINE KINASE
  申请人：Hoffmann-La Roche Inc.

  公开号：US20130178461A1

  公开（公告）日：2013-07-11

  This application discloses 6-(2-Hydroxymethyl-phenyl)-2-methyl-2H-pyridazin-3-one derivatives according to generic Formula I: wherein, variables X, R, and Y 4 , 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 Formula I and at least one carrier, diluent or excipient.

  本申请披露了根据通用式I定义的6-(2-羟甲基苯基)-2-甲基-2H-吡啶并[3,4-b][1,4]嗪衍生物，其中，变量X、R和Y4如本文所述，这些衍生物可抑制Btk。本申请所披露的化合物可用于调节Btk的活性并治疗与过度Btk活性相关的疾病。这些化合物还可用于治疗与异常B细胞增殖相关的炎症和自身免疫性疾病，例如类风湿性关节炎。本申请还披露了含有通用式I化合物和至少一种载体、稀释剂或赋形剂的组合物。
• [EN] NITROGEN-CONTAINING TRICYCLIC BIFUNCTIONAL COMPOUND, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF<br/>[FR] COMPOSÉ BIFONCTIONNEL TRICYCLIQUE CONTENANT DE L'AZOTE, SON PROCÉDÉ DE PRÉPARATION ET SON APPLICATION<br/>[ZH] 含氮三并环双功能化合物及其制备方法和应用
  申请人：MEDSHINE DISCOVERY INC

  公开号：WO2022206924A1

  公开（公告）日：2022-10-06

  提供了一类含氮三并环双功能化合物及其制备方法和应用，具体为式(Ⅳ)所示化合物及其药学上可接受的盐。
• Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma
  作者：Sarah M. Bronner、Karl A. Merrick、Jeremy Murray、Laurent Salphati、John G. Moffat、Jodie Pang、Christopher J. Sneeringer、Nicholas Dompe、Patrick Cyr、Hans Purkey、Gladys de Leon Boenig、Jun Li、Aleksandr Kolesnikov、Robin Larouche-Gauthier、Kwong Wah Lai、Xiaoli Shen、Samuel Aubert-Nicol、Yi-Chen Chen、Jonathan Cheong、James J. Crawford、Marc Hafner、Pouyan Haghshenas、Araz Jakalian、Jean-Philippe Leclerc、Ngiap-Kie Lim、Tom O'Brien、Emile G. Plise、Hadil Shalan、Claudio Sturino、John Wai、Yang Xiao、Jianping Yin、Liang Zhao、Stephen Gould、Alan Olivero、Timothy P. Heffron

  DOI：10.1016/j.bmcl.2019.06.021

  日期：2019.8

  CDK4 and CDK6 are kinases with similar sequences that regulate cell cycle progression and are validated targets in the treatment of cancer. Glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease. Abemaciclib, ribociclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of HR+/HER2- breast cancer, but these drugs are not expected to show strong activity in brain tumors due to poor blood brain barrier penetration. Herein, we report the identification of a brain-penetrant CDK4/6 inhibitor derived from a literature molecule with low molecular weight and topological polar surface area (MW = 285 and TPSA = 66 angstrom(2)), but lacking the CDK2/1 selectivity profile due to the absence of a basic amine. Removal of a hydrogen bond donor via cyclization of the pyrazole allowed for the introduction of basic and semi-basic amines, while maintaining in many cases efflux ratios reasonable for a CNS program. Ultimately, a basic spiroazetidine (cpK(a) = 8.8) was identified that afforded acceptable selectivity over anti-target CDK1 while maintaining brain-penetration in vivo (mouse K-p,K-uu = 0.20-0.59). To probe the potency and selectivity, our lead compound was evaluated in a panel of glioblastoma cell lines. Potency comparable to abemaciclib was observed in Rb-wild type lines U87MG, DBTRG-05MG, A172, and T98G, while Rb-deficient cell lines SF539 and M059J exhibited a lack of sensitivity.