3,6-二溴异噻唑并[4,3-B]吡啶 | 1643854-33-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 3,6-二溴异噻唑并[4,3-B]吡啶
• 英文名称: 3,6-dibromoisothiazolo[4,3-b]pyridine
• 英文别名: 3,6-Dibromo-[1,2]thiazolo[4,3-b]pyridine
• CAS: 1643854-33-4
• 化学式: C₆H₂Br₂N₂S
• 分子量: 293.969
• InChiKey: XFINWAKFJGTYGZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  11
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  54
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3,6-二溴异噻唑并[4,3-B]吡啶 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 生成 4-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)isothiazolo[4,3-b]pyridin-6-yl)-2-methoxyaniline
  参考文献：
  名称：

  Optimization of Isothiazolo[4,3-b]pyridine-Based Inhibitors of Cyclin G Associated Kinase (GAK) with Broad-Spectrum Antiviral Activity

  摘要：

  There is an urgent need for strategies to combat dengue and other emerging viral infections. We reported that cyclin G-associated kinase (GAK), a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, regulates intracellular trafficking of multiple unrelated RNA viruses during early and late stages of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leading to the discovery of novel isothiazolo[4,3-b]pyridines that maintain high GAK affinity and selectivity. These compounds demonstrate improved in vitro activity against dengue virus, including in human primary dendritic cells, and efficacy against the unrelated Ebola and chikungunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compounds. These findings demonstrate the potential utility of a GAK-targeted broad-spectrum approach for combating currently untreatable emerging viral infections.

  DOI：

  10.1021/acs.jmedchem.8b00613
• 作为产物：
  描述：

  3-amino-5-bromo-2-pyridinecarbothioamide 在 氢溴酸 、 双氧水 、 sodium nitrite 作用下， 以 甲醇 、 水 为溶剂， 反应 0.5h， 生成 3,6-二溴异噻唑并[4,3-B]吡啶
  参考文献：
  名称：

  [EN] GAK MODULATORS AS ANTIVIRALS
  [FR] MODULATEURS DE GAK A TITRE D'AGENTS ANTIVIRAUX

  摘要：

  本发明涉及一类新型异噻唑并[4,3-b]吡啶衍生物的使用，以及包含一种或多种所述异噻唑并[4,3-b]吡啶衍生物和一种或多种药学上可接受的赋形剂作为生物活性成分的药物组合物，更具体地，作为用于治疗诸如病毒性疾病等疾病和病理状况的药物。

  公开号：

  WO2016012536A1

文献信息

• [EN] NOVEL GAK MODULATORS<br/>[FR] NOUVEAUX MODULATEURS DE LA GAK
  申请人：UNIV LEUVEN KATH

  公开号：WO2015001076A1

  公开（公告）日：2015-01-08

  The present invention relates to a class of novel isothiazolo[4,3-b]pyridine derivatives and a method for their preparation, as well as to pharmaceutical compositions comprising one or more of said isothiazolo[4,3-b]pyridine derivatives and one or more pharmaceutically acceptable excipients. The present invention further relates to the use of said novel isothiazolo[4,3-b]pyridine derivatives as biologically active ingredients, more specifically as medicaments for the treatment of disorders and pathologic conditions such as, but not limited to, cell-proliferative and neurodegenerative diseases.

  本发明涉及一类新型的异噻唑并[4,3-b]吡啶衍生物及其制备方法，以及包含一种或多种所述异噻唑并[4,3-b]吡啶衍生物和一种或多种药学上可接受的赋形剂的药物组合物。本发明还涉及所述新型异噻唑并[4,3-b]吡啶衍生物作为生物活性成分的用途，更具体地，作为用于治疗诸如但不限于细胞增殖性和神经退行性疾病等障碍和病理状况的药物。
• Cyclin G-associated kinase (GAK) affinity and antiviral activity studies of a series of 3-C-substituted isothiazolo[4,3-b]pyridines
  作者：Randy Wouters、Szu-Yuan Pu、Mathy Froeyen、Eveline Lescrinier、Shirit Einav、Piet Herdewijn、Steven De Jonghe

  DOI：10.1016/j.ejmech.2018.11.065

  日期：2019.2

  G-associated kinase (GAK) is a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, which regulates intracellular trafficking of dengue virus during early and late stages of the viral lifecycle. Previously, the discovery of isothiazolo[4,3-b]pyridines as potent and selective GAK inhibitors with promising antiviral activity was reported. In this manuscript, the synthesis of isothiazolo[4

  细胞周期蛋白G相关激酶（GAK）是网格蛋白相关宿主衔接蛋白AP-1和AP-2的细胞调节剂，可在病毒生命周期的早期和后期调节登革热病毒在细胞内的运输。以前，已经报道了异噻唑并[4，3- b ]吡啶类化合物作为具有前途抗病毒活性的强效和选择性GAK抑制剂的报道。在本手稿中，异噻唑啉的合成[4,3- b通过应用区域选择性Suzuki和Sonogashira偶联反应描述了在3位具有碳连接的取代基的]吡啶。在位置3具有3,4-二甲氧基苯基残基的衍生物表现出对GAK的低纳摩尔结合亲和力和对登革热病毒的抗病毒活性。这些发现表明适当地替换支架的3位上的苯基部分可以改善GAK结合亲和力。
• Isothiazolo[4,3-b]pyridines as inhibitors of cyclin G associated kinase: synthesis, structure–activity relationship studies and antiviral activity
  作者：Jiahong Li、Sona Kovackova、Szuyuan Pu、Jef Rozenski、Steven De Jonghe、Shirit Einav、Piet Herdewijn

  DOI：10.1039/c5md00229j

  日期：——

  Starting from a known isothiazolo[4,3-b]pyridine scaffold, different series of novel, potent GAK ligands were synthesized.

  从已知的异噻唑并[4,3-b]吡啶骨架出发，合成了不同系列的新型、有效的GAK配体。
• NOVEL GAK MODULATORS
  申请人：KATHOLIEKE UNIVERSITEIT LEUVEN

  公开号：US20160122364A1

  公开（公告）日：2016-05-05

  The present invention relates to a class of novel isothiazolo[4,3-b]pyridine derivatives and a method for their preparation, as well as to pharmaceutical compositions comprising one or more of said isothiazolo[4,3-b]pyridine derivatives and one or more pharmaceutically acceptable excipients. The present invention further relates to the use of said novel isothiazolo[4,3-b]pyridine derivatives as biologically active ingredients, more specifically as medicaments for the treatment of disorders and pathologic conditions such as, but not limited to, cell-proliferative and neurodegenerative diseases.

  本发明涉及一类新型异噻唑并[4,3-b]吡啶衍生物及其制备方法，以及包含一种或多种所述异噻唑并[4,3-b]吡啶衍生物和一种或多种药学上可接受的辅料的制药组合物。本发明还涉及使用所述新型异噻唑并[4,3-b]吡啶衍生物作为生物活性成分，更具体地作为治疗细胞增殖和神经退行性疾病等疾病和病理情况的药物。
• Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents
  作者：Sona Kovackova、Lei Chang、Elena Bekerman、Gregory Neveu、Rina Barouch-Bentov、Apirat Chaikuad、Christina Heroven、Michal Šála、Steven De Jonghe、Stefan Knapp、Shirit Einav、Piet Herdewijn

  DOI：10.1021/jm501759m

  日期：2015.4.23

  Cyclin G associated kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Cocrystallization experiments revealed that these compounds behaved as classic type I ATP-competitive kinase inhibitors. In addition, we have demonstrated that these compounds exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors represent chemical probes to study GAK function in different disease areas where GAK has been implicated (including viral infection, cancer, and Parkinsons disease).