4-fluoro-1H-indazol-6-ylboronic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: 4-fluoro-1H-indazol-6-ylboronic acid
• 英文别名: (4-Fluoro-1H-indazol-6-yl)boronic acid；(4-fluoro-1H-indazol-6-yl)boronic acid
• 化学式: C₇H₆BFN₂O₂
• 分子量: 179.946
• InChiKey: BDQHXQXQAVKTSF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.62
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  69.1
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-fluoro-1H-indazol-6-ylboronic acid 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 copper(l) iodide 、 sodium carbonate 、 potassium carbonate 、 N,N'-二甲基乙二胺 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 26.0h， 生成 tert-butyl 4-(6-(4-fluoro-6-(6-methylpyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate
  参考文献：
  名称：

  Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability

  摘要：

  Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.

  DOI：

  10.1021/acs.jmedchem.7b00418
• 作为产物：
  描述：

  5-溴-3-氟-2-甲基苯胺 在 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 potassium acetate 、 乙酸酐 作用下， 以 氯仿 、 二甲基亚砜 为溶剂， 反应 23.5h， 生成 4-fluoro-1H-indazol-6-ylboronic acid
  参考文献：
  名称：

  Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability

  摘要：

  Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.

  DOI：

  10.1021/acs.jmedchem.7b00418

文献信息

• Identification of 1<i>H</i>-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study
  作者：Yin Sun、Haotian Tang、Xiaoyan Wang、Fang Feng、Tiantian Fan、Dongmei Zhao、Bing Xiong、Hua Xie、Tongchao Liu

  DOI：10.1080/14756366.2022.2076674

  日期：2022.12.31

  signalling pathways of innate immunity, involving in the process of neuroinflammation, autophagy, and oncogenesis. In current study, based on rational drug design strategy, we discovered a series of 1H-pyrazolo[3,4-b]pyridine derivatives as potent TBK1 inhibitors and dissected the structure–activity relationships (SARs). Through the several rounds of optimisation, compound 15y stood out as a potent inhibitor

  摘要 TANK 结合激酶 1 (TBK1) 是抑制剂-kappaB 激酶 (IKKs) 家族的非经典成员，在协调先天免疫信号通路方面发挥着至关重要的作用，涉及神经炎症、自噬和肿瘤发生的过程。在目前的研究中，基于合理的药物设计策略，我们发现了一系列 1 H-吡唑并[3,4-b]吡啶衍生物作为有效的 TBK1 抑制剂，并剖析了构效关系 (SARs)。经过多轮优化，化合物15y作为TBK1的强效抑制剂脱颖而出，IC 50值为0.2 nM，并显示出良好的选择性。TBK1下游基因的mRNA检测表明化合物15y在受刺激的 THP-1 和 RAW264.7 细胞中有效抑制 TBK1 下游 IFN 信号传导。同时，化合物15y对 A172、U87MG、A375、A2058 和 Panc0504 细胞系表现出微摩尔抗增殖作用。总之，目前的结果提供了一种有前途的 TBK1 抑制剂15年作为免疫和癌症相关药物发现的先导化合物。
• Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability
  作者：Xiaojing Wang、Aleksandr Kolesnikov、Suzanne Tay、Grace Chan、Qi Chao、Steven Do、Jason Drummond、Allen J. Ebens、Ning Liu、Justin Ly、Eric Harstad、Huiyong Hu、John Moffat、Veerendra Munugalavadla、Jeremy Murray、Dionysos Slaga、Vickie Tsui、Matthew Volgraf、Heidi Wallweber、Jae H. Chang

  DOI：10.1021/acs.jmedchem.7b00418

  日期：2017.5.25

  Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.