5-溴-1H-吡唑并[3,4-c]吡啶-1-羧酸叔丁酯 | 929617-41-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 5-溴-1H-吡唑并[3,4-c]吡啶-1-羧酸叔丁酯
• 英文名称: tert-butyl 5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate
• 英文别名: tert-butyl 5-bromopyrazolo[3,4-c]pyridine-1-carboxylate
• CAS: 929617-41-4
• 化学式: C₁₁H₁₂BrN₃O₂
• 分子量: 298.139
• InChiKey: WFQXTZNDXLYCJP-UHFFFAOYSA-N

物化性质

• 沸点：
  402.7±48.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  57
• 氢给体数：
  0
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P264,P280,P302+P352,P337+P313,P305+P351+P338,P362+P364,P332+P313
• 危险性描述：
  H315,H319

反应信息

• 作为反应物：
  描述：

  5-溴-1H-吡唑并[3,4-c]吡啶-1-羧酸叔丁酯 在 盐酸 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四(三苯基膦)钯 、 碘 、 potassium acetate 、 potassium carbonate 、 caesium carbonate 、 三氟乙酸 、 联硼酸频那醇酯 、 potassium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 36.5h， 生成 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid
  参考文献：
  名称：

  [EN] ARYL, HETEROARY, AND HETEROCYCLIC PHARMACEUTICAL COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
  [FR] COMPOSÉS PHARMACEUTIQUES ARYLE, HÉTÉROARYLES ET HÉTÉROCYCLIQUES POUR LE TRAITEMENT DE TROUBLES MÉDICAUX

  摘要：

  提供了抑制补体因子D的抑制剂、药物组合物及其用途，以及它们的制备方法。所提供的化合物包括公式I、公式II、公式III、公式IV和公式V，或其药学上可接受的盐、前药、同位素类似物、N-氧化物或其分离异构体，可选地在药学上可接受的组合物中。本文描述的抑制剂针对因子D并抑制或调节补体级联反应。

  公开号：

  WO2018160889A1
• 作为产物：
  描述：

  2-溴-4-甲基-5-氨基吡啶 在 4-二甲氨基吡啶 、 溶剂黄146 、 三乙胺 、 sodium nitrite 作用下， 以 水 、 乙腈 为溶剂， 反应 72.0h， 生成 5-溴-1H-吡唑并[3,4-c]吡啶-1-羧酸叔丁酯
  参考文献：
  名称：

  Design and synthesis of pyridine–pyrazolopyridine-based inhibitors of protein kinase B/Akt

  摘要：

  Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.01.010

文献信息

• [EN] ERK INHIBITORS<br/>[FR] INHIBITEURS D'ERK
  申请人：MERCK SHARP & DOHME

  公开号：WO2016100050A1

  公开（公告）日：2016-06-23

  The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

  本发明提供了一种化合物(I)或其药学上可接受的盐、酯和前药，这些化合物是ERK2抑制剂。该发明还提供了一种包括至少一种化合物(I)和药学上可接受的载体的有效量的药物组合物。该发明还提供了一种包括至少一种化合物(I)的有效量和至少一种其他药学活性成分的有效量（例如，化疗药物等）以及药学上可接受的载体的药物组合物。
• ジヒドロピラゾロピラジノン誘導体
  申请人：大日本住友製薬株式会社

  公开号：JP2019182784A

  公开（公告）日：2019-10-24

  【課題】代謝型グルタミン酸受容体サブタイプ２及び／又は代謝型グルタミン酸受容体サブタイプ３が関与する疾患の治療剤として有用な化合物の提供。【解決手段】式（１）で表される化合物又はその製薬学的に許容される塩。（Ｒ１、Ｒ２：Ｈ、ハロゲン、シアノ、Ｃ１−４アルキル等。環Ａ：Ｃ６−１０芳香族炭素環、４〜１０員の飽和複素環、５〜１０員の芳香族複素環。Ｒ３、Ｒ４：Ｈ、ハロゲン、Ｃ１−６アルキル、５又は６員の芳香族複素環基等。環Ｂ：含窒素縮合複素環）【選択図】なし

  提供作为治疗代谢型谷氨酸受体亚型2和/或代谢型谷氨酸受体亚型3参与的疾病的治疗剂的有用化合物。 化合物或其在药学上可接受的盐，由式（1）表示。（R1、R2：H、卤素、氰基、C1-4烷基等。环A：C6-10芳香族碳环、4~10元饱和复合环、5~10元芳香族复合环。R3、R4：H、卤素、C1-6烷基、5或6元芳香族复合环基等。环B：含氮缩合复合环）【选择图】无
• Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3Kδ inhibitor: Design, synthesis and biological evaluation
  作者：Chengbin Yang、Chenyue Xu、Zhipeng Li、Yi Chen、Tianze Wu、Hui Hong、Mingzhu Lu、Yu Jia、Yongtai Yang、Xiaofeng Liu、Mingli Deng、Zhenxia Chen、Qingquan Li、Yun Ling、Yaming Zhou

  DOI：10.1016/j.ejmech.2021.113661

  日期：2021.11

  Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro studies revealed that FD223 displays high potency (IC50 = 1 nM) and selectivity (29–51 fold over other PI3K isoforms) against PI3Kδ, and exhibits

  基于吲哚支架，一种有效的选择性磷酸肌醇 3-激酶δ (PI3K δ ) 抑制剂，即FD223，是通过生物等排替代药物发现方法开发的，并研究用于治疗急性髓系白血病 (AML)。体外研究表明，FD223 对 PI3K δ显示出高效力 (IC 50 = 1 nM) 和选择性（比其他 PI3K 异构体高 29-51 倍），并显示出对 AML 细胞系（MOLM-16、HL- 60、EOL-1 和 KG-1）通过抑制 p-AKT Ser473 从而导致细胞周期中的 G1 期停滞。进一步考虑到FD223的有利药代动力学 (PK) 特征，在体内在裸鼠中使用异种移植模型对研究进行了评估，证实了其显着的抗肿瘤功效，同时没有可观察到的毒性。所有这些结果都与 Idelalisib (CAL-101) 的阳性组相当，表明FD223作为一种有前景的 PI3K δ抑制剂有潜力进一步发展，用于治疗白血病等白血病。
• [EN] MACROCYCLES AND THEIR USE<br/>[FR] MACROCYCLES ET LEUR UTILISATION
  申请人：BLOSSOMHILL THERAPEUTICS INC

  公开号：WO2022133037A1

  公开（公告）日：2022-06-23

  The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as cancer.

  本公开涉及大环化合物、含有大环化合物的药物组合物、以及使用大环化合物治疗疾病（如癌症）的方法。
• Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension
  作者：Gui-Dong Zhu、Viraj B. Gandhi、Jianchun Gong、Sheela Thomas、Keith W. Woods、Xiaohong Song、Tongmei Li、R. Bruce Diebold、Yan Luo、Xuesong Liu、Ran Guan、Vered Klinghofer、Eric F. Johnson、Jennifer Bouska、Amanda Olson、Kennan C. Marsh、Vincent S. Stoll、Mulugeta Mamo、James Polakowski、Thomas J. Campbell、Ruth L. Martin、Gary A. Gintant、Thomas D. Penning、Qun Li、Saul H. Rosenberg、Vincent L. Giranda

  DOI：10.1021/jm0701019

  日期：2007.6.1

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.