tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate | 929617-42-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate
• 英文别名: tert-butyl 5-bromo-3-methylpyrazolo[3,4-c]pyridine-1-carboxylate
• CAS: 929617-42-5
• 化学式: C₁₂H₁₄BrN₃O₂
• 分子量: 312.166
• InChiKey: HQFRKNIUNZECLM-UHFFFAOYSA-N

物化性质

• 沸点：
  417.3±55.0 °C(Predicted)
• 密度：
  1.50±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  57
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以28%的产率得到5-bromo-1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazolo[3,4-c]pyridine 6-oxide
  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
• 作为产物：
  描述：

  6-溴-4-乙基吡啶-3-胺 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 24.0h， 生成 tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate
  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] METHODS AND COMPOUNDS FOR RESTORING MUTANT p53 FUNCTION<br/>[FR] MÉTHODES ET COMPOSÉS DESTINÉS À LA RESTAURATION D'UNE FONCTION DE MUTANTS DE P53
  申请人：PMV PHARMACEUTICALS INC

  公开号：WO2021262684A1

  公开（公告）日：2021-12-30

  Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. The present disclosure describes compounds and methods that restore DNA binding affinity of p53 mutants. The compounds of the present disclosure can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA and activate downstream effectors involved in tumor suppression. The disclosed compounds can be used to reduce the progression of cancers that contain a p53 mutation.

  癌基因和肿瘤抑制基因的突变促成了癌症的发展和进展。本公开披露描述了一种恢复p53突变体DNA结合亲和力的化合物和方法。本公开披露的化合物可以结合突变型p53，并恢复p53突变体结合DNA并激活参与肿瘤抑制的下游效应子的能力。披露的化合物可用于减少含有p53突变的癌症的进展。
• [EN] PYRAZOLO[3,4-c]PYRIDINE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS DE PYRAZOLO[3,4-C]PYRIDINE ET PROCÉDÉS D'UTILISATION
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013024002A1

  公开（公告）日：2013-02-21

  Pyrazolo[3,4-c]pyridine compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are as defined herein, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式I中的吡唑并[3,4-c]吡啶化合物，包括立体异构体、几何异构体、互变异构体和其药用可接受盐，其中R1和R2如本文所定义，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用公式I化合物对哺乳动物细胞中的这些疾病进行体外、体内和体内诊断、预防或治疗的方法，或相关的病理状况。
• PYRAZOLO[3,4-c]PYRIDINE COMPOUNDS AND METHODS OF USE
  申请人：Do Steven

  公开号：US20130039906A1

  公开（公告）日：2013-02-14

  Pyrazolo[3,4-c]pyridine compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are as defined herein, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式I中的Pyrazolo [3,4-c] pyridine化合物，包括立体异构体，几何异构体，互变异构体和其药学上可接受的盐，其中R1和R2如本文所定义，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用公式I中化合物进行哺乳动物细胞中的体外，原位和体内诊断，预防或治疗此类疾病或相关病理条件的方法。
• Pyrazolo[3,4-c]pyridine compounds and methods of use
  申请人：Do Steven

  公开号：US09260425B2

  公开（公告）日：2016-02-16

  Pyrazolo[3,4-c]pyridine compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are as defined herein, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  本发明提供了式I的吡唑并[3,4-c]吡啶化合物，包括立体异构体、几何异构体、互变异构体和其药学上可接受的盐。其中，R1和R2如本文所定义，可用于抑制Pim激酶并治疗由Pim激酶介导的癌症等疾病。本发明还公开了使用式I的化合物在哺乳动物细胞中进行体外、体内和原位诊断、预防或治疗此类疾病或相关病理状态的方法。
• 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.