6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole | 1448429-59-1

• 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: 6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole
• 英文别名: 6-(1-methylpyrazol-4-yl)-1H-indazole
• CAS: 1448429-59-1
• 化学式: C₁₁H₁₀N₄
• 分子量: 198.227
• InChiKey: SQHMXXKTQYXFRK-UHFFFAOYSA-N

物化性质

• 沸点：
  450.9±28.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-溴-2-吗啉吡啶 、 6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole 在 copper(l) iodide 、 (±)-N,N-dimethyl-trans-1,2-diaminocyclohexane 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 4-(4-(6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)morpholine
  参考文献：
  名称：

  [EN] COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY
  [FR] COMPOSÉS INHIBANT L'ACTIVITÉ ENZYMATIQUE DE LA KINASE À SÉQUENCE RÉPÉTÉE RICHE EN LEUCINE

  摘要：

  本发明涉及一种反向吲唑化合物的取代物，其化学式为(I)：及其在药学上可接受的盐，其中R1、R2、R3、R4、R9和A如本文所定义，这些化合物是LRRK2激酶的强效抑制剂，并且在涉及LRRK2激酶的疾病的治疗或预防中有用，如帕金森病。本发明还涉及包含这些化合物的药物组合物以及这些化合物和组合物在涉及LRRK-2激酶的疾病的预防或治疗中的用途。

  公开号：

  WO2016036586A1
• 作为产物：
  描述：

  6-溴吲唑 、 1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以68%的产率得到6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole
  参考文献：
  名称：

  Indazoles as potential c-met inhibitors: Design, synthesis and molecular docking studies

  摘要：

  Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of indazoles were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibition on c-Met and compound 4d showed highest activity against c-Met with IC50 value of 0.17 mu M in TR-FRET-based assay and IC50 value of 5.45 mu M in cell-based assay as compared to other tested compounds. Molecular docking experiments verified the results and explained the molecular mechanism of pretty activities to c-Met. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.04.004

文献信息

• Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1<i>H</i>-Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson’s Disease
  作者：David A. Candito、Vladimir Simov、Anmol Gulati、Solomon Kattar、Ryan W. Chau、Blair T. Lapointe、Joey L. Methot、Duane E. DeMong、Thomas H. Graham、Ravi Kurukulasuriya、Mitchell H. Keylor、Ling Tong、Gregori J. Morriello、John J. Acton、Barbara Pio、Weiguo Liu、Jack D. Scott、Michael J. Ardolino、Theodore A. Martinot、Matthew L. Maddess、Xin Yan、Hakan Gunaydin、Rachel L. Palte、Spencer E. McMinn、Lisa Nogle、Hongshi Yu、Ellen C. Minnihan、Charles A. Lesburg、Ping Liu、Jing Su、Laxminarayan G. Hegde、Lily Y. Moy、Janice D. Woodhouse、Robert Faltus、Tina Xiong、Paul Ciaccio、Jennifer A. Piesvaux、Karin M. Otte、Matthew E. Kennedy、David Jonathan Bennett、Erin F. DiMauro、Matthew J. Fell、Santhosh Neelamkavil、Harold B. Wood、Peter H. Fuller、J. Michael Ellis

  DOI：10.1021/acs.jmedchem.2c01605

  日期：2022.12.22

  activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson’s disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with

  抑制富含亮氨酸重复激酶 2 (LRRK2) 激酶活性代表了一种治疗帕金森病的遗传支持、化学易处理和潜在的疾病缓解机制。在此，我们描述了一系列新型强效选择性中枢神经系统 (CNS) 渗透剂 1-杂芳基-1 H-吲唑 I 型（ATP 竞争性）LRRK2 抑制剂的优化。I 型 ATP 竞争性激酶物理化学特性通过基于结构的药物设计与 sp 3 –sp 2交叉偶联技术实现的平行药物化学相结合，与 CNS 类药物特性相结合。这导致发现了一个独特的 sp 3- 丰富的螺腈基序赋予非凡的效力、药代动力学和有利的 CNS 药物样特性。先导化合物25在人外周血单核细胞中表现出卓越的靶向效力、出色的脱靶激酶选择性和大鼠的良好脑暴露，最终实现低预计人体剂量和临床前安全性，值得进步对临床前候选启用研究。
• 1-cyano-pyrrolidine compounds as USP30 inhibitors
  申请人：MISSION THERAPEUTICS LIMITED

  公开号：US10343992B2

  公开（公告）日：2019-07-09

  The present invention relates to novel compounds and method for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and cancer. Compounds of the invention include compounds having the formula (II) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R8, R9, R10, R12, Z, Y and m are as defined herein.

  本发明涉及新型化合物和去泛素化酶（DUB）抑制剂的制造方法。特别是，本发明涉及泛素 C 端水解酶 30（USP30）的抑制。本发明还涉及 DUB 抑制剂在治疗线粒体功能障碍和癌症方面的用途。本发明的化合物包括具有式(II)的化合物或其药学上可接受的盐，其中R1、R2、R3、R4、R5、R8、R9、R10、R12、Z、Y和m如本文所定义。
• Compounds inhibiting leucine-rich repeat kinase enzyme activity
  申请人：Merck Sharp & Dohme Corp.

  公开号：US10954240B2

  公开（公告）日：2021-03-23

  The present invention is directed to substituted certain reversed indazole compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R9, and A are as defined herein, which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK-2 kinase is involved.

  本发明涉及式（I）的取代的某些反式吲唑化合物：及其药学上可接受的盐，其中R1、R2、R3、R4、R9和A如本文所定义，它们是LRRK2激酶的强效抑制剂，可用于治疗或预防LRRK2激酶参与的疾病，如帕金森病。本发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在预防或治疗涉及LRRK-2激酶的此类疾病中的用途。
• COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP3190889A1

  公开（公告）日：2017-07-19
• 1-CYANO-PYRROLIDINE COMPOUNDS AS USP30 INHIBITORS
  申请人：MISSION THERAPEUTICS LIMITED

  公开号：US20180086708A1

  公开（公告）日：2018-03-29

  The present invention relates to novel compounds and method for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and cancer. Compounds of the invention include compounds having the formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 12 , Z, Y and m are as defined herein.