3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole | 918440-06-9

• 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: 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole
• 英文别名: 2-[(3-iodoindazol-1-yl)methoxy]ethyl-trimethylsilane
• CAS: 918440-06-9
• 化学式: C₁₃H₁₉IN₂OSi
• 分子量: 374.297
• InChiKey: QVFYFWBKAHGCJT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.95
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四丁基氟化铵 、 水 、 sodium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 56.0h， 生成 tert-butyl 3-(4-(1H-indazol-3-yl)benzamido)propylcarbamate
  参考文献：
  名称：

  Design and Characterization of a Potent and Selective Dual ATP- and Substrate-Competitive Subnanomolar Bidentate c-Jun N-Terminal Kinase (JNK) Inhibitor

  摘要：

  c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC50 = 18 nM; K-i = 1.5 nM) and JNK/substrate association in a displacement assay (IC50 = 46 nM; K-i = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell-based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice.

  DOI：

  10.1021/jm200479c
• 作为产物：
  描述：

  吲唑 在 氢氧化钾 、 四丁基溴化铵 、 碘 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole
  参考文献：
  名称：

  3-碘吲唑与2-(乙酰氨基)丙烯酸甲酯的Heck交叉偶联反应合成新型脱氢2-氮杂色氨酸及其衍生物

  摘要：

  本文描述了 3-碘吲唑与 2-(乙酰氨基)丙烯酸甲酯的 Heck 交叉偶联反应，作为催化氢化后新脱氢 2-氮杂色氨酸和受保护氨基酸衍生物的一般途径。

  DOI：

  10.1055/s-2006-950242

文献信息

• Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
  作者：Jack D. Scott、Duane E. DeMong、Thomas J. Greshock、Kallol Basu、Xing Dai、Joel Harris、Alan Hruza、Sarah W. Li、Sue-Ing Lin、Hong Liu、Megan K. Macala、Zhiyong Hu、Hong Mei、Honglu Zhang、Paul Walsh、Marc Poirier、Zhi-Cai Shi、Li Xiao、Gautam Agnihotri、Marco A. S. Baptista、John Columbus、Matthew J. Fell、Lynn A. Hyde、Reshma Kuvelkar、Yinghui Lin、Christian Mirescu、John A. Morrow、Zhizhang Yin、Xiaoping Zhang、Xiaoping Zhou、Ronald K. Chang、Mark W. Embrey、John M. Sanders、Heather E. Tiscia、Robert E. Drolet、Jonathan T. Kern、Sylvie M. Sur、John J. Renger、Mark T. Bilodeau、Matthew E. Kennedy、Eric M. Parker、Andrew W. Stamford、Ravi Nargund、John A. McCauley、Michael W. Miller

  DOI：10.1021/acs.jmedchem.7b00045

  日期：2017.4.13

  set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

  富含亮氨酸的重复激酶2（LRRK2）是一种大型的多结构域蛋白，除其他区域外，还包含一个激酶结构域和GTPase结构域。具有在激酶结构域中获得功能突变（例如最普遍的G2019S突变）的个体与帕金森氏病（PD）发生的风险增加相关。鉴于这种抑制LRRK2激酶活性作为影响疾病进展的潜在手段的基因验证，我们的团队着手开发LRRK2抑制剂来验证这一假设。我们化合物收集物的高通量筛选提供了许多有前途的吲唑线索，这些线索被截短以鉴定最小的药效团。这些吲唑的进一步优化导致MLi-2（1）：一种有效的，高度选择性的，口服可得的LRRK2脑渗透抑制剂。
• Catalyst Selection Facilitates the Use of Heterocyclic Sulfinates as General Nucleophilic Coupling Partners in Palladium-Catalyzed Coupling Reactions
  作者：Tim Markovic、Benjamin N. Rocke、David C. Blakemore、Vincent Mascitti、Michael C. Willis

  DOI：10.1021/acs.orglett.7b02944

  日期：2017.11.17

  heterocycle-derived sulfinates are shown to be effective nucleophilic coupling partners with aryl chlorides and bromides using Pd(0) catalysis. The use of optimal reaction conditions, specifically incorporating a P(t-Bu)2Me-derived Pd catalyst, allowed reactions to be performed at moderate temperatures and enabled the inclusion of a variety of sensitive functional groups. Challenging heterocyclic sulfinates, including

  一系列5元和6元杂环衍生的亚磺酸盐显示是使用Pd（0）催化与芳基氯化物和溴化物的有效亲核偶联伙伴。使用最佳反应条件，特别是掺入P（t - Bu）2 Me衍生的Pd催化剂，可以在中等温度下进行反应，并可以包含各种敏感的官能团。具有挑战性的杂环亚磺酸盐，包括吡嗪，哒嗪，嘧啶，吡唑和咪唑，均表现出良好的性能。
• [EN] BI-DENTATE COMPOUNDS AS KINASE INHIBITORS<br/>[FR] COMPOSÉS BIDENTATE EN TANT QU'INHIBITEURS DE KINASE
  申请人：BURNHAM INST MEDICAL RESEARCH

  公开号：WO2009018490A1

  公开（公告）日：2009-02-05

  The present invention provides compound having the general structure A or pharmaceutically acceptable salts thereof: Het-L-P (A) wherein Het is an aromatic moiety comprising a heterocyclic structure mimicking ATP, P is a docking site derived peptide or a docking site peptide mimetic, and L is a linking moiety, wherein L links the ATP mimetic to the docking site peptide moiety. The compounds having the general structure A can serve as inhibitors of kinases, such as the kinases JNK, Erk and P38.

  本发明提供了具有一般结构A或其药学上可接受的盐的化合物：Het-L-P（A），其中Het是包含模拟ATP的杂环结构的芳香基团，P是源自肽的结合位点或模拟结合位点的肽，L是连接基团，其中L将ATP模拟物连接到结合位点肽基团。具有一般结构A的化合物可以作为激酶的抑制剂，例如激酶JNK、Erk和P38。
• Synthesis of (Hetero)biaryls via Nickel Catalyzed Reductive Cross‐Electrophile Coupling Between (Hetero)aryl Iodides and Bromides
  作者：Richard R. Surgenor、Hyelee Lee

  DOI：10.1002/chem.202401552

  日期：2024.8.6

  The (hetero)biaryls are fundamental to drug discovery and rapid, general access to these motifs is essential for medicinal chemistry. Herein, a nickel catalyzed reductive cross-electrophile coupling between heteroaryl iodides and bromides is described. We demonstrated that the reaction is chemoselective, scalable, and amenable to library fashion with an array of scaffolds (45 examples).

  （杂）联芳基是药物发现的基础，快速、普遍地获取这些基序对于药物化学至关重要。本文描述了杂芳基碘化物和溴化物之间的镍催化还原交叉亲电子偶联。我们证明了该反应具有化学选择性、可扩展，并且适合具有一系列支架的库时尚（45 个示例）。
• Synthetic Approaches to 3,3’-Biindolyl and 3,3’-Biindazolyl Derivatives
  作者：Jan Bergman、Azadeh Nakhai

  DOI：10.3987/com-13-s(s)17

  日期：——

  In this paper new syntheses of 3,3'-biindolyl and 3,3'-biindazolyl derivatives are described. Formation of 3,3'-biindolyl derivatives by oxidative coupling of N-acetylindole with TeCl4 gave a good yield, while attempt to use the same reaction conditions for synthesis of 3,3'-biindazolyl derivatives failed. However, conversion of 3-haloindazole derivatives to its trimethylstannane derivative, followed by palladium-catalyzed Stille cross-coupling reaction, resulted in formation of 3,3'-biindazolyl derivatives.