N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide | 1931994-81-8

• 物质功能分类: 医药中间体 - 杂环化合物
• 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: N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide
• 英文别名: BAY 1834845；Zabedosertib；N-[6-(2-hydroxypropan-2-yl)-2-(2-methylsulfonylethyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide
• CAS: 1931994-81-8
• 化学式: C₂₀H₂₁F₃N₄O₄S
• 分子量: 470.472
• InChiKey: OQAMEEFUUFJZRS-UHFFFAOYSA-N

物化性质

• 沸点：
  620.7±55.0 °C(Predicted)
• 密度：
  1.44±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：125 mg/mL（265.69 mM；超声加热至 60°C）

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  6-(三氟甲基)吡啶-2-甲酸 在 1-丙基磷酸酐 、 N,N-二异丙基乙胺 、 lithium chloride 作用下， 以 四氢呋喃 、 乙酸乙酯 、 甲苯 为溶剂， 反应 76.92h， 生成 N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide
  参考文献：
  名称：

  [EN] POLYMORPHIC FORM OF N-{6-(2-HYDROXYPROPAN-2-YL)-2-[2-(METHYLSULPHONYL)ETHYL]-2H-INDAZOL-5-YL}-6-(TRIFLUOROMETHYL)PYRIDINE-2-CARBOXAMIDE
  [FR] FORME POLYMORPHE DE N-{6-(2-HYDROXYPROPAN-2-YL)-2-[2-(MÉTHYLSULFONYL)ÉTHYL]-2H-INDAZOL-5-YL}-6-(TRIFLUOROMÉTHYL)PYRIDINE-2-CARBOXAMIDE

  摘要：

  本发明涉及N-{6-(2-羟基丙烷-2-基)-2-[2-(甲磺基)乙基]-2H-吲哚-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的晶型形式，其制备方法，包含它们的药物组合物以及它们在控制疾病中的用途。

  公开号：

  WO2017186703A1

文献信息

• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 POLYPEPTIDES
  申请人：Arvinas, Inc.

  公开号：US20190151295A1

  公开（公告）日：2019-05-23

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为白细胞介素-1受体相关激酶4（IRAK-4；目标蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合E3泛素连接酶的Von Hppel-Lindau、cereblon配体的双功能化合物，另一端结合目标蛋白的部分，使得目标蛋白靠近泛素连接酶以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。
• [EN] COMBINATIONS OF INHIBITORS OF IRAK4 WITH INHIBITORS OF BTK<br/>[FR] COMBINAISONS D'INHIBITEURS DE L'IRAK4 À L'AIDE D'INHIBITEURS DE LA BTK
  申请人：BAYER PHARMA AG

  公开号：WO2016174183A1

  公开（公告）日：2016-11-03

  The present application relates to novel combinations of at least two components, component A and component B: · component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; · component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, · one or more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.

  本申请涉及至少两种组分的新型组合，组分A和组分B：·组分A是根据本文所定义的式(I)的IRAK4抑制化合物，或其对映体、对映异构体、代谢物、盐、溶剂合物或其盐的溶剂合物；·组分B是BTK抑制化合物，或其药学上可接受的盐；以及，可选地，·一种或多种组分C，它们是药用产品；其中上述定义的化合物A和B中的一种或两种可选择地存在于用于治疗和/或预防疾病的制剂中，准备用于同时、分开或顺序给药，用于治疗和/或预防疾病，以及用于生产用于治疗和/或预防疾病的药物的用途，特别是用于治疗和/或预防子宫内膜异位症、淋巴瘤、黄斑变性、慢性阻塞性肺病、肿瘤性疾病和牛皮癣。
• [EN] COMBINATIONS OF COPANLISIB<br/>[FR] COMBINAISONS DE COPANLISIB
  申请人：BAYER PHARMA AG

  公开号：WO2017157792A1

  公开（公告）日：2017-09-21

  The present invention relates to * combinations of : component A : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) or (A2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; component B : one or more IRAK4-inhibiting compounds of general formula (I) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; in which optionally some or all of the components are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. dependently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route; * use of such combinations for the preparation of a medicament for the treatment or prophylaxis of a cancer; and * a kit comprising such a combination.

  本发明涉及以下组合物：组分A：一种或多种2,3-二氢咪唑[1,2-c]喹唑啉化合物，其通式为(Al)或(A2)，如本文所定义，或其生理上可接受的盐、溶剂化合物、水合物或立体异构体；组分B：一种或多种IRAK4抑制剂，其通式为(I)，如本文所定义，或其生理上可接受的盐、溶剂化合物、水合物或立体异构体；其中，可选地，某些或所有组分以制药配方的形式存在，该配方可同时、同时、分别或依次通过口服、静脉注射、局部安装、腹腔注射或鼻路给予；使用这种组合物制备治疗或预防癌症的药物；以及包含这种组合物的试剂盒。
• NEW SUBSTITUTED INDAZOLES, METHODS FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS THAT CONTAIN SAID NEW SUBSTITUTED INDAZOLES, AND USE OF SAID NEW SUBSTITUTED INDAZOLES TO PRODUCE DRUGS
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20170349570A1

  公开（公告）日：2017-12-07

  The present application relates to novel substituted indazoles, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia, of lymphoma, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver disorders, insulin resistance, neoplastic disorders and psoriasis.

  本申请涉及新型取代吲哚唑化合物，其制备方法，其单独或组合用于治疗和/或预防疾病的用途，以及其用于制备治疗和/或预防疾病的药物的用途，特别是用于治疗和/或预防子宫内膜异位症和子宫内膜异位症相关疼痛以及其他子宫内膜异位症相关症状，如经痛、性交痛、排尿困难和排便困难，淋巴瘤、类风湿关节炎、脊柱关节炎（特别是银屑病性脊柱关节炎和贝克特列夫病）、红斑狼疮、多发性硬化症、黄斑变性、慢性阻塞性肺病、痛风、脂肪肝疾病、胰岛素抵抗、肿瘤性疾病和银屑病。
• Discovery of IRAK4 Inhibitors <b>BAY1834845</b> (Zabedosertib) and <b>BAY1830839</b>
  作者：Ulrich Bothe、Judith Günther、Reinhard Nubbemeyer、Holger Siebeneicher、Sven Ring、Ulf Bömer、Michaele Peters、Alexandra Rausch、Karsten Denner、Herbert Himmel、Andreas Sutter、Ildiko Terebesi、Martin Lange、Antje M. Wengner、Nicolas Guimond、Tobias Thaler、Johannes Platzek、Uwe Eberspächer、Martina Schäfer、Holger Steuber、Thomas M. Zollner、Andreas Steinmeyer、Nicole Schmidt

  DOI：10.1021/acs.jmedchem.3c01714

  日期：2024.1.25

  Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer’s compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities

  白细胞介素-1 受体相关激酶 4 （IRAK4） 在先天性炎症过程中起关键作用。在这里，我们描述了两种临床候选 IRAK4 抑制剂 BAY1834845 （zabedosertib） 和 BAY1830839 的发现，它们从源自拜耳化合物库的高通量筛选命中开始。通过使用内部对接模型利用 IRAK4 特有的结合位点特征，可以令人惊讶地克服原始命中的责任，从而赋予两个候选药物良好的效力和选择性的独特组合。在动物炎症模型中有利的 DMPK 谱和活性导致选择这两种化合物用于患者的临床开发。