4-amino-N-methyl-2-(4-(4-morpholino)phenyl)thieno[3,2-c]-pyridine-7-carboxamide | 1350455-43-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 4-amino-N-methyl-2-(4-(4-morpholino)phenyl)thieno[3,2-c]-pyridine-7-carboxamide
• 英文别名: 4-Amino-N-Methyl-2-[4-(Morpholin-4-Yl)phenyl]thieno[3,2-C]pyridine-7-Carboxamide；4-amino-N-methyl-2-(4-morpholin-4-ylphenyl)thieno[3,2-c]pyridine-7-carboxamide
• CAS: 1350455-43-4
• 化学式: C₁₉H₂₀N₄O₂S
• 分子量: 368.459
• InChiKey: JNNQSTULXLHQBB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-amino-2-iodothieno[3,2-c]pyridine-7-carboxylic acid 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 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 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 4-amino-N-methyl-2-(4-(4-morpholino)phenyl)thieno[3,2-c]-pyridine-7-carboxamide
  参考文献：
  名称：

  Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors

  摘要：

  Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.

  DOI：

  10.1021/jm200911r

文献信息

• [EN] COMPOUNDS USEFUL FOR PROMOTING PROTEIN DEGRADATION AND METHODS USING SAME<br/>[FR] COMPOSÉS UTILES POUR STIMULER LA DÉGRADATION DES PROTÉINES ET PROCÉDÉS UTILISANT CEUX-CI
  申请人：UNIV YALE

  公开号：WO2013170147A1

  公开（公告）日：2013-11-14

  The present invention includes compounds that act as degraders of a target protein, wherein degradation is independent of the class of the target protein or its localization. In one embodiment, the invention comprises a compound comprising a protein degradation moiety covalently bound to a linker, wherein the ClogP of the compound is equal to or higher than 1.5. The target protein contemplated within the invention comprises a posttranslational modified protein or intracellular protein. Compounds of the present invention may be used to treat disease states wherein protein degradation is a viable therapeutic approach, such as cancer or any sort of oxidative stress disease state.

  本发明包括作为目标蛋白质降解剂的化合物，其中降解与目标蛋白质的类别或其定位无关。在一种实施方式中，该发明包括一种化合物，其中蛋白质降解基团与连接剂共价结合，该化合物的ClogP等于或高于1.5。本发明中考虑的目标蛋白质包括后转录修饰蛋白质或细胞内蛋白质。本发明的化合物可用于治疗蛋白质降解是一种可行的治疗方法的疾病状态，如癌症或任何一种氧化应激疾病状态。
• Compounds Useful for Promoting Protein Degradation and Methods Using Same
  申请人：Yale University

  公开号：US20160022642A1

  公开（公告）日：2016-01-28

  The present description includes compounds that act as degraders of a target protein, wherein degradation is independent of the class of the target protein or its localization. In certain embodiments, the description includes a compound comprising a protein degradation moiety covalently bound to a linker, wherein the ClogP of the compound is equal to or higher than 1.5. The target protein contemplated within the description comprises an androgen receptor. Compounds of the present description may be used to treat disease states wherein protein degradation is a viable therapeutic approach, such as cancer or any sort of oxidative stress disease state.

  本描述包括作为目标蛋白质降解剂的化合物，其中降解与目标蛋白质的类别或其定位无关。在某些实施例中，描述包括一种化合物，其中蛋白质降解基团与连接剂共价结合，该化合物的ClogP等于或高于1.5。描述中考虑的目标蛋白质包括雄激素受体。本描述的化合物可用于治疗蛋白质降解是可行治疗方法的疾病状态，如癌症或任何一种氧化应激疾病状态。
• CEREBLON LIGANDS AND BIFUNCTIONAL COMPOUNDS COMPRISING THE SAME
  申请人：Arvinas, Inc.

  公开号：US20180215731A1

  公开（公告）日：2018-08-02

  The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

  该描述涉及cereblon E3连接酶结合化合物，包括包含相同成分的双功能化合物，这些化合物作为靶向泛素化的调节剂具有实用价值，尤其是抑制剂，可降解和/或以其他方式抑制根据本公开的双功能化合物。特别是，该描述提供了化合物，其一端含有与cereblon E3泛素连接酶结合的配体，另一端含有与目标蛋白结合的部分，使目标蛋白位于泛素连接酶附近以降解（和抑制）该蛋白。可以合成表现出广泛药理活性的化合物，与几乎所有类型的靶向多肽的降解/抑制一致。
• COMPOUNDS TARGETING PROTEINS, COMPOSITIONS, METHODS, AND USES THEREOF
  申请人：BioTheryX, Inc.

  公开号：US20180170948A1

  公开（公告）日：2018-06-21

  The present invention provides compounds that modulate protein function, to restore protein homeostasis, including cytokine, CK1α, GSPT1, aiolos, and/or ikaros activity, and cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions, including in combination with other cytokine and inflammatory mediators, are provided. Methods of treatment, amelioration, or prevention of diseases, disorders, or conditions associated with a protein, such as diseases, disorders, and conditions associated with cytokines, including inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer's disease, and cancer, are provided.

  本发明提供了调节蛋白功能的化合物，以恢复蛋白稳态，包括细胞因子、CK1α、GSPT1、艾奥洛斯和/或伊卡洛斯活性和细胞间粘附。该发明提供了一种调节蛋白介导的疾病的方法，如细胞因子介导的疾病、障碍、状况或反应。提供了包括与其他细胞因子和炎症介质结合的组合物。提供了治疗、改善或预防与蛋白相关的疾病、障碍或状况的方法，包括与细胞因子相关的疾病、障碍和状况，包括炎症、纤维肌痛、类风湿性关节炎、骨关节炎、强直性脊柱炎、银屑病、银屑病关节炎、炎症性肠病、克罗恩病、溃疡性结肠炎、葡萄膜炎、炎症性肺病、慢性阻塞性肺病、阿尔茨海默病和癌症。
• [EN] OXOINDOLINE DERIVATIVES AS PROTEIN FUNCTION MODULATORS<br/>[FR] DÉRIVÉS D'OXOINDOLINE UTILISÉS COMME MODULATEURS DE LA FONCTION PROTÉIQUE
  申请人：BIOTHERYX INC

  公开号：WO2017201069A1

  公开（公告）日：2017-11-23

  The present invention provides chimeric compounds of formula (II) that modulate protein function, to restore protein homeostasis, including cytokine, aiolos, and/or ikaros activity, TNF-alpha activity, CKl-alpha activity and cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions, including in combination with other cytokine and inflammatory mediators, are provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions, such as cytokine-mediated diseases, disorders, and conditions, including inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant rejection, and cancer, are provided.

  本发明提供了公式（II）的嵌合化合物，用于调节蛋白功能，恢复蛋白稳态，包括细胞因子、aiolos和/或ikaros活性，TNF-alpha活性，CKl-alpha活性和细胞间黏附。该发明提供了调节蛋白介导疾病的方法，如细胞因子介导的疾病、紊乱、状况或反应。提供了与其他细胞因子和炎症介质结合的组合物。提供了治疗、改善或预防蛋白介导疾病、紊乱和状况的方法，如细胞因子介导的疾病、紊乱和状况，包括炎症、纤维肌痛综合征、类风湿关节炎、骨关节炎、强直性脊柱炎、牛皮癣、银屑病性关节炎、炎症性肠病、克罗恩病、溃疡性结肠炎、葡萄膜炎、炎症性肺部疾病、慢性阻塞性肺疾病、阿尔茨海默病、器官移植排斥反应和癌症。