tert-butyl 4-(4-((6-bromoimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate | 1021154-34-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: tert-butyl 4-(4-((6-bromoimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate
• 英文别名: 4-[4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester；tert-butyl 4-[4-[(6-bromoimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]piperazine-1-carboxylate
• CAS: 1021154-34-6
• 化学式: C₂₁H₂₅BrN₆O₂
• 分子量: 473.373
• InChiKey: WXYXXLMKMLZAFF-UHFFFAOYSA-N

物化性质

• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  75
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(4-((6-bromoimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate 在 盐酸 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 3.0h， 生成 6-(1H-indazol-6-yl)-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine
  参考文献：
  名称：

  口服脾酪氨酸激酶（SYK）抑制剂的设计和优化，用于治疗实体瘤。

  摘要：

  为了发现口服SYK抑制剂治疗实体瘤的目的，设计，合成和评估了一系列基于咪唑并[1,2-a]吡嗪骨架的新型衍生物。酶和细胞分析的结构-活性关系研究导致了化合物12f的鉴定。新型SYK抑制剂12f对实体瘤表现出有效的抗肿瘤活性，并具有亲脂性和溶解性等良好的类药物性质。12f可以诱导卵巢癌细胞和肺癌细胞凋亡。在SKOV3异种移植小鼠模型中，口服12f导致明显的肿瘤消退而没有明显的毒性。12f在体外和体内改善了传统SYK抑制剂在实体瘤中的有限反应。在一起

  DOI：

  10.1016/j.bioorg.2019.103547
• 作为产物：
  描述：

  4-(4-硝基苯基)哌嗪-1-羧酸叔丁酯 在 palladium 10% on activated carbon 、 一水合肼 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 异丙醇 为溶剂， 反应 16.0h， 生成 tert-butyl 4-(4-((6-bromoimidazo[1,2-a]pyrazin-8-yl)amino)phenyl)piperazine-1-carboxylate
  参考文献：
  名称：

  口服脾酪氨酸激酶（SYK）抑制剂的设计和优化，用于治疗实体瘤。

  摘要：

  为了发现口服SYK抑制剂治疗实体瘤的目的，设计，合成和评估了一系列基于咪唑并[1,2-a]吡嗪骨架的新型衍生物。酶和细胞分析的结构-活性关系研究导致了化合物12f的鉴定。新型SYK抑制剂12f对实体瘤表现出有效的抗肿瘤活性，并具有亲脂性和溶解性等良好的类药物性质。12f可以诱导卵巢癌细胞和肺癌细胞凋亡。在SKOV3异种移植小鼠模型中，口服12f导致明显的肿瘤消退而没有明显的毒性。12f在体外和体内改善了传统SYK抑制剂在实体瘤中的有限反应。在一起

  DOI：

  10.1016/j.bioorg.2019.103547

文献信息

• [EN] IMIDAZO[1,2-A]PYRAZIN-8-YLAMINES AND METHOD OF INHIBITION OF BRUTON'S TYROSINE KINASE BY SUCH COMPOUNDS<br/>[FR] IMIDAZO[1,2-A]PYRAZIN-8-YLAMINES ET METHODES D'INHIBITION DE LA TYROSINE KINASE DE BRUTON PAR DE TELS COMPOSES
  申请人：CELLULAR GENOMICS INC

  公开号：WO2005014599A1

  公开（公告）日：2005-02-17

  Compounds of Formula (I-a) and all pharmaceutically-acceptable forms thereof, are described herein. The variables R1, R2, R3, Z1, Q, and A shown in Formula I-a are defined herein. Pharmaceutical compositions containing one or more compounds of Formula (I-a), or a pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents are provided herein. Methods of treating patients suffering from certain diseases responsive to inhibition of tyrosine kinase activity are also given. In certain embodiments the diseases are responsive to inhibition of Btk activity and/or B-cell proliferation. Such methods comprise administering to such patients an amount of a compound of Formula (I-a) effective to reduce signs or symptoms of the disease. These diseases include cancer, an autoimmune and/or inflammatory disease, or an acute inflammatory reaction. Thus methods of treatment include administering a sufficient amount of a compound or salt as provided herein to decrease the symptoms or slow the progression of these diseases. Other embodiments include methods of treating other animals, including livestock and domesticated companion animals, suffering from a disease responsive to inhibition of kinase activity. Methods of treatment include administering a compound of Formula (I-a) as a single active agent or administering a compound of Formula (I-a) in combination with one or more other therapeutic agent. A method for determining the presence of Btk in a sample, comprising contacting the sample with a compound or form thereof of Formula (I-a) under conditions that permit detection of Btk activity, detecting a level of Btk activity in the sample, and therefrom determining the presence or absence of Btk in the sample.

  本文描述了化合物的化学式（I-a）及其所有药用可接受形式。在化学式I-a中显示的变量R1、R2、R3、Z1、Q和A在此处被定义。本文提供了含有一个或多个化学式（I-a）化合物或该化合物的药用可接受形式以及一个或多个药用可接受载体、辅料或稀释剂的药物组合物。还提供了治疗对酪氨酸激酶活性抑制敏感的患者的方法。在某些实施例中，这些疾病对Btk活性和/或B细胞增殖的抑制敏感。这些方法包括向这些患者投予有效减轻疾病症状的化学式（I-a）化合物的量。这些疾病包括癌症、自身免疫和/或炎症性疾病或急性炎症反应。因此，治疗方法包括向患者投予足够量的本文所述的化合物或盐，以减轻这些疾病的症状或减缓其进展。其他实施例包括治疗其他动物，包括牲畜和驯养的伴侣动物，患有对激酶活性抑制敏感的疾病的方法。治疗方法包括将化学式（I-a）的化合物作为单一活性剂或将化学式（I-a）的化合物与一个或多个其他治疗剂结合使用。一种确定样品中Btk存在的方法，包括将样品与化学式（I-a）的化合物或其形式接触，在允许检测Btk活性的条件下，检测样品中Btk活性的水平，并从中确定样品中Btk的存在或不存在。
• Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of bruton's tyrosine kinase by such compounds
  申请人：Currie S. Kevin

  公开号：US20050090499A1

  公开（公告）日：2005-04-28

  Compounds of Formula I-a and all pharmaceutically-acceptable forms thereof, are described herein. The variables R 1 , R 2 , R 3 , Z 1 , Q, and A shown in Formula I-a are defined herein. Pharmaceutical compositions containing one or more compounds of Formula I-a, or a pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents are provided herein. Methods of treating patients suffering from certain diseases responsive to inhibition of tyrosine kinase activity are also given. In certain embodiments the diseases are responsive to inhibition of Btk activity and/or B-cell proliferation. Such methods comprise administering to such patients an amount of a compound of Formula I-a effective to reduce signs or symptoms of the disease. These diseases include cancer, an autoimmune and/or inflammatory disease, or an acute inflammatory reaction. Thus methods of treatment include administering a sufficient amount of a compound or salt as provided herein to decrease the symptoms or slow the progression of these diseases. Other embodiments include methods of treating other animals, including livestock and domesticated companion animals, suffering from a disease responsive to inhibition of kinase activity. Methods of treatment include administering a compound of Formula I-a as a single active agent or administering a compound of Formula I-a in combination with one or more other therapeutic agent. A method for determining the presence of Btk in a sample, comprising contacting the sample with a compound or form thereof of Formula I-a under conditions that permit detection of Btk activity, detecting a level of Btk activity in the sample, and therefrom determining the presence or absence of Btk in the sample.

  本文介绍了I-a公式化合物及其所有药学上可接受的形式。公式I-a中所示的变量R1、R2、R3、Z1、Q和A在本文中有定义。本文提供了含有一种或多种I-a公式化合物或其药学上可接受的形式以及一种或多种药学上可接受的载体、赋形剂或稀释剂的制药组合物。本文还提供了治疗对酪氨酸激酶活性抑制具有反应性的某些疾病的方法。在某些实施例中，这些疾病对Btk活性和/或B细胞增殖的抑制具有反应性。这些方法包括向这些患者施用足够量的I-a公式化合物，以减少疾病的症状或症状。这些疾病包括癌症、自身免疫和/或炎症性疾病或急性炎症反应。因此，治疗方法包括向患者施用足够量的本文所提供的化合物或盐，以减轻这些疾病的症状或减缓其进展。其他实施例包括治疗其他动物，包括牲畜和驯养的伴侣动物，这些动物患有对激酶活性抑制具有反应性的疾病。治疗方法包括将I-a公式化合物作为单一活性剂或与一种或多种其他治疗剂联合使用。一种用于确定样品中Btk存在的方法，包括将样品与I-a公式化合物或其形式接触，在允许检测Btk活性的条件下，检测样品中Btk活性的水平，然后确定样品中Btk的存在或不存在。
• Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds
  申请人：Currie S. Kevin

  公开号：US20060183746A1

  公开（公告）日：2006-08-17

  Certain compounds, such as at least one chemical entity choen from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, crystal forms, chelates, non-covalent complexes, prodrugs, and mixtures thereof, may in certain embodiments be used to treat patients suffering from one or more diseases responsive to inhibition of tyrosine kinase activity. The diseases may, for instance, be responsive to inhibition of Btk activity and/or B-cell proliferation. Example diseases include cancer, an autoimmune and/or inflammatory disease, and an acute inflammatory reaction.

  某些化合物，例如从公式1的化合物中至少选择一个化学实体和药学上可接受的盐、溶剂化物、晶体形式、螯合物、非共价复合物、前药和它们的混合物，在某些实施例中可用于治疗患有一种或多种对酪氨酸激酶活性抑制敏感的疾病的患者。这些疾病可能对Btk活性和/或B细胞增殖的抑制敏感。例如，这些疾病包括癌症、自身免疫和/或炎症性疾病以及急性炎症反应。
• CERTAIN IMIDAZO[1,2-A]PYRAZIN-8-YLAMINES AND METHOD OF INHIBITION OF BRUTON'S TYROSINE KINASE BY SUCH COMPOUNDS
  申请人：Currie Kevin S.

  公开号：US20110177011A1

  公开（公告）日：2011-07-21

  Compounds of Formula I-a and all pharmaceutically-acceptable forms thereof, are described herein. The variables R 1 , R 2 , R 3 , Z 1 , Q, and A shown in Formula I-a are defined herein. Pharmaceutical compositions containing one or more compounds of Formula I-a, or a pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents are provided herein. Methods of treating patients suffering from certain diseases responsive to inhibition of tyrosine kinase activity are also given. In certain embodiments the diseases are responsive to inhibition of Btk activity and/or B-cell proliferation. Such methods comprise administering to such patients an amount of a compound of Formula I-a effective to reduce signs or symptoms of the disease. These diseases include cancer, an autoimmune and/or inflammatory disease, or an acute inflammatory reaction. Thus methods of treatment include administering a sufficient amount of a compound or salt as provided herein to decrease the symptoms or slow the progression of these diseases. Other embodiments include methods of treating other animals, including livestock and domesticated companion animals, suffering from a disease responsive to inhibition of kinase activity. Methods of treatment include administering a compound of Formula I-a as a single active agent or administering a compound of Formula I-a in combination with one or more other therapeutic agent. A method for determining the presence of Btk in a sample, comprising contacting the sample with a compound or form thereof of Formula I-a under conditions that permit detection of Btk activity, detecting a level of Btk activity in the sample, and therefrom determining the presence or absence of Btk in the sample.

  本文描述了化合物I-a及其所有药学上可接受的形式。在公式I-a中显示的变量R1、R2、R3、Z1、Q和A在此定义。本文提供了含有一种或多种化合物I-a或其药学上可接受的形式以及一种或多种药学上可接受的载体、辅料或稀释剂的制药组合物。本文还提供了治疗对酪氨酸激酶活性抑制有反应的某些疾病的方法。在某些实施例中，这些疾病对Btk活性和/或B细胞增殖的抑制有反应。这些方法包括向这些患者施用足够量的化合物I-a，以减少疾病的症状或迹象。这些疾病包括癌症、自身免疫和/或炎症性疾病或急性炎症反应。因此，治疗方法包括向患者施用足够量的化合物或盐，以减轻这些疾病的症状或减缓其进展。其他实施例包括治疗其他动物，包括家畜和驯养伴侣动物，患有对激酶活性抑制有反应的疾病的方法。治疗方法包括将化合物I-a作为单一活性剂或与一种或多种其他治疗剂联合使用。一种用于确定样品中Btk存在的方法，包括将样品与公式I-a的化合物或其形式在允许检测Btk活性的条件下接触，检测样品中Btk活性的水平，并从中确定样品中Btk的存在或不存在。
• US7405295B2
  申请人：——

  公开号：US7405295B2

  公开（公告）日：2008-07-29