9-ethyl-6,6-dimethyl-11-oxo-8-(1H-pyrazol-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 9-ethyl-6,6-dimethyl-11-oxo-8-(1H-pyrazol-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
• 英文别名: 9-ethyl-6,6-dimethyl-11-oxo-8-(1H-pyrazol-4-yl)-5H-benzo[b]carbazole-3-carbonitrile
• 化学式: C₂₄H₂₀N₄O
• 分子量: 380.449
• InChiKey: BUHLWVQDHMLTPT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  29
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  85.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  9-ethyl-6,6-dimethyl-11-oxo-8-(1H-pyrazol-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile 、 3-氯-1,2-丙二醇 在 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 以63%的产率得到8-(1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
  参考文献：
  名称：

  Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure—activity relationship study

  摘要：

  Four series of tetracyclic benzo[b]carbazolone compounds possessing more rotatable bonds and higher molecular flexibility were designed by either inserting a linker within the C8-side chain or by opening the middle ketone ring on the basis of compound 5 (Alectinib, CH5424802). Compound 15b was identified showing nearly identical high potency against both wild-type and the gatekeeper mutant ALK kinase (3.4 vs 3.9 nM). This compound has favorable PK profile with an oral bioavailability of 67.1% in rats. Moreover, compound 15b showed significant growth inhibition against ALK driven cancer cells and KARPAS-299 xenograft model. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.10.005
• 作为产物：
  描述：

  4-吡唑硼酸频哪醇酯 、 9-ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium carbonate 、 2-二-叔丁膦基-2',4',6'-三异丙基联苯 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 以41%的产率得到9-ethyl-6,6-dimethyl-11-oxo-8-(1H-pyrazol-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
  参考文献：
  名称：

  Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation

  摘要：

  The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of "second-generation" ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JET-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing.

  DOI：

  10.1021/acs.jmedchem.5b01136

文献信息

• 杂环基取代的吲哚并萘酮衍生物及其医药用 途
  申请人：中国科学院上海药物研究所

  公开号：CN104177342B

  公开（公告）日：2018-01-05

  本发明涉及杂环基取代的吲哚并萘酮衍生物及其医药用途。具体地，本发明涉及一类具有酪氨酸激酶ALK选择性抑制活性的化合物及其药学上可接受的盐或药学上可接受的溶剂合物，其制备方法、包含该化合物的药物组合物，以及这些化合物在制备用于预防或治疗与生物体内的渐变性淋巴瘤酶相关的伴随细胞异常增殖、形态变化和/或运动功能亢进等的疾病的药物中的用途，以及在制备用于治疗或预防与血管新生或癌转移相关的疾病的药物中的用途，尤其是在制备用于治疗或预防肿瘤生长与转移的药物中的用途。
• Substituted 6,11-dihydro-5H-benzo[B]carbazoles as inhibitors of ALK and SRPK
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US11066363B2

  公开（公告）日：2021-07-20

  The application relates to a compound of Formula (I): which modulates the activity of ALK or SRPK, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which ALK or SRPK plays a role.

  本申请涉及一种式 (I) 化合物： 调节 ALK 或 SRPK 活性的化合物、包含该化合物的药物组合物，以及治疗或预防 ALK 或 SRPK 在其中起作用的疾病的方法。
• Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation
  作者：John M. Hatcher、Magda Bahcall、Hwan Geun Choi、Yang Gao、Taebo Sim、Rani George、Pasi A. Jänne、Nathanael S. Gray

  DOI：10.1021/acs.jmedchem.5b01136

  日期：2015.12.10

  The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of "second-generation" ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JET-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing.
• INHIBITORS OF ALK AND SRPK AND METHODS OF USE
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US20180258040A1

  公开（公告）日：2018-09-13

  The application relates to a compound of Formula (I): which modulates the activity of ALK or SRPK, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which ALK or SRPK plays a role.
• 6,11-DIHYDRO-5H-BENZO[B]CARBAZOLE INHIBITORS OF ALK AND SRPK AND METHODS OF USE
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US20200223798A1

  公开（公告）日：2020-07-16

  The application relates to a compound of Formula (I): which modulates the activity of ALK or SRPK, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which ALK or SRPK plays a role.