6-chloro-10-(propane-2-sulfonyl)-17-(4-methylpiperazin-1-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene | 1352244-65-5

• 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: 6-chloro-10-(propane-2-sulfonyl)-17-(4-methylpiperazin-1-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene
• 英文别名: 6-Chloro-17-(4-methylpiperazin-1-yl)-10-propan-2-ylsulfonyl-2,4,8,22-tetrazatetracyclo[14.3.1.13,7.19,13]docosa-1(20),3,5,7(22),9,11,13(21),16,18-nonaene
• CAS: 1352244-65-5
• 化学式: C₂₆H₃₁ClN₆O₂S
• 分子量: 527.09
• InChiKey: CALYEAJTMOGFMG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  36
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  98.8
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  6-chloro-10-(propane-2-sulfonyl)-17-(4-methylpiperazin-1-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene 、 (14Z)-6-chloro-17-(4-methylpiperazin-1-yl)-10-propan-2-ylsulfonyl-2,4,8,22-tetrazatetracyclo[14.3.1.13,7.19,13]docosa-1(20),3,5,7(22),9,11,13(21),14,16,18-decaene 在 6-chloro-10-(methanesulfonyl)-17-(4-methylpiperazin-1-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,14,16,18-nonaene 作用下， 以The desired product 6-Chloro-10-(methanesulfonyl)-17-(4-methylpiperazin-1-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.13,7.19,13]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene was isolated in 20% yield as a yellow tinted solid, mp>250° C的产率得到6-chloro-10-(methanesulfonyl)-17-(4-methylpiperazin-1-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,14,16,18-nonaene
  参考文献：
  名称：

  Macrocyclic Compounds as ALK, FAK and JAK2 Inhibitors

  摘要：

  本发明提供了I式化合物或其药学上可接受的盐形式，其中R1、R2、R3、R4、R5、A和X的定义如本文所述，以及其治疗方法和用途。

  公开号：

  US20140031351A1
• 作为产物：
  描述：

  4-bromo-1-(isopropylsulfonyl)-2-nitrobenzene 在 吡啶 、 甲烷磺酸 、 palladium diacetate 、 potassium diazodicarboxylate 、 铁粉 、 sodium hydride 、 溶剂黄146 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 四氢呋喃 、 甲乙醚 、 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 129.0h， 生成 6-chloro-10-(propane-2-sulfonyl)-17-(4-methylpiperazin-1-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene
  参考文献：
  名称：

  Design, Synthesis, and Anaplastic Lymphoma Kinase (ALK) Inhibitory Activity for a Novel Series of 2,4,8,22-Tetraazatetracyclo[14.3.1.1^3,7.1^9,13]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene Macrocycles

  摘要：

  A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC50 = 0.5 nM) and cellular (IC50 = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.

  DOI：

  10.1021/jm201333e

文献信息

• [EN] MACROCYCLIC COMPOUNDS AS ALK, FAK AND JAK2 INHIBITORS<br/>[FR] COMPOSÉS MACROCYLCIQUES COMME INHIBITEURS D'ALK, DE FAK ET DE JAK2
  申请人：CEPHALON INC

  公开号：WO2012125603A1

  公开（公告）日：2012-09-20

  The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.

  本发明提供了式I的化合物或其药用可接受的盐形式，其中R1、R2、R3、R4、R5、A和X如本文所定义，以及其治疗方法和用途。
• MACROCYCLIC COMPOUNDS AS ALK, FAK AND JAK2 INHIBITORS
  申请人：Cephalon, Inc.

  公开号：US20170027948A1

  公开（公告）日：2017-02-02

  The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.
• US9487529B2
  申请人：——

  公开号：US9487529B2

  公开（公告）日：2016-11-08
• Design, Synthesis, and Anaplastic Lymphoma Kinase (ALK) Inhibitory Activity for a Novel Series of 2,4,8,22-Tetraazatetracyclo[14.3.1.1^3,7.1^9,13]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene Macrocycles
  作者：Henry J. Breslin、Brandon M. Lane、Gregory R. Ott、Arup K. Ghose、Thelma S. Angeles、Mark S. Albom、Mangeng Cheng、Weihua Wan、R. Curtis Haltiwanger、Kevin J. Wells-Knecht、Bruce D. Dorsey

  DOI：10.1021/jm201333e

  日期：2012.1.12

  A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC50 = 0.5 nM) and cellular (IC50 = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.
• Macrocyclic Compounds as ALK, FAK and JAK2 Inhibitors
  申请人：Cephalon, Inc.

  公开号：US20140031351A1

  公开（公告）日：2014-01-30

  The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.

  本发明提供了I式化合物或其药学上可接受的盐形式，其中R1、R2、R3、R4、R5、A和X的定义如本文所述，以及其治疗方法和用途。