1-Chloro-5-cyclobutyloxy-2-methyl-4-nitrobenzene | 1445894-86-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-Chloro-5-cyclobutyloxy-2-methyl-4-nitrobenzene
• 英文别名: 1-chloro-5-cyclobutyloxy-2-methyl-4-nitrobenzene
• CAS: 1445894-86-9
• 化学式: C₁₁H₁₂ClNO₃
• 分子量: 241.674
• InChiKey: MMIFNXPJOFEOJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  55
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-Chloro-5-cyclobutyloxy-2-methyl-4-nitrobenzene 在 2-双环己基膦-2',6'-二甲氧基联苯 、 platinum(IV) oxide 、 tris-(dibenzylideneacetone)dipalladium(0) 、 氢气 、 palladium diacetate 、 caesium carbonate 、 溶剂黄146 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 20.0~150.0 ℃ 、101.33 kPa 条件下， 反应 0.5h， 生成 5-chloro-N2-(2-cyclobutoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine
  参考文献：
  名称：

  Synthesis, Structure–Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials

  摘要：

  The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

  DOI：

  10.1021/jm400402q
• 作为产物：
  描述：

  2-氯-4-氟甲苯 在 硫酸 、 caesium carbonate 、 potassium nitrate 作用下， 生成 1-Chloro-5-cyclobutyloxy-2-methyl-4-nitrobenzene
  参考文献：
  名称：

  Synthesis, Structure–Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials

  摘要：

  The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

  DOI：

  10.1021/jm400402q

文献信息

• Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-<i>a</i>]pyridine Scaffold: SAR of the Aryloxyaryl Moiety
  作者：Stefano Sainas、Marta Giorgis、Paola Circosta、Giulio Poli、Marta Alberti、Alice Passoni、Valentina Gaidano、Agnese C. Pippione、Nicoletta Vitale、Davide Bonanni、Barbara Rolando、Alessandro Cignetti、Cristina Ramondetti、Alessia Lanno、Davide M. Ferraris、Barbara Canepa、Barbara Buccinnà、Marco Piccinini、Menico Rizzi、Giuseppe Saglio、Salam Al-Karadaghi、Donatella Boschi、Riccardo Miggiano、Tiziano Tuccinardi、Marco L. Lolli

  DOI：10.1021/acs.jmedchem.2c00496

  日期：2022.10.13

  In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure–activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design

  近年来，人类二氢乳清酸脱氢酶抑制剂与急性髓性白血病有关，并被研究为有效的靶向抗病毒药物宿主。从MEDS433（IC 50 1.2 nM）开始，我们不断完善这类以2-羟基吡唑并[1,5- a ]吡啶骨架为特征的化合物的构效关系。使用计算机/晶体学支持的设计，我们鉴定了化合物4 (IC 50 7.2 nM)，其特征是存在取代联苯支架的修饰芳氧基芳基部分，对 AML THP1 细胞具有有效的抑制和促分化能力 (EC 50 74 nM)，优于布喹那 (EC 50 249 nM)，与双嘧达莫合用时效果增强。最后，化合物4对非 AML 细胞以及 MEDS433 具有极低的细胞毒性；它在 AML 异种移植小鼠模型中显示出显着的体内抗白血病活性。
• Synthesis, Structure–Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-<i>N</i>2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-<i>N</i>4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials
  作者：Thomas H. Marsilje、Wei Pei、Bei Chen、Wenshuo Lu、Tetsuo Uno、Yunho Jin、Tao Jiang、Sungjoon Kim、Nanxin Li、Markus Warmuth、Yelena Sarkisova、Frank Sun、Auzon Steffy、AnneMarie C. Pferdekamper、Allen G. Li、Sean B. Joseph、Young Kim、Bo Liu、Tove Tuntland、Xiaoming Cui、Nathanael S. Gray、Ruo Steensma、Yongqin Wan、Jiqing Jiang、Greg Chopiuk、Jie Li、W. Perry Gordon、Wendy Richmond、Kevin Johnson、Jonathan Chang、Todd Groessl、You-Qun He、Andrew Phimister、Alex Aycinena、Christian C. Lee、Badry Bursulaya、Donald S. Karanewsky、H. Martin Seidel、Jennifer L. Harris、Pierre-Yves Michellys

  DOI：10.1021/jm400402q

  日期：2013.7.25

  The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.