tert-butyl 4-((6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate | 1346151-06-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: tert-butyl 4-((6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate
• 英文别名: Tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate；tert-butyl 4-[(6-hydroxy-3-oxo-1-benzofuran-7-yl)methyl]piperazine-1-carboxylate
• CAS: 1346151-06-1
• 化学式: C₁₈H₂₄N₂O₅
• 分子量: 348.399
• InChiKey: QXOVXHJBAWQSOP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  79.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-((6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate 在 哌啶 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 为溶剂， 反应 7.0h， 生成 (Z)-tert-butyl 4-({2-[(1H-indol-3-yl)methylene]-3-oxo-6-propropoxy-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate
  参考文献：
  名称：

  ANTICANCER AGENT

  摘要：

  公开号：

  EP2565192B9
• 作为产物：
  描述：

  聚合甲醛 、 6-羟基-2H-苯并呋喃-3-酮 、 N-Boc-哌嗪 以 乙醇 为溶剂， 以43%的产率得到tert-butyl 4-((6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate
  参考文献：
  名称：

  第四代EGFR抑制剂抗药性非小细胞肺癌的合理计算设计

  摘要：

  尽管单突变表皮生长因子受体（EGFR）激酶的抑制剂可有效治疗非小细胞肺癌（NSCLC），但由于各种具有耐药性的双重和三重EGFR突变体的出现，其临床疗效受到了限制。因此，鉴定对第一，第二和第三代EGFR抑制剂具有抗性的三重突变EGFR的有效和选择性抑制剂已变得迫在眉睫。在此，我们报告了发现了有效且高度选择性的EGFR外显子19 p.E746_A750del / EGFR外显子20 p.T790M / EGFR外显子20 p.C797S（d746-750 / T790M / C797S）突变体的抑制剂，这些突变体是通过两个跟踪虚拟筛选和从头设计。进行这种两轨方法以便最大化和最小化分别对三重突变体和野生型的抑制活性。最初命中化合物的广泛化学修饰导致鉴定了d746-750 / T790M / C797S突变体的几种低纳摩尔抑制剂。其中，与野生型相比，两种化合物在抑制EGFRd746-750 / T790M

  DOI：

  10.3390/ijms21239323

文献信息

• Design and Synthesis of Potent and Selective PIM Kinase Inhibitors by Targeting Unique Structure of ATP-Binding Pocket
  作者：Hirofumi Nakano、Tsukasa Hasegawa、Hirotatsu Kojima、Takayoshi Okabe、Tetsuo Nagano

  DOI：10.1021/acsmedchemlett.6b00518

  日期：2017.5.11

  In the development of kinase inhibitors, one of the major concerns is selectivity. An effective strategy to achieve high selectivity is to utilize structural differences among kinases to inform inhibitor design. Here, we set out to improve the PIM (proviral integration site for Moloney murine leukemia virus) kinase-inhibitory selectivity of our previously reported 7-azaindole derivative 2, which has

  在激酶抑制剂的开发中，主要关注之一是选择性。实现高选择性的有效策略是利用激酶之间的结构差异来指导抑制剂设计。在这里，我们着眼于通过ATP结合口袋中的独特凸起来改善我们先前报道的7-氮杂吲哚衍生物2的PIM（莫洛尼鼠白血病病毒的肠道整合位点）激酶抑制选择性。6位取代的7-氮杂吲哚，尤其是6位氯化的衍生物，被证明是有效的选择性PIM激酶抑制剂，并且似乎是未来药物开发的有前途的先导化合物。
• KINASE INHIBITOR
  申请人：THE UNIVERSITY OF TOKYO

  公开号：US20170145005A1

  公开（公告）日：2017-05-25

  [Problem] To provide a novel PIM-3 inhibitor and a novel cancer therapeutic drug, in particular, a therapeutic drug for pancreatic cancer. [Solution] A PIM-3 kinase inhibitor comprising a compound represented by general formula (I) or a pharmacologically acceptable salt, hydrate or solvate thereof.

  提供一种新颖的PIM-3抑制剂和一种新型的癌症治疗药物，特别是胰腺癌的治疗药物。解决方案是一种包括通用式(I)所代表的化合物或其药理学上可接受的盐、水合物或溶剂的PIM-3激酶抑制剂。
• Anticancer agent
  申请人：Nagano Tetsuo

  公开号：US09156827B2

  公开（公告）日：2015-10-13

  An anticancer agent comprising a compound represented by the formula (I) [R1 represents hydrogen atom, hydroxyl group, a C1-6 alkoxy group and the like; R2 and R3 represents hydrogen atom, a halogen atom, a C1-6 alkyl group and the like; R4 represents hydrogen atom, a C1-6 alkyl group, a C1-6 alkylsulfonyl group and the like; R5 represents hydrogen atom or a substituent; represents a single bond or a double bond; R6 and R7 represents hydrogen atom, a C1-6 alkyl group and the like; R8 represents hydrogen atom, a C1-6 alkyl group and the like; A represents —O—, —S—, or —CH2—; D represents —C═ or —N═; X represents methylene group, —O—, or —CO—; Q represents —N═ or —C(R8)═; and Y represents a heterocyclic group or amino group], which shows a superior inhibitory activity against pim-1 kinase.

  一种抗癌剂，包括由公式（I）所代表的化合物 [ R1 代表氢原子、羟基、C1-6烷氧基等； R2 和 R3 代表氢原子、卤素原子、C1-6烷基等； R4 代表氢原子、C1-6烷基、C1-6烷基磺酰基等； R5 代表氢原子或取代基； 表示单键或双键； R6 和 R7 代表氢原子、C1-6烷基等； R8 代表氢原子、C1-6烷基等； A 代表-O-、-S-或-CH2-； D 代表-C═或-N═； X 代表亚甲基基、-O-或-CO-； Q 代表-N═或-C(R8)═； Y 代表杂环基或氨基]，该化合物对pim-1激酶具有卓越的抑制活性。
• Synthesis of (Z)-2-((1H-indazol-3-yl)methylene)-6-[11C]methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one as a new potential PET probe for imaging of the enzyme PIM1
  作者：Mingzhang Gao、Min Wang、Kathy D. Miller、Qi-Huang Zheng

  DOI：10.1016/j.bmcl.2013.05.091

  日期：2013.8

  (Z)-2-((1H-Indazol-3-yl)methylene)-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one is a potent and selective proviral integration site in moloney murine leukemia virus kinase 1 (PIM1) inhibitor with an IC50 value of 3 nM. (Z)-2-((1H-Indazol-3-yl)methylene)-6-[C-11]methoxy-7-(piperazin-1-ylmethyl) benzofuran-3(2H)-one, a new potential PET probe for imaging of the enzyme PIM1, was first designed and synthesized in 20-30% decay corrected radiochemical yield and 370-740 GBq/mu mol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled Boc-protected intermediate followed by a quick acidic de-protection. (C) 2013 Elsevier Ltd. All rights reserved.
• Rational Evolution of a Novel Type of Potent and Selective Proviral Integration Site in Moloney Murine Leukemia Virus Kinase 1 (PIM1) Inhibitor from a Screening-Hit Compound
  作者：Hirofumi Nakano、Nae Saito、Lorien Parker、Yukio Tada、Masanao Abe、Keiko Tsuganezawa、Shigeyuki Yokoyama、Akiko Tanaka、Hirotatsu Kojima、Takayoshi Okabe、Tetsuo Nagano

  DOI：10.1021/jm3001289

  日期：2012.6.14

  Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.