3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺 | 1350377-66-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺
• 英文名称: 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• 英文别名: 3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
• CAS: 1350377-66-0
• 化学式: C₁₃H₂₀BNO₃
• 分子量: 249.118
• InChiKey: ZYFRJTZQMFNEHS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.58
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  53.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺 在 potassium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 4.0h， 生成 N-[4-[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3-methoxyphenyl]acetamide
  参考文献：
  名称：

  Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

  摘要：

  The present study describes our continuous effort to develop epidermal growth factor receptor (EGFR) inhibitors based on the 6-aryl-pyrrolo[2,3-d]pyrimidin-4-amine scaffold. The activity-ADME space has been evaluated by synthesizing 43 new structures, including four variations of the 4-amino group and 34 different substitution patterns in the 6-aryl moiety. Most of the new pyrrolopyrimidines were highly active, with twelve analogues possessing lower IC50 values than the commercial drug Erlotinib in enzymatic assays. Ten EGFR inhibitors were also profiled in cell studies using the Ba/F3-EGFR(L858R) reporter cells, and all revealed nanomolar activity. However, some of the privileged structures in terms of potency had ADME short-comings: compounds containing amides, sulfonamides, amine and hydroxymethyl substituents in the 6-aryl group had low permeability and high efflux, derivatives having (R)-3amino-3-phenylpropan-1-ol at C-4 induced hERG inhibition properties, and metabolic lability was seen for compounds having (S)-2-methoxy-1-phenylethan-1-amine at C-4. Based on a trade-off between enzymatic activity, cellular potency and ADME properties, (S)-2-phenyl-2-((6-phenyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino)ethan-1-ol appeared as the most promising drug candidate. Cellular studies indicate this compound to have therapeutic use in EGFR driven diseases. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.08.068
• 作为产物：
  描述：

  间氨基苯甲醚 在 2-双环己基膦-2',6'-二甲氧基联苯 、 双(乙腈)氯化钯(II) 、 N-溴代丁二酰亚胺(NBS) 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 42.0h， 生成 3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺
  参考文献：
  名称：

  Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

  摘要：

  The present study describes our continuous effort to develop epidermal growth factor receptor (EGFR) inhibitors based on the 6-aryl-pyrrolo[2,3-d]pyrimidin-4-amine scaffold. The activity-ADME space has been evaluated by synthesizing 43 new structures, including four variations of the 4-amino group and 34 different substitution patterns in the 6-aryl moiety. Most of the new pyrrolopyrimidines were highly active, with twelve analogues possessing lower IC50 values than the commercial drug Erlotinib in enzymatic assays. Ten EGFR inhibitors were also profiled in cell studies using the Ba/F3-EGFR(L858R) reporter cells, and all revealed nanomolar activity. However, some of the privileged structures in terms of potency had ADME short-comings: compounds containing amides, sulfonamides, amine and hydroxymethyl substituents in the 6-aryl group had low permeability and high efflux, derivatives having (R)-3amino-3-phenylpropan-1-ol at C-4 induced hERG inhibition properties, and metabolic lability was seen for compounds having (S)-2-methoxy-1-phenylethan-1-amine at C-4. Based on a trade-off between enzymatic activity, cellular potency and ADME properties, (S)-2-phenyl-2-((6-phenyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino)ethan-1-ol appeared as the most promising drug candidate. Cellular studies indicate this compound to have therapeutic use in EGFR driven diseases. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.08.068

文献信息

• Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors
  作者：Veronica Calvo、David Surguladze、An-Hu Li、Matthew D. Surman、Srikanth Malibhatla、Madhavarao Bandaru、Suresh Krishna Jonnalagadda、Ravi Adarasandi、Madhusudhan Velmala、Durga Rama Prasad Singireddi、Mahendar Velpuri、Bhaskar Reddy Nareddy、Visweswara Sastry、Chiranjeevi Mandati、Rambabu Guguloth、Shapi Siddiqui、Basanagoud S. Patil、Elena Chad、Jennifer Wolfley、Jennifer Gasparek、Kirsten Feldman、Matthew Betzenhauser、Brent Wiens、Mary Koszelak-Rosenblum、Guangyu Zhu、Hongwen Du、Alan C. Rigby、Mark J. Mulvihill

  DOI：10.1016/j.bmcl.2021.128058

  日期：2021.7

  identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Given these data, this compound (28) was studied in the

  蛋白激酶 R (PKR) 样内质网激酶 (PERK) 是未折叠蛋白反应 (UPR) 的三种内质网 (ER) 跨膜传感器之一，可调节蛋白质合成、减轻细胞内质网应激并与肿瘤发生有关并延长癌细胞的存活时间。在这项研究中，我们报告了一系列 2-amino-3-amido-5-aryl-pyridines，我们已将其确定为有效、选择性和口服生物可利用的 PERK 抑制剂。在本文研究的系列中，化合物( 28 )a( R )-2-氨基-5-(4-(2-(3,5-二氟苯基)-2-羟基乙酰氨基)-2-乙基苯基) -N-异丙基烟酰胺已在小鼠中显示出有效的生化和细胞活性、强大的药代动力学和 70% 的口服生物利用度。鉴于这些数据，在 786-O 肾细胞癌异种移植模型中研究了该化合物 ( 28 )。我们观察到剂量依赖性、统计学上显着的肿瘤生长抑制，支持在其他机制研究中使用该工具化合物。
• PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS
  申请人：ALMIRALL, S.A.

  公开号：US20150291595A1

  公开（公告）日：2015-10-15

  New pyrrolotriazinone derivatives having the chemical structure of Formula (I) are disclosed; as well as process for theft preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).

  本发明揭示了具有化学结构式（I）的新吡咯三唑酮衍生物；以及其制备过程，包括它们的药物组合物和它们作为磷脂酰肌醇3-激酶（PI3Ks）抑制剂在治疗中的用途。
• Pyrrolotriazinone derivatives as PI3K inhibitors
  申请人：ALMIRALL, S.A.

  公开号：US09388189B2

  公开（公告）日：2016-07-12

  New pyrrolotriazinone derivatives having the chemical structure of Formula (I) are disclosed; as well as process for theft preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).

  本发明揭示了具有化学结构式（I）的新吡咯三嗪衍生物；以及制备它们的方法，包括含有它们的制药组合物和它们作为磷脂酰肌醇3-激酶（PI3Ks）抑制剂在治疗中的用途。
• Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors
  作者：Michael E. Stokes、Matthew D. Surman、Veronica Calvo、David Surguladze、An-Hu Li、Jennifer Gasparek、Matthew Betzenhauser、Guangyu Zhu、Hongwen Du、Alan C. Rigby、Mark J. Mulvihill

  DOI：10.3390/pharmaceutics14102233

  日期：——

  alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway

  蛋白激酶 R (PKR) 样内质网激酶 (PERK) 是负责调节蛋白质合成和缓解 ER 应激的未折叠蛋白反应 (UPR) 的三种内质网 (ER) 跨膜传感器之一。PERK 与肿瘤发生、癌细胞存活以及糖尿病等代谢疾病有关。本文所述的新型扁桃酰胺衍生的吡咯并嘧啶系列 PERK 抑制剂的基于结构的设计和优化导致化合物26的鉴定，该化合物是一种有效的、选择性的和口服生物可利用的化合物，适用于体外和体内研究 PERK 通路生物学, 具有适用于小鼠每天一次口服给药的药代动力学。
• [EN] CITRON KINASE INHIBITORS<br/>[FR] INHIBITEURS DE CITRON KINASE
  申请人：CLEVELAND CLINIC FOUND

  公开号：WO2022216717A1

  公开（公告）日：2022-10-13

  Disclosed herein are compounds that are citron kinase inhibitors, pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in a method of treating cancer, such as medulloblastoma or prostate cancer.

  本文披露了一些柠檬酸激酶抑制剂化合物，包括含有这些化合物的制药组合物以及使用这些化合物的方法，例如用于治疗癌症的方法，例如髓母细胞瘤或前列腺癌。