4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluoroaniline | 228559-74-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluoroaniline
• 英文别名: 4-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-fluoroaniline；4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline；4-(6,7-dimethoxyquinolin-4-yl)oxy-2-fluoroaniline
• CAS: 228559-74-8
• 化学式: C₁₇H₁₅FN₂O₃
• 分子量: 314.316
• InChiKey: ZFGMJQSRPRXGMR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  66.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluoroaniline 在 二苯基膦叠氮化物 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 1.17h， 生成 1-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluorophenyl)-3-(4-(piperidin-4-ylidenemethyl)phenyl)urea
  参考文献：
  名称：

  发现具有 II 型抑制剂药效团的有效恶性疟原虫蛋白激酶 6 (PfPK6) 抑制剂

  摘要：

  疟疾是一种毁灭性的疾病，导致全球发病率和死亡率很高。对青蒿素联合疗法耐药性的上升表明有必要开发具有新作用机制的替代抗疟药。我们报告发现Ki8751作为必需激酶 PfPK6 的抑制剂。设计、合成并评估了 79 种衍生物的 PfPK6 抑制和抗疟原虫活性。通过群体效率分析，我们确定了与 II 型抑制剂药效团一致的支架上关键群体的重要性。我们强调了尾部基团上有助于抗疟原虫活性的修饰，最终发现了化合物67 （一种 PfPK6 抑制剂（IC 50 = 13 nM），对恶性疟原虫血液阶段（EC 50 = 160 nM）具有活性）和化合物79 ，一种 PfPK6 抑制剂 (IC 50 < 5 nM)，对恶性疟原虫血液期 (EC 50 = 39 nM) 和伯氏疟原虫肝脏期 (EC 50 = 220 nM) 具有双阶段抗疟原虫活性。

  DOI：

  10.1016/j.ejmech.2022.115043
• 作为产物：
  描述：

  2'-氨基-4',5'-二甲氧基苯乙酮 在 sodium methylate 、 氯化铵 、 锌 、 三氯氧磷 作用下， 以 甲醇 、 乙二醇二甲醚 、 氯苯 为溶剂， 反应 23.17h， 生成 4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluoroaniline
  参考文献：
  名称：

  Novel Potent Orally Active Selective VEGFR-2 Tyrosine Kinase Inhibitors:  Synthesis, Structure−Activity Relationships, and Antitumor Activities of N-Phenyl-N‘-{4-(4-quinolyloxy)phenyl}ureas

  摘要：

  N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC50 value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFR(x and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.

  DOI：

  10.1021/jm030427r

文献信息

• Nitrogen-containing aromatic derivatives
  申请人：——

  公开号：US20040053908A1

  公开（公告）日：2004-03-18

  Compounds represented by the following general formula: 1 [wherein A g is an optionally substituted 5- to 14-membered heterocyclic group, etc.; X g is —O—, —S—, etc.; Y g is an optionally substituted C 6 - 14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group, etc.; and T g1 is a group represented by the following general formula: 2 (wherein E g is a single bond or —N(R g2 )—, R g1 and R g2 each independently represent a hydrogen atom, an optionally substituted C 1-6 alkyl group, etc. and Z g represents a C 1-8 alkyl group, a C 3-8 alicyclic hydrocarbon group, a C 6-14 aryl group, etc.)], salts thereof or hydrates of the foregoing.

  由以下一般式表示的化合物： 1 [其中 A g 是可选择地取代的5-至14-成员杂环基团，等等；X g 是—O—，—S—，等等；Y g 是可选择地取代的C 6 - 14 芳基团，可选择地取代的5-至14-成员杂环基团，等等；以及 T g1 是由以下一般式表示的基团： 2 [其中 E g 是单键或—N(R g2 )—，R g1 和R g2 各自独立地表示氢原子，可选择地取代的C 1-6 烷基基团，等等，Z g 表示C 1-8 烷基基团，C 3-8 脂环烃基团，C 6-14 芳基团，等等]， 其盐或上述化合物的水合物。
• [EN] ECTONUCLEOTIDE PYROPHOSPHATASE-PHOSPHODIESTERASE 1 (ENPP-1) INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ECTONUCLÉOTIDE PYROPHOSPHATASE-PHOSPHODIESTÉRASE (ENPP-1) ET UTILISATIONS DE CES DERNIERS
  申请人：MAVUPHARMA INC

  公开号：WO2019046778A1

  公开（公告）日：2019-03-07

  Disclosed herein are methods and compounds of augmenting and enhancing the production of type I IFNs in vivo. In some embodiments, the compounds disclosed herein are ENPP-1 inhibitors, pharmaceutical compositions, and methods for the treatment of cancer or a viral infection.

  本文揭示了一种增强和促进体内I型干扰素产生的方法和化合物。在某些实施例中，本文所披露的化合物是ENPP-1抑制剂，药物组合物，以及用于治疗癌症或病毒感染的方法。
• Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)-<i>N</i>-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors
  作者：Yun Wu、Beilei Wang、Junjie Wang、Shuang Qi、Fengming Zou、Ziping Qi、Feiyang Liu、Qingwang Liu、Cheng Chen、Chen Hu、Zhenquan Hu、Aoli Wang、Li Wang、Wenchao Wang、Tao Ren、Yujiao Cai、Mingfeng Bai、Qingsong Liu、Jing Liu

  DOI：10.1021/acs.jmedchem.9b00280

  日期：2019.7.11

  Starting from our previously developed c-KIT kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding element hybrid design approach, we discovered a novel c-KIT kinase inhibitor compound 18 (CHMFL-KIT-64), which is potent against c-KIT wt and a broad spectrum of drug-resistant mutants with improved bioavailability. 18 exhibits single-digit nM potency against c-KIT kinase and c-KIT

  从我们先前开发的c-KIT激酶抑制剂CHMFL-KIT-8140开始，通过II型激酶抑制剂结合元件杂交设计方法，我们发现了一种新型的c-KIT激酶抑制剂化合物18（CHMFL-KIT-64），对抗c-KIT wt和具有改善的生物利用度的广谱耐药突变体。18在生化分析中显示出对c-KIT激酶和c-KIT T670I突变体的个位数nM效价，并且对近膜域中大多数功能获得性突变，ATP结合口袋中的耐药性突变均显示出极大的效价（V654A除外）和激活循环（D816V除外）。此外，18在不同物种（包括小鼠，大鼠和狗）中表现出良好的体内药代动力学（PK）特性。它还在c-KIT T670I，D820G，和Y823D突变体介导的小鼠模型以及在已知对伊马替尼具有抗性的c-KIT wt患者原代细胞中。结合广泛的临床重要c-KIT突变体的强大活性（具有良好的体内PK /药效学特性18）表明，它可能是胃肠道间质瘤的新潜在治疗候选物。
• [EN] QUINOLINE DERIVATIVES AS INHIBITORS OF AXL/MER RTK AND CSF1R<br/>[FR] DÉRIVÉS DE QUINOLÉINE UTILISÉS EN TANT QU'INHIBITEURS D'AXL/MER RTK ET CSF1R
  申请人：QURIENT CO LTD

  公开号：WO2019229251A1

  公开（公告）日：2019-12-05

  The present invention relates to quinoline derivatives which are inhibitors for Axl/Mer RTK (receptor tyrosine kinase) and CSF1R (colony stimulating factor 1 receptor). These compounds are suitable for the treatment of disorders associated with, accompanied by, caused by or induced by Axl/Mer RTK and CSF1R, in particular a hyperfunction thereof. The compounds are suitable for the treatment of hyperproliferative disorders, such as cancer, particularly immune-suppressive cancer (such as those cancers with an immunosuppression of innate immunity in a tumor microenvironment (TME), refractory cancer and cancer metastases. They are also useful in the treatment of inflammatory diseases and/or neurodegenerative diseases.

  本发明涉及喹啉衍生物，其为Axl/Mer RTK（受体酪氨酸激酶）和CSF1R（集落刺激因子1受体）的抑制剂。这些化合物适用于治疗与Axl/Mer RTK和CSF1R相关、伴随、由其引起或诱导的疾病，特别是其中的过度功能。这些化合物适用于治疗过度增殖性疾病，如癌症，特别是免疫抑制性癌症（例如在肿瘤微环境中具有天然免疫抑制的癌症、难治性癌症和癌症转移）。它们还可用于治疗炎症性疾病和/或神经退行性疾病。
• [EN] URACIL DERIVATIVES AS AXL AND C-MET KINASE INHIBITORS<br/>[FR] DÉRIVÉS D'URACILE COMME INHIBITEURS D'AXL ET C-MET KINASES
  申请人：CEPHALON INC

  公开号：WO2013074633A1

  公开（公告）日：2013-05-23

  The present invention provides compounds of Formula I, or pharmaceutically acceptable salt forms thereof, wherein Ra, Rb, Rc, Rd, D, W, R1a, R1b, R1c,Y, R3, X, E and G are as defined herein, methods of treatment and uses thereof.

  本发明提供了式I的化合物，或其药用盐形式，其中Ra、Rb、Rc、Rd、D、W、R1a、R1b、R1c、Y、R3、X、E和G的定义如本文所述，以及其治疗方法和用途。