4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methylaniline | 347161-76-6

• 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)-3-methylaniline
• 英文别名: 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methyl-aniline；4-(6,7-dimethoxyquinolin-4-yl)oxy-3-methylaniline
• CAS: 347161-76-6
• 化学式: C₁₈H₁₈N₂O₃
• 分子量: 310.353
• InChiKey: UOZCXYMRQHMNRC-UHFFFAOYSA-N

物化性质

• 沸点：
  483.3±45.0 °C(Predicted)
• 密度：
  1.222±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  66.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-三氟甲基苯磺酰氯 、 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methylaniline 在 吡啶 作用下， 反应 48.0h， 以59%的产率得到N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-methylphenyl]-2-trifluoromethylbenzenesulfonamide
  参考文献：
  名称：

  Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors

  摘要：

  The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL kinase. Through optimization and detailed SAR studies we developed low nanomolar inhibitors, and after further biological characterization we identified a potent AXL kinase inhibitor with favorable pharmacokinetic profile. The antitumor activity was determined in xenograft models, and the lead compounds reduced the tumor size by 40% with no observed toxicity as well as lung metastasis formation by 66% when compared to vehicle control.

  DOI：

  10.1021/acs.jmedchem.8b00672
• 作为产物：
  描述：

  2-甲基-4-硝基苯酚 以 氯苯 为溶剂， 生成 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methylaniline
  参考文献：
  名称：

  Orally active anti-proliferation agents: novel diphenylamine derivatives as FGF-R2 autophosphorylation inhibitors

  摘要：

  (6,7-二取代喹啉-4-基氧苯基)(4-取代苯基)胺衍生物通过在人瘢痕胃癌细胞系OCUM-2MD3中进行成纤维细胞生长因子受体2（FGF-R2）的细胞自体磷酸化试验而被合成和评估。我们还进行了代谢稳定性研究，结果显示喹啉环7位的取代基会影响其生物稳定性。在本研究中，我们显著改善了双苯胺衍生物的溶解性和代谢稳定性。最具潜力的化合物15e在口服给药时表现出肿瘤体积的显著减少。 ©2003 Elsevier Ltd. 保留所有权利。

  DOI：

  10.1016/j.bmcl.2003.12.019

文献信息

• 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。
• Pharmaceutically active compounds as Axl inhibitors
  申请人：Lead Discovery Center GmbH

  公开号：EP2423208A1

  公开（公告）日：2012-02-29

  The present invention relates to 1-nitrogen-heterocyclic-2-carboxamides of general formula (I): and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the treatment and/or prevention of Axl receptor tyrosine kinase subfamily induced disorders, including cancer and primary tumor metastases, and pharmaceutical compositions containing at least one of said 1-nitrogen-heterocyclic-2-carboxamide derivatives and/or pharmaceutically acceptable salts thereof.

  本发明涉及一般式(I)的1-氮杂环-2-羧酰胺及/或其药学上可接受的盐，这些衍生物作为药理活性剂的用途，特别用于治疗和/或预防Axl受体酪氨酸激酶亚家族引起的疾病，包括癌症和原发性肿瘤转移，以及含有至少一种上述1-氮杂环-2-羧酰胺衍生物和/或其药学上可接受的盐的药物组合物。
• [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。
• Quinoline derivatives and quinazoline derivatives having azolyl group
  申请人：KIRIN BEER KABUSHIKI KAISHA

  公开号：US20030087907A1

  公开（公告）日：2003-05-08

  An object of the present invention is to provide compounds having potent antitumor activity. The compounds according to the present invention are compounds represented by formula (I) or pharmaceutically acceptable salts or solvates thereof: 1 wherein X and Z represent CH or N; Y represents O or S; R 1 , R 2 , and R 3 represent H, alkoxy or the like; R 4 represents H; R 5 , R 6 , R 7 , and R 8 represent H, halogen, alkoxy or the like; R 9 and R 10 represent H, alkyl or the like; and R 11 represents optionally substituted azolyl.

  本发明的一个目的是提供具有强效抗肿瘤活性的化合物。根据本发明的化合物是由式（I）表示的化合物或其药学上可接受的盐或溶剂：其中X和Z表示CH或N；Y表示O或S；R1、R2和R3表示H、烷氧基或类似物；R4表示H；R5、R6、R7和R8表示H、卤素、烷氧基或类似物；R9和R10表示H、烷基或类似物；R11表示选择性取代的唑基。