3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline | 347161-75-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline
• 英文别名: 3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine；3-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline；3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)aniline；4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-chloroaniline；3-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyaniline
• CAS: 347161-75-5
• 化学式: C₁₇H₁₅ClN₂O₃
• 分子量: 330.771
• InChiKey: DCFZOECVVBSZLL-UHFFFAOYSA-N

物化性质

• 沸点：
  493.3±45.0 °C(Predicted)
• 密度：
  1.325±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 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：
  5

反应信息

• 作为反应物：
  描述：

  2,4-二氟苯基异氰酸酯 、 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline 以 甲苯 为溶剂， 反应 0.5h， 以74%的产率得到1-[3-Chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea
  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
• 作为产物：
  描述：

  2'-氨基-4',5'-二甲氧基苯乙酮 在 sodium methylate 、 sodium hydride 、 三氯氧磷 作用下， 以 乙二醇二甲醚 、 二甲基亚砜 为溶剂， 反应 15.34h， 生成 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline
  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

• 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。
• 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。
• Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor and medicinal composition containing the same
  申请人：——

  公开号：US20040242603A1

  公开（公告）日：2004-12-02

  An objective of the present invention is to provide compounds having potent antitumor activity. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: 1 wherein X=CH or N; Z=O or S; L=O or S; M=CR 10 R 11 , wherein R 10 and R 11 =H, alkyl, or alkoxy, NR 12 wherein R 12 =H or alkyl; R 1 , R 2 , and R 3 =H or optionally substituted alkoxy; R 4 =H; R 5-8 =H, halogen, alkoxy or the like; and R 9 =alkyl optionally substituted by —R 14 , -T-R 15 , or —NR 16 R 17 wherein T=O, S, or NH; R 14 =an optionally substituted carbocyclic or heterocyclic ring; and R 15-17 =alkyl or an optionally substituted carbocyclic or heterocyclic ring, or —NR 18 R 19 wherein R 18 and R 19 =H, optionally substituted alkyl, or an optionally substituted carbocylic or heterocyclic ring, or optionally substituted carbocyclic or heterocyclic ring.

  本发明的目标是提供具有强效抗肿瘤活性的化合物。本发明的化合物由以下式子（I）或其药学上可接受的盐或溶剂表示：1其中X = CH或N；Z = O或S；L = O或S；M = CR10R11，其中R10和R11 = H，烷基或烷氧基，NR12，其中R12 = H或烷基；R1、R2和R3 = H或可选取代烷氧基；R4 = H；R5-8 = H、卤素、烷氧基或类似物；以及R9 = 烷基，可选取代-R14、-T-R15或-NR16R17，其中T = O、S或NH；R14 = 可选取代的碳环或杂环；R15-17 = 烷基或可选取代的碳环或杂环，或-NR18R19，其中R18和R19 = H、可选取代的烷基或可选取代的碳环或杂环，或可选取代的碳环或杂环。