N-(4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)-6-(2-(dimethylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine | 2102887-41-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-(4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)-6-(2-(dimethylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
• 英文别名: 484Eda7kem；N-[4-(3-cyclopropyl-7-fluoro-2-methylbenzimidazol-5-yl)-5-fluoropyrimidin-2-yl]-6-[2-(dimethylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine
• CAS: 2102887-41-0
• 化学式: C₂₇H₃₀F₂N₈
• 分子量: 504.586
• InChiKey: UZUCFTPPULEGQO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  75
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-(4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)-6-(2-(dimethylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine 在 盐酸 作用下， 以 丙酮 为溶剂， 生成
  参考文献：
  名称：

  WO2022/171117

  摘要：

  公开号：
• 作为产物：
  描述：

  1,1-二甲基乙基2-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸 在 盐酸 、 tris-(dibenzylideneacetone)dipalladium(0) 、 三乙酰氧基硼氢化钠 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 35.0h， 生成 N-(4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)-6-(2-(dimethylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  参考文献：
  名称：

  Discovery of 6-(2-(dimethylamino)ethyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine as a highly potent cyclin-dependent kinase 4/6 inhibitor for treatment of cancer

  摘要：

  Targeting CDK4/6 has been identified as an effective therapeutics for treatment of cancer. We herein reported the discovery of a series of 6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine derivatives as CDK4/6 inhibitors against cancer. Compound 3c, which displayed high potency and selectivity on CDK4/6 (IC50 = 0.710/1.10 nM) over a variety of other kinases, possessed desirable antiproliferative activities, excellent metabolic properties, and favorable pharmacokinetic characters. In MCF-7, Colo-205, and A549 xenograft models, compound 3c exhibited significant tumor growth inhibitions with low toxicities, which could be a promising drug candidate for further development. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.06.005

文献信息

• NITROGEN-CONTAINING FUSED HETEROCYCLIC COMPOUND, AS WELL AS PREPARATION METHOD, INTERMEDIATE, COMPOSITION AND APPLICATION THEREOF
  申请人：SHANGHAI PHARMACEUTICALS HOLDING CO., LTD.

  公开号：US20190010153A1

  公开（公告）日：2019-01-10

  The present invention discloses a nitrogen-containing fused heterocyclic compound, as well as a preparation method, intermediate, composition and application thereof. The nitrogen-containing fused heterocyclic compound of the present invention as represented by formula (I), as well as the pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, metabolite or drug precursor thereof, exhibit a high selectivity and a high inhibitory activity with respect to CDK4 and CDK6 at a molecular level, an excellent inhibitory activity with respect to breast cancer cells at a cellular level, and significant inhibition of tumor cell proliferation associated with cyclin-dependent kinase activity at an animal level. The invention also exhibits a good stability with respect to human or mouse liver microsomes without significant inhibition of metabolic enzymes, good in vivo absorption in mice and rats, a high bioavailability and good druggability.

  本发明公开了一种含氮融合杂环化合物，以及其制备方法、中间体、组合物和应用。本发明的含氮融合杂环化合物如公式(I)所示，以及其药学上可接受的盐、对映体、二对映体、互变异构体、溶剂合物、代谢物或药物前体，在分子水平上对CDK4和CDK6表现出高选择性和高抑制活性，在细胞水平上对乳腺癌细胞表现出优异的抑制活性，并在动物水平上显著抑制与细胞周期依赖性激酶活性相关的肿瘤细胞增殖。该发明还在人类或小鼠肝微粒体中表现出良好的稳定性，没有显著抑制代谢酶，对小鼠和大鼠体内吸收良好，具有高生物利用度和良好的药物可用性。
• Substituted pyrimidines as cyclin-dependent kinase inhibitors
  申请人：SHANGHAI PHARMACEUTICALS HOLDING CO., LTD.

  公开号：US10662186B2

  公开（公告）日：2020-05-26

  The present invention discloses a nitrogen-containing fused heterocyclic compound, as well as a preparation method, intermediate, composition and application thereof. The nitrogen-containing fused heterocyclic compound of the present invention as represented by formula (I), as well as the pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, metabolite or drug precursor thereof, exhibit a high selectivity and a high inhibitory activity with respect to CDK4 and CDK6 at a molecular level, an excellent inhibitory activity with respect to breast cancer cells at a cellular level, and significant inhibition of tumor cell proliferation associated with cyclin-dependent kinase activity at an animal level. The invention also exhibits a good stability with respect to human or mouse liver microsomes without significant inhibition of metabolic enzymes, good in vivo absorption in mice and rats, a high bioavailability and good druggability.

  本发明公开了一种含氮融合杂环化合物及其制备方法、中间体、组合物和应用。本发明的由式（I）表示的含氮融合杂环化合物及其药学上可接受的盐、对映体、非对映体、同分异构体、溶媒、代谢物或药物前体、在分子水平上对 CDK4 和 CDK6 具有高选择性和高抑制活性，在细胞水平上对乳腺癌细胞具有优异的抑制活性，在动物水平上显著抑制与细胞周期蛋白依赖性激酶活性相关的肿瘤细胞增殖。本发明在人或小鼠肝脏微粒体中也表现出良好的稳定性，对代谢酶无明显抑制作用，在小鼠和大鼠体内吸收良好，生物利用度高，可药用性好。
• [EN] NITROGEN-CONTAINING FUSED HETEROCYCLIC COMPOUND, AS WELL AS PREPARATION METHOD, INTERMEDIATE, COMPOSITION AND APPLICATION THEREOF<br/>[FR] COMPOSÉ HÉTÉROCYCLIQUE CONDENSÉ CONTENANT DE L'AZOTE, AINSI QUE PROCÉDÉ DE PRÉPARATION, INTERMÉDIAIRE, COMPOSITION ET APPLICATION ASSOCIÉS<br/>[ZH] 含氮稠杂环化合物、制备方法、中间体、组合物和应用
  申请人：SHANGHAI PHARMACEUTICALS HOLDING CO LTD

  公开号：WO2017114512A1

  公开（公告）日：2017-07-06

  本发明公开了含氮稠杂环化合物、制备方法、中间体、组合物和应用。本发明的如式I所示的含氮稠杂环化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其代谢产物或其药物前体，在分子水平对CDK4和CDK6的选择性高，且对其的抑制活性高，其在细胞水平对乳腺癌细胞的抑制活性较佳，其在动物水平对与周期蛋白依赖性激酶活性相关的肿瘤细胞也具有显著的抑制增殖作用，而且其对于人、鼠的肝微粒体稳定性良好，代谢酶无明显抑制，大小鼠体内吸收性质好，生物利用度高，具有较好的成药性。
• [EN] SALT OF NITROGEN-CONTAINING FUSED HETEROCYCLIC COMPOUND OR CRYSTAL FORM THEREOF, AND PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION THEREOF, AND USE THEREOF<br/>[FR] SEL DE COMPOSÉ HÉTÉROCYCLIQUE CONDENSÉ CONTENANT DE L'AZOTE OU FORME CRISTALLINE DE CELUI-CI, ET PROCÉDÉ DE PRÉPARATION CORRESPONDANT, COMPOSITION PHARMACEUTIQUE ET UTILISATION ASSOCIÉES<br/>[ZH] 含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途
  申请人：[en]SHANGHAI PHARMACEUTICALS HOLDING CO., LTD.;[zh]上海医药集团股份有限公司

  公开号：WO2022171117A1

  公开（公告）日：2022-08-18

  含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途，特别是涉及如下所示的化合物I的盐、晶型及制备方法、药物组合物和用途。所述的化合物I盐或其晶型表现出了以下至少一方面优势：改善的生物利用率，良好的力学性质、改善的化学稳定性，优秀的流动性质，良好的压缩性和改善的溶解特征。
• Substituted Pyrimidine Compound for Treating Cancer
  申请人：SHANGHAI PHARMACEUTICALS HOLDING CO., LTD.

  公开号：US20200239470A1

  公开（公告）日：2020-07-30

  The present invention discloses a substituted pyridine compound represented by formula I, and a pharmaceutically acceptable salt, stereoisomer and tautomer thereof. The compounds of the present invention are useful in the treatment of cancers.