N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4-methylphenyl)-3-(trifluoromethyl)benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4-methylphenyl)-3-(trifluoromethyl)benzamide
• 英文别名: N-[4-methyl-3-[[3-(7H-purin-6-yl)pyridin-2-yl]amino]phenyl]-3-(trifluoromethyl)benzamide
• 化学式: C₂₅H₁₈F₃N₇O
• 分子量: 489.459
• InChiKey: ANPGGCNBNSJETG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3-三氟甲基苯甲酸 在 盐酸 、 5%-palladium/activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.17h， 生成 N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4-methylphenyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors

  摘要：

  By combining the scaffolds of UI-125 and Sorafenib, a series of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine moiety were designed and synthesized as novel DFG-out B-Raf(V600E) inhibitors. Among them, 20c-e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-Raf(V600E)) cell lines with IC50 values of 3.190, 2276, 1.856, 1.632 mu M and 1.839 mu M, respectively, comparable with the positive control Vemurafenib (IC50 = 3.32 mu M). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-Raf(V600E)) and SK-MEL-2 (B-Raf(WT)) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-Raf(V600E)) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-Rat(WT)). Eventually, 20g and 21h were selected to confirm their inhibitory effects on tumor growth in A375 xenograft models in mice. Compound 20g exhibited equivalent antitumor efficacy in vivo (T/C = 44.37%), compared to Sorafenib (T/C = 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.10.039

文献信息

• [EN] 6-SUBSTITUTED-9H-PURINE DERIVATIVES AND RELATED USES<br/>[FR] DÉRIVÉS DE 9H-PURINE SUBSTITUÉS EN POSITION 6 ET UTILISATIONS ASSOCIÉES
  申请人：BLACK DIAMOND THERAPEUTICS INC

  公开号：WO2022178256A1

  公开（公告）日：2022-08-25

  The present disclosure relates compounds of Formula (I'): and pharmaceutically acceptable salts and stereoisomers thereof. The present disclosure also relates to methods of preparing the compounds, compositions comprising the compounds, and methods of using the compounds, e.g., in the treatment of cancer.

  本公开涉及公式（I'）化合物及其药学上可接受的盐和立体异构体。本公开还涉及制备该化合物的方法，包含该化合物的组合物，以及使用该化合物的方法，例如在癌症治疗中的应用。
• Discovery of dual inhibitors of <scp>pan‐RAF</scp> and <scp>VEGFR2</scp>
  作者：Eun Sun Park、Jihye Choi、Sung Pyo Hong、Ho‐Seok Kwon、Jinho Kim、Soon Kil Ahn

  DOI：10.1002/bkcs.12721

  日期：2023.10

  45% of colorectal cancer patients. Early-stage BRAF-specific inhibitors have been developed to prevent aberrant activation of RAS/RAF/MEK/ERK signaling caused by K-Ras mutation, however, these BRAF-specific inhibitors lead to RAF dimer formation and paradoxical CRAF activation. Consequently, there is a need to develop pan-RAF inhibitors. In addition, it was reported that the inhibition of vascular

  结直肠癌是全球最常见和致命的恶性肿瘤之一，约 45% 的结直肠癌患者存在 K-RAs 突变。早期 BRAF 特异性抑制剂已被开发用于防止 K-RAs 突变引起的 RAS/RAF/MEK/ERK 信号传导异常激活，然而，这些 BRAF 特异性抑制剂导致 RAF 二聚体形成和矛盾的 CRAF 激活。因此，需要开发泛RAF抑制剂。此外，据报道，抑制血管内皮生长因子受体2（VEGFR2）对于结直肠癌的治疗至关重要。本研究中，我们设计并合成了94个N- (苯基)-3-(9H-嘌呤-6-基)吡啶-2-胺衍生物，并发现N- (5-(3-(9H-嘌呤) -6-基)吡啶-2-基氨基)-2-氟苯基)-3-(三氟甲基)苯甲酰胺 ( 15h )、3-(2-氰基丙烷-2-基)苯甲酰胺衍生物16h和 3,5-双(三氟甲基) ) 苯甲酰胺衍生物17ab是针对 LS513（分别为 GI 50  = 0.08、0.2 和 0
• PYRIDINE DERIVATIVE INHIBITING RAF KINASE AND VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR, METHOD FOR PREPARING SAME, PHARMACEUTICAL COMPOSITION CONTAINING SAME, AND USE THEREOF
  申请人：Samjin Pharmaceutical Co., Ltd.

  公开号：EP3412670A1

  公开（公告）日：2018-12-12

  The present invention provides a novel pyridine derivative, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient. The pyridine derivative according to the present invention inhibits Raf kinase (B-Raf, Raf-1, or B-RafV600E) and a vascular endothelial growth factor receptor (VEGFR2) involved in angiogenesis, and thus, can be favorably used for the prevention or treatment of melanoma, colorectal cancer, prostate cancer, thyroid cancer, lung cancer, pancreatic cancer, ovarian cancer, or the like, which is induced by RAS mutation.

  本发明提供了一种新型吡啶衍生物、其药学上可接受的盐、制备方法以及含有其作为活性成分的药物组合物。根据本发明的吡啶衍生物可抑制 RAf 激酶（B-RAf、RAf-1 或 B-RAfV600E）和参与血管生成的血管内皮生长因子受体（VEGFR2），因此可用于预防或治疗由 RAS 突变诱发的黑色素瘤、结直肠癌、前列腺癌、甲状腺癌、肺癌、胰腺癌、卵巢癌等。
• Pyridine derivative inhibiting RAF kinase and vascular endothelial growth factor receptor, method for preparing same, pharmaceutical composition containing same, and use thereof
  申请人：SAMJIN PHARMACEUTICAL CO., LTD.

  公开号：US10844062B2

  公开（公告）日：2020-11-24

  The present invention provides a novel pyridine derivative, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient. The pyridine derivative according to the present invention inhibits Raf kinase (B-Raf, Raf-1, or B-RafV600E) and a vascular endothelial growth factor receptor (VEGFR2) involved in angiogenesis, and thus, can be favorably used for the prevention or treatment of melanoma, colorectal cancer, prostate cancer, thyroid cancer, lung cancer, pancreatic cancer, ovarian cancer, or the like, which is induced by RAS mutation.

  本发明提供了一种新型吡啶衍生物、其药学上可接受的盐、制备方法以及含有其作为活性成分的药物组合物。 根据本发明的吡啶衍生物可抑制 RAf 激酶（B-RAf、RAf-1 或 B-RAfV600E）和参与血管生成的血管内皮生长因子受体（VEGFR2），因此可用于预防或治疗由 RAS 突变诱发的黑色素瘤、结直肠癌、前列腺癌、甲状腺癌、肺癌、胰腺癌、卵巢癌等。
• Pyridine Derivative Inhibiting RAF Kinase and Vascular Endothelial Growth Factor Receptor, Method for Preparing Same, Pharmaceutical Composition Containing Same, and Use Thereof
  申请人：SAMJIN PHARMACEUTICAL CO., LTD.

  公开号：US20190300531A1

  公开（公告）日：2019-10-03

  The present invention provides a novel pyridine derivative, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient. The pyridine derivative according to the present invention inhibits Raf kinase (B-Raf, Raf-1, or B-RafV600E) and a vascular endothelial growth factor receptor (VEGFR2) involved in angiogenesis, and thus, can be favorably used for the prevention or treatment of melanoma, colorectal cancer, prostate cancer, thyroid cancer, lung cancer, pancreatic cancer, ovarian cancer, or the like, which is induced by RAS mutation.