4-[(3-氯-4-氟苯基)氨基]-6-[(3-吡啶甲基)氨基]-1,7-萘啶-3-甲腈 | 871307-18-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 4-[(3-氯-4-氟苯基)氨基]-6-[(3-吡啶甲基)氨基]-1,7-萘啶-3-甲腈
• 中文别名: 4-(3-氯-4-氟苯胺)-6-(吡啶-3-甲胺)-3-氰基-1,7-萘杂环
• 英文名称: Tpl2 Kinase Inhibitor
• 英文别名: 4-(3-chloro-4-fluoroanilino)-6-(pyridin-3-ylmethylamino)-1,7-naphthyridine-3-carbonitrile
• CAS: 871307-18-5
• 化学式: C₂₁H₁₄ClFN₆
• 分子量: 404.834
• InChiKey: NMEUKWOOQOHUNA-UHFFFAOYSA-N

物化性质

• 沸点：
  616.3±55.0 °C(Predicted)
• 密度：
  1.45
• 溶解度：
  DMF：1mg/mL； DMF:PBS(pH7.2)(1:2)：0.33mg/ml；二甲基亚砜：1mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  86.5
• 氢给体数：
  2
• 氢受体数：
  7

安全信息

• 海关编码：
  2933990090
• 储存条件：
  -20°C，密闭保存，干燥条件

制备方法与用途

生物活性

Tpl2 Kinase Inhibitor 1（化合物 1）是一种有效的选择性 Tpl2（COT 激酶，MAP3K8）抑制剂，适用于炎症反应和某些癌症的研究。

靶点

| MAP3K8 |

体外研究

Cancer Osaka thyroid (COT) 蛋白激酶 (Tpl2) 是调节巨噬细胞中促炎细胞因子的关键调控因子。

反应信息

• 作为产物：
  描述：

  4-氯-6-氟-1,7-萘啶-3-甲腈 以 四氢呋喃 为溶剂， 生成 4-[(3-氯-4-氟苯基)氨基]-6-[(3-吡啶甲基)氨基]-1,7-萘啶-3-甲腈
  参考文献：
  名称：

  Inhibition of Tpl2 kinase and TNF-α production with 1,7-naphthyridine-3-carbonitriles: Synthesis and structure–activity relationships

  摘要：

  The synthesis and structure-activity studies of a series of 6-substituted-4-anilino-[1,7]-naphthyridine-3-carbonitriles as inhibitors of Tpl2 kinase are described. The early exploratory work described here may lead to the discovery of compounds with significant therapeutic potential for treating rheumatoid arthritis and other inflammatory diseases. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.08.029

文献信息

• 4,6-diamino-[1,7]naphthyridine-3-carbonitrile inhibitors of Tpl2 kinase and methods of making and using the same
  申请人：Green Jeffrey Neal

  公开号：US20060276498A1

  公开（公告）日：2006-12-07

  The present invention provides compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m and n are defined as described herein. The invention also provides methods of making the compounds of formula (I), and methods of treating inflammatory diseases, such as rheumatoid arthritis, in a mammal comprising administering a therapeutically effective amount of a compound of formula (I) to the mammal.

  本发明提供了式(I)化合物及其药学上可接受的盐，其中R1、R2、R3、R4、R5、R6、m和n的定义如本文所述。本发明还提供了制备式(I)化合物的方法，以及治疗哺乳动物的炎症性疾病，如类风湿性关节炎的方法，包括向哺乳动物施用式(I)化合物的治疗有效量。
• Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy
  申请人：Garraway Levi A.

  公开号：US11078540B2

  公开（公告）日：2021-08-03

  A method of identifying a subject having cancer who is likely to benefit from treatment with a combination therapy with a RAF inhibitor and a second inhibitor is provided. A method of treating cancer in a subject in need thereof is also provided and includes administering to the subject an effective amount of a RAF inhibitor and an effective amount of a second inhibitor, wherein the second inhibitor is a MEK inhibitor, a CRAF inhibitor, a CrkL inhibitor or a TPL2/COT inhibitor. A method of identifying a kinase target that confers resistance to a first inhibitor is also provided.

  本发明提供了一种方法，用于鉴定可能受益于RAF抑制剂和第二抑制剂联合疗法的癌症受试者。还提供了一种治疗有需要的受试者癌症的方法，包括向受试者施用有效量的RAF抑制剂和有效量的第二抑制剂，其中第二抑制剂是MEK抑制剂、CRAF抑制剂、CrkL抑制剂或TPL2/COT抑制剂。还提供了一种鉴定对第一种抑制剂产生抗性的激酶靶点的方法。
• WO2006/124944
  申请人：——

  公开号：——

  公开（公告）日：——
• Identification of a novel class of selective Tpl2 kinase inhibitors: 4-Alkylamino-[1,7]naphthyridine-3-carbonitriles
  作者：Neelu Kaila、Neal Green、Huan-Qiu Li、Yonghan Hu、Kristin Janz、Lori Krim Gavrin、Jennifer Thomason、Steve Tam、Dennis Powell、John Cuozzo、J. Perry Hall、Jean-Baptiste Telliez、Sang Hsu、Cheryl Nickerson-Nutter、Qin Wang、Lih-Ling Lin

  DOI：10.1016/j.bmc.2007.06.054

  日期：2007.10

  We have previously reported the discovery and initial SAR of the [1,7]naphthyridine-3-carbonitriles and quinoline-3-carbonitriles as Tumor Progression Loci-2 (Tp12) kinase inhibitors. In this paper, we report new SAR efforts which have led to the identification of 4-alkylamino-[1,7]naphthyridine-3-carbonitriles. These compounds show good in vitro and in vivo activity against Tp12 and improved pharmacokinetic properties. In addition they are highly selective for Tp12 kinase over other kinases, for example, EGFR, MEK, MK2, and p38. Lead compound 4-cycloheptylamino-6-[(pyridin-3-ylmethyl)-amino]-[1,7]naphthyridine-3-carbonit-rile (30) was efficacious in a rat model of LPS-induced TNF-alpha production. (C) 2007 Elsevier Ltd. All rights reserved.
• METHODS OF DIAGNOSING AND TREATING CANCER IN PATIENTS HAVING OR DEVELOPING RESISTANCE TO A FIRST CANCER THERAPY
  申请人：Dana-Farber Cancer Institute Inc.

  公开号：EP2545187A1

  公开（公告）日：2013-01-16