N-[3-[[5-环丙基-2-[[3-(4-吗啉基甲基)苯基]氨基]-4-嘧啶基]氨基]丙基]环丁烷甲酰胺 | 1190378-57-4

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: N-[3-[[5-环丙基-2-[[3-(4-吗啉基甲基)苯基]氨基]-4-嘧啶基]氨基]丙基]环丁烷甲酰胺
• 中文别名: N-(3-((5-环丙基-2-((3-(吗啉代甲基)苯基)氨基)嘧啶-4-基)氨基)丙基)环丁烷；N-[3-[[5-环丙基-2-[[3-（4-吗啉基甲基）苯基]氨基]-4-嘧啶基]氨基]丙基]-环丁基甲酰胺
• 英文名称: N-{3-[(5-Cyclopropyl-2-{[3-(Morpholin-4-Ylmethyl)phenyl]amino}pyrimidin-4-Yl)amino]propyl}cyclobutanecarboxamide
• 英文别名: N-[3-[[5-cyclopropyl-2-[3-(morpholin-4-ylmethyl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide
• CAS: 1190378-57-4
• 化学式: C₂₆H₃₆N₆O₂
• 分子量: 464.6
• InChiKey: UKBGBACORPRCGG-UHFFFAOYSA-N

物化性质

• 密度：
  1.270
• 溶解度：
  H2O：可溶15mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  91.4
• 氢给体数：
  3
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

MRT67307是一种高效的双重IKKϵ/TBK1抑制剂，其IC50分别为160 nM和19 nM。该化合物能够有效抑制ULK1和ULK2，并限制自噬。

Target	Value
IKKϵ	160 nM
TBK1	190 nM

体外研究

在巨噬细胞中，MRT67307阻止了IRF3的磷酸化以及IFNβ的产生。在野生型MEF细胞中，该化合物增强了IL-1刺激下的p105 Ser933位点的磷酸化、RelA Ser468和Ser536位点的磷酸化，并且促进了IL-1刺激下NF-κB依赖性基因转录激活。此外，MRT67307通过CRTC3依赖的方式促进IL-10产生并抑制促炎症细胞因子的生成。同时，该化合物还抑制了MEF细胞中的ULK活性并阻断了自噬过程。

文献信息

• [EN] PYRIMIDINE DERIVATIVES CAPABLE OF INHIBITING ONE OR MORE KINASES<br/>[FR] DÉRIVÉS DE PYRIMIDINE CAPABLES D'INHIBER UNE OU PLUSIEURS KINASES
  申请人：MEDICAL RES COUNCIL

  公开号：WO2009122180A1

  公开（公告）日：2009-10-08

  A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, formula (I): wherein: R1 is C3-8-cycloalkyl; X is O, NR7 or C3-6-heterocycloalkyl; R2 is aryl, heteroaryl, fused or unfused aryl-C3-6-heterocycloalkyl or fused or unfused heteroaryl-C3-6-heterocycIoalkyl, each of which is optionally substituted by one or more substitutents selected from aryl, heteroaryl, C1-6-alkyl, C3-7-cycloalkyl and a group A, wherein said C1-6-alkyl group is optionally substituted by one or more substituents selected from aryl, heteroaryl, R10 and a group A, said heteroaryl group is optionally substituted by one or more R10 groups; and wherein said C3-6-heterocycloalkyl group optionally contains one or more groups selected from oxygen, sulfur, nitrogen and CO; R3 is C1-6-alkyl optionally substituted by one or more substituents selected from aryl, heteroaryl, -NR4R5, -OR6, -NR7(CO)R6, -NR7(CO)NR4R5, -NR7SO2R6, -NR7COOR7, -CONR4R5, C3-6-heterocycloalkyl and formula (a, b, c): wherein R4-7 and A are as defined in the claims. Further aspects relate to the use of said compounds in the treatment of various therapeutic disorders, and more particularly as inhibitors of one or more kinases.

  本发明的第一个方面涉及式(I)的化合物，或其药学上可接受的盐或酯，式(I)如下：其中：R1为C3-8环烷基；X为O、NR7或C3-6杂环烷基；R2为芳基、杂芳基、融合或未融合的芳基-C3-6杂环烷基或融合或未融合的杂芳基-C3-6杂环烷基，每个基可选择地由来自芳基、杂芳基、C1-6烷基、C3-7环烷基和A基的一个或多个取代基取代，其中所述C1-6烷基基可选择地由来自芳基、杂芳基、R10和A基的一个或多个取代基取代，所述杂芳基可选择地由一个或多个R10基取代；以及所述C3-6杂环烷基基可选择地包含一个或多个来自氧、硫、氮和CO的基；R3为C1-6烷基，可选择地由一个或多个来自芳基、杂芳基、-NR4R5、-OR6、-NR7(CO)R6、-NR7(CO)NR4R5、-NR7SO2R6、-NR7COOR7、-CONR4R5、C3-6杂环烷基和式(a, b, c)的取代基取代；其中R4-7和A如权利要求中所定义。进一步方面涉及所述化合物在治疗各种治疗性疾病中的使用，特别是作为一个或多个激酶的抑制剂。
• [EN] A SIK INHIBITOR FOR USE IN A METHOD OF TREATING AN INFLAMMATORY AND/OR IMMUNE DISORDER<br/>[FR] INHIBITEUR DE SIK POUR L'UTILISATION DANS UNE MÉTHODE DE TRAITEMENT D'UN TROUBLE INFLAMMATOIRE ET/OU IMMUNITAIRE
  申请人：UNIV DUNDEE

  公开号：WO2013136070A1

  公开（公告）日：2013-09-19

  The present invention relates to the discovery that salt inducible kinases (SIKs) suppress the formation of anti-inflammatory molecules such as IL-10, which are important for the resolution of inflammation and identifies SIK inhibitors that may be used to treat disorders associated with undesirable inflammation, such as inflammatory bowel disease and/or autoimmune disorders.

  本发明涉及到一个发现，即盐诱导激酶（SIKs）抑制抗炎分子的形成，例如IL-10，这些分子对于炎症的解决非常重要，并且鉴定出可能用于治疗与不良炎症相关的疾病的SIK抑制剂，例如炎症性肠病和/或自身免疫性疾病。
• SIK INHIBITOR FOR USE IN A METHOD OF TREATING AN INFLAMMATORY AND/OR IMMUNE DISORDER
  申请人：UNIVERSITY COURT OF THE UNIVERSITY OF DUNDEE

  公开号：US20150045370A1

  公开（公告）日：2015-02-12

  The present invention relates to the discovery that salt inducible kinases (SIKs) suppress the formation of anti-inflammatory molecules such as IL-10, which are important for the resolution of inflammation and identifies SIK inhibitors that may be used to treat disorders associated with undesirable inflammation, such as inflammatory bowel disease and/or autoimmune disorders.

  本发明涉及到一个发现：盐诱导激酶（SIKs）可以抑制抗炎分子的形成，例如重要的解决炎症的分子IL-10，并且鉴定出了SIK抑制剂，可以用于治疗与不良炎症有关的疾病，例如炎症性肠病和/或自身免疫性疾病。
• Compound
  申请人：Mciver Edward Giles

  公开号：US20100056524A1

  公开（公告）日：2010-03-04

  A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein: R 1 is C 3-8 -cycloalkyl; X is O, NR 7 or C 3-6 -heterocycloalkyl; R 2 is aryl, heteroaryl, fused or unfused aryl-C 3-6 -heterocycloalkyl or fused or unfused heteroaryl-C 3-6 -heterocycloalkyl, each of which is optionally substituted by one or more substitutents selected from aryl, heteroaryl, C 1-6 -alkyl, C 3-7 -cycloalkyl and a group A, wherein said C 1-6 -alkyl group is optionally substituted by one or more substituents selected from aryl, heteroaryl, R 10 and a group A, said heteroaryl group is optionally substituted by one or more R 10 groups; and wherein said C 3-6 -heterocycloalkyl group optionally contains one or more groups selected from oxygen, sulfur, nitrogen and CO; R 3 is C 1-6 -alkyl optionally substituted by one or more substituents selected from aryl, heteroaryl, —NR 4 R 5 , —OR 6 , —NR 7 (CO)R 6 , —NR 7 (CO)NR 4 R 5 , —NR 7 SO 2 R 6 , —NR 7 COOR 7 , —CONR 4 R 5 , C 3-6 -heterocycloalkyl and wherein R 4-7 and A are as defined in the claims. Further aspects relate to the use of said compounds in the treatment of various therapeutic disorders, and more particularly as inhibitors of one or more kinases.

  本发明的第一方面涉及化合物(I)的公式，或其药学上可接受的盐或酯，其中： R1是C3-8环烷基；X是O，NR7或C3-6杂环烷基；R2是芳基、杂芳基、融合或未融合的芳基-C3-6杂环烷基或融合或未融合的杂芳基-C3-6杂环烷基，其中每个基团可选地由一个或多个取代基选自芳基、杂芳基、C1-6烷基、C3-7环烷基和A组成，其中所述的C1-6烷基可选地由一个或多个取代基选自芳基、杂芳基、R10和A组成，所述的杂芳基可选地由一个或多个R10基团取代；其中所述的C3-6杂环烷基可选地包含一个或多个选自氧、硫、氮和CO的基团；R3是C1-6烷基，可选地被一个或多个取代基选自芳基、杂芳基、-NR4R5、-OR6、-NR7(CO)R6、-NR7(CO)NR4R5、-NR7SO2R6、-NR7COOR7、-CONR4R5、C3-6杂环烷基和其中R4-7和A如权利要求所定义。 进一步的方面涉及所述化合物在治疗各种治疗性疾病中的应用，特别是作为一个或多个激酶的抑制剂。
• SIK inhibitor for use in a method of treating an inflammatory and/or immune disorder
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10233157B2

  公开（公告）日：2019-03-19

  The present invention relates to the discovery that salt inducible kinases (SIKs) suppress the formation of anti-inflammatory molecules such as IL-10, which are important for the resolution of inflammation and identifies SIK inhibitors that may be used to treat disorders associated with undesirable inflammation, such as inflammatory bowel disease and/or autoimmune disorders.

  本发明涉及盐诱导激酶（SIKs）抑制抗炎分子（如 IL-10）的形成这一发现，IL-10 对于炎症的解决非常重要，本发明还确定了 SIK 抑制剂，可用于治疗与不良炎症相关的疾病，如炎症性肠病和/或自身免疫性疾病。