3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 英文名称: 3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine
• 英文别名: 3-chloro-5-nitro-2-(triazol-2-yl)pyridine；3-Chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine
• 化学式: C₇H₄ClN₅O₂
• 分子量: 225.594
• InChiKey: UOVBIABPHJGCHB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  89.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine 在 盐酸 、 二苯基膦叠氮化物 、 三乙胺 、 tin(ll) chloride 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 4.5h， 生成 1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1-methoxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)urea
  参考文献：
  名称：

  Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood

  摘要：

  The paracaspase MALT1 has gained increasing interest as a target for the treatment of subsets of lymphomas as well as autoimmune diseases, and there is a need for suitable compounds to explore the therapeutic potential of this target. Here, we report the optimization of the in vivo potency of pyrazolopyrimidines, a class of highly selective allosteric MALT1 inhibitors. High doses of the initial lead compound led to tumor stasis in an activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model, but this compound suffered from a short in vivo half-life and suboptimal potency in whole blood. Guided by metabolism studies, we identified compounds with reduced metabolic clearance and increased in vivo half-life. In the second optimization step, masking one of the hydrogen-bond donors of the central urea moiety through an intramolecular interaction led to improved potency in whole blood. This was associated with improved in vivo potency in a mechanistic model of B cell activation. The optimized compound led to tumor regression in a CARD11 mutant ABC-DLBCL lymphoma xenograft model.

  DOI：

  10.1021/acs.jmedchem.0c01246
• 作为产物：
  描述：

  1H-1,2,3-三氮唑 、 5-硝基-2,3-二氯吡啶 在 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 生成 3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine
  参考文献：
  名称：

  N-芳基-哌啶-4-羧酰胺类是一类新型的MALT1蛋白水解活性强抑制剂

  摘要：

  从筛选力较弱的角度出发，详细介绍了MALT1蛋白酶功能的有效和选择性抑制剂。先进的化合物在生化和细胞分析中显示出很高的效价。化合物在机制性Jurkat T细胞活化试验以及B细胞淋巴瘤细胞系OCI-Ly3中显示出活性，这表明MALT1抑制剂在治疗自身免疫性疾病以及NF-κB失调的B细胞淋巴瘤方面有潜在用途。 κB途径。最初，该化合物系列的大鼠药代动力学特性主要由很高的清除率决定，该清除率可能与酰胺裂解有关。使用大鼠肝细胞分析可以建立良好的体外-体内相关性，从而鉴定出具有改善的PK特性的化合物。

  DOI：

  10.1016/j.bmcl.2018.05.017

文献信息

• N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of MALT1 proteolytic activity
  作者：Achim Schlapbach、Laszlo Revesz、Carole Pissot Soldermann、Thomas Zoller、Catherine H. Régnier、Frédéric Bornancin、Thomas Radimerski、Jutta Blank、Ansgar Schuffenhauer、Martin Renatus、Paulus Erbel、Samu Melkko、Richard Heng、Oliver Simic、Ralf Endres、Markus Wartmann、Jean Quancard

  DOI：10.1016/j.bmcl.2018.05.017

  日期：2018.7

  Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases

  从筛选力较弱的角度出发，详细介绍了MALT1蛋白酶功能的有效和选择性抑制剂。先进的化合物在生化和细胞分析中显示出很高的效价。化合物在机制性Jurkat T细胞活化试验以及B细胞淋巴瘤细胞系OCI-Ly3中显示出活性，这表明MALT1抑制剂在治疗自身免疫性疾病以及NF-κB失调的B细胞淋巴瘤方面有潜在用途。 κB途径。最初，该化合物系列的大鼠药代动力学特性主要由很高的清除率决定，该清除率可能与酰胺裂解有关。使用大鼠肝细胞分析可以建立良好的体外-体内相关性，从而鉴定出具有改善的PK特性的化合物。
• [EN] COMPOUNDS FOR MALT1 DEGRADATION<br/>[FR] COMPOSÉS POUR LA DÉGRADATION DE MALT1
  申请人：UNIV CORNELL

  公开号：WO2018085247A1

  公开（公告）日：2018-05-11

  Provided herein are bifunctional compounds that inhibit MALTl and/or promote targeted ubiquitination for the degradation of MALTl. In particular, provided are compounds that can bind MALTl, a protein whose activity is responsible for constitutive NF-KB signaling in certain cancers (e.g., activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL)), and can assist in its degradation by recruiting an E3 ubiquitin ligase (e.g., Cereblon, VHL), which can ubiquitinate MALTl, marking it for proteasome degradation. Also provided are pharmaceutical compositions comprising the bifunctional compounds, methods of treating cancer with the bifunctional compounds, methods of promoting the degradation of MALTl, and methods of binding E3 ubiquitin ligase activity in a subject by administering a compound or composition described herein.

  本文提供了一种双功能化合物，可以抑制MALT1并/或促进靶向泛素化以降解MALT1。具体而言，提供了可以结合MALT1的化合物，MALT1是一种蛋白质，在某些癌症中负责构成性NF-KB信号（例如，激活的B细胞弥漫性大B细胞淋巴瘤（ABC-DLBCL）），并且可以通过招募E3泛素连接酶（例如，Cereblon，VHL）协助其降解，后者可以泛素化MALT1，标记其进行蛋白酶体降解。还提供了包含这些双功能化合物的药物组合物，使用这些双功能化合物治疗癌症的方法，促进MALT1的降解的方法，以及通过给予本文描述的化合物或组合物在受试者中结合E3泛素连接酶活性的方法。
• [EN] CYCLIC COMPOUNDS AND METHODS OF USING SAME<br/>[FR] COMPOSÉS CYCLIQUES ET LEURS PROCÉDÉS D'UTILISATION
  申请人：SCHRODINGER INC

  公开号：WO2021134004A1

  公开（公告）日：2021-07-01

  The present application relates to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof which are MALT1 inhibitors. The present application also describes pharmaceutical composition comprising a compound of Formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for treating diseases, such as cancer, autoimmune disorders, and inflammatory disorders.

  本申请涉及以下式（I）的化合物及其药用盐，其在此处定义为MALT1抑制剂。本申请还描述了包括式（I）化合物及其药用盐的药物组合物，以及使用这些化合物和组合物治疗疾病（如癌症、自身免疫性疾病和炎症性疾病）的方法。
• PYRAZOLE DERIVATIVES AS MALT1 INHIBITORS
  申请人：Janssen Biotech, Inc.

  公开号：US20180170909A1

  公开（公告）日：2018-06-21

  Disclosed are compounds, compositions and methods for treating of diseases, syndromes, conditions, and disorders that are affected by the modulation of MALT1. Such compounds are represented by Formula (I) as follows: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 5 , G 1 , and G 2 are defined herein.

  揭示了一种通过调节MALT1来治疗受影响的疾病、综合症、症状和疾病的化合物、组合物和方法。这些化合物由以下式（I）表示：其中R1、R2、R3、R4、R5、R6、R5、G1和G2在此处定义。
• [EN] NOVEL PYRAZOLO PYRIMIDINE DERIVATIVES AND THEIR USE AS MALT1 INHIBITORS<br/>[FR] NOUVEAUX DÉRIVÉS PYRAZOLO-PYRIMIDINE ET LEUR UTILISATION COMME INHIBITEURS DE MALT1
  申请人：NOVARTIS AG

  公开号：WO2015181747A1

  公开（公告）日：2015-12-03

  The present invention describes new pyrazolo-pyrimidine derivatives of formula (I) or a pharmaceutically acceptable salt thereof; (I) wherein, R1 is halogen, cyano, or C1-C3alkyl optionally substituted by halogen; R2 is C1-C6alkyl optionally substituted one or more times by C1-C6alkyl, C2-C6alkenyl, hydroxyl, N,N-di-C1-C6alkyl amino, N-mono-C1-C6alkyl amino, O-Rg, Rg, phenyl, or by C1-C6alkoxy wherein said alkoxy again may optionally be substituted by C1-C6alkoxy, N,N-di-C1-C6alkyl amino, Rg or phenyl; C3-C6cycloalkyl optionally substituted by C1-C6alkyl, N,N-di-C1-C6alkyl amino or C1-C6alkoxy-C1-C6alkyl, and/or two of said optional substituents together with the atoms to which they are bound may form an annulated or spirocyclic 4 - 6 membered saturated heterocyclic ring comprising 1 - 2 O atoms; phenyl optionally substituted by C1-C6alkoxy; a 5 - 6 membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O said ring being optionally substituted by C1-C6alkyl which may be optionally substituted by amino or hydroxy; Rg; or N,N-di-C1-C6alkyl amino carbonyl; and R is phenyl independently substituted two or more times by Ra, 2-pyridyl independently substituted one or more times by Rb, 3-pyridyl independently substituted one or more times by Rc, or 4-pyridyl independently substituted one or more times by Rd; which are generally interacting with MALT1 proteolytic and/or autoproteolytic activity, and in particular which may inhibit said activity. The present invention further describes the synthesis of said new pyrazolo-pyrimidine derivatives, their use as a medicament, especially by interacting with MALT1 proteolytic and/or autoproteolytic activity.

  本发明描述了新的吡唑基嘧啶衍生物（I）或其药学上可接受的盐；（I）其中，R1是卤素、氰基或由卤素取代的C1-C3烷基；R2是C1-C6烷基，可选地由C1-C6烷基、C2-C6烯基、羟基、N,N-二C1-C6烷基氨基、N-单C1-C6烷基氨基、O-Rg、Rg、苯基或由C1-C6烷氧基取代的C1-C6烷基取代一次或多次，其中该烷氧基再次可选地由C1-C6烷氧基、N,N-二C1-C6烷基氨基、Rg或苯基取代；C3-C6环烷基，可选地由C1-C6烷基、N,N-二C1-C6烷基氨基或C1-C6烷氧基-C1-C6烷基取代，和/或两个可选取代基与它们连接的原子一起可以形成1-2个氧原子的环化或螺环4-6成员饱和杂环环，包括苯基，可选地由C1-C6烷氧基取代；具有1至3个异原子（N和O）的5-6成员杂环环，该环可选地由C1-C6烷基取代，该烷基可选地由氨基或羟基取代；Rg；或N,N-二C1-C6烷基氨基羰基；R独立地由Ra取代两次或两次以上，独立地由Rb取代一次或多次的2-吡啶基，独立地由Rc取代一次或多次的3-吡啶基，或独立地由Rd取代一次或多次的4-吡啶基；这些基本上与MALT1蛋白酶和/或自体蛋白酶活性相互作用，特别是可能抑制该活性。本发明进一步描述了所述新的吡唑基嘧啶衍生物的合成，它们作为药物的用途，特别是通过与MALT1蛋白酶和/或自体蛋白酶活性相互作用。