methyl [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻烯杂卓类
• 英文名称: methyl [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate
• 英文别名: methyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno-[3,2-f ][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate；(±)-JQ1-OMe；MS-417; MS 417; Gtpl7512; gtpl-7512; gtpl 7512；methyl 2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate
• 化学式: C₂₀H₁₉ClN₄O₂S
• 分子量: 414.915
• InChiKey: GGRCIHACOIMRKY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  97.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate 在 4-二甲氨基吡啶 、 双(三甲基硅烷基)氨基钾 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 反应 39.0h， 生成 (S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)-benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl (R*)-2-((S*)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f ][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butanoate
  参考文献：
  名称：

  Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins

  摘要：

  DOI：

  10.1021/acs.jmedchem.1c01532
• 作为产物：
  描述：

  C₁₉H₁₉ClN₂O₆S 在 potassium tert-butylate 、 溶剂黄146 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 为溶剂， 反应 3.25h， 生成 methyl [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate
  参考文献：
  名称：

  Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins

  摘要：

  DOI：

  10.1021/acs.jmedchem.1c01532

文献信息

• 9H-PYRIMIDO[4,5-B]INDOLES AND RELATED ANALOGS AS BET BROMODOMAIN INHIBITORS
  申请人：THE REGENTS OF THE UNIVERSITY OF MICHIGAN

  公开号：US20150246923A1

  公开（公告）日：2015-09-03

  The present disclosure provides substituted 9H-pyrimido[4,5-b]indoles and 5H-pyrido[4,3-b]indoles and related analogs represented by Formula I: and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R 1a , A, B 1 , B 2 , G, X 1 , Y 1 , Y 2 , and Y 3 are as defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a condition or disorder responsive to inhibition of BET bromodomains. Compounds of the present disclosure are especially useful for treating cancer.

  本公开提供了代表为式I的替代的9H-嘧啶并[4,5-b]吲哚和5H-吡啶并[4,3-b]吲哚及相关类似物的药用可接受的盐、水合物和溶剂合物，其中R1a、A、B1、B2、G、X1、Y1、Y2和Y3如规范中所定义。本公开还涉及使用式I的化合物来治疗对BET溴结构域抑制敏感的状况或疾病。本公开的化合物特别适用于治疗癌症。
• [EN] LIGAND DRUG CONJUGATES AND MODIFIED BET INHIBITORS<br/>[FR] CONJUGUÉS LIGAND-MÉDICAMENT ET INHIBITEURS DE BET MODIFIÉS
  申请人：HOVIONE SCIENTIA LTD

  公开号：WO2021140343A1

  公开（公告）日：2021-07-15

  A ligand drug conjugate comprising a) a targeting ligand; b) a cleavable bridge; and a bromodomain and extraterminal (BET) inhibitor is provided. The targeting ligand may comprise a cancer targeting ligand. The BET inhibitor may comprise I-BET762, (+)-JQ1, MS417, OXT015, (2), RVX-208, (3), OXFBD02, OXFBD03, I-BET151, (4), PFI-1, I-BET726, MS436, XD14 or a modified BET inhibitor. Modified BET inhibitors are also provided, including RT48 ((S) -2- (6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-4-yl)-1-(4-(dimethylamino) piperidin-1-yl) ethan-1-one) and RT53 ((S) -2- (6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo[f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-4-yl) -N-(4- (4- (dimethylamino) piperidin-1-yl) phenyl) acetamide). A pro-drug of a BET inhibitor is also provided. A method of preparing a ligand drug conjugate according to the invention is also provided. The method comprises i) functionalising a BET inhibitor with a tertiary amine to form a modified BET inhibitor according to the invention; ii) bonding the modified BET inhibitor formed in step i) to a cleavable bridge; and iii) bonding the cleavable bridge bound to the modified BET inhibitor formed in step ii) to a targeting ligand. A ligand drug conjugate according to the invention for use as a medicament is also provided.

  提供了一种配体药物偶联物，包括a) 靶向配体；b) 可切断的桥接物；以及一种溴域和外端（BET）抑制剂。靶向配体可能包括肿瘤靶向配体。BET抑制剂可能包括I-BET762，(+)-JQ1，MS417，OXT015，RVX-208，OXFBD02，OXFBD03，I-BET151，PFI-1，I-BET726，MS436，XD14或经修改的BET抑制剂。还提供了经修改的BET抑制剂，包括RT48（（S）-2-（6-（4-氯苯基）-8-甲氧基-1-甲基-4H-苯并[f] [1,2,4] 三唑[4,3-a] [1,4] 二氮杂并-4-基）-1-（4-（二甲胺基）哌啶-1-基）乙酮）和RT53（（S）-2-（6-（4-氯苯基）-8-甲氧基-1-甲基-4H-苯并[f] [1,2,4] 三唑[4,3-a] [1,4] 二氮杂并-4-基）-N-（4-（4-（二甲胺基）哌啶-1-基）苯基）乙酰胺）。还提供了BET抑制剂的前药。还提供了根据该发明制备配体药物偶联物的方法。该方法包括i) 用三级胺对BET抑制剂进行功能化，以形成根据该发明的经修改的BET抑制剂；ii) 将步骤i)中形成的经修改的BET抑制剂与可切断的桥接物结合；以及iii) 将步骤ii)中结合到经修改的BET抑制剂的可切断桥接物结合到靶向配体。还提供了用作药物的根据该发明的配体药物偶联物。
• AMIDE COMPOUND HAVING BET PROTEOLYSIS-INDUCING ACTION AND MEDICINAL APPLICATION THEREOF
  申请人：MITSUBISHI TANABE PHARMA CORPORATION

  公开号：US20210284654A1

  公开（公告）日：2021-09-16

  Provided are a compound superior in a cytotoxic action on cancer cells, an action inducing degradation of BET protein in cancer cells, and an inhibitory action on the binding of BET protein and acetylated histone, and useful as an anticancer agent, a BET protein degradation inducer or a BET protein inhibitor. A compound represented by the following formula (I) wherein each symbol is as defined in the specification, or a pharmacologically acceptable salt thereof
• US9580430B2
  申请人：——

  公开号：US9580430B2

  公开（公告）日：2017-02-28