ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate
• 化学式: C₁₆H₁₃BrN₂O₃
• 分子量: 361.195
• InChiKey: URONPBLOOOUUDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  85.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate 在 lithium hydroxide monohydrate 、 1-羟基苯并三唑 、 1,2-二氯乙烷 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 4-bromo-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide
  参考文献：
  名称：

  Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177)

  摘要：

  Bruton's tyrosine,kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous auto-immune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and, selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oXo-3,4-dihydroquinazdlin-3-yl)phenyl]-9H-carbazole-1-carboxarnide 6 (BMS-935177) was selected:to advance into clinical development.

  DOI：

  10.1021/acs.jmedchem.6b00722
• 作为产物：
  描述：

  3-羟基苯甲酸乙酯 在 ammonium hydroxide 、 Rh/Al₂O₃ 、 氢气 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 1,2-二氯乙烷 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 溶剂黄146 为溶剂， 反应 3.5h， 生成 ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate
  参考文献：
  名称：

  Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177)

  摘要：

  Bruton's tyrosine,kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous auto-immune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and, selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oXo-3,4-dihydroquinazdlin-3-yl)phenyl]-9H-carbazole-1-carboxarnide 6 (BMS-935177) was selected:to advance into clinical development.

  DOI：

  10.1021/acs.jmedchem.6b00722

文献信息

• SUBSTITUTED TETRAHYDROCARBAZOLE AND CARBAZOLE CARBOXAMIDE COMPOUNDS
  申请人：Bristol-Myers Squibb Company

  公开号：US20140378475A1

  公开（公告）日：2014-12-25

  Disclosed are compounds of Formula (I) wherein: the two dotted lines represent either two single or two double bonds; Q is: R 1 is F, Cl, —CN, or —CH 3 ; R 2 is Cl or —CH 3 ; R 3 is —C(CH 3 ) 2 OH or —CH 2 CH 2 OH; R a is H or —CH 3 ; each R b is independently F, Cl, —CH 3 , and/or —OCH 3 ; and n is zero, 1, or 2. Also disclosed are methods of using such compounds as inhibitors of Bruton's tyrosine kinase (Btk), and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

  公开的是Formula (I)的化合物，其中：两条虚线代表两个单键或两个双键；Q是：R1是F、Cl、—CN或—CH3；R2是Cl或—CH3；R3是—C(CH3)2OH或—CH2CH2OH；Ra是H或—CH3；每个Rb独立地是F、Cl、—CH3和/或—OCH3；n为零、1或2。还公开了将这些化合物用作Bruton酪氨酸激酶（Btk）抑制剂的方法，以及包含这些化合物的药物组合物。这些化合物在治疗、预防或减缓多种治疗领域的疾病或疾病的进展方面非常有用，如自身免疫疾病和血管疾病。
• CARBAZOLE CARBOXAMIDE COMPOUNDS USEFUL AS KINASE INHIBITORS
  申请人：Liu Qingjie

  公开号：US20100160303A1

  公开（公告）日：2010-06-24

  Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, thereof, are useful as kinase modulators, including Btk modulation.

  具有化学式(I)的化合物，以及其对映体、非对映异构体、药用可接受的盐，可用作激酶调节剂，包括Btk调节。
• [EN] CARBAZOLE DERIVATIVES<br/>[FR] DÉRIVÉS DE CARBAZOLE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2016065236A1

  公开（公告）日：2016-04-28

  Disclosed are compounds of Formula (I): (I) or a salt thereof, wherein Q, R1a, R1b, R2a, R2b, R3, R4, R5a, R5b, R6a, R6c, R7a, R7b, R7c, and R7d are defined herein. Also disclosed are methods of using such compounds as inhibitors of Bruton's tyrosine kinase (Btk), and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

  揭示了Formula (I)的化合物：(I)或其盐，其中Q、R1a、R1b、R2a、R2b、R3、R4、R5a、R5b、R6a、R6c、R7a、R7b、R7c和R7d在此处有定义。还揭示了将这些化合物用作Bruton's酪氨酸激酶（Btk）的抑制剂的方法，以及包含这些化合物的药物组合物。这些化合物在治疗、预防或减缓各种治疗领域的疾病或紊乱方面非常有用，如自身免疫疾病和血管疾病。
• Discovery of 6-Fluoro-5-(<i>R</i>)-(3-(<i>S</i>)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4<i>H</i>)-yl)-2-methylphenyl)-2-(<i>S</i>)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1<i>H</i>-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers
  作者：Scott H. Watterson、George V. De Lucca、Qing Shi、Charles M. Langevine、Qingjie Liu、Douglas G. Batt、Myra Beaudoin Bertrand、Hua Gong、Jun Dai、Shiuhang Yip、Peng Li、Dawn Sun、Dauh-Rurng Wu、Chunlei Wang、Yingru Zhang、Sarah C. Traeger、Mark A. Pattoli、Stacey Skala、Lihong Cheng、Mary T. Obermeier、Rodney Vickery、Lorell N. Discenza、Celia J. D’Arienzo、Yifan Zhang、Elizabeth Heimrich、Kathleen M. Gillooly、Tracy L. Taylor、Claudine Pulicicchio、Kim W. McIntyre、Michael A. Galella、Andy J. Tebben、Jodi K. Muckelbauer、ChiehYing Chang、Richard Rampulla、Arvind Mathur、Luisa Salter-Cid、Joel C. Barrish、Percy H. Carter、Aberra Fura、James R. Burke、Joseph A. Tino

  DOI：10.1021/acs.jmedchem.6b01088

  日期：2016.10.13

  Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated

  Bruton的酪氨酸激酶（BTK）是一种非受体酪氨酸激酶，是Tec家族激酶的成员。BTK在B细胞受体（BCR）介导的信号传导以及单核细胞中的Fcγ受体信号传导以及肥大细胞和嗜碱性粒细胞中的Fcε受体信号传导中起着至关重要的作用，所有这些都与自身免疫性疾病的病理生理学有关。结果，预期对BTK的抑制将为临床治疗自身免疫性疾病如狼疮和类风湿性关节炎提供有效的策略。本文详细介绍了结构-活性关系（SAR），从而形成了一系列新型的高效，选择性咔唑和四氢咔唑可逆性BTK抑制剂。特别令人感兴趣的是，将两个阻转异构体中心旋转锁定，以提供一个稳定的阻转异构体，从而提高了效力和选择性，并减少了安全责任。具有显着增强的效价和选择性，出色的体内特性和功效以及非常理想的耐受性和安全性，14f（BMS-986142）已进入临床研究。
• Carbazole carboxamide compounds useful as kinase inhibitors
  申请人：Bristol-Myers Squibb Company

  公开号：US08084620B2

  公开（公告）日：2011-12-27

  Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, thereof, are useful as kinase modulators, including Btk modulation.

  具有公式（I）的化合物，其对映异构体，顺反异构体，以及其药学上可接受的盐，可用作激酶调节剂，包括Btk调节。