4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

• 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: 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
• 化学式: C₁₆H₁₅BrN₂O₂
• 分子量: 347.211
• InChiKey: KLVOFXAHVNNWFX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  79.1
• 氢给体数：
  3
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide 在 四(三苯基膦)钯 、 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 potassium acetate 作用下， 以 1,4-二氧六环 、 乙醇 、 甲苯 为溶剂， 反应 32.0h， 生成 7-(2-hydroxypropan-2-yl)-4-(3-(N-methylacrylamido)phenyl)-9H-carbazole-1-carboxamide
  参考文献：
  名称：

  将咔唑基于羧酰胺的布鲁顿酪氨酸激酶（BTK）可逆抑制剂转化为咔唑，四氢咔唑和新的2,3-二甲基吲哚系列中的有效，选择性不可逆抑制剂

  摘要：

  适当放置的亲电基团的引入将基于咔唑-1-甲酰胺和四氢咔唑-1-甲酰胺的一系列可逆BTK抑制剂转化为有效的不可逆抑制剂。从这些化合物的核心上除去一个环，提供了一系列有效的不可逆的2,3-二甲基吲哚-7-羧酰胺，具有优异的效能和改进的选择性，并具有降低亲脂性和分子量的其他优点。

  DOI：

  10.1016/j.bmcl.2018.07.041
• 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 、 正己烷 、 二氯甲烷 、 溶剂黄146 为溶剂， 反应 4.0h， 生成 4-bromo-7-(2-hydroxypropan-2-yl)-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

文献信息

• Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton’s Tyrosine Kinase (BTK)
  作者：Scott H. Watterson、Qingjie Liu、Myra Beaudoin Bertrand、Douglas G. Batt、Ling Li、Mark A. Pattoli、Stacey Skala、Lihong Cheng、Mary T. Obermeier、Robin Moore、Zheng Yang、Rodney Vickery、Paul A. Elzinga、Lorell Discenza、Celia D’Arienzo、Kathleen M. Gillooly、Tracy L. Taylor、Claudine Pulicicchio、Yifan Zhang、Elizabeth Heimrich、Kim W. McIntyre、Qian Ruan、Richard A. Westhouse、Ian M. Catlett、Naiyu Zheng、Charu Chaudhry、Jun Dai、Michael A. Galella、Andrew J. Tebben、Matt Pokross、Jianqing Li、Rulin Zhao、Daniel Smith、Richard Rampulla、Alban Allentoff、Michael A. Wallace、Arvind Mathur、Luisa Salter-Cid、John E. Macor、Percy H. Carter、Aberra Fura、James R. Burke、Joseph A. Tino

  DOI：10.1021/acs.jmedchem.9b00167

  日期：2019.4.11

  Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated

  布鲁顿酪氨酸激酶（BTK）是一种非受体酪氨酸激酶，是Tec家族激酶的成员，对于B细胞受体（BCR）介导的信号传导至关重要。BTK在单核细胞中Fcγ受体，粒细胞中的Fcε受体和破骨细胞中的RANK受体的下游信号通路中也起着关键作用。结果，预期对BTK的药理学抑制将为临床治疗自身免疫性疾病例如类风湿性关节炎和狼疮提供有效的策略。本文将概述我们用于鉴定共价，不可逆的BTK抑制剂的策略的发展，该抑制剂具有在非常低的剂量下全身快速灭活所需的内在效力，选择性和药代动力学特性。
• 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。
• [EN] CARBAZOLE CARBOXAMIDE COMPOUNDS USEFUL AS KINASE INHIBITORS<br/>[FR] COMPOSÉS DE CARBAZOLE-CARBOXAMIDE UTILES COMME INHIBITEURS DE KINASES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2014210087A1

  公开（公告）日：2014-12-31

  Disclosed are compounds of Formula (I); and salts thereof, wherein:Formula (II); Q is: R1 is -C(CH3)2OH, -NHC(=0)C(CH3)3, -N(CH3)2, or -CH2Rd; R2 is CI or -CH3; R3 is H, F, or -CH3; Ra is H or -CH3; Rb is H, F, CI, or -OCH3 Rc is H or F; and Rd is -OH, -OCH3, -NHC(=0)CH3, or fORMULA (III), 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.

  公开了Formula (I)的化合物及其盐，其中：Formula (II)；Q是：R1为-C(CH3)2OH，-NHC(=0)C(CH3)3，-N(CH3)2，或-CH2Rd；R2为CI或-CH3；R3为H，F或-CH3；Ra为H或-CH3；Rb为H，F，CI或-OCH3；Rc为H或F；Rd为-OH，-OCH3，-NHC(=0)CH3，或Formula (III)。还公开了使用这些化合物作为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、预防或减缓各种治疗领域的疾病或障碍方面具有用途，如自身免疫疾病和血管疾病。