3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid | 494799-85-8

• 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: 3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid
• 英文别名: 3-cyclopentyl-1-methyl-2-(pyridine-2-yl)-1H-indole-6-carboxylic acid；3-cyclopentyl-1-methyl-2-pyridin-2-ylindole-6-carboxylic acid
• CAS: 494799-85-8
• 化学式: C₂₀H₂₀N₂O₂
• 分子量: 320.391
• InChiKey: GYCVMJQCOXVUNV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid 在 乙酸酐 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 溶剂黄146 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 二甲基亚砜 、 甲苯 为溶剂， 反应 3.05h， 生成 (E)-3-[4-[[1-[(3-cyclopentyl-1-methyl-2-pyridin-2-ylindole-6-carbonyl)amino]cyclobutanecarbonyl]amino]-3-methylphenyl]prop-2-enoic acid
  参考文献：
  名称：

  Discovery of BI 207524, an Indole Diamide NS5B Thumb Pocket 1 Inhibitor with Improved Potency for the Potential Treatment of Chronic Hepatitis C Virus Infection

  摘要：

  The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.

  DOI：

  10.1021/jm501532z
• 作为产物：
  描述：

  6-吲哚甲酸 在 正丁基锂 、 20% Pd(OH)2/C 、 水 、 氢气 、 溴 、 sodium acetate 、 palladium diacetate 、 potassium carbonate 、 三对苯甲基膦 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 醋酸异丙酯 、 水 、 N,N-二甲基甲酰胺 为溶剂， -71.0~75.0 ℃ 、101.33 kPa 条件下， 反应 49.67h， 生成 3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid
  参考文献：
  名称：

  Discovery of the First Thumb Pocket 1 NS5B Polymerase Inhibitor (BILB 1941) with Demonstrated Antiviral Activity in Patients Chronically Infected with Genotype 1 Hepatitis C Virus (HCV)

  摘要：

  Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.

  DOI：

  10.1021/jm3006788

文献信息

• [EN] VIRAL POLYMERASE INHIBITORS<br/>[FR] INHIBITEURS DE LA POLYMERASE VIRALE
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2005080388A1

  公开（公告）日：2005-09-01

  An enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein either A or B is nitrogen and the other B or A is C, and the radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined herein, or a salt or ester thereof as viral polymerase inhibitors. The compound is used as an inhibitor of RNA dependent RNA polymerases, particularly those viral polymerases within the Flaviviridae family, more particularly to HCV polymerase.

  一个化合物的对映异构体、顺反异构体或互变异构体，由式(I)表示：其中A或B为氮，另一个为B或A为C，基团R1、R2、R3、R4、R5、R6、R7、R8、R9和R10如本文所定义，或其盐或酯作为病毒聚合酶抑制剂。该化合物用作RNA依赖性RNA聚合酶的抑制剂，特别是用于Flaviviridae家族内的病毒聚合酶，更具体地用于HCV聚合酶。
• [EN] PROCESS FOR CROSS COUPLING INDOLES<br/>[FR] PROCEDE DE COUPLAGE CROISE D'INDOLES
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2005092855A1

  公开（公告）日：2005-10-06

  The present invention provides a process for making a compound of general formula (I) wherein: R = H or C1-8 alkyl X = C3 -C8 cycloalkyl, C3 -C8 aryl or C3 -C8 alkyl; Y = heteroaryl or aryl; Z = H, HO2C-, C1-8 alkyl O2C-, C1-6 alkyl HNC(O)- and as described herein.

  本发明提供了一种制备通式(I)化合物的方法，其中：R = H或C1-8烷基；X = C3-C8环烷基，C3-C8芳基或C3-C8烷基；Y = 杂芳基或芳基；Z = H，HO2C-，C1-8烷基O2C-，C1-6烷基HNC(O)-，以及如本文所述。
• Viral polymerase inhibitors
  申请人：Beaulieu Louis Pierre

  公开号：US20060160798A1

  公开（公告）日：2006-07-20

  An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula I: wherein: A is O, S, NR 1 , or CR 1 , wherein R 1 is defined herein; represents either a single or a double bond; R 2 is selected from 6 or 10-membered aryl and Het, each optionally substituted with R 20 ; provided that Het is not a 5- or 6-membered monocyclic heterocycle having 1 or 2 nitrogen heteroatoms; B is NR 3 or CR 3 , with the proviso that one of A or B is either CR 1 or CR 3 , wherein R 3 is defined herein; K is N or CR 4 , wherein R 4 is defined herein; L is N or CR 5 , wherein R 5 has the same definition as R 4 ; M is N or CR 7 , wherein R 7 has the same definition as R 4 ; Y 1 is O or S; Z is N(R 6a )R 6 or OR 6 , wherein R 6a is H or alkyl or NR 61 R 62 wherein R 61 and R 62 are defined herein; and R 6 is H, alkyl, cycloalkyl, alkenyl, Het, alkyl-aryl, alkyl-Het; or R 6 is wherein R 7 and R 8 and Q are as defined herein; Y 2 is O or S; R 9 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het, all of which optionally substituted with R 90 ; or R 9 is covalently bonded to either of R 7 or R 8 to form a 5- or 6-membered heterocycle; a salt or a derivative thereof, as an inhibitor of HCV NS 5 B polymerase.

  化合物的异构体、对映异构体、非对映异构体或互变异构体，由式I表示：其中：A是O、S、NR1或CR1，其中R1的定义如下；表示单键或双键；R2选自6或10元芳基和Het，每个可选择用R20取代；但是，Het不是具有1或2个氮杂原子的5-或6元单环杂环；B是NR3或CR3，但其中A或B之一是CR1或CR3，其中R3的定义如下；K是N或CR4，其中R4的定义如下；L是N或CR5，其中R5的定义与R4相同；M是N或CR7，其中R7的定义与R4相同；Y1是O或S；Z是N（R6a）R6或OR6，其中R6a为H或烷基或NR61R62，其中R61和R62的定义如下；而R6是H、烷基、环烷基、烯基、Het、烷基-芳基、烷基-Het；或R6是其中R7和R8和Q的定义如下；Y2是O或S；R9是H、（C1-6烷基）、（C3-7环烷基）或（C1-6烷基-（C3-7）环烷基）、芳基、Het、（C1-6烷基-芳基）或（C1-6烷基-Het），所有这些都可以选择用R90取代；或者R9与R7或R8中的任一种共价键结合形成5-或6元杂环；作为HCV NS5B聚合酶的抑制剂，其盐或衍生物。
• Process for cross coupling indoles
  申请人：Khodabocus Ahmad

  公开号：US20050234242A1

  公开（公告）日：2005-10-20

  The present invention provides a process for making a compound of general formula I: wherein: R=H or C 1-8 alkyl X=C 3 -C 8 cycloalkyl, C 3 -C 8 aryl or C 3 -C 8 alkyl; Y=heteroaryl or aryl; Z=H, HO 2 C—, C 1-8 alkyl O 2 C—, C 1-6 alkyl HNC(O)—, and as described herein.

  本发明提供了一种制备通式I化合物的过程：其中：R = H或C1-8烷基，X = C3-C8环烷基，C3-C8芳基或C3-C8烷基; Y = 杂环芳基或芳基; Z = H，HO2C—，C1-8烷基O2C—，C1-6烷基HNC（O）—，并如本文所述。
• Viral Polymerase Inhibitors
  申请人：BEAULIEU Pierre

  公开号：US20070249629A1

  公开（公告）日：2007-10-25

  A compound, represented by formula (I): wherein A, B, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 9 , and R 10 are as defined herein, or an enantiomer, diastereoisomer or tautomer thereof, including a salt, ester or derivative thereof, as an inhibitor of HCV NS5B polymerase.

  一种化合物，用公式(I)表示：其中A，B，R1，R2，R3，R5，R6，R7，R9和R10如本文所定义，或其对映异构体、顺反异构体或互变异构体，包括其盐、酯或衍生物，作为HCV NS5B聚合酶的抑制剂。