(1R,3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid | 2041841-30-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: (1R,3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid
• 英文别名: BMS-986251；Bms-986251；(1R,3S,4R)-4-[(3aR,9bR)-9b-(4-fluorophenyl)sulfonyl-7-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,3a,4,5-tetrahydro-1H-benzo[e]indole-3-carbonyl]-3-methylcyclohexane-1-carboxylic acid
• CAS: 2041841-30-7
• 化学式: C₃₀H₂₉F₈NO₅S
• 分子量: 667.617
• InChiKey: JQORWGARJVSRBA-QOTTZFGFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  45
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  (1R,2S)-2-methyl-4-oxocyclohexane-1-carboxylic acid 在 N-甲基吗啉 、 水 、 双(三甲基硅烷基)氨基钾 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， -78.0~80.0 ℃ 、101.33 kPa 条件下， 反应 4.0h， 生成 (1R,3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid
  参考文献：
  名称：

  Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

  摘要：

  Novel tricyclic analogues were designed, synthesized, and evaluated as ROR gamma t inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.

  DOI：

  10.1021/acsmedchemlett.0c00063

文献信息

• Development of a Scalable Synthetic Route to BMS-986251, Part 2: Synthesis of the Tricyclic Core and the API
  作者：Srinivas Kalidindi、Aravind S. Gangu、Sankar Kuppusamy、Shunmugaraj Sathasivam、Vijaykumar Shekarappa、Saravanan Murugan、Sivasankar Bondigela、Moorthy Kandasamy、Kishore Ghanta、Arun Vinodini、Abhishek Shrikant、Ravikumar Ramachandran、William P. Gallagher、Nathaniel Kopp、Francisco González-Bobes、Martin D. Eastgate、Rajappa Vaidyanathan

  DOI：10.1021/acs.oprd.1c00125

  日期：2021.7.16

  BMS-986251, a potent and efficacious RORγt inverse agonist, was synthesized starting from 6-iodotetralone using 13 chemical transformations with only eight isolated intermediates. The synthesis involved a four-step telescoped diastereoselective aza-Michael reaction-annulation sequence followed by installation of the heptafluoro-iso-propyl side chain and final amidation to furnish the desired API.

  BMS-986251 是一种有效且有效的 RORγt 反向激动剂，从 6-碘四氢萘酮开始合成，使用 13 次化学转化，仅分离出 8 个中间体。合成所涉及的四步骤伸缩非对映选择性氮杂-迈克尔反应成环序列，随后安装七氟的异-丙基侧链和最终的酰胺化，得到所需的API。
• TRICYCLIC SULFONE COMPOUND AS A ROR GAMMA MODULATOR
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20190352261A1

  公开（公告）日：2019-11-21

  There is described a RORγ modulator of the formula (I), or stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. Also provided are pharmaceutical compositions comprising the same. The compound of the invention may be useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

  本发明揭示了一种RORγ调节剂，其化学式为(I)，或其立体异构体，药学上可接受的盐、溶剂化合物或前药。同时提供了包含该化合物的药物组合物。本发明的化合物可用于调节细胞中的RORγ活性的方法以及治疗患有自身免疫和/或炎症性疾病或障碍的受试者的方法，该受试者从调节RORγ活性中获得治疗效益。
• Tricyclic sulfones as RORγ modulators
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US10273259B2

  公开（公告）日：2019-04-30

  There are described RORγ modulators of the formula (I), and formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

  描述了式 (I) 的 RORγ 调节剂、 和式(II) 或其立体异构体、同系物、药学上可接受的盐、溶液或原药，其中所有取代基均在本文中定义。还提供了包含上述化合物的药物组合物。此类化合物和组合物可用于调节细胞中RORγ活性的方法和治疗患有疾病或失调的受试者的方法，其中受试者将从调节RORγ活性中获得治疗益处，例如自身免疫和/或炎症性失调。
• Tricyclic sulfone compound as a ROR gamma modulator
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US10633339B2

  公开（公告）日：2020-04-28

  There is described a RORγ modulator of the formula (I), or stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. Also provided are pharmaceutical compositions comprising the same. The compound of the invention may be useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

  这里介绍一种式 (I) 的 RORγ 调节剂、 或其立体异构体、药学上可接受的盐、溶液或原药。还提供了包含上述化合物的药物组合物。本发明的化合物可用于调节细胞中 RORγ 活性的方法和治疗患有疾病或失调的受试者的方法，其中受试者将从调节 RORγ 活性中获益，例如自身免疫和/或炎症性失调。
• Synthesis of 1-(tert-Butyl) 4-Methyl (1R,2S,4R)-2-Methylcyclohexane-1,4-dicarboxylate from Hagemann’s tert-Butyl Ester for an Improved Synthesis of BMS-986251
  作者：Lyndon A. M. Cornelius、Jianqing Li、Daniel Smith、Subramaniam Krishnananthan、Shiuhang Yip、Dauh-Rurng Wu、Joseph Pawluczyk、Darpandeep Aulakh、Amy A. Sarjeant、James Kempson、Joseph A. Tino、Arvind Mathur、T. G. Murali Dhar、Robert J. Cherney

  DOI：10.1021/acs.joc.0c01169

  日期：2020.8.21

  methoxycarbonylation of an enol triflate derived from a Hagemann’s ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical

  我们描述了一种有效的合成路线，可通过钯-来实现差动保护的二酯1-（叔丁基）4-甲基（1 R，2 S，4 R）-2-甲基环己烷-1,4-二羧酸（+）- 1催化由Hagemann酯衍生物衍生的烯醇三氟甲磺酸酯的甲氧基羰基化，然后进行立体选择性Crabtree氢化。Diester 1是一种新颖的手性合成子，可用于药物开发，并且在RORγt反向激动剂程序过程中有助于生成有用的SAR。此外，我们描述了使用二酯1作为关键成分的临床候选药物BMS-986251的第二代合成。