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Inhibitors of indoleamine 2,3-dioxygenase and methods of their use

A -OH, C1-C6 technology, applied in the field of enzymatically active compounds, can solve problems such as different functions

Inactive Publication Date: 2019-03-01
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

An IDO analog (IDO2) that shares 44% amino acid sequence identity with IDO has been identified, but functions largely differently from IDO

Method used

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  • Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
  • Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
  • Inhibitors of indoleamine 2,3-dioxygenase and methods of their use

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Experimental program
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Embodiment approach

[0063] In another embodiment, the present invention provides a combination comprising one or more compounds of the present invention and / or pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof or solvates thereof thing.

[0064] In another embodiment, the present invention provides a compound comprising a pharmaceutically acceptable carrier and at least one compound of the present invention and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or Pharmaceutical compositions of its solvates.

[0065] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention and / or pharmaceutically acceptable salts, stereoisomers thereof body, its tautomer or its solvate.

[0066] In another embodiment, the present invention provides a process for the preparation ...

Embodiment 1

[0208] N-((1-(6-fluoroquinolin-4-yl)piperidin-4-yl)methyl)-2-( right- Tolyl)acetamide

[0209]

[0210] 1A. Tert-butyl ((1-(6-fluoroquinolin-4-yl)piperidin-4-yl)methyl)carbamate

[0211] To a homogeneous mixture of 4-chloro-6-fluoroquinoline (220.0 mg, 1.2 mmol) in anhydrous NMP (4 mL) in a sealable vial was added (piperidin-4-ylmethyl)carbamate tert-Butyl ester (350.0 mg, 1.6 mmol) followed by DIPEA (0.8 mL, 4.6 mmol). The vial was sealed and the mixture was stirred at 60°C for 2 hours, then at 90°C for 17 hours, then at 120°C for 24 hours. After cooling to room temperature, the reaction mixture was purified by Isco chromatography to afford tert-butyl ((1-(6-fluoroquinolin-4-yl)piperidin-4-yl)methyl)carbamate as an off-white solid ( 323.7 mg; 74% yield). MS (ES): m / z = 360 [M+H] + . t R = 0.71 min ( Method B ). 1 H NMR (400MHz, DMSO-d 6 ) δ8.66 (d, J =5.0 Hz, 1H), 8.01 (dd, J =9.1, 5.7 Hz, 1H), 7.66 - 7.51 (m, 2H),7.01 (d, J =4.9 Hz, 1H), 6.93 (t, J =5.7 H...

Embodiment 2

[0217] 2-(4-fluorophenyl)-N-((1-(6-fluoroquinolin-4-yl)piperidin-4-yl)methyl)acetamide

[0218]

[0219] Under nitrogen atmosphere, (1-(6-fluoroquinolin-4-yl)piperidin-4-yl)methanamine TFA salt (1B, 41.8 mg, 0.09mmol) in anhydrous THF (1 mL) and To a heterogeneous mixture in dioxane (0.5 mL) was added DIPEA (0.06 mL, 0.3 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (15.5 mg, 0.09 mmol). After stirring at ambient temperature for 15 hours, the mixture was diluted with DMSO, filtered through a syringe filter, and purified by preparative HPLC / MS to afford the title compound (6.1 mg; 18% yield). MS (ES): m / z = 396 [M+H] + . t R = 1.19 min ( Method A ). 1 H NMR (500MHz, DMSO-d 6 ) δ 8.60 (d, J =6.7 Hz, 1H), 8.23 ​​- 8.19 (m, 1H), 8.02 (dd, J =9.2, 5.1 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.76 (d, J =9.9 Hz, 1H), 7.31 - 7.26(m, 2H), 7.15 (d, J =6.7 Hz, 1H), 7.09 (t, J =8.8 Hz, 2H), 4.03 (d, J =12.4 Hz,2H), 3.41 (s, 2H), 3.31 (t, J =12.2 Hz, 2H), 3.10 - 3.00 (m, 2H),...

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Abstract

There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and / or inflammatory disorders utilizing the compounds of the invention.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 62 / 331,857, filed May 4, 2016, which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention generally relates to compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and the use of compounds of the present invention in the treatment of proliferative disorders such as cancer, viral infections and / or methods for autoimmune diseases. Background of the invention [0004] Indoleamine 2,3-dioxygenase (IDO; also known as IDO1) is an IFN-γ target gene that plays a role in immune regulation. IDO is an oxidoreductase and is one of two enzymes that catalyze the first and rate-limiting step in the conversion of tryptophan to N-formyl-kynurenine. It exists as a 41 kD monomer found in several cell populations including ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/166A61K31/277A61K31/445C07C233/65C07C255/50C07D487/04
CPCC07C255/50C07C233/65A61K31/165A61K31/4418A61K31/451A61K31/4545A61K31/47A61K31/4709C07D401/04C07D215/18A61P35/00A61P25/28A61P25/24A61P31/12Y02A50/30A61K2300/00A61P29/00A61K31/4725A61K47/42
Inventor E.C.彻尔尼单伟芳L.张D.K.威廉斯郭伟巍A.黄J.A.巴洛格
Owner BRISTOL MYERS SQUIBB CO
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