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Biaryl compound useful as ROR gamma modulator

A compound, solvate technology, applied in the field of chemical medicine, can solve the problem of reduced ability of differentiation and so on

Pending Publication Date: 2021-11-19
SHANGHAI LITEDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thp cells isolated from RORγt-deficient mice have significantly reduced ability to differentiate into Th17 cell lines

Method used

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  • Biaryl compound useful as ROR gamma modulator
  • Biaryl compound useful as ROR gamma modulator
  • Biaryl compound useful as ROR gamma modulator

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0217] The technical solutions of the present invention are further described below, but the scope of the invention is not limited to these embodiments. Alternatively, alterations that do not depart from the concepts of the present invention are included within the scope of the invention.

[0218] The experimental method of the specific condition is not indicated in the following examples, usually in accordance with the conventional conditions of this type, or according to the conditions recommended in the manufacturer. Unless otherwise stated, the number of percentages and copies is the number of weights and weights. The ratio of liquid is a volume ratio unless otherwise stated.

[0219]Materials and reagents used in the following embodiments unless otherwise specified and can be obtained from commercial sources, or prepared according to the present application have disclosed a method similar to the method according to the prior art.

[0220] As used herein, the chemical name IUP...

Embodiment 1 and Embodiment 2

[0243] Example 1 and Example 2: R-2- acetyl -N- (2'- fluoro-4 '- (1,1,1,3,3,3-hexafluoro-2-hydroxy-2-yl ) - [1,1'-biphenyl] -4-yl) -5- (methylsulfonyl) isoindoline-1-carboxamide or S-2- acetyl -N- (2'- fluoro - 4 '- (1,1,1,3,3,3-hexafluoro-2-hydroxy-2-yl) - [1,1'-biphenyl] -4-yl) -5- (methyl sulfonamide acyl) isoindoline-1-carboxamide

[0244]

[0245] Synthesis of 1,1,1,3,3,3-hexafluoro-propan-2-ol - Intermediate 2- ([1,1'-biphenyl] -4-amino-2-fluoro-4'-yl)

[0246] Step 1: 4-bromo-perfluorophenyl Synthesis of 3-fluoro-benzoate

[0247]

[0248] Sequentially bromo-3-fluorobenzoic acid (30.0g, 137mmol), pentafluorophenol (28.2g, 153mmol) and dicyclohexyl carbodiimide (31.9g, 155mmol) was dissolved in dry tetrahydrofuran (900 mL) in . The reaction mixture was stirred at room temperature overnight, complete reaction was monitored by TLC. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product Purification by silica gel co...

Embodiment 3

[0293] Example 3: 2-Acetyl-N- (4 '- (1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl) - [1,1'-biphenyl] -4-yl) -6- (methylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-1-formamide

[0294]

[0295] Synthesis of intermediate 2- (tert-butoxycarbonyl) -6- (methylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-1-formic acid

[0296] Step 1: 3- (2-aminoethyl) phenolic bromide synthesis

[0297]

[0298] 2- (3-methoxyphenyl) ethylamine (9.00 g, 59.5 mmol) was dissolved in a 40% hydrobromide solution (120 g, 595 mmol). The reaction mixture was stirred at 110 ° C for 6 hours, and the LC-MS monitored reaction was complete. The reaction mixture was concentrated under reduced pressure to give the target compound (9.00 g, crude, light brown solid). LC-MS (ESI) M / Z: 179.1 [M + ACN + H] + .

[0299] Step 2: Synthesis of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-formate hydrochloride

[0300]

[0301] 3- (2-aminoethyl) phenolic bromide (9.00 g, 65.6 mmol) was dissolved in ethanol (90 mL). 50% acetan...

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Abstract

The present invention relates to a compound of formula (I), a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, a pharmaceutical composition comprising the same, a method for treating or preventing diseases associated with ROR gamma t by using the same, and use thereof in the preparation of a medicament for treating or preventing diseases associated with ROR gamma t.

Description

Technical field [0001] The present invention belongs to the chemical medicine technology, and more particularly to a combination-based compound having RORγT inhibitory activity, a pharmaceutical composition comprising the compound, a method of preparing the compound, and the compound is prepared for prevention or treatment with RORγT. Use of drugs related to diseases. Background technique [0002] Retinoic Acid Recetor-Recend Orphanreceptors, Rors, also known as NF1R, a sub-family of the ligand-dependent transcription factor core surcharge. The RORS Sian family mainly includes three subtypes of RORα, RORβ and RORγ. RORγ contains two members: RORγ1 (also known as RORγ) and RORγ2 (also known as RORγT), where RORγ1 is distributed in skeletal muscle, thymus, testicular, pancreas, prostate, heart and liver, and RORγT only expresses some immunization Cells. [0003] Little et al. Earliest reported RORγT is required for initial CD4 + T cells into Th17 cells (Cell, 2006 126, 1121-1133). ...

Claims

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Application Information

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IPC IPC(8): C07D209/44C07D217/26A61K31/4035A61K31/472A61P17/06A61P19/02A61P19/08A61P25/28A61P11/00A61P11/06A61P13/12A61P9/00A61P27/02A61P17/00A61P17/02A61P11/02A61P1/00A61P1/04A61P1/16A61P3/10A61P29/00A61P35/00A61P37/08A61P37/06
CPCC07D209/44C07D217/26A61P17/06A61P19/02A61P19/08A61P25/28A61P11/00A61P11/06A61P13/12A61P9/00A61P27/02A61P17/00A61P17/02A61P11/02A61P1/00A61P1/04A61P1/16A61P3/10A61P29/00A61P35/00A61P37/08A61P37/06A61K31/4035A61K31/472C07D221/02C07D217/24A61P37/00
Inventor 程耀邦黄亚飞周娟董志强
Owner SHANGHAI LITEDD CO LTD
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