Modulators of the retinoid-related orphan receptor gamma (ror-gamma) for use in the treatment of autoimmune and inflammatory diseases

A technology selected from, halogen, applied in the field of orphan receptor gamma modulators

Active Publication Date: 2015-12-02
GLAXO GRP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, RORγt deficiency leads to improved EAE

Method used

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  • Modulators of the retinoid-related orphan receptor gamma (ror-gamma) for use in the treatment of autoimmune and inflammatory diseases
  • Modulators of the retinoid-related orphan receptor gamma (ror-gamma) for use in the treatment of autoimmune and inflammatory diseases
  • Modulators of the retinoid-related orphan receptor gamma (ror-gamma) for use in the treatment of autoimmune and inflammatory diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0609] 3-chloro-N-(2-chloro-3-{[(3R,5S)-4-(cyclopentylcarbonyl)-3,5-dimethyl-1-piperazinyl]methyl}phenyl) Benzamide, Trifluoroacetate (E1)

[0610]

[0611] 2-Chloro-3-{[(3R,5S)-4-(cyclopentylcarbonyl)-3,5-dimethyl-1-piperazinyl]methyl}aniline (60mg, 0.171mmol) and pyridine (0.028 mL, 0.343 mmol) was dissolved in DCM (15 mL), and to this solution was gradually added 3-chlorobenzoyl chloride (36.0 mg, 0.206 mmol). The reaction mixture was stirred at room temperature for 2 hours. Remove DCM. The obtained mixture was redissolved in DMF and the solid was filtered off. The filtrate was purified by MPAP to give the title compound (69 mg) as a white solid. 1 H-NMR (MeOD-d 4 ,400MHz): 7.90(s,1H),7.82(d,1H),7.59(d,1H),7.53(d,1H),7.45(m,2H),7.32(t,1H),4.51(brs, 1H), 4.21 (brs, 1H), 3.81 (brs, 2H), 2.93 (m, 3H), 2.41 (brs, 2H), 1.74--1.52 (m, 8H), 1.28 (m, 6H). δF(MeOD-d 4 ,376MHz): -77.1.MS(ES): C 26 h 31 Cl 2 N 3 o 2 Requirement 487; measured value 488 (M+H + ).

Embodiment 2-9

[0613] Examples 2-9 were prepared using similar procedures as described for Example 1 .

[0614] E2N-(2-chloro-3-{[(3R,5S)-4-(cyclopentylcarbonyl)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-2-( 4-Chlorophenyl)acetamide, trifluoroacetate

[0615] E3N-(2-chloro-3-{[(3R,5S)-4-(cyclopentylcarbonyl)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-2-ethane Butyramide, trifluoroacetate

[0616] E4N-(2-chloro-3-{[(3R,5S)-4-(cyclopentylcarbonyl)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-8-quinone Phenylsulfonamide, Trifluoroacetate

[0617] E5(S)-N-(3-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-4-fluoro-2-methylphenyl)cyclopropane Amide, trifluoroacetate

[0618] E6(S)-N-(3-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-4-fluoro-2-methylphenyl)-2- Phenylacetamide, trifluoroacetate

[0619] E7N-(2-chloro-3-(((3S,5R)-4-(cyclopentanecarbonyl)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)isobutyramide

[0620] E8N-(2-chloro-3-(((3S,5R)-4-(cyclopentanecarbonyl)-3,5-dimet...

Embodiment 10

[0626] (S)-N-(3-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-5-fluoro-2-methylphenyl)cyclopentane Amide, trifluoroacetate

[0627]

[0628] Add cyclopentanecarbonyl chloride (38.2 mg, 0.288 mmol) to (S)-(4-(3-amino-5-fluoro-2-methylbenzyl)-2-methylpiperazine-1- In a solution of (cyclopentyl)methanone (80mg, 0.240mmol) and pyridine (38.0mg, 0.480mmol) in DCM. The reaction mixture was stirred overnight at room temperature. After checking by LCMS, the reaction was complete. The mixture was concentrated and then purified by MDAP to afford the title compound (43 mg, 31.3% yield) as a white solid. 1 HNMR (400MHz, MeOD-d 4 )δ1.16-1.42(m,4H),1.55-2.09(m,18H),2.12-2.20(m,1H),2.22(s,3H),2.72(t,1H),2.78-3.08(m, 3H),3.34-3.41(m,1H),3.41-3.53(m,2H),3.83(d,0.5H),4.19-4.39(m,1H),4.66(brs,0.5H),6.97(d, 1H), 7.05(d, 1H). 19 FNMR (376MHz, MeOD-d 4 )δ-78.6,-119.0.MS (ESI): C 25 h 36 FN 3 o 2 Requirement: 429, measured value 430 (M+H + ).

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Abstract

The present invention relates to novel retinoid-related orphan receptor gamma (ROR gamma) modulators and their use in the treatment of diseases mediated by ROR gamma.

Description

technical field [0001] The present invention relates to novel retinoid-related orphan receptor gamma (RORy) modulators and their use in the treatment of RORy-mediated diseases. Background technique [0002] Retinoid-related orphan receptors (RORs) are transcription factors belonging to the steroid hormone nuclear receptor superfamily (Jetten & Joo (2006) Adv. Dev. Biol. 16:313-355). The ROR family consists of three members, RORalpha (RORα), RORbeta (RORβ) and RORgamma (RORγ), each of which is encoded by a separate gene (RORA, RORB and RORC, respectively). RORs contain four main domains shared by most nuclear receptors: N-terminal A / B domain, DNA-binding domain, hinge domain, and ligand-binding domain. Each ROR gene produces several isoforms that differ only in their N-terminal A / B domains. Two isoforms of RORγ have been identified: RORγ1 and RORγt (also known as RORγ2). RORγ is a term used to describe RORγ1 and / or RORγt. [0003] While RORγ1 is expressed in multiple tiss...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D401/14C07D413/14C07D401/12C07D407/12C07D241/04C07D413/12C07D417/12C07D417/14C07D471/04A61K31/495A61K31/496A61K31/506A61K31/501A61K31/497
CPCC07D403/12C07D401/14C07D413/14C07D401/12C07D407/12C07D241/04C07D413/12C07D417/12C07D417/14C07D471/04C07D211/16C07D405/12A61P1/04A61P11/06A61P17/06A61P19/02A61P25/00A61P29/00A61P37/00A61P37/02
Inventor F.韩H.雷X.林Q.孟Y.王
Owner GLAXO GRP LTD
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