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Hetero-aromatic compounds and applications thereof in pharmacy

A technology of compounds and hydrates, applied in the field of medicine, can solve problems such as signal transduction disorders

Active Publication Date: 2016-07-06
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Consistent with this, primary cells derived from TYK2-deficient humans have impairments in the signaling of type I interferons, IL-6, IL-10, IL-12, and IL-23

Method used

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  • Hetero-aromatic compounds and applications thereof in pharmacy
  • Hetero-aromatic compounds and applications thereof in pharmacy
  • Hetero-aromatic compounds and applications thereof in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0297] Example 14-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine)piperidine-1-carbonyl)benzonitrile

[0298]

[0299] Step 1: Synthesis of compound 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine

[0300] Dissolve 4-chloropyrrolo[2,3-d]pyrimidine (5.00g, 32.56mmol) and p-toluenesulfonic acid chloride (6.83g, 35.82mmol) in acetone (50mL), and add to the reaction solution at 0°C A solution of sodium hydroxide (1.56g, 39.07mmol) in water (20mL) was slowly added dropwise to the mixture, and after the addition was completed, the reaction was stirred at room temperature for 8 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with a mixed solvent of acetone / water (10 mL, v / v=1 / 1) and then dried to obtain 9.39 g of a white solid with a yield of 93.71%.

[0301] MS(ESI,pos.ion)m / z:308.2[M+1] + .

[0302] Step 2: Compound N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7-p-toluenesulfonyl-7H-p...

Embodiment 23

[0315] Example 23-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine)piperidine-1-carbonyl)benzenesulfonate Amide

[0316]

[0317] N-Methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (114.0mg, 0.46mmol) , m-sulfonamide benzoic acid (185.1mg, 0.92mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (349.8mg, 0.92mmol) was dissolved in DMF (8mL), then N,N-diisopropylethylamine (237.8mg, 1.84mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (20 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (60 mL), and the combined organic phase was washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure, and the resulting residue is subjected to silica gel column chromatography (eluent: CH 2 Cl 2 / MeOH (v / v)=10 / 1), purified to obtain 46.0 mg of white solid, yield: 23.34%.

[0...

Embodiment 3

[0320] Example 31-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine)piperidine-1-carbonyl)-3 -Cyanoazetidine

[0321]

[0322] 3-cyanoazetidine hydrochloride (162.4mg, 1.377mmol) and N,N-diisopropylethylamine (389.0mg, 3.01mmol) were added to triphosgene (69.6mg, 0.51mmol) in di Methyl chloride (12mL) solution, stirred at room temperature for 1h, then added N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3 -d] Pyrimidin-4-amine (336mg, 1.37mmol), then slowly drop N,N-diisopropylethylamine (195.2mg, 1.51mmol) in dichloromethane (8mL) solution, react at room temperature for 48h. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH 2 Cl 2 / CH 3 OH (v / v)=14 / 1), purified to obtain 47.7 mg of white solid, yield: 9.85%.

[0323] MS(ESI,pos.ion)m / z:354.3[M+1] + ;

[0324] 1 HNMR (400MHz, CDCl 3 ):δ(ppm)10.83(s,1H),8.28(s,1H),7.07(d,J=3.6H...

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Abstract

The invention discloses hetero-aromatic compounds and applications thereof in pharmacy. Specifically, the invention provides hetero-aromatic compounds, and steric isomers, geometric isomers, tautomers, racemic bodies, nitrogen oxides, hydrates, solvates, metabolism products, and pharmaceutically acceptable salts or prodrug thereof. The compounds mentioned above can be used to treat autoimmune diseases or proliferative diseases. The invention also discloses a pharmaceutical composition comprising the compounds mentioned above, and an application of the compounds or the pharmaceutical composition in the preparation of drugs for treating autoimmune diseases or proliferative diseases.

Description

field of invention [0001] The invention belongs to the technical field of medicine, and specifically relates to a class of heteroaryl compounds with protein kinase inhibitory activity and a pharmaceutical composition comprising the compound of the invention. The present invention also relates to the use of the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention in medicine. Background of the invention [0002] Janus kinases (JAKs) belong to the tyrosine kinase family consisting of JAK1, JAK2, JAK3 and TYK2. JAKs play an important role in cytokine signaling. JAK1, JAK2 and TYK2 can repress the expression of multiple genes, whereas JAK3 only functions in granulocytes. Cytokine receptors typically function as heterodimers, and thus usually not one JAK kinase interacts with cytokine receptors. [0003] Each JAK associates preferentially with the intracytoplasmic portion of a discrete cytokine receptor (Annu. Rev....

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D491/056A61K31/519A61K31/5377A61K31/541A61P35/00A61P25/28A61P11/00A61P9/10A61P19/02A61P29/00A61P17/06A61P3/10A61P11/06A61P37/02A61P1/04A61P35/02
CPCC07D487/04C07D491/056
Inventor 刘兵黄九忠任兴业李志龙伯华张英俊郑常春
Owner SUNSHINE LAKE PHARM CO LTD
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