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Compounds used as JAK inhibitor, and use of compounds

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

Active Publication Date: 2017-01-18
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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  • Compounds used as JAK inhibitor, and use of compounds
  • Compounds used as JAK inhibitor, and use of compounds
  • Compounds used as JAK inhibitor, and use of compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0574] 3-((3-(2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile

[0575]

[0576] Step 1: Compound 3-((3-(2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- Synthesis of 5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile

[0577] To 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2 ,3-b]pyrazine (30mg, 0.07mmol) in 1,4-dioxane (4mL) solution was added successively 3-((3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl)amino)propionitrile (24mg, 0.08mmol), potassium carbonate (16mg, 0.12mmol), Pd(dppf)Cl 2 (10mg, 0.01mmol) and water (1mL), heated at 110°C for 7 hours under nitrogen atmosphere, diluted with water (10mL), extracted with dichloromethane (15mLx3), dried over anhydrous sodium sulfate, concentrated column chromatography (petroleum ether / ethyl acetate (v / v)=2 / 1) to obtain 26 mg of brown oil, yield: 74.74%.

[0578] MS(ESI,pos.ion)m / z:474.3[M+1] + .

[0579] Ste...

Embodiment 2

[0597] 3-((3-(2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propanamide

[0598]

[0599] Step 1: Compound 3-((3-(2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyr Synthesis of oxazin-7-yl)phenyl)amino)propionitrile

[0600] Under nitrogen protection, toluene (10 mL) and water (1.2 mL) were added to 7-bromo-2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H- Pyrrolo[2,3-b]pyrazine (200mg, 0.42mmol), cyclopropylboronic acid (72mg, 0.85mmol), potassium phosphate heptahydrate (440mg, 1.36mmol), palladium acetate (6mg, 0.02mmol), three In a mixture of cyclohexylphosphine (15mg, 0.04mmol), reflux at 110°C for 19h, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and subjected to column separation (petroleum ether / ethyl acetate (v / v) = 4 / 1) Obtained 160 mg of light red solid, yield: 87.2%.

[0601] MS(ESI,pos.ion)m / z:434.3[M + 1] + .

[0602] S...

Embodiment 3

[0618] 3-((3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl) Amino)propionitrile

[0619]

[0620] Step 1: Compound 3-((3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy) Synthesis of methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)amino)propionitrile

[0621]Under nitrogen protection, 3-((3-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine -7-yl)phenyl)amino)propionitrile (200mg, 0.42mmol), 6-fluoro-1-methyl-3-(tributylstannane)-1H-indazole (380mg, 0.85mmol), iodide Copper (16mg, 0.08mmol) and tetrakistriphenylphosphine palladium (26mg, 0.02mmol) were added together, then DMF (15mL) was added, the temperature was raised to 90°C for 4.5h, the reaction liquid was cooled to room temperature, ethyl acetate (50mL ×3) extraction, with anhydrous Na 2 SO 4 Drying, removal of solvent, and column separation (petroleum ether / ethyl acetate (v / v)=4 / 1) gave 200 mg of light yellow oil, yield: 84.7%.

[0622] MS(ESI...

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Abstract

The invention provides compounds used as a JAK inhibitor, and a use of the compounds, and concretely provides compounds (represented by formula (I)) with JAK inhibition activity or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a medicinal composition including the compounds. The invention also discloses a use of the compounds or the medicinal composition thereof in the preparation of medicines used for treating autoimmune diseases or proliferative diseases.

Description

[0001] field of invention [0002] The invention belongs to the technical field of medicine, and specifically relates to a class of compounds with JAK inhibitory activity, a pharmaceutical composition comprising the compound of the present invention, and the application of the compound of the present invention or the pharmaceutical composition comprising the compound of the present invention in medicine. [0003] Background of the invention [0004] Janus kinases (JAKs) belong to the tyrosine kinase family consisting of JAK1, JAK2, JAK3 and TYK2. JAKs play an important role in cytokine signaling. Downstream substrates of JAK family kinases include signal transducer and activator of transcription (STAT) proteins. JAK / STAT signaling has been implicated in the mediation of many aberrant immune responses, such as allergy, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and Solid and hematologica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04C07D471/14C07D487/14A61K31/4985A61K31/541A61K31/506A61K31/519A61K31/437A61K45/06A61P19/04A61P21/00A61P19/02A61P29/00A61P17/06A61P3/10A61P11/06A61P17/00A61P25/28A61P35/00A61P35/02A61P37/06A61P1/00A61P37/02
CPCA61K31/437A61K31/4985A61K31/506A61K31/519A61K31/541A61K45/06C07D471/04C07D471/14C07D487/04C07D487/14
Inventor 刘兵黄九忠郑常春张英俊欧阳罗毛洪芬聂飚许娟陈红分
Owner SUNSHINE LAKE PHARM CO LTD
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