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Heterarylation compound and application thereof to drugs

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

Active Publication Date: 2016-05-11
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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  • Heterarylation compound and application thereof to drugs
  • Heterarylation compound and application thereof to drugs
  • Heterarylation compound and application thereof to drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0257] Example 1N-(2,6-dichloro-4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxamide

[0258]

[0259] Under ice-cooling, add oxalyl chloride (391.0mg, 3.08mmol) to a solution of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (100.0mg, 0.62mmol) in dichloromethane (5mL), 2 drops DMF was used as a catalyst, and the reaction was heated at 40°C for 2h. The reaction solution was concentrated, and the resulting residue was dissolved in DMF (5 mL), and 4-amino-3,5-dichlorobenzonitrile (173.0 mg, 0.93 mmol) and sodium hydride (60%, 74.0 mg, 1.85mmol) in DMF (5mL) solution, react at room temperature for 12h. After completion of the reaction, water (20 mL) was added to the reaction solution to quench the reaction, extracted with dichloromethane (30 mL × 3), 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 separated by silica gel column chromatography (eluent: CH 2 Cl 2 / MeOH (v / v)...

Embodiment 2

[0262] Example 23-(4-methyl-3-(methyl(6-(methylamino)pyridazin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile

[0263]

[0264] Step 1: Compound N 3 ,N 5 -Synthesis of dimethylpyridazine-3,5-diamine

[0265] At room temperature, add 3,5-dichloropyridazine (1.20g, 8.1mmol) and methylamine aqueous solution (10mL) into a 25mL digestion tank, seal it; react in an oil bath at 150°C for 22h, cool to room temperature, and the reaction solution Concentrate directly, and the residue is separated by column chromatography (eluent: CH 2 Cl 2 / MeOH (v / v)=6 / 1), to obtain 1.1 g of light yellow solid, yield: 98%.

[0266] MS(ESI,pos.ion)m / z:139.1[M+1] + .

[0267] Step 2: Compound N 5 -(1-Benzyl-4-methylpiperidin-3-yl)-N 3 ,N 5 -Synthesis of dimethylpyridazine-3,5-diamine

[0268] At room temperature, N,N-dimethylformamide (4 mL) was added to N 3 ,N 5 - In a mixture of dimethylpyridazine-3,5-diamine (146mg, 1.06mmol) and sodium hydride (60%, 84.8mg, 2.12mmol), react at 50°C for ...

Embodiment 33

[0274] Example 33-((3R,4R)-3-((6-amino-5-methylpyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3- Oxopropionitrile

[0275]

[0276] Step 1: Synthesis of the compound N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-6-chloro-N,5-dimethylpyrimidin-4-amine

[0277] 4,6-dichloro-5-methylpyrimidine (0.60g, 3.68mmol) and (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine (0.80g, 3.68 mmol) was dissolved in DMF (5 mL), potassium carbonate (1.02 g, 7.36 mmol) was added, and the reaction was stirred overnight at 70° C. under nitrogen protection. Add water (100mL) to quench the reaction, extract with ethyl acetate (70mL×3), wash the organic phase with water (50mL), wash with saturated aqueous sodium chloride solution (50mL), dry the organic layer with anhydrous sodium sulfate, concentrate under reduced pressure, and carry out Separation by column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to obtain 1.08 g of product, yield: 85.0%.

[0278] MS(ESI,pos.ion)m / z:345.3[M+1] + .

[0...

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Abstract

The invention discloses a heterarylation compound and application thereof to drugs, and particularly discloses a heterarylation compound or stereoisomers, geometric isomers, tautomers, nitrogen oxide, hydrate, solvates, metabolites, pharmaceutically acceptable salt or pro-drugs of the heterarylation compound and a drug composition with the heterarylation compound. The invention further discloses application of the compound or the drug composition to drug preparation. The drugs can be used 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, a pharmaceutical composition comprising the compound of the present invention; and the compound of the present invention or the pharmaceutical composition comprising the compound of the present invention in medicine. application. 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. Immunol. 1998, 16, pp. 29...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D498/04C07D401/12C07D519/00A61K31/437A61K31/501A61K31/519A61K31/506A61K31/4985A61K31/454A61K31/4545A61P37/02A61P21/00A61P19/02A61P17/06A61P3/10A61P37/06A61P35/00A61P11/06A61P17/00A61P29/00A61P5/14A61P1/04A61P1/00A61P25/28A61P35/02A61P35/04A61P9/10A61P11/00
CPCC07D401/12C07D471/04C07D487/04C07D498/04C07D519/00
Inventor 刘兵黄九忠任兴业李志张英俊郑常春
Owner SUNSHINE LAKE PHARM CO LTD
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