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Hetero-aromatic compounds and applications thereof in pharmacy

A compound, heteroaryl technology, applied in drug combinations, antipyretics, digestive system, etc., can solve problems such as signal conduction 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

[0330] Example 1 (R)-N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methyl)-2-cyano-N-methyl Acetamide

[0331]

[0332] Step 1: Synthesis of compound (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid

[0333] At room temperature, D-proline (10.0g, 86.80mmol) was dissolved in tetrahydrofuran (16mL) and water (40mL), and sodium bicarbonate (18.2g, 217.14mmol) and di-tert-butyl dicarbonate (27.3 mL, 130.20mmol), react overnight at room temperature, quench with water (50mL), extract with ethyl acetate (150mL×3), and use anhydrous Na 2 SO 4 Drying, solvent removal, concentrated solution is carried out column chromatography separation (eluent: CH 2 Cl 2 / MeOH (v / v)=30 / 1), to obtain 9.3 g of colorless oil, yield: 50%.

[0334] MS(ESI,pos.ion)m / z:160.1[M-t-Bu+2] + .

[0335] Step 2: Synthesis of compound (R)-tert-butyl 2-(methylcarbamoyl)pyrrolidine-1-carboxylate

[0336] At room temperature, (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.30g, 6...

Embodiment 2

[0349] Example 2 (S)-N-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methyl)-2-cyanoacetamide

[0350]

[0351] Step 1: Synthesis of compound (S)-tert-butyl-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

[0352] At 0°C, dissolve tert-butyl L-prolinol-1-carboxylate (5.0g, 24.8mmol) in dichloromethane (50mL), add triethylamine (5.16mL, 38.2mmol), and slowly drop Add methanesulfonyl chloride (2.94mL, 38.2mmol), move to room temperature and stir overnight, the reaction solution is washed with saturated ammonium chloride solution (20mL×2), dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (eluent: PE / EtOAc (v / v)=5 / 1), 6.0 g of colorless oil was obtained, yield: 87%.

[0353] MS(ESI,pos.ion)m / z:224.1[M-t-Bu+2] + .

[0354] Step 2: Synthesis of compound (S)-tert-butyl-2-(azidomethyl)pyrrolidine-1-carboxylate

[0355] At room temperature, add DMF (3 mL) to (S)-tert-butyl-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carbox...

Embodiment 3

[0368] Example 3 (S)-2-cyano-N-((4,4-difluoro-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl) Methyl)-N-methylacetamide

[0369]

[0370] Step 1: Synthesis of compound (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid

[0371] Dissolve (2S)-4-oxopyrrolidine-2-carboxylic acid (5.00g, 30.20mmol) in tetrahydrofuran (150mL), add triethylamine (15mL) and Boc 2 O (7 mL), stirred overnight at room temperature. After tetrahydrofuran was evaporated under reduced pressure, hydrochloric acid (1M) was added to acidify to pH 2, extracted with ethyl acetate (200mL×3), the organic phase was washed with water (150mL), saturated sodium chloride solution (150mL), and anhydrous sulfuric acid Sodium-dried, concentrated under reduced pressure and fully dried, it was directly used in the next step of synthesis.

[0372] Step 2: Synthesis of compound (S)-diethyl 1-tert-butyl-2-methyl-4-oxopyrrolidine-1,2-dicarboxylate

[0373] Dissolve (S)-1-(tert-butoxycarbonyl)-4-oxopyrroli...

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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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61P37/02A61P21/00A61P19/02A61P29/00A61P17/06A61P3/10A61P35/00A61P11/06A61P17/00A61P1/04A61P1/00A61P25/28A61P35/02A61P35/04A61P9/10A61P11/00
CPCC07D487/04C07D519/00
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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