Imidazopyridine derivative, preparation method and medical uses thereof

A pharmacy and compound technology, applied in the fields of imidazopyridine derivatives and their preparation and their use in medicine, can solve the problems of unsatisfactory effectiveness, safety or applicability

Inactive Publication Date: 2020-02-25
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compounds and experimental drugs disclosed in the prior art are still unsatisfactory in terms of effectiveness, safety or applicability, and it is still necessary to continue research and development of new interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors agents to meet people's growing medical and health needs

Method used

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  • Imidazopyridine derivative, preparation method and medical uses thereof
  • Imidazopyridine derivative, preparation method and medical uses thereof
  • Imidazopyridine derivative, preparation method and medical uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] N-(2-(3-hydroxy-3-methylbutyl)-7-(2-hydroxypropan-2-yl)imidazol[1,2-a]pyridin-6-yl)-6-(trifluoro Methyl)pyridine-2-carboxamide

[0055]

[0056] The first step is to synthesize 2-amino-5-nitroisonicotinic acid methyl ester

[0057]

[0058] At 0°C, slowly add 10g of 2-aminoisonicotinic acid methyl ester into 100mL of concentrated sulfuric acid with mechanical stirring, stir until dissolved and then lower the temperature to -10°C, slowly drop the mixed acid prepared by 10mL of concentrated nitric acid and 6mL of concentrated sulfuric acid Add it to the reaction (dropping for about 30 minutes), after the dropwise addition is complete, control the reaction temperature below -5°C and continue stirring overnight. After the reaction was completed, the reaction solution was added to a large amount of ice, the pH was adjusted to neutral to slightly alkaline with concentrated ammonia water, the solid was precipitated by stirring, filtered with suction, and vacuum-dried at...

Embodiment 2

[0077] N-(7-(2-Hydroxypropan-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)pyridine -2-Carboxamide

[0078]

[0079] The first step is to synthesize 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-nitroimidazo[1,2-a]pyridine-7-carboxylic acid methyl ester

[0080]

[0081] Weigh 1b (1g, 5mmol), 2a (2eq, 3.1g) and magnesium oxide (2eq, 0.4g), add THF (50mL), seal the tube at 100°C for 24h, cool the reaction solution to room temperature, suction filter, and wash with THF , the filtrate was spin-dried, purified by silica gel column, and eluted with Hex / THF to obtain 2b (1.13g, 56%).

[0082] The second step is to synthesize 6-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester

[0083]

[0084] Weigh 2b (1.13g, 2.8mmol), iron powder (1.57g, 10eq) and ammonium chloride (0.45g, 3eq), add ethanol / water (100mL, volume ratio 4 / 1), and react at 90°C until raw material 2b The reaction was complete, filtere...

Embodiment 3

[0098] N-(7-(2-hydroxypropan-2-yl)-2-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoro Methyl)pyridine-2-carboxamide

[0099]

[0100] Weigh 2 (45mg, 0.1mmol) and dissolve it in DMF (5mL), add potassium carbonate (27mg, 2eq), react at room temperature for 30min, add iodomethane (21mg, 1.5eq), TLC detection until the reaction of raw material 2 is complete, add saturated salt Washed with water (20 mL), added 100 mL of ethyl acetate for extraction, separated the organic layer, dried over anhydrous sodium sulfate, filtered, concentrated, purified on a silica gel column, and eluted with dichloromethane / methanol to obtain compound 3 (27 mg, 60%). 1 H NMR (400MHz, CDCl 3 )δδ12.44(s,1H),9.78(s,1H),8.43(d,J=7.8Hz,1H),8.14(t,J=7.8Hz,1H),7.90-7.80(m,2H), 7.44(s,1H),4.12(br,1H),3.90-3.80(m,2H),2.95-2.84(m,2H),2.81(s,3H),2.35-2.25(m,2H),1.90- 1.83(m,2H),1.77(s,6H).

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Abstract

The invention relates to an imidazopyridine derivative represented by a general formula (I) or a pharmaceutically acceptable salt thereof, and a preparation method thereof, uses of the imidazopyridinederivative or the pharmaceutically acceptable salt thereof as treatment agents, especially as IRAK4 kinase inhibitors. According to the invention, R1, R2, R3 and R4 in the general formula (I) are defined in the specification.

Description

technical field [0001] The present invention relates to a novel imidazo[1,2-a]pyridine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as an IRAK4 inhibitor. [0002] technical background [0003] Interleukin-1 receptor-associated kinase 4 (IRAK-4) is a member of the IRAK family of intracellular serine-threonine kinases. Other members of the kinase family include IRAK-1, IRAK-2, and IRAK-M. IRAK-M is only expressed in monocytes and macrophages, and the expression of IRAK-1, IRAK-2 and IRAK4 is ubiquitous. IRAK4 is mainly composed of a conserved death domain (DD) at the N-terminus, a hinge region, and a central kinase domain (KD) at the C-terminus. The DD region is the region where IRAK4 binds to the adapter protein myeloid differentiation factor primary response gene 88 (MyD88). The KD region is composed of 12 subregions and has typical serine-threonine kinase domain characteris...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4545A61K31/4427A61P37/00A61P29/00A61P35/00A61P17/06A61P37/02A61P19/02A61P15/00
CPCA61P15/00A61P17/06A61P19/02A61P29/00A61P35/00A61P37/00A61P37/02C07D471/04A61K31/4188A61K31/4427A61K31/4545
Inventor 翟文强卢勇平程超英云虹伟钱文建施正政胡泰山陈磊白骅
Owner ZHEJIANG HISUN PHARMA CO LTD
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