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A kind of imidazopyridine derivatives

A technology of pyridine derivatives and imidazolo, which is applied in the field of small molecules that can inhibit Trk activity, and can solve problems such as stability and insufficient activity

Active Publication Date: 2022-01-14
FORELAND PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The present invention proposes a novel substituted imidazopyridine compound as a Trk kinase inhibitor to overcome the problems of insufficient stability and activity in the prior art and meet the growing clinical needs

Method used

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  • A kind of imidazopyridine derivatives
  • A kind of imidazopyridine derivatives
  • A kind of imidazopyridine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1-Compound 1

[0094] Prepare M1

[0095]

[0096] (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitro-2-(3-benzylureido)pyridine

[0097] (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitro-2-(diphenoxycarbonyl)aminopyridine (2g, 3.5mmol) , benzylamine (0.56g, 5.3mmol) and sodium carbonate (0.74g, 7mmol) were suspended in 25mL of acetonitrile and stirred at room temperature for 12 hours. After the reaction was detected by TLC, 20 ml of water was added to quench the reaction, extracted with ethyl acetate (3×50 ml), the organic phases were combined, dried, and spin-dried to obtain a crude product. The crude product was purified by a silica gel column (ethyl acetate / petroleum ether=1 / 3, V / V) to obtain 1.4 g of a yellow solid product with a yield of 85.7%. LC-MS(ESI)m / z:454[M+H] + .

[0098]

[0099] (R)-N-Benzyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3H-imidazo[4,5-b]pyridine-3-carboxamide

[0100] Intermediate M1 (200 mg, 0.44 mmol) was dissolv...

Embodiment 2

[0103] Example 2-Compound 2

[0104]

[0105] (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-fluorobenzyl)-3H-imidazo[4,5-b]pyridine- 3-formamide

[0106] Step A: (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitro-2-(3-(4-fluorobenzyl)ureido) Preparation of pyridine. Prepared as in the preparation of M1, using 4-fluorobenzylamine instead of benzylamine.

[0107] Step B: (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-fluorobenzyl)-3H-imidazo[4,5-b ] Preparation of pyridine-3-carboxamide. The intermediate (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitro-2-(3-(4-fluorobenzyl)ureido) Pyridine (300 mg, 0.63 mmol) was dissolved in 5 mL of THF, 10% palladium on carbon (30 mg) was added, hydrogen was replaced, and stirred at room temperature for 12 hours. After the reaction was detected by TLC, it was filtered and spin-dried to obtain the crude product. The crude product was dissolved in 5 mL of triethyl orthoformate, p-toluenesulfonic acid (15 mg) was added,...

Embodiment 3

[0110] Example 3-Compound 3

[0111]

[0112] (R)-N-(3,5-difluorobenzyl)-5-(2-(3,5-difluorophenyl)pyrrolidin-1-yl)-3H-imidazo[4,5-b ]pyridine-3-carboxamide

[0113] Step A: (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitro-2-(3-(3,5-difluorobenzyl) Preparation of ureido)pyridines. Prepared as in the preparation of M1, using 3,5-difluorobenzylamine instead of benzylamine.

[0114] Step B: Add (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitro-2-(3-(3,5-difluorobenzyl )ureido)pyridine (200mg, 0.41mmol) was dissolved in 5mL THF, 10% palladium carbon (20mg) was added to replace the hydrogen, and stirred at room temperature for 12 hours. TLC detection, after the reaction was completed, filtered and spin-dried to obtain the crude product. The crude product was dissolved in 5 mL of triethyl orthoformate, p-toluenesulfonic acid (10 mg) was added, and reacted at 135° C. for 4 hours. TLC detection, after the reaction, the reaction solution was concentrated and purified b...

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Abstract

An imidazopyridine derivative of the invention relates to the field of biologically active small molecules, in particular to a small molecule capable of inhibiting Trk activity. A novel substituted imidazopyridine compound is proposed as a Trk kinase inhibitor, which overcomes the problem of drug resistance produced by a generation of Trk inhibitors in clinical applications. The imidazopyridine compound provided by the invention can be used for Mutant Trk kinase has a strong inhibitory effect.

Description

technical field [0001] The invention relates to the field of biologically active small molecules, in particular to a small molecule capable of inhibiting Trk activity. Background technique [0002] Tropomyosin-related kinase (Trk) is a kind of nerve growth factor receptor, and its family has highly homologous tropomyosin-related kinase A (tropomyosin-related kinase A, TrkA), tropomyosin Globulin-related kinase B (TrkB) and tropomyosin-related kinase C (TrkC) are encoded by NTRK1, NTRK2 and NTRK3, respectively. Among the neurotrophic factors are (i) nerve growth factor (NGF) that activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4 / 5 that activate TrkB, and (iii) TrkC that activates NT3. Trk is widely expressed in neuronal tissues and is related to the maintenance, signal transduction and survival of neuronal cells (Current Opinion in Neurobiology, 2001, 11:272-280). [0003] Trk kinase is considered to be related to the growth, differentiation, and apopt...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P29/00A61P35/00
CPCC07D471/04A61P29/00A61P35/00
Inventor 卢法冠王磊杜镇建杜美静
Owner FORELAND PHARM CO LTD