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Fused heterocyclic biaryl benzyl alcohol compound, and preparation method and application thereof

A technology of aryl benzyl alcohol and heteroaryl, applied in the field of medicinal chemistry, can solve the problems of insufficient selectivity, limiting the anti-tumor potential of biological functions of bromodomain-containing proteins, and the mechanism to be further elucidated

Active Publication Date: 2020-04-07
RUDONG RINGENE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are few structural types of small molecule inhibitors of BRD4 protein and the selectivity is not outstanding enough, which limits people's in-depth research on the biological functions of bromodomain-containing proteins and their anti-tumor potential
In addition, the effect of existing BRD4 protein inhibitors needs to be improved, and the mechanism needs to be further elucidated

Method used

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  • Fused heterocyclic biaryl benzyl alcohol compound, and preparation method and application thereof
  • Fused heterocyclic biaryl benzyl alcohol compound, and preparation method and application thereof
  • Fused heterocyclic biaryl benzyl alcohol compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0328] Example 1: N-ethyl-6-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-3- Methyl-9H-pyrrole[2,3-c][1,2,4]triazol[4,3-a]pyridine-8-amide

[0329]

[0330] The first step: 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (190mg, 0.7mmol), ethylamine hydrochloride (254mg, 3.12mmol) and HATU (593mg, 1.56mmol) was dissolved in N,N-dimethylformamide DMF (20mL), added diisopropylethylamine (DIEA) (536mg, 4.16mmol), reacted at room temperature for 3 hours, LCMS detection showed that the reaction was complete . Diluted with ethyl acetate, washed with saturated brine, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4-bromo-7-chloro-N-ethyl-1H-pyrrolo[2,3-c]pyridine-2- Amide (130 mg, yellow solid). LC-MS (M+H) 301.7 / 303.7. 1 H-NMR (400MHz, DMSO-d6) δ12.82(s, 1H), 8.50(s, 1H), 8.13(s, 1H), 7.26(s, 1H), 3.35(q, J=7.2Hz, 2H ), 1.17 (t, J=7.2Hz, 3H).

[0331] The second step: 4-bromo-7-chloro-N...

Embodiment 2

[0333] Example 2: N-ethyl-6-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-3- Methyl-7H-pyrrole[3,2-c][1,2,4]triazol[4,3-a]pyridine-8-amide

[0334]

[0335] The first step: the compound 7-bromo-4-hydroxyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (623mg, 2.4mmol) was dissolved in DMF (10mL), and HATU (1.4g, 3.6mmol) and DIEA (619mg, 4.8mmol), stirred at room temperature for 5 minutes, then added ethylamine (2M in THF, 2.4mL, 4.8mmol), and reacted overnight at room temperature. LCMS detection showed that the reaction was complete, diluted with ethyl acetate, washed with saturated brine, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 7-bromo-N-ethyl-4-hydroxy-1H-pyrrolo[3,2- c] Pyridine-2-amide (695 mg, white solid). LC-MS (M+H) 284.0 / 286.0.

[0336] Second step: Dissolve 7-bromo-N-ethyl-4-hydroxy-1H-pyrrolo[3,2-c]pyridine-2-amide (695 mg, 2.4 mmol) in phosphorus oxychloride POCl 3 (6mL), heated...

Embodiment 3

[0339] Example 3: N-ethyl-6-(5-(2-hydroxypropyl-2-yl)-2-((4-methylcyclohexyl)oxo)phenyl)-3-methyl-9H -Pyrrole[2,3-c][1,2,4]triazol[4,3-a]pyridine-8-amide

[0340] The operation is the same as in Example 1, 1H-NMR (400MHz, CD3OD) δ7.96(s, 1H), 7.70(d, J=2.4Hz, 1H), 6.49(d, J=8.4Hz, 1H), 4.32–4.25 (m,1H),3.41(q,J=7.2Hz,2H),2.79(s,3H),2.12-2.06(m,2H),1.80-1.74(m,2H),1.56(s,6H), 1.53-1.47(m,2H),1.43-1.39(m,1H),1.25(t,J=7.2Hz,3H),1.07-0.95(m,2H),0.86(d,J=6.4Hz,3H) ; LC-MS (M+H) 490.3.

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Abstract

The invention discloses a fused heterocyclic biaryl benzyl alcohol compound, and a preparation method and an application thereof. The fused heterocyclic biaryl benzyl alcohol compound disclosed by theinvention is represented by a formula (IA). The fused heterocyclic biaryl benzyl alcohol compound disclosed by the invention has relatively good inhibitory activity on BRD enzyme and quite excellentBRD / c-Myc related cell proliferation inhibitory activity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of condensed heterocyclic biaryl benzyl alcohol compounds, a preparation method and application. Background technique [0002] The abnormality of epigenetic regulation is one of the important factors leading to tumorigenesis. The latest research has found that BRD protein-mediated epigenetic abnormalities are closely related to the overexpression of oncogenes, and are closely related to the growth and proliferation of cancer cells. BRD4 is a member of the BET protein family. Due to its potential value in anti-tumor, it has attracted great attention from major pharmaceutical companies and scientific research institutions. [0003] BET protein, also known as epigenetic recognition protein, can recognize changes in epigenetic information in cellular histones and transmit signals that stimulate cell division, etc. Taking leukemia as an example, the gene mutati...

Claims

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Application Information

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IPC IPC(8): C07D471/14C07D487/14A61K31/437A61K31/4985A61K31/519A61K31/4427A61P35/00A61P35/02A61P37/00A61P37/06A61P19/06A61P11/00A61P17/14A61P17/00A61P13/12A61P1/00A61P29/00A61P1/16A61P25/28A61P25/00A61P9/10A61P11/06A61P21/04A61P7/06A61P25/16A61P17/06A61P37/02A61P3/10A61P15/00
CPCA61P1/00A61P1/16A61P3/10A61P7/06A61P9/10A61P11/00A61P11/06A61P13/12A61P15/00A61P17/00A61P17/06A61P17/14A61P19/06A61P21/04A61P25/00A61P25/16A61P25/28A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06C07D471/14C07D487/14A61K31/437A61K31/4427A61K31/4985A61K31/519
Inventor 万惠新潘建峰马金贵
Owner RUDONG RINGENE PHARMA CO LTD
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