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A class of pyrrole amidopyridone compounds, preparation method and use

一种吡咯酰胺、化合物的技术，应用在药物化学领域，能够解决选择性不够突出、BRD蛋白抑制剂作用效果尚待提高、小分子抑制剂结构类型少等问题，达到抑制多种肿瘤细胞的效果

Active Publication Date: 2022-03-22
RUDONG RINGENE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, most of the known small molecule inhibitors of BRD4 protein have few structural types and the selectivity for BD1 and BD2 bromodomains is not prominent enough, which limits people's understanding of the biological functions of bromodomain-containing proteins and their anti-tumor effects. conduct in-depth research on potential
In addition, the effect of existing BRD protein inhibitors needs to be improved, and the mechanism needs to be further elucidated
ABBV744 from AbbVie is a BRD4-BD2 selective inhibitor with high selectivity and high killing effect on some leukemia and prostate cancer cell lines. At the same time, the ADME properties of ABBV744 need to be further optimized and improved

Method used

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  • A class of pyrrole amidopyridone compounds, preparation method and use
  • A class of pyrrole amidopyridone compounds, preparation method and use
  • A class of pyrrole amidopyridone compounds, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0319] Example 1: N-ethyl-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5- Methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0320]

[0321] Step 1: Dissolve Intermediate A (100mg, 0.34mmol) in ethanol (10mL), add water (5mL) and sodium hydroxide (53mg, 1.32mmol), and heat to 80°C for 4h. The reaction solution was concentrated to remove most of the ethanol, a small amount of water was added, the pH value was adjusted to 3-4 with dilute hydrochloric acid, and lyophilized to obtain 7-bromo-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole[ 3,2-c]pyridine-2-carboxylic acid (90 mg, white solid). 1 H NMR (400MHz, DMSO_d6): δ 13.13 (brs, 1H), 12.39 (s, 1H), 7.87 (s, 1H), 7.20 (s, 1H), 3.46 (s, 3H).

[0322] The second step: 7-bromo-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-carboxylic acid (90mg, 0.33mmol) was dissolved in In DMF (5mL), ethylamine hydrochloride (54mg, 0.67mmol) and N,N-isopropylethyldiamine DIEA (213mg, 1.65mmol) were added suc...

Embodiment 2

[0324] Example 2: N-ethyl-5-methyl-4-oxo-7-(2,2,4-trimethyl-6-(methylsulfone)-3-oxo-3,4-dihydro -2H-Benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-amide

[0325]

[0326] Under nitrogen protection, 8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (35mg, 0.1mmol) was dissolved in DMF (3mL), and bis-pinacol boroester (51mg, 0.2mmol), cesium carbonate (98mg, 0.3mmol) and Pd(dppf)Cl 2 (7mg, 0.01mmol), heated to 110 degrees and stirred for 2 hours, then added 7-bromo-N-ethyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole[3,2 -c] Pyridine-2-amide (30 mg, 0.1 mmol), continue stirring overnight. Cool down to room temperature, add water, extract with dichloromethane DCM, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by preparative chromatography to obtain N-ethyl-5-methyl-4-oxo-7-(2,2,4- Trimethyl-6-(methylsulfone)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro - 1H-pyrrole[2,3-c]pyridine-2-amide (3....

Embodiment 3

[0327] Example 3: N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)pent-4-yn-1-yl) -7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo- 4,5-Dihydro-1H-pyrrole[3,2-c]pyridine-2-amide

[0328]

[0329] The first step: Intermediate A (500mg, 1.68mmol) and 2-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol was dissolved in DMF (10 mL), cesium carbonate Cs was added 2 CO 3 (1.6g, 4.91mmol) and Pd(dppf)Cl 2 (245mg, 0.33mmol), under the protection of nitrogen, the temperature was raised to 100°C to react overnight. Directly concentrated, the residue was purified by column chromatography to obtain 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5 - Ethyl methyl-4-oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-carboxylate (420 mg, white solid). LC-MS: m / z 493.5[M+H] + .

[0330] Second step: Sodium hydroxide NaOH (136 mg, 1.68 mmol) was added to 7-(2-(4-fluoro-2,6-dimet...

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Abstract

The invention discloses a pyrrole amidopyridone represented by the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer, a tautomer, and a solvent Compounds, polymorphs or prodrugs, their preparation methods and pharmaceutical applications, wherein the definition of each group is as described in the description.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of pyrroloamidopyridone BET-BRD signaling pathway inhibitor compounds, preparation methods and uses. 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 mut...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/538A61K31/5386A61K31/4545A61P35/02A61P35/00A61P37/02A61P29/00A61P37/06A61P19/06A61P11/02A61P17/14A61P25/28A61P1/00A61P9/10A61P11/06A61P19/02A61P37/08A61P1/16A61P11/00A61P17/00A61P21/00A61P25/00A61P13/12A61P5/14A61P21/04A61P31/10A61P1/18A61P25/16A61P7/06A61P17/06A61P3/10A61P13/02
CPCC07D471/04A61P35/02A61P35/00A61P37/02A61P29/00A61P37/06A61P19/06A61P11/02A61P17/14A61P25/28A61P1/00A61P9/10A61P11/06A61P19/02A61P37/08A61P11/00A61P1/16A61P17/00A61P21/00A61P25/00A61P13/12A61P5/14A61P21/04A61P31/10A61P1/18A61P25/16A61P7/06A61P17/06A61P3/10A61P13/02A61P43/00A61P9/00A61P37/00A61P13/00A61K31/437A61K31/538A61K31/4545
Inventor 万惠新潘建峰马金贵
Owner RUDONG RINGENE PHARMA CO LTD
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