Pyrrolopyridone double-functional molecule compound based on Cereblon ligand induced BET degradation

A technology of pyrrolopyridone and bifunctional molecules, applied in the field of pyrrolopyridone bifunctional molecular compounds based on Cereblon ligand-induced BET degradation, which can solve the problems of weakened inhibitory effect and BRD4 protein enrichment

Active Publication Date: 2019-09-06
JIANGSU PROVINCE INST OF TRADITIONAL CHINESE MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Studies have found that the inhibition of BRD4 protein often requires the drug to be maintained at a high concentration for a long time, and high-dose administration will lead to enrichment of BRD4 protein due to negative feedback, thus greatly weakening its inhibitory effect; Obvious drug resistance has been observed in tumor studies (such as triple-negative breast cancer)

Method used

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  • Pyrrolopyridone double-functional molecule compound based on Cereblon ligand induced BET degradation
  • Pyrrolopyridone double-functional molecule compound based on Cereblon ligand induced BET degradation
  • Pyrrolopyridone double-functional molecule compound based on Cereblon ligand induced BET degradation

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Preparation of 4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-N-((1-(2-(2-((2-(2, 6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)-2-oxoethoxy)ethyl)-1H-1,2,3-tri Azol-4-yl)methyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1), its structural formula as follows:

[0099]

[0100] Step 1: Preparation of 2-hydroxyethyl-4-methylbenzenesulfonate (1a)

[0101]

[0102] Ethylene glycol (3.91g, 62.95mmol) was bathed in 5mL pyridine, p-toluenesulfonyl chloride (6g, 31.47mmol) was added in batches, after stirring at room temperature for 4 hours, 6mol / L hydrochloric acid (40mL) was added, and ethyl acetate Extraction, washing with saturated brine, collecting the organic layer, drying over sodium sulfate, and evaporating the organic solvent under reduced pressure, the residue was purified by silica gel column chromatography, using petroleum ether / ethyl acetate (V / V=20 / 1-10 / 1) was eluted to obtain a colorless liquid weighing 2 g with a ...

Embodiment 2

[0126] Preparation of 4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-N-((1-(2-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)-2-oxoethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- Formamide (2), its structural formula is as follows:

[0127]

[0128] The ethylene glycol in the embodiment 1 step 1 is changed to diethylene glycol, and the synthetic method is the same as in the embodiment 1.

[0129] 1 H NMR (400MHz, DMSO) δ (ppm): 12.35(s, 1H), 11.01(s, 1H), 9.83(s, 1H), 9.68(s, 1H), 8.87(s, 1H), 7.99(s , 1H), 7.72(d, J=7.9Hz, 1H), 7.54(d, J=7.0Hz, 1H), 7.52-7.45(m, 1H), 7.34(d, J=6.6Hz, 3H), 7.22 (d, J=8.7Hz, 1H), 7.06(d, J=6.0Hz, 1H), 7.00(d, J=7.8Hz, 1H), 6.95-6.81(m, 2H), 5.13(d, J= 8.5Hz, 1H), 4.50(d, J=12.7Hz, 4H), 4.43-4.30(m, 2H), 4.09(s, 2H), 3.84(s, 2H), 3.62(d, J=4.5Hz, 4H), 3.52(s, 3H), 3.10(d, J=7.1Hz, 2H), 2.89(d, J=12.6Hz, 1H), 2.60(s, 1H), 2.35(d, J=13.8Hz, 1H), 2.00(d,...

Embodiment 3

[0132] Preparation of 4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-N-((1-(2-(2-(2-(2-( (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)-2-oxoethoxy)ethoxy)ethoxy ) ethyl)-1H-1,2,3-triazol-4-yl)methyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3- c] pyridine-2-carboxamide (3), its structural formula is as follows:

[0133]

[0134] The ethylene glycol in the step 1 of embodiment 1 is replaced with triethylene glycol, and the synthetic method is the same as in embodiment 1.

[0135] 1 H NMR (300MHz, DMSO) δ (ppm): 12.33(s, 1H), 11.00(s, 1H), 9.82(s, 1H), 9.67(s, 1H), 8.86(s, 1H), 7.96(s , 1H), 7.73(d, J=7.5Hz, 1H), 7.52(dt, J=15.0, 7.5Hz, 2H), 7.40-7.30(m, 3H), 7.23(dd, J=8.8, 2.6Hz, 1H), 7.13-6.97(m, 2H), 6.94(d, J=8.7Hz, 1H), 6.89(d, J=2.2Hz, 1H), 5.14(dd, J=13.3, 5.0Hz, 1H), 4.48(dd, J=9.3, 4.9Hz, 4H), 4.37(d, J=6.7Hz, 2H), 4.11(s, 2H), 3.77(t, J=5.0Hz, 2H), 3.64-3.61(m , 2H), 3.54(d, J=4.7Hz, 2H), 3.53(s, 3H), 3.50(s, 4H), 3.11(d, J=7.4Hz, 2H), 2.96...

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Abstract

The invention relates to a novel pyrrolopyridone double-functional molecule, and pharmaceutically acceptable salts, hydrates, prodrug thereof, and a pharmaceutical composition taking the novel pyrrolopyridone double-functional molecule as an active component, and applications of the above compounds and the pharmaceutical composition in treatment or prevention of tumor, inflammation, and immunity diseases. The double-functional molecule is a proteolytic targeting chimera (PROTAC); the preparation method is mature; connecting arms are adopted to connect BET protein small molecular inhibitors andCereblon protein ligand in E3 ubiquitin ligase complex so as to obtain the double-functional molecule; the obtained compound is capable of realizing selective induction of BET protein degradation; and the tumor prevention effect is obvious.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to a pyrrolopyridone bifunctional PROTAC molecular compound based on Cereblon ligand-induced BET degradation, and pharmaceutically acceptable salts, hydrates, prodrugs and the compound as active The pharmaceutical combination of ingredients, as well as the preparation of these compounds and their pharmaceutical compositions and their use in the treatment or prevention of tumors, inflammation, metabolism and other diseases. Background technique [0002] Histone lysine acetylation is an important post-translational modification of gene transcription. BET protein plays a role through the recognition of acetyllysine (KAc) by the bromodomain in its structure, and the abnormal function of BET is related to various diseases such as tumors, inflammation, and metabolism. Inhibiting the combination of BET protein and KAc can effectively inhibit various diseases such as tumor and inf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4545A61P35/00A61P35/02
CPCC07D471/04A61K31/4545A61P35/00A61P35/02
Inventor 曹鹏张惠斌张剑魏清筠周金培郑培源朱佩钰
Owner JIANGSU PROVINCE INST OF TRADITIONAL CHINESE MEDICINE
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