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Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

A methyl and alkyl technology, applied in the field of PRMT5 inhibitors, can solve problems such as gene expression repression

Active Publication Date: 2020-08-14
PRELUDE THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PRMT5 can directly modify histones H3 and H4, leading to repression of gene expression

Method used

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  • Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
  • Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
  • Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0377] Example 1. (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-1-(bicyclo [4.2.0] Oct-1,3,5-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol (1)

[0378]

[0379] Step 1. Bicyclo[4.2.0]oct-1,3,5-trien-3-yl((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3- d] Synthesis of pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanone (1b)

[0380] A 50 mL RBF with a septum containing magnesium (208 mg, 8.56 mmol) was dried under high vacuum with a heat gun and cooled under Ar. The flask was charged with THF (3.4 mL), 4 / 10 parts of 4-bromobicyclo[4.2.0]oct-1(6), 2,4-triene (1.01 mL, 8.11 mmol) and 1 M diisobutylaluminum hydride in toluene (20 uL, 0.0200 mmol). After stirring for 1 min, magnesium initiation was observed by self-heating of the reaction solution. The reaction mixture was stirred for an additional 10 minutes, diluted with THF (3 mL), and the remaining 4-bromobicyclo[4.2.0]oct-1(6),2,4-triene was charged in two portions over 10 mi...

Embodiment 2

[0391] Example 2. (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2. 0]oct-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol (2)

[0392]

[0393] Step 1. (R)-bicyclo[4.2.0]oct-1,3,5-trien-3-yl ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2a) and (R)-bicyclo[4.2.0]oct-1,3,5-trien-3-yl((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3 Synthesis of -d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2b)

[0394] Under argon will contain [(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4 ,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-triene A solution of methanone (1200.mg, 2.82mmol) in toluene (25mL) in 100mL RBF with septum was cooled to -76°C in an acetone / dry ice bath. A 1M solution of diisobutylaluminum hydride (DIBAL) in toluene (5.4 mL, 5.4 mmol) was added dropwise over 4 minutes. ...

Embodiment 6

[0400] Example 6. (2R,3R,4S,5R)-2-(4-Amino-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-4- Bicyclo[4.2.0]oct-1,3,5-trienyl (hydroxyl)methyl]tetrahydrofuran-3,4-diol hydrochloride (Example 6)

[0401]

[0402] a) (S)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1 ,3]Synthesis of dioxol-6-yl]-(4-bicyclo[4.2.0]oct-1,3,5-trienyl)methanol (6a)

[0403] To a solution of 4-bicyclo[4.2.0]oct-1,3,5-trienylboronic acid (3500.0 mg, 23.65 mmol) in toluene (90 mL) was slowly added diethylzinc (23.74 mL) at 25 °C , 47.48 mmol). The mixture was stirred at 60°C for 1 hour. Slowly add (3aR,4R,6S,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1 ,3] Dioxol-6-carbaldehyde (3200.0 mg, 15.83 mmol) in toluene (40 mL). The mixture was stirred at 60°C for 2 hours. TLC (PE / EA=5 / 1) showed the reaction was complete. Water (10ml) was added to quench the reaction. The mixture was filtered. The filtrate was concentrated and passed through CH with 5 / 95 to ...

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Abstract

The disclosure is directed to compounds of Formula (I) and Formula (II). Formula (I) and Formula (II) and pharmaceutically acceptable salts or solvates thereof. Pharmaceutical compositions comprisingcompounds of Formula (I) or Formula (II), as well as methods of their use and preparation, are also described.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 577,448, filed October 26, 2017, and U.S. Provisional Application No. 62 / 666,724, filed May 4, 2018. Each of these applications is hereby incorporated by reference in its entirety. technical field [0003] The present disclosure relates to PRMT5 inhibitors and methods of use thereof. Background technique [0004] Protein arginine methylation is a common post-translational modification that regulates numerous cellular processes, including gene transcription, mRNA splicing, DNA repair, protein cellular localization, cell fate determination, and signal transduction. There are three types of methyl-arginine species: ωNG monomethylarginine (MMA), ωNG,NG asymmetric dimethylarginine (ADMA) and ωNG,N'G symmetric dimethylarginine acid (SDMA). The formation of methylated arginine is catalyzed by methyltransferases of the protein arginine me...

Claims

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Application Information

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IPC IPC(8): C07D473/00A61K31/52C07D473/34C07D487/04A61P35/00A61K31/517
CPCC07D473/00C07D473/34C07D487/04A61P35/00A61K45/06
Inventor 胡安·卢恩戈林虹迈克尔·霍金斯
Owner PRELUDE THERAPEUTICS INC
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