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Macrocyclic azolopyridine derivatives as EED and PRC2 modulators

A solvate, C2-C6 technology, applied in the direction of drug combination, medical preparations containing active ingredients, extracellular fluid diseases, etc.

Pending Publication Date: 2022-03-04
FULCRUM THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although EZH2 is the catalytic subunit, the methyltransferase activity of PRC2 minimally requires EED and SUZ12

Method used

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  • Macrocyclic azolopyridine derivatives as EED and PRC2 modulators
  • Macrocyclic azolopyridine derivatives as EED and PRC2 modulators
  • Macrocyclic azolopyridine derivatives as EED and PRC2 modulators

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preparation example Construction

[0839] Compound preparation

[0840] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof understood by those skilled in the art. General methods include, but are not limited to, those described below. In addition, suitable starting materials that are readily available and known to those skilled in the art can be selected to obtain a particular compound of the present disclosure. Compounds of formula I of the present invention can be synthesized according to the steps outlined in Schemes 1-4, wherein R 1 , R 2 and R 3 defined in Formula I. Starting materials are either commercially available or prepared by known procedures in the reported literature or as exemplified.

[0841] plan 1

[...

Embodiment 1

[0937] Example 1: 5-Bromo-6-chloropyridin-3-ol

[0938]

[0939] NaNO at 0°C 2 (31.9 g, 4620 mmol, 1.20 equiv) in water (80.0 mL) was added ice-cold 5-bromo-6-chloropyridin-3-amine (80.0 g, 386 mmol, 1.00 equiv) in H 2 SO 4 (567 g, 2.89 mol, 308 mL, 50% purity, 7.50 equiv), then the mixture was stirred at 25 °C for 30 min. The mixture was added to AcOH (400 mL) at 100 °C. The mixture was stirred at 100 °C for 12 h. LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The mixture was added to ice water (2000 mL) with saturated Na 2 CO 3 The aqueous solution adjusted the pH to 6-7. The mixture was extracted with EtOAc (5000 mL). The organic layer was washed with brine (2000 mL), washed with Na 2 CO 3 Dry, filter and concentrate under reduced pressure. The residue was subjected to column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0-4 / 1, petroleum ether / ethyl acetate = 2 / 1, R f = 0.56) purification. ...

Embodiment 2

[0941] Example 2: 5-Bromo-6-chloro-2-nitropyridin-3-ol

[0942]

[0943] Reactions were set up in two separate batches. 5-Bromo-6-chloropyridin-3-ol (46.0 g, 220 mmol, 1.00 equiv) was dissolved in H 2 SO 4 The mixture in (138 mL, 98% purity) was stirred at 0 °C for 75 min. H at 0°C 2 SO 4 (42.3 g, 423 mmol, 23.0 mL, 98% pure, 1.92 equiv) and fuming HNO 3 (19.3 g, 294 mmol, 13.8 mL, 96% purity, 1.33 equiv) was added to the reaction mixture. The mixture was stirred at 0 °C for 2 h. After stirring for 2 h, the mixture was stirred at 20 °C for 12 h. LCMS indicated a small amount of 5-bromo-6-chloropyridin-3-ol remaining and the expected mass detected. The two batches of reaction mixtures were combined and neutralized by adding ice water (3000 mL) and stirred at 20°C for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to give 5-bromo-6-chloro-2-nitropyridin-3-ol (83.0 g, crude) as a yellow solid.

[0944]

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Abstract

The present invention relates to modulators of embryonic ectoderm development (EED) and / or multi-comb protein inhibition complex 2 (PRC2), which are useful in the treatment of disorders and diseases associated with EEC and PRC2, the modulators are macrocyclic azolopyridine derivatives of formula (I) and compositions thereof or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, enantiomers, isomers or tautomers thereof: wherein X1, X2, X3, A1, A2, Y, R1, R2, R3 and R4 are as described herein.

Description

[0001] Related applications [0002] This application claims the benefit of and priority to US Provisional Patent Application No. 62 / 819,064, filed March 15, 2019, the entire contents of each of which are incorporated by reference in their entirety. [0003] Description of Electronically Submitted Text File [0004] This application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy was created on March 11, 2020, named "FULC-034-01WO_SeqList.txt", and is 6 KB in size. [0005] Field of Invention [0006] The present disclosure relates to macrocyclic azolopyridine derivatives, compositions comprising these compounds, for the treatment of diseases or disorders associated with embryonic ectodermal development (EED) and / or polycomb repressive complex 2 (PRC2). Methods, for example, by modulating gene expression, and methods of synthesizing these compounds. [0007] Background o...

Claims

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Application Information

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IPC IPC(8): A61P35/00C07D471/04C07D491/18C07D491/22
CPCA61P35/00C07D491/18C07D491/22A61K31/4355A61K31/437A61K45/06C07D498/16C07D498/22A61K31/5365A61P7/00A61P7/06A61P35/02
Inventor I·V·埃夫雷莫夫S·卡兹米尔斯基Q·李L·A·汤普森三世O·B·华莱士S·D·约翰斯通F·周P·拉尔
Owner FULCRUM THERAPEUTICS INC
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