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3-(5-methoxy-1-oxoisoindoline-2-yl) piperidine-2, 6-diketone derivative and application thereof

A C1-C6, alkoxy technology, applied in the field of treatment of hereditary blood diseases, can solve the problems of low response rate and genotoxicity

Pending Publication Date: 2022-07-29
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hydroxyurea is the current standard of care for SCD and is thought to provide benefit via induction of HbF, but is genotoxic, causes dose-limiting neutropenia, and has a response rate of less than 40%

Method used

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  • 3-(5-methoxy-1-oxoisoindoline-2-yl) piperidine-2, 6-diketone derivative and application thereof
  • 3-(5-methoxy-1-oxoisoindoline-2-yl) piperidine-2, 6-diketone derivative and application thereof
  • 3-(5-methoxy-1-oxoisoindoline-2-yl) piperidine-2, 6-diketone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] Embodiment 1. A compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof,

[0176]

[0177] in:

[0178] Y is selected from O, CH 2 , CF 2 , and CHF;

[0179] z is an integer from 0 to 2;

[0180] R X1 and R X2 each independently selected from hydrogen and C 1 -C 6 alkyl;

[0181] R Y1 and R Y2 each independently selected from hydrogen and C 1 -C 6 alkyl;

[0182] R Z1 and R Z2 all hydrogen

[0183] or

[0184] R Z1 and R Z2 1 of the and R Y1 and R Y2 1 of them together form C 1 -C 2 an alkylene bridging group, and R Z1 and R Z2 and R Y1 and R Y2 The other one is hydrogen;

[0185] R 1 selected from hydrogen and C 1 -C 6 alkyl;

[0186] R 2 selected from hydrogen, -C(=O)-R 3 , C 3 -C 8 Cycloalkyl, C 1 -C 6 haloalkyl, and C 1 -C 10 Alkyl, wherein the alkyl is substituted with 0-1 substituents independently selected from: C 6 -C 10 Aryl, 5- to 10-membered hetero...

Embodiment 2

[0208] Embodiment 2. The compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein : z is 1; and R Z1 and R Z2 1 of the and R Y1 and R Y2 1 of them together form C 1 -C 2 an alkylene bridging group, and R Z1 and R Z2 and R Y1 and R Y2 The other one is all hydrogen.

Embodiment 3

[0209] Embodiment 3. The compound of formula (I') according to claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof , where: z is 1; and R Z1 and R Z2 1 of the and R Y1 and R Y2 1 of them together form C 1 an alkylene bridging group, and R Z1 and R Z2 and R Y1 and R Y2 The other one is all hydrogen.

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Abstract

The present disclosure relates to compounds of Formula (I ') and pharmaceutical compositions and their use in reducing the expression levels of Wide Interval Zinc Finger Motif (WIZ) or inducing the expression of fetal hemoglobin (HbF) and in the treatment of hereditary hematological disorders (e.g., hemoglobinopathy, e.g., beta-hemoglobinopathy) such as sickle cell disease and beta-thalassemia.

Description

[0001] priority claim [0002] This application claims the benefit of priority to US Provisional Application No. 62 / 950,048, filed on December 18, 2019, the disclosure of which is incorporated herein by reference in its entirety. technical field [0003] The present disclosure relates to 3-(5-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione compounds and pharmaceutical compositions and their reduction in broad spaced zinc finger motifs (WIZ) protein expression levels, and / or induced fetal hemoglobin (HbF) protein expression levels, and in the treatment of inherited blood disorders (hemoglobinopathies such as beta-hemoglobinopathies) such as sickle cell disease and beta-thalassemia use. Background technique [0004] Sickle cell disease (SCD) is a group of serious inherited blood disorders that cause red blood cells to twist into a sickle shape. These cells can cause blockages in blood flow, which can lead to severe pain, organ damage and premature death. Beta thalassemia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P7/00C07D401/12C07D401/14A61K31/4035
CPCC07D401/14C07D401/12A61P7/00A61K31/4545A61K31/5377A61K31/506A61K31/497A61P7/06C07D471/04C07D413/14C07D405/14C07D417/14A61K45/06
Inventor S·波纳齐A·塞尔尼延科J·S·科布N·达莱斯J·R·克里根P·拉穆H·A·马利克G·奥布赖恩A·W·帕特森N·M-F·汤姆森P·汀
Owner NOVARTIS AG
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