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Sulfoximide substituted indazole IRAK4 kinase inhibitor as well as preparation method and application thereof

A technology of sulfinimides and indazoles, applied in the field of biomedicine, can solve the problems of unsatisfactory efficacy, safety, pharmacokinetics, low pharmacokinetics and bioavailability, and animal safety risks To achieve good pharmacokinetic properties, reduce the risk of hERG inhibition, and good IRAK4 inhibitory activity

Active Publication Date: 2021-09-17
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main defects are: low IRAK4 inhibitory activity, animal safety risk, low pharmacokinetics and bioavailability, etc.
[0016] The compounds and experimental drugs disclosed in the prior art are still unsatisfactory in terms of effectiveness, safety, pharmacokinetics, etc. It is still necessary to continue research and development of new IRAK4 inhibitors to meet people's growing medical and health needs

Method used

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  • Sulfoximide substituted indazole IRAK4 kinase inhibitor as well as preparation method and application thereof
  • Sulfoximide substituted indazole IRAK4 kinase inhibitor as well as preparation method and application thereof
  • Sulfoximide substituted indazole IRAK4 kinase inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: Synthesis of I-1

[0077] synthetic route:

[0078]

[0079] Steps:

[0080] step 1:

[0081] Compound IA-1 (1.63 g, 0.01 mol), IB-1 (1.91 g, 0.01 mol) were added to dichloromethane (DCM, 30 mL), followed by N,N-diisopropylethylamine (DIPEA, 1.94 g, 0.015mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (2.3g, 0.015mol), the reaction system was stirred at 30°C for 12h. The reaction mixture was extracted with water (20 mL), the organic layer was concentrated to dryness under reduced pressure, and recrystallized by adding absolute ethanol (10 mL) to obtain a pale yellow solid IC-1 (2.67 g, yield 79.5%). 1 H NMR (400MHz, DMSO-d 6 ): δ=13.10(br,1H),11.55(br,1H),8.35(d,J=8.0Hz,1H),8.14(m,1H),7.98(d,J=8.0Hz,1H),7.72 (s, 1H), 7.47 (s, 1H), 7.04 (s, 1H), 3.92 (s, 3H). LCMS: MS Calcd.: 336.3, MS Found: 337.2 [M+1].

[0082] Step 2:

[0083] Compound IC-1 (400 mg, 1.2 mmol), ID-1 (327 mg, 1.32 mmol), K 2 CO 3 (332 mg, 2.4 mmol), KI (17 mg, 0.1 mmo...

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PUM

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Abstract

The invention relates to the technical field of biological medicine, in particular to a sulfinyl imide substituted indazole compound, or an isomer and pharmaceutically acceptable salt thereof, and the structure of the sulfinyl imide substituted indazole compound is shown as a formula I. Compared with the prior art, the novel aryl(hetero) sulfoximide substituted indazole compound and the pharmaceutically acceptable salt thereof provided by the invention have better IRAK4 inhibitory activity and better safety, and the preferable compound disclosed by the invention shows good pharmacokinetic properties and has the potential of being developed into a selective IRAK4 inhibitor.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to an aryl (hetero) sulfinyl imide-substituted indazole IRAK4 kinase inhibitor and isomers thereof, pharmaceutically acceptable salts thereof, and preparation methods and uses thereof . Background technique [0002] Interleukin-1 receptor-associated kinase 4 (IRAK-4) is a member of the IRAK family of intracellular serine-threonine kinases. Other members of the kinase family include IRAK-1, IRAK-2 and IRAK-M. IRAK-M is only expressed in monocytes and macrophages, and the expression of IRAK-1, IRAK-2 and IRAK4 is ubiquitous. IRAK4 is mainly composed of a conserved N-terminal death domain (DD), a hinge region, and a C-terminal central kinase domain (KD). The DD region is the region where IRAK4 binds to the adaptor protein myeloid differentiation factor primary response gene 88 (MyD88). The KD region is composed of 12 subregions with typical serine-threonine kinase domain featur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D409/14C07D413/14C07D487/04C07D417/14A61P37/02A61P29/00A61P11/00A61P1/00A61P37/08A61P31/00A61P17/02A61P27/02A61P19/02A61P19/08A61P21/00A61P17/00A61P13/12A61P7/00A61P1/16A61P1/02A61P3/00A61P9/00A61P9/14A61P25/00A61P25/28A61P43/00A61P17/06A61P19/06A61P11/06A61P11/08A61P35/00A61P35/02A61K31/4439A61K31/5377A61K31/444A61K31/4709A61K31/519A61K31/506A61K31/517
CPCC07D401/12C07D401/14C07D409/14C07D413/14C07D487/04C07D417/14A61P37/02A61P29/00A61P11/00A61P1/00A61P37/08A61P31/00A61P17/02A61P27/02A61P19/02A61P19/08A61P21/00A61P17/00A61P13/12A61P7/00A61P1/16A61P1/02A61P3/00A61P9/00A61P9/14A61P25/00A61P25/28A61P43/00A61P17/06A61P19/06A61P11/06A61P11/08A61P35/00A61P35/02Y02A50/30
Inventor 郑永勇魏农农金华周峰黄美花
Owner SHANGHAI XUNHE PHARMA TECH CO LTD
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