A kind of indazole irak4 kinase inhibitor substituted by sulfenimide, preparation method and application

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: 2022-05-13
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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  • A kind of indazole irak4 kinase inhibitor substituted by sulfenimide, preparation method and application
  • A kind of indazole irak4 kinase inhibitor substituted by sulfenimide, preparation method and application
  • A kind of indazole irak4 kinase inhibitor substituted by sulfenimide, preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Embodiment 1: the synthesis of I-1

[0077] synthetic route:

[0078]

[0079] Steps:

[0080] step 1:

[0081] Compound IA-1 (1.63g, 0.01mol), IB-1 (1.91g, 0.01mol), add dichloromethane (DCM, 30mL), then add N,N-diisopropylethylamine (DIPEA, 1.94 g, 0.015mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (2.3g, 0.015mol), and 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 IC-1 as a light yellow solid (2.67 g, yield 79.5%). 1 HNMR (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 (400mg, 1.2mmol), ID-1 (327mg, 1.32mmol), K 2 CO 3 (332mg, 2.4mmol), KI (17mg, 0.1mmol) were added in DMF (...

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PUM

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Abstract

The present invention relates to the technical field of biomedicine, in particular to a sulfinimide-substituted indazole compound, or its isomer, and a pharmaceutically acceptable salt, the structure of which is shown in formula I: Compared with, the novel aromatic (hetero) sulfinimide substituted indazole compounds provided by the present invention and pharmaceutically acceptable salts thereof have better IRAK4 inhibitory activity and better safety, and the preferred The compound exhibits good pharmacokinetic properties and has the potential to be developed as a selective IRAK4 inhibitor.

Description

technical field [0001] The present invention relates to the technical field of biomedicine, in particular to an aromatic (hetero)sulfinimide-substituted indazole IRAK4 kinase inhibitor and its isomer, its pharmaceutically acceptable salt, and its preparation method and application . 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 death domain (DD) at the N-terminus, a hinge region, and a central kinase domain (KD) at the C-terminus. The DD region is the region where IRAK4 binds to the adapter protein myeloid differentiation factor primary response gene 88 (MyD88). The KD region is composed of 12 subregions and has typical serine-threonine ki...

Claims

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Application Information

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Patent Type & Authority Patents(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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