Substituted indazole compound, preparation method, application and composition containing substituted indazole compound

A technology of compounds and indazoles, applied in drug combination, metabolic diseases, organic chemistry, etc., can solve animal safety risks, effectiveness, unsatisfactory safety pharmacokinetics, pharmacokinetics and biological Problems such as low utilization

Active Publication Date: 2021-08-20
SHANGHAI APPLIED TECHNOLOGIES COLLEGE
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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.
[0007] Compounds and experimental drugs disclosed in the prior art are still unsatisfactory in terms of effectiveness, safety, pharmacokinetics, etc., and it is still necessary to continue research and To develop new IRAK4 inhibitors to meet the growing medical and health needs of people

Method used

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  • Substituted indazole compound, preparation method, application and composition containing substituted indazole compound
  • Substituted indazole compound, preparation method, application and composition containing substituted indazole compound
  • Substituted indazole compound, preparation method, application and composition containing substituted indazole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: the synthesis of I-1 (replacing compound with the general formula label of structural formula, the same below)

[0035] A kind of substituted indazole compound, has the structure shown in general formula (I-1), and synthetic route is specifically as follows:

[0036]

[0037] The specific steps are:

[0038] S1: Add compound Ia-1 (1.63g, 0.01mol) and compound Ib-1 (1.91g, 0.01mol) into dichloromethane (30mL), then add N,N-diisopropylethylamine (DIPEA, 1.94g, 0.015mol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 5.7g, 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 (2.85 g, yield 85%). The hydrogen spectrum of Ic-1 is 1 HNMR (400MHz, DMSO-d 6 ): δ=13.10(br,1H), 11.55(br,1H), 8.35(d,J=8.0Hz,1H), 8.14(...

Embodiment 2

[0040] The synthesis of embodiment 2:1-2

[0041] A substituted indazole compound has a structure shown in general formula (I-2), and the synthetic route is specifically as follows:

[0042]

[0043] Except reaction raw material Ia-2, all the other operation steps are all identical with embodiment 1, and the yield of product I-2 is 15%, and hydrogen spectrum is 1 HNMR (400MHz, DMSO-d 6 ):δ=11.56(br,1H),8.38(d,J=8.0Hz,1H),8.15(m,2H),8.01(s,1H),7.95(d,J=8.0Hz,1H),7.85 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.23 (d, J = 8.4Hz, 1H), 5.56 (br, 1H), 4.12 (t, J = 4.8Hz, 2H), 3.05 (t, J=4.8Hz, 2H), 1.38(s, 6H). LCMS: MS Calcd.: 459.4, MS Found: 460.3 [M+1].

Embodiment 3

[0044] The synthesis of embodiment 3:1-3

[0045] A kind of substituted indazole compound, has the structure shown in general formula (I-3), and synthetic route is specifically as follows:

[0046]

[0047] Except reaction raw material Ia-3, all the other operation steps are all the same as embodiment 1, and the yield of product I-3 is yield 13%, and hydrogen spectrum is 1 HNMR (400MHz, DMSO-d 6 ):δ=11.53(br,1H), 8.35(d,J=8.0Hz,1H), 8.13(m,2H), 8.01(s,1H),7.96(d,J=8.0Hz,1H),7.88 (s, 1H), 7.73(d, J=8.4Hz, 1H), 7.23(d, J=8.4Hz, 1H), 4.15(t, J=4.8Hz, 2H), 3.09(t, J=4.8Hz ,2H), 2.10(s,3H). LCMS: MS Calcd.: 415.3, MS Found: 416.3 [M+1].

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Abstract

The invention relates to a substituted indazole compound, a preparation method, application and a composition containing the substituted indazole compound. The substituted indazole compound is a compound with a structure as shown in a general formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar1 is a group shown in the specification, R1 is one of hydrogen, cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C8 cycloalkyl and groups shown in the specification, R2 and R3 are the same, R2 and R3 are both hydrogen or C1-C3-alkyl, Ar2 is a five-membered heteroaryl group or a five-membered heteroaryl group monosubstituted by an R4 substituent group, the five-membered heteroaryl group contains at least one heteroatom, the heteroatom is N, O or S, and R4 is hydrogen, hydroxyl, cyano, halogen, C1-C3 alkyl or C1-C3 alkoxy. Compared with the prior art, the substituted indazole compound provided by the invention has better IRAK4 inhibitory activity, shows good pharmacodynamic activity, pharmacokinetic properties and safety advantages, and has the potential of being developed into an IRAK4 kinase inhibitor.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a substituted indazole compound, a preparation method, an application and a composition containing the same. 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. Among them, IRAK-M is only expressed in monocytes and macrophages, and the expressions of IRAK-1, IRAK-2 and IRAK4 are ubiquitous. [0003] 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 kinase domain characteristics. The main ...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D401/14C07D417/14A61K31/4439A61K31/5377A61P37/06A61P37/02A61P9/10A61P19/02A61P17/06A61P19/06A61P17/04A61P11/06A61P11/00A61P15/00A61P31/20A61P31/14A61P31/22A61P5/14A61P3/10A61P25/28A61P27/02A61P35/00A61P35/02A61P17/00
CPCC07D413/14C07D401/14C07D417/14A61P37/06A61P37/02A61P9/10A61P19/02A61P17/06A61P19/06A61P17/04A61P11/06A61P11/00A61P15/00A61P31/20A61P31/14A61P31/22A61P5/14A61P3/10A61P25/28A61P27/02A61P35/00A61P35/02A61P17/00Y02P20/55
Inventor 方亚辉王丽媛宋丹丹
Owner SHANGHAI APPLIED TECHNOLOGIES COLLEGE
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