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irak4 inhibitor and its application

A technology of inhibitors and alkyl groups, applied in the field of medicine, can solve problems such as partial blockage of signal transduction

Active Publication Date: 2020-02-14
BEIJING HANMI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In contrast, deletion of IRAK1 (Thomas, J.A. et al, 1999, J. Immunol.163: 978-984; Swantek, J.L. et al, 2000, J. Immunol. 164: 4301-4306) or IRAK2 (Wan, Y. et al , 2009, J.Biol.Chem.284: 10367-10375) only partially blocked signaling

Method used

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Examples

Experimental program
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preparation example Construction

[0190] Preparation of compounds of the present invention

[0191] The following reaction schemes illustrate the preparation of the compounds of the present invention.

[0192] Those skilled in the art will understand that in the description herein, combinations of substituents are permissible only if such combinations result in stable compounds.

[0193] Those skilled in the art will also understand that in the methods described below, intermediate compound functional groups may need to be protected by an appropriate protecting group "PG". Such functional groups include hydroxyl, amino, mercapto and carboxyl. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C(=O)-R" ...

Embodiment 1

[0216] trans-4-[2-(3-methylisothiazol-5-ylamino)-5-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrole[3,2-d] Preparation of pyrimidin-4-ylamino]cyclohexanol

[0217]

[0218] The first step: the preparation of 2,4-dichloro-5-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrole[3,2-d]pyrimidine

[0219]

[0220] 2,4-dichloro-5H-pyrrole[3,2-d]pyrimidine (376mg, 2mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1H-pyrazole (832 mg, 4 mmol), anhydrous copper acetate (363 mg, 2 mmol) and pyridine (158 mg, 2 mmol) were added to dimethylsulfoxide (10 mL) . The reaction solution was heated to 110°C and stirred overnight. The reaction solution was naturally cooled to room temperature, added ethyl acetate (50mL), filtered to remove insoluble matter, the filtrate was washed with water (40mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and washed with n-hexane / ethyl acetate (2 / 1 , 30mL) of the mixed solution was beaten and filtered to obtain 150mg of light y...

Embodiment 45

[0239] N 2 -(1-cyclohexyl-1H-pyrazol-4-yl)-N 4 - Preparation of isopropyl-5-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine:

[0240]

[0241] The first step: the preparation of 2,4-dichloro-5-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrole[3,2-d]pyrimidine

[0242]

[0243] 2,4-dichloro-5H-pyrrole[3,2-d]pyrimidine (376mg, 2mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1H-pyrazole (832 mg, 4 mmol), anhydrous copper acetate (363 mg, 2 mmol) and pyridine (158 mg, 2 mmol) were added to dimethylsulfoxide (10 mL) . The reaction solution was heated to 110°C and stirred overnight. The reaction solution was naturally cooled to room temperature, added ethyl acetate (50mL), filtered to remove insoluble matter, the filtrate was washed with water (40mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and washed with n-hexane / ethyl acetate (2 / 1 , 30mL) of the mixed solution was beaten and filtered to obtain 150mg of light ...

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PUM

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Abstract

A compound related to inhibiting IRAK4 kinase activity, pharmaceutical composition thereof, use thereof in pharmacy, method for inhibiting IRAK4 kinase activity thereof and use thereof to treat and / or prevent IRAK4 kinase-mediated method of disease or disease. The compound has the structural formula I.

Description

technical field [0001] The invention relates to the field of medicine, in particular to IRAK4 inhibitors and applications thereof. Background technique [0002] Members of the Toll / IL-1 receptor family are important regulators of inflammation and host resistance. The Toll-like receptor (TLR) family recognizes molecular patterns from pathogens such as bacteria, fungi, parasites and viruses (for review see Kawai, T., et al. 2010, Nature Immunol. 77:373-384). Ligands bound to the receptor induce dimerization of the adapter molecule and can recruit the adapter molecule to a conserved cytoplasmic motif in the receptor known as the Toll / IL-1 receptor (TIR) ​​domain. The adapter molecule recruited by all TLRs except TLR3 is myeloid differentiation factor 88 (MyD88). The IL-1 receptor family also contains a TIR domain and likewise recruits MyD88 upon ligand binding (for review, see Sims, J.E. et al, 2010, Nature Rev. Immunol. 10:89-102). [0003] Members of the human interleukin ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/4162A61P29/00
CPCA61K31/4162C07D487/04A61P35/00A61K31/519A61K31/5377A61K31/541C07D519/00A61P37/00A61P7/02A61P29/00A61K45/06
Inventor 许江城蔡青圆车美英金孟燮
Owner BEIJING HANMI PHARMA CO LTD
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