Compound for inhibiting kinase activity of BTK and/or JAK3

A compound and solvate technology, applied in the field of compounds that inhibit BTK and/or JAK3 kinase activity, can solve problems such as toxic and side effects

Active Publication Date: 2015-01-07
BEIJING HANMI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But due to EGFR WT Widely distributed in mammalian cells, EGFR WT Inhibition may have certain toxic side effects

Method used

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  • Compound for inhibiting kinase activity of BTK and/or JAK3
  • Compound for inhibiting kinase activity of BTK and/or JAK3
  • Compound for inhibiting kinase activity of BTK and/or JAK3

Examples

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preparation example Construction

[0280] Preparation of compounds of the present invention

[0281] The following reaction scheme illustrates the preparation method of the compound of formula I of the present invention by taking compounds of formula Ia and formula Ib as examples.

[0282] It should be understood by those skilled in the art that in the following description, combinations of substituents are permissible only when such combination can result in a stable compound.

[0283] 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 carboxylic acid. 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-...

Embodiment 1

[0336] Preparation of 4-((cis-4-acryloylaminocyclohexyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide

[0337]

[0338] Step 1: Preparation of tert-butyl (cis-4-((5-aminoacyl-2-chloropyrimidin-4-yl)amino)cyclohexyl)aminocarboxylate

[0339]

[0340] Dissolve 2,4-dichloropyrimidine-5-carboxamide (191 mg, 1 mmol) and cis-4-aminocyclohexylaminocarboxylate tert-butyl ester (235 mg, 1.1 mmol) in dichloromethane (5 mL), add N , N-diisopropylethylamine (521 μL, 3 mmol). The reaction solution was stirred at room temperature overnight, then concentrated. The residue was added to water (20 mL), extracted with ethyl acetate (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain 150 mg of a light yellow solid. Yield: 40.6%. MS(ESI,m / z):[M+H] + :370.1; 1 H-NMR (300MHz, DMSO-d 6 ):8.58(s,1H),8.21(s,1H),7.66(s,1H),4....

Embodiment 8

[0351] Preparation of 4-((cis-4-propioloylaminocyclohexyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide

[0352]

[0353] Step 1: (cis-4-((5-aminoacyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)aminocarboxylic acid Preparation of tert-butyl ester

[0354]

[0355]The product obtained in Step 1 of Example 1 (370 mg, 1 mmol) and 1-methyl-1H-pyrazol-4-amine (107 mg, 1.1 mmol) were dissolved in 1,4-dioxane (5 mL). The pH of the reaction solution was adjusted to 5 with trifluoroacetic acid, and reacted under microwave irradiation at 90° C. for 0.5 hour. The reaction solution was cooled to room temperature, and the pH was adjusted to 8 with 1N sodium hydroxide solution. Extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane / methanol=30:1) to obtain 362 mg of a yellow solid. Yi...

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Abstract

The invention relates to a compound for inhibiting kinase activity of BTK and/or JAK3, as well as a pharmaceutical composition of the compound use of the compound in pharmaceuticals, a method for inhibiting the activity of BTK and/or JAK3 by virtue of the compound and a method for treating and/or preventing BTK and/or JAK3 mediated diseases or symptoms of mammals (particularly human) by virtue of the compound. The compound has a structural formula I shown in the specification.

Description

technical field [0001] The present invention relates to compounds that inhibit BTK (Bruton's tyrosine kinase) and / or JAK3 (Janus tyrosine kinase 3) kinase activity, their pharmaceutical compositions, their use in pharmacy, and their use to inhibit BTK and / or Methods of JAK3 activity and methods of using same to treat and / or prevent BTK and / or JAK3 mediated diseases or conditions in mammals, especially humans. Background technique [0002] Protein kinases constitute one of the largest families of human enzymes, with more than 500 species identified in humans so far. They modulate complex signaling pathways by transferring phosphate groups to proteins to regulate the activity of specific proteins. Aberrant protein kinase activity is associated with a variety of diseases, from cancer to autoimmune diseases. In view of the key role of protein kinases in signal transduction pathways and the correlation between kinase activity and various diseases, kinase inhibitors have become ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D417/14C07D417/12C07D239/48A61K31/506A61K31/505A61P37/02A61P29/00A61P7/02A61P35/00A61P19/02A61P19/08A61P11/00A61P25/00A61P17/06A61P1/00A61P35/02
CPCC07D239/48C07D403/12C07D417/12C07D417/14A61K31/506A61K45/06A61P1/00A61P1/04A61P7/02A61P11/00A61P17/06A61P19/02A61P19/08A61P25/00A61P29/00A61P35/00A61P35/02A61P37/02A61K2300/00
Inventor 刘金明车美英李功李占梅张烜金孟燮
Owner BEIJING HANMI PHARMA CO LTD
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