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
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[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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