Pyrazolo and triazolo bicyclic compounds as jak kinase inhibitors
A technology for compounds and heterocyclic groups, applied in the field of preparing these compounds, can solve problems such as unfavorable systemic immunosuppression
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[0374] The following synthetic and biological examples are provided to illustrate the present invention, and are not construed as limiting the scope of the present invention in any way. In the following examples, unless otherwise indicated, the following abbreviations have the following meanings. The following undefined abbreviations have their generally accepted meanings.
[0375] ACN = Acetonitrile
[0376] Calcd = calculated value
[0377] Boc = tert-Butoxycarbonyl
[0378] d = days
[0379] DIPEA = N,N-Diisopropylethylamine
[0380] DMF=N,N-Dimethylformamide
[0381] DMSO = dimethyl sulfoxide
[0382] EtOAc = ethyl acetate
[0383] EtOH = ethanol
[0384] h = hour
[0385] HATU=N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate
[0386] IPA = isopropanol
[0387] MeOH = methanol
[0388] min = minutes
[0389] RT or rt = room temperature
[0390] SiG = silica gel
[0391] TEA = triethylamine
[0392] THF = tetrahydrofuran
[0393] THP = Tetrahydropyran
[0394] TFA = tri...
example 1A
[0443] Example 1A: (E)-4-(dimethylamino)-1-(3-(((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)methyl)aza Cyclobutane-1-yl)but-2-en-1-one
[0444]
[0445] HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 817mg, 2.150mmol) was added to the (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (405 mg, 2.44 mmol) in DMF (2.00 mL) and the reaction mixture was stirred at room temperature for 5 minutes. Add 4-(4-(azetidine-3-ylmethoxy)-1H-indazol-6-yl)phenol TFA salt (800mg, 1.954mmol), followed by DIPEA (1.707ml, 9.77mmol) And the reaction mixture was stirred at room temperature for 15 minutes and then concentrated in vacuo to obtain a yellow liquid. The crude liquid was purified by preparative C18 column chromatography using a gradient of 20 to 80% acetonitrile / water containing 0.05% trifluoroacetic acid to obtain (E)-4-(dimethylamino)- as TFA salt 1-(3-(((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)methyl)azetidine-1-yl)but-2-ene-1 -Ketone (235.0 mg, 0....
example 1B
[0446] Example 1B: Crystalline (E)-4-(dimethylamino)-1-(3-(((6-(4-hydroxyphenyl)-1H-indazol-4-yl)oxy)methyl)nitrogen Etidine-1-yl)but-2-en-1-one type 4
[0447]
[0448] step 1
[0449] To a suspension of 6-bromo-4-fluoro-1H-indazole (20.0 g, 93 mmol) in 200 ml DCM was added p-toluenesulfonic acid monohydrate (1.769 g, 9.30 mmol). The reaction mixture remains as a suspension. Then 3,4-dihydro-2H-pyran (16.97ml, 186mmol) was added. After 5 minutes, complete dissolution of the solid was observed. The reaction mixture was stirred at room temperature overnight to form a black solution. 200 mL aqueous bicarbonate solution was added, the phases were separated and the organic layer was washed with 200 mL brine and dried over sodium sulfate. The solution was filtered through a silica plug to remove the black color and the silica was washed with 300 ml DCM. The solvent was evaporated to give 25 g of product as an off-white solid.
[0450] Step 2A
[0451] In a 500ml round bottom flask...
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