Pyridopyrimidine derivatives as protein kinase inhibitors
A technology of compounds, mixtures, applied in the field of treatment of kinase-induced diseases, which can solve the problems of poor response and only modest anti-tumor efficacy
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Embodiment 70 and 71
[0510] (cis)-2-[8-(1-Benzenesulfonyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexanol ("A70 ") enantiomer 1 and (cis)-2-[8-(1-benzenesulfonyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidine-2- Amino]-cyclohexanol, enantiomer 2 ("A71");
[0511]
[0512] Preparation of intermediate cis-2-(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexanol
[0513]
[0514] 2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine (500.00mg; 1.098mmol; 1.00eq), cis-2-amino-cyclohexanol hydrochloride (166.47mg; 1.098mmol; 1.00 equiv), ethanol (2.00 mL), and triethylamine (456.55 µL; 3.294 mmol; 3.00 equiv) were placed in a microwave container and sealed with a septum. The reaction mixture was now heated by microwave to 120 °C for 10 minutes. Solvent was removed in vacuo. The product was purified by flash chromatography and afforded 107 mg (26%) of the title compound as a yellow amorphous powder; HPLC (Method A) RT 2.36 min.; HPLC MS (Method G): (M+H) 371; RT 1.519 min. .
[0515] "A70" and "A71"...
Embodiment 72
[0520] 3-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-7-carbonitrile ("A72" )
[0521]
[0522] 72.1
[0523]
[0524] 97% 1H-indole-7-carbonitrile (1.00 g; 6.823 mmol; 1.000 equiv) was dissolved in toluene (20.00 mL; 188.843 mmol; 27.676 equiv). Tetra-n-butylammonium hydrogensulfate (347.52 mg; 1.024 mmol; 0.150 equiv) was added. 32% sodium hydroxide solution (20.00 mL; 216.016 mmol; 31.658 equiv) and 4-toluenesulfonyl chloride (1.34 mL; 10.235 mmol; 1.500 equiv) were added to the suspension at 0°C and stirred vigorously at room temperature for 14 hours. The reaction mixture was treated with toluene and water, the layers were separated and the organic extract was washed with saturated ammonium chloride solution. The organic layer was treated with MgSO 4 Dry, filter and concentrate under reduced pressure. The residue was treated with DCM and concentrated under reduced pressure to afford 2 g (69%) of the title compound as an off-white s...
Embodiment 73
[0537] Enantiomerization of 3-[2-((cis)-2-hydroxy-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile Body 1 ("A73")
[0538]
[0539] 73.1 Enantiomer 1 and Enantiomer 2: cis-2-(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexanol
[0540]
[0541] 2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine (1.00 g; 2.556 mmol; 1.00 equiv), cis-2-amino-cyclohexanol hydrochloride (387.57 mg; 2.556 mmol; 1.00 eq), ethanol (10.00 mL; 0.171 mol; 67.09 eq) and triethylamine (1.06 mL; 7.668 mmol; 3.00 eq) were placed in a microwave vessel and sealed with a septum. The reaction mixture was heated in the microwave to 120 °C for 10 min. The reaction mixture was evaporated to dryness and the product was purified by flash chromatography. The enantiomers were separated by chiral SFC.
[0542] Enantiomer 1: with solvent CO 2 + 20% MOH + 0.5% DEA Stereoisomer eluting first from column Chiralpak AS-H; absolute configuration arbitrary; 61 mg (6%) of title compound as yellow amorpho...
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