9‑(aryl or heteroaryl)‑2‑(pyrazolyl, pyrrolidinyl or cyclopentyl) aminopurine derivatives as anticancer agents
A pyrrolidinyl and pyrazolyl-based technology, which can be used in the field of compounds for treating kinase-induced diseases and preparing medicines, and can solve the problems of increased CD4 proliferation response and the like
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Embodiment 1
[0437] 9-(4-ethoxyphenyl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-9H-purin-2-amine ("A1 ")Synthesis
[0438] step 1 :
[0439] 1-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine
[0440]
[0441] program : in N 2 Under atmosphere, DIAD (6.32 mL, 0.026 mol) was added dropwise to 4-nitropyrazole (3.23 g, 0.0286 mol), 1-methylpiperidin-4-ol (3 g, 0.026 mol ) and PPh 3 (10.49 g, 0.039 mol) in a stirred solution in THF (50 mL). The resulting solution was stirred at 0 °C for 10 minutes, then allowed to warm to room temperature and stir overnight. The mixture was diluted with hexanes (80 mL) and EtOAc (20 mL), then stirred vigorously. The mixture was filtered, and the solid was washed with hexanes. The combined filtrates were evaporated and the residue was purified by chromatography to give 1-methyl-4-(4-nitro-1 H -pyrazol-1-yl)piperidine;
[0442] Yield: 38% (2.1 g, light yellow solid); LCMS: (Method A) 210.1 (M+H).
[0443] Step 2:
[0444] 1-(1-M...
Embodiment 2
[0469] 9-(4-(2-methoxyethoxy)phenyl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-9H-purine -Synthesis of 2-amine ("A2")
[0470] step 1:
[0471] 2-Chloro-N-[4-(2-methoxyethoxy)phenyl]-5-nitropyrimidin-4-amine
[0472]
[0473] program : To a stirred solution of 2,4-dichloro-5-nitropyrimidine (0.25 g, 0.013 mol) in 1,4-dioxane (10 mL) was added [4-(2 -A solution of -methoxyethyl)phenyl]amine (0.217 g, 0.0013 mol) in 1,4-dioxane (5 mL). The reaction mixture was stirred for 2 h. After confirming the completion of the reaction by TLC, the solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography to obtain 2-chloro- N -[4-(2-Methoxyethoxy)phenyl]-5-nitropyrimidin-4-amine; Yield: 40% (0.17 g, yellow solid); LCMS: (Method A) 325.0 (M +H).
[0474] Step 2:
[0475] N 4 -(4-(2-Methoxyethoxy)phenyl) -N 2 - (1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-nitro pyrimidine-2,4-diamine
[0476]
[0477...
Embodiment 3
[0491] 4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-9H-purin-9-yl)benzamide (“A3” )Synthesis
[0492] step 1 :
[0493] 4-Nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole
[0494]
[0495] program : To a stirred solution of di-tert-butyl azodicarboxylate (2.6 g, 11.5 mmol) in THF (5 mL) was added tetrahydro-pyran-4-ol (903 mg, 8.85 mmol), 4- Nitro-1H-pyrazole (1.0 g, 8.85 mmol) and PPh 3 (2.8 g, 10.62 mmol) in THF (35 mL) for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product; yield: 91% (1.59 g, white solid);
[0496] 1 H NMR: (400 MHz, DMSO-d 6 ): δ [ppm] 2.04-1.90 (m, 4 H), 3.44-3.41 (m,2 H), 3.99-3.92 (m, 2 H), 4.55-4.46 (m, 1 H), 8.29 (s, 1 H), 8.96 (s, 1 H).
[0497] step 2 :
[0498] 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine
[0499]
[0500] program : in H 2 To a solution of 4-nitro-l...
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