Novel indolizine-2-carboxamides active against the hepatitis b virus (HBV)
A compound and solvate technology, applied in the field of new antiviral agents, can solve problems such as low solubility, poor bioavailability, and mutagenicity
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Embodiment 1
[0981] 8-Chloro-2-(3-{6,6-difluoro-4-azaspiro[2.4]heptane-4-carbonyl}-2H,4H,5H,6H,7H-pyrazolo[4,3 -c]pyridine-5-carbonyl)indoxazine
[0982]
[0983] 3-(6,6-difluoro-4-azaspiro[2.4]heptane-4-carbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2 , tert-butyl 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.298g, 0.581mmol) was dissolved in 4M HCl-di Alkanes (4 mL, 16.00 mmol) and stirred overnight. Add additional 4M HCl-di Alkane (4 mL, 16.00 mmol). After 6 h, the mixture was concentrated, the residue was treated with DIPEA (0.305 mL, 1.744 mmol) and 1 / 4 of the mixture was transferred to a new vial. To this new vial was added a solution of 8-chloroindolezine-2-carboxylic acid (0.028 g, 0.145 mmol) and HATU (0.055 g, 0.145 mmol) in dry N,N-dimethylformamide (1 mL) . The mixture was stirred overnight at room temperature and then directly purified by preparative HPLC to afford the desired product (0.035 g, 0.076 mmol, 52% yield) as a white solid.
[0984] Rt (Me...
Embodiment 2
[0987] 6,8-difluoro-2-(3-{6,6-difluoro-4-azaspiro[2.4]heptane-4-carbonyl}-2H,4H,5H,6H,7H-pyrazolo[ 4,3-c]pyridine-5-carbonyl)indoxazine
[0988]
[0989] 3-(6,6-difluoro-4-azaspiro[2.4]heptane-4-carbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2 , tert-butyl 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.298g, 0.581mmol) was dissolved in 4M HCl-di Alkanes (4 mL, 16.00 mmol) and stirred overnight. Add additional 4M HCl-di Alkane (4 mL, 16.00 mmol). After 6 h, the mixture was concentrated, the residue was treated with DIPEA (0.305 mL, 1.744 mmol) and 1 / 4 of the mixture was transferred to a new vial. To this new vial was added 6,8-difluoro-indolezine-2-carboxylic acid (0.029 g, 0.145 mmol) and HATU (0.055 g, 0.145 mmol) in anhydrous N,N-dimethylformamide (1 mL ) in the solution. The mixture was stirred overnight at room temperature and then directly purified by preparative HPLC to afford the desired product (0.024 g, 0.052 mmol, 36% yield) as a white solid....
Embodiment 3
[0993] 5-(8-chloroindolezine-2-carbonyl)-N-[1-(methoxymethyl)cyclopropyl]-N-methyl-2H,4H,5H,6H,7H-pyrazolo [4,3-c]pyridine-3-carboxamide
[0994]
[0995]To a solution of 8-chloroindolezine-2-carboxylic acid (11.0 mg, 0.056 mmol) in anhydrous N,N-dimethylformamide (0.4 mL) was added HATU (25.7 mg, 0.068 mmol). In a separate vial, N-(1-(methoxymethyl)cyclopropyl)-N-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c] Pyridine-3-carboxamide dihydrochloride (19 mg, 0.056 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.400 mL) and TEA (0.039 mL, 0.282 mmol) was added. After 5 minutes the flasks were combined and stirred overnight. A few drops of water were added, and the mixture was directly purified by chromatography to afford the desired product (0.0094 g, 0.021 mmol, 38% yield).
[0996] Rt (method A) 3.11 min, m / z 442 / 444 [M+H] +
[0997] 1H NMR (400MHz, DMSO-d6) δ13.19–12.81(m, 1H), 8.31(d, J=6.8Hz, 1H), 8.00(s, 1H), 6.98(d, J=7.2Hz, 1H) ,6.69–6.62(m,2H),4.96–4.51...
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