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US 10,377,709 B2Granted
Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
AssigneeJanssen Sciences Ireland UC
InventorsKoen Vandyck, Geerwin Yvonne Paul Haché, Bart Rudolf Romanie Kesteleyn, Pierre Jean-Marie Bernard Raboisson
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Abstract
Inhibitors of HBV replication of formula (I) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X, R1 to R7 have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.
Claims17
A compound selected from the group consisting of:
- (S)-N-(3-bromo-4,5-difluorophenyl)-1-(2-oxo-2-((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;
- (S)-N-(3-bromo-4,5-difluorophenyl)-1-(2-(3-methyloxetan-3-yl)amino)-2-oxoacetyl)pyrrolidine-3-carboxamide;
- (S)-N-(3-bromo-4,5-difluorophenyl)-1-(2-(tert-butylamino)-2-oxoacetyl)pyrrolidine-3-carboxamide;
- (3S)-N-(4-fluoro-3-methylphenyl)-1-{[(1-methylethyl)amino] (oxo)acetyl}pyrrolidine-3-carboxamide;
- (S)-1-(2-(cyclopentylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)pyrrolidine-3-carboxamide;
- (S)-N-(4-fluoro-3-methylphenyl)-1-(2-((R)-1-hydroxypropan-2-yl)amino)-2-oxoacetyl)pyrrolidine-3-carboxamide;
- (3S)-N-(4-fluoro-3-methylphenyl)-1-{[(3-methyloxetan-3-yl)amino]-(oxo)acetyl}pyrrolidine-3-carboxamide;
- (3S)-N-(4-fluoro-3-methylphenyl)-1-[{[(1R)-1-methylpropyl]amino}(oxo)acetyl]pyrrolidine-3-carboxamide;
- (3S)-N-(4-fluoro-3-methylphenyl)-1-{oxo[(3S)-tetrahydrofuran-3-ylamino]-acetyl}pyrrolidine-3-carboxamide;
- (2S, 3S)-N-(4-fluoro-3-methylphenyl)-2-methyl-1-{[(3-methyloxetan-3-yl)-amino](oxo)acetyl}pyrrolidine-3-carboxamide;
- (S-N-(3-chloro-4,5-difluorophenyl)-1-(2-oxo-2-((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;
- (3S)-N-(4-fluoro-3-methylphenyl)-1-{[(1-methylethyl)amino] (oxo)acetyl }piperidine-3-carboxamide;
- (S)-N-(3-chloro-4,5-difluorophenyl)-1-(2-oxo-2-(1-(trifluoromethyl)cyclopropyl)amino)acetyl)pyrrolidine-3-carboxamide;
- (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-oxo-2-((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;
- (S)-N-(3-chloro-4-fluorophenyl)-1-(2-oxo-2-((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;
- (S)-N-(3-chloro-4,5-difluorophenyl)-1-(2-oxo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;
- N-(4-fluoro-3-methylphenyl)-5-methyl-1-(2-(3-methyloxetan-3-yl)amino)-2-oxoacetyl)pyrrolidine-3-carboxamide;
- N-(3-chloro-4,5-difluoro-phenyl)-2,2-dimethyl-1-[2-oxo-2-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]acetyl]pyrrolidine-3-carboxamide;
- (3S)-1-[2-(tert-butylamino)-2-oxo-acetyl]-N-(3-chloro-2,4-difluoro-phenyl)pyrrolidine-3-carboxamide;
- (3S)-1-[2-(tert-butylamino)-2-oxo-acetyl]-N-(3-cyano-4-fluorophenyl)pyrrolidine-3-carboxamide;
- (3S)-N-(3-chloro-2,4-difluoro-phenyl)-1-[2-oxo-2-[[(1R)-2,2,2-trifluoro-1-methyl -ethyl]amino]acetyl]pyrrolidine-3-carboxamide;
- (3S)-N-(3-cyano-4-fluoro-phenyl)-1-[2-oxo-2-[[(1R)-2,2,2-trifluoro-1-methyl -ethyl]amino]acetyl]pyrrolidine-3-carboxamide;
- (3S)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[2-(isopropylamino)-2-oxo -acetyl]pyrrolidine-3-carboxamide;
- (3S)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[2-[[(1R)-1-methylpropyl]amino]-2-oxo -acetyl]pyrrolidine-3-carboxamide;
- (3S)-N-(3-chloro-4-fluoro-phenyl)-1-[2-oxo-2-[[1-(trifluoromethyl)cyclo-propyl]amino]acetyl]pyrrolidine-3-carboxamide;
- (3S)-N-(3-chloro-4-fluoro-phenyl)-1-[2oxo-2-[[(1S)-2,2,2-trifluoro-1-methyl -ethyl]amino]acetyl]pyrrolidine-3-carboxamide;
- (2S)-N-(3-cyano-4-fluoro-phenyl)-1-[2-(isopropylamino)-2-oxo-acetyl]-2-methyl-pyrrolidine-3-carboxamide;
- (2S)-N-(3-chloro-2,4-difluoro-phenyl)-1-[2-(isopropylamino)-2-oxo-acetyl]-2-methyl-pyrrolidine-3-carboxamide;
- (2S)-N-(3-chloro-4,5-difluoro-phenyl)-1-[2-(isopropylamino)-2-oxo-acetyl]-2-methyl-pyrrolidine-3-carboxamide;
- (3S)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[2-oxo-2-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]acetyl]pyrrolidine-3-carboxamide;
- (3S)-N-[3-(difluoromethyl)-4-fluoro-phenyl ]-1-[2-(isopropylamino)-2-oxo-acetyl]pyrrolidine-3-carboxamide;
- (3S)-1-[2-oxo-2-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]acetyl]-N-(3,4,5-trifluorophenyl)pyrrolidine-3-carboxamide;
- (2S)-N-(3-chloro-4,5-difluoro-phenyl)-2-methyl-1-[2-oxo-2-[(1R)-(2,2,2-trifluoro-1-methyl-ethyl)amino]acetyl]pyrrolidine-3-carboxamide;
- (2S)-2-methyl-1-[2-oxo-2-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]acetyl]-N-(3,4,5-trifluorophenyl)pyrrolidine-3-carboxamide;
- N-(3-chloro-2,4-difluoro-phenyl)-2-methyl-1-[2-oxo-2-[(1R)-2,2,2-trifluoro-1-methyl-ethyl)amino]acetyl]piperidine-3-carboxamide;
- and a pharmaceutically acceptable salt or a solvate thereof.
33 more elements
A compound selected from the group consisting of:
- and a pharmaceutically acceptable salt or a solvate thereof.
A method of preparing a compound of Formula (I)
- wherein:
- represents
- Ra, Rb, Rc, Rd, Re, Rf and Rg are each independently selected from the group consisting of hydrogen and methyl;
- Rh is hydrogen;
- Ri is hydrogen;
- R1, R2 and R3 are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, —CHF2, —CH2F, —CF3, —CN and methyl;
- R6 is selected from the group consisting of
- C1-C6alkyl, and
- a 3-7 membered saturated ring optionally containing one or more heteroatoms each heteroatom independently selected from the group consisting of O, S and N,
- wherein said C1-C6alkyl or 3-7 membered saturated ring is optionally substituted with one or more substituents selected from the group consisting of fluoro and C1-C3alkyl optionally substituted with one or more fluoro, —CN or OH;
- and
- R7 is hydrogen, said method comprising
- reacting a compound having the structure of Formula IV with a compound having the structure of Formula V to form a compound having the structure of Formula VI
- wherein PG is a protecting group.
11 more elements
Dependencies are inferred from the claim text.