Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B

Patent metadata

Field	Value
Publication number	US-10457638-B2
Application number	US-201815875929-A
Country	US
Kind code	B2
Filing date	Jan 19, 2018
Priority date	May 17, 2013
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

Inhibitors of HBV replication of Formula (ID)

including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X, R a to R d and R 4 to R 6 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.

First claim

The invention claimed is:

1. A method of treating Hepatitis B virus infection in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (ID)

or a stereoisomer or tautomeric form thereof, wherein:
each X is independently CR 7 ;
R a , R b and R c are each independently selected from the group consisting of hydrogen, fluoro, bromo, chloro, —CHF 2 , —CF 2 -methyl, —CH 2 F, —CF 3 , —OCF 3 , —CN, C 1 -C 3 alkyl and C 3 -C 4 cycloalkyl;
R d is hydrogen or fluoro;
R 4 is hydrogen, C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl;
R 5 is hydrogen;
R 6 is selected from the group consisting of C 2 -C 6 alkyl, C 1 -C 4 alkyl-R 8 optionally substituted with one or more fluoro, C 1 -C 4 alkyl-R 9 optionally substituted with one or more fluoro, and a 3-7 membered mono or polycyclic saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or C 2 -C 6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, —OH, fluoro, oxo, R 9 , R 10 and C 1 -C 4 alkyl optionally substituted with R 10 ;
R 7 is selected from the group consisting of hydrogen, —CN, fluoro, chloro, bromo, —CHF 2 , —CF 2 — methyl, —CH 2 F, —CF 3 , C 1 -C 3 alkyl optionally substituted with methoxy, C 2 -C 3 alkenyl and C 3 -C 4 cycloalkyl;
R 8 is a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally substituted with one or more C 1 -C 4 alkyl optionally substituted with R 10 ;
R 9 is selected from the group consisting of C 1 -C 4 alkyloxy, —SO 2 -methyl, —C(═O)—OR 11 and —C(═O)—N(R 11 ) 2 ;
R 10 is selected from the group consisting of —CN, —OH, fluoro, —CHF 2 , —CH 2 F and —CF 3 ;
R 11 is hydrogen or C 1 -C 3 alkyl;
or a pharmaceutically acceptable salt or a solvate thereof wherein such compound is not

2. The method of claim 1 , wherein
R a is —CN;
R b , R c and R d are each independently selected from the group consisting of hydrogen and fluoro;
R 4 is C 1 -C 3 alkyl;
R 6 is selected from the group consisting of C 2 -C 6 alkyl, optionally substituted with one or more fluoro; and
R 7 is hydrogen.

3. The method of claim 1 , wherein the compound is selected from the group consisting of:
N-(4-fluoro-3-methyl-phenyl)-4-(isopropylsulfamoyl)-1H-pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)methylsulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-4-[[3-(hydroxymethyl)oxetan-3-yl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[(3-methyltetrahydrofuran-3-yl)sulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-4-[[1-(hydroxymethyl)cyclopropyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[(1-methyl-5-oxo-pyrrolidin-3-yl)sulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3-methy-phenyl)-4-[[3-(2-hydroxyethyl)oxetan-3-yl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
N-(4-fluoro-3-methy-phenyl)-4-[(3-hydroxycyclobutyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
4-(tert-butylsulfamoyl)-N-(4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide
4-[[3-(cyanomethyl)oxetan-3-yl]sulfamoyl]-N-(4-fluoro-3-methy-phenyl)-1-methyl-pyrrole-2-carboxamide;
4-[[1-(cyanomethyl)cyclopropyl]sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide;
4-(tert-butylsulfamoyl)-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide;
N-(3,4-difluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide;
N-(3,4-difluorophenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole-2-carboxamide;
N-(3,4-difluorophenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide;
N-(3,4-difluorophenyl)-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxamide;
N-(3,4-difluorophenyl)-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
N-(3,4-difluorophenyl)-4-[(3-hydroxycyclobutyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide;
1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide;
1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-N-[3-(trifluoromethyl)phenyl]pyrrole-2-carboxamide;
1-ethyl-N-(4-fluoro-3-methyl-phenyl)-4-(isopropylsulfamoyl)pyrrole-2-carboxamide;
1-ethyl-N-(4-fluoro-3-methyl-phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole-2-carboxamide;
N-(4-fluoro-3,5-dimethyl-phenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole-2-carboxamide;
N-(3-fluoro-5-methyl-phenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole-2-carboxamide;
N-(3,4-difluoro-5-methyl-phenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide;
N-(3,4-difluoro-5-methyl-phenyl)-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxamide;
N-(3,4-difluoro-5-methyl-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide;
N-(3,4-difluoro-5-methyl-phenyl)-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
N-(3,4-difluoro-5-methyl-phenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole-2-carboxamide;
4-(tert-butylsulfamoyl)-N-(3,4-difluoro-5-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide;
N-[3-(difluoromethyl)-4-fluoro-phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide;
N-[3-(difluoromethyl)-4-fluoro-phenyl]-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole-2-carboxamide;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide;
N-[3-fluoro-5-(trifluoromethyl)phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide;
N-(3-bromo-4,5-difluoro-phenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide;
N-(3-bromo-4,5-difluoro-phenyl)-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxamide;
N-(3-bromo-4,5-difluoro-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide;
methyl 2-[[5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrol-3-yl]sulfonylamino]-2-methyl-propanoate;
N-(3-cyano-4-fluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide;
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide;
N-(3-cya

Assignees

• Janssen Sciences Ireland Uc

Inventors

• Vandyck Koen
• Haché Geerwin Yvonne Paul
• Last Stefaan Julien
• Mcgowan David Craig
• Rombouts Geert
• Verschueren Wim Gaston
• Raboisson Pierre Jean-Marie Bernard

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61K31/401

  Proline; Derivatives thereof, e.g. captopril · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title