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

Patent metadata

Field	Value
Publication number	US-9884818-B2
Application number	US-201414891864-A
Country	US
Kind code	B2
Filing date	May 16, 2014
Priority date	May 17, 2013
Publication date	Feb 6, 2018
Grant date	Feb 6, 2018

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 compounds of Formula (ID), 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 compound of Formula (ID)

or a stereoisomer or tautomeric form thereof, wherein:
each X independently is 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 heteroatom independently selected from the group consisting of O, S and N, wherein said 3-7 membered saturated ring or C 2 -C 6 alkyl is each independently 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 2 -C 3 alkenyl, C 3 -C 4 cycloalkyl, and C 1 -C 3 alkyl optionally substituted with methoxy;
R 8 is 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 3-7 membered saturated ring is optionally substituted with one or more C 1 -C 4 alkyl optionally substituted with R 10 ;
R 9 is C 1 -C 4 alkyloxy, —SO 2 -methyl, —C(═O)—OR 11 or —C(═O)—N(R 11 ) 2 ;
R 10 is —CN, —OH, fluoro, —CHF 2 , —CH 2 F or —CF 3 ; and
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. A compound according to claim 1 having Formula (IB)

3. A compound according to claim 1 wherein R 4 is methyl.

4. A compound according to claim 1 wherein R 6 contains a 3-7 membered saturated ring optionally containing one oxygen.

5. A compound according to claim 4 wherein R 6 is a 4 or 5 membered saturated ring containing one oxygen, wherein said 4 or 5 membered saturated ring is optionally substituted with C 1 -C 4 alkyl optionally substituted with R 10 .

6. A compound according to claim 1 wherein R 6 is selected from the group consisting of a branched C 3 -C 6 alkyl optionally substituted with one or more fluoro, a C 3 -C 6 cycloalkyl wherein such C 3 -C 6 cycloalkyl is substituted with one or more fluoro or substituted with C 1 -C 4 alkyl substituted with one or more fluoro and a C 3 -C 6 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of fluoro and C 1 -C 4 alkyl optionally substituted with one or more fluoro.

7. A compound according to claim 6 wherein R 6 is a branched C 3 -C 6 alkyl substituted with one or more fluoro.

8. A compound according to claim 1 wherein R b is hydrogen or fluoro.

9. A compound according to claim 1 wherein R a and R c are independently selected from the group consisting of hydrogen, fluoro, chloro, CN and methyl.

10. A compound according to claim 1 having Formula (IC)

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

11. A compound according to claim 10 , wherein
R 4 is C 1 -C 3 alkyl;
R 6 is C 2 -C 6 alkyl optionally substituted with one or more fluoro; and
R 7 is hydrogen, fluoro, chloro or C 1 -C 3 alkyl.

12. A compound according to claim 11 wherein R 4 is methyl, R 6 is C 2 -C 6 alkyl substituted with one or more fluoro, R 7 is hydrogen, and R a , R b and R c are each independently selected from the group consisting of hydrogen, fluoro, chloro, methyl and —CN.

13. A compound 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-methyl-phenyl)-4-[[3-(2-hydroxyethyl)oxetan-

Assignees

• Janssen Sciences Ireland Uc

Inventors

• Vandyck Koen
• Hache Geerwin Yvonne Paul
• Last Stefaan Julien
• Mc Gowan David Craig
• Rombouts Geert
• Verschueren Wim Gaston
• Raboisson Pierre Jean Marie Bernard

Classifications

• A61P31/00

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

• A61P31/20

  for DNA viruses · CPC title

• C07D403/12

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

• C07D207/40 Primary

  2,5-Pyrrolidine-diones · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title