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

Patent metadata

Field	Value
Publication number	US-10875876-B2
Application number	US-201615195809-A
Country	US
Kind code	B2
Filing date	Jun 28, 2016
Priority date	Jul 2, 2015
Publication date	Dec 29, 2020
Grant date	Dec 29, 2020

Abstract

Inhibitors of HBV replication of Formula (I-A)

including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein R a to R d , and R 1 to R 8 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 compound of Formula (I-A)

or a stereoisomer or tautomeric form thereof, wherein

represents

wherein R 4 is selected the group consisting of hydrogen, C 1 -C 3 alkyl and C 3 -C 4 -cycloalkyl, and R 6 is selected from the group consisting of hydrogen, methyl, —CN and halogen;

represents a 6 membered aryl optionally containing one nitrogen atom;
X represents —CR 2 R 3 —;
Y represents C 1 -C 7 alkanediyl or C 2 -C 7 alkenediyl, each optionally substituted with one or more substituents each independently selected from the group consisting of C 1 -C 4 alkyl, fluoro, and —OH;
Z represents a heteroatom or a single bond;
R a , R b , R c and R d are each independently selected from the group consisting of hydrogen, halogen, —CHF 2 , —CF 2 -methyl, —CH 2 F, —CF 3 , —OCF 3 , —CN, C 3 -C 4 cycloalkyl and —C 1 -C 4 alkyl;
R 1 is hydrogen or C 1 -C 10 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of —OH, fluoro and oxo;
R 2 is selected from the group consisting of hydrogen; C 1 -C 10 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of —OH, fluoro, methoxy, oxo and —C(═O)OC 1 -C 4 alkyl; C 1 -C 3 alkyl-R 7 ; C 2 -C 4 alkynyl; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N: and monocyclic aryl optionally containing one or two heteroatoms, wherein C 1 -C 3 alkyl-R 7 , 3-7 membered saturated ring and monocyclic aryl are each optionally substituted with one or more R 8 substituents;
R 3 is hydrogen or C 1-6 alkyl optionally substituted with —OH,
or R 2 and R 3 taken together with the carbon atom to which they are attached form a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, wherein said ring is optionally substituted with one or more substituents each independently selected from the group consisting of —OH, fluoro, methoxy, oxo, —C(═O)OC 1 -C 4 alkyl, benzyl, and C 1 -C 4 alkyl optionally substituted with one or more substituents each independently selected from fluoro and —OH;
R 7 is a monocyclic aryl optionally containing one or two heteroatoms, wherein said aryl is optionally substituted with one or two substituents each independently selected from the group consisting of halo and C 1-3 alkyl; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or —NR 9 R 10 , wherein R 9 and R 10 are each independently selected from hydrogen and C 1 -C 3 alkyl optionally substituted with one or more fluoro substituent;
each R 8 is independently selected from the group consisting of —OH, fluoro, methoxy, oxo, C(═O)OC 1 -C 4 alkyl, C 1 -C 4 alkyloxyC 1 -C 4 alkyloxy, and C 1 -C 4 alkyl optionally substituted with one or more substituents each independently selected from fluoro and —OH;
or a pharmaceutically acceptable salt or a solvate thereof.

2. The compound according to claim 1 , wherein
Y represents C 1 -C 2 alkanediyl or C 2 alkenediyl each optionally substituted with one or more substituents each independently selected from C 1 -C 4 alkyl and —OH; and
Z represents oxygen or a single bond.

3. The compound according to claim 2 , wherein
Y represents a C 1 alkanediyl optionally substituted with one or more C 1 -C 4 alkyl or —OH; and
Z represents O.

4. The compound according to claim 1 , wherein

represents phenyl, and R a , R b and R d are each independently hydrogen or halogen; and R c is selected from the group consisting of hydrogen, halogen, CH 3 , CHF 2 , CF 3 and —CN.

5. The compound according to claim 1 , wherein ring C consists of 6 to 8 atoms.

6. The compound according to claim 1 , wherein R 4 is methyl, and R 6 is hydrogen.

7. The compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl.

8. The compound according to claim 7 , wherein R 2 is methyl.

9. The compound according to claim 7 , wherein R 2 is optionally substituted with one or more substituents each independently selected from the group consisting of —OH, fluoro, and methoxy.

10. The compound according to claim 1 , wherein R 2 is C 1 -C 4 alkyl optionally substituted with one or more fluoro.

11. The compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl optionally substituted with one or more —OH.

12. The compound according to claim 1 , wherein R 1 is hydrogen.

13. The compound according to claim 1 , wherein said compound is selected from the group consisting of:

Assignees

• Janssen Sciences Ireland Uc

Inventors

• Vendeville Sandrine Marie Helene
• Last Stefaan Julien
• Demin Samuël Dominique
• Grosse Sandrine Céline
• Haché Geerwin Yvonne Paul
• Hu Lili
• Pieters Serge Maria Aloysius
• Rombouts Geert
• Vandyck Koen
• Verschueren Wim Gaston
• Raboisson Pierre Jean-Marie Bernard

Classifications

• A61P31/20

  for DNA viruses · CPC title

• C07D291/08

  condensed with carbocyclic rings or ring systems · CPC title

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

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