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

Patent metadata

Field	Value
Publication number	US-10071961-B2
Application number	US-201715807468-A
Country	US
Kind code	B2
Filing date	Nov 8, 2017
Priority date	Oct 23, 2013
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

Inhibitors of HBV replication of formula (I)

including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein, X, R 1 to R 7 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)

or a stereoisomer or tautomeric form thereof, wherein:

each of Ra, Rb, Rc, Rd, Re, Rf and Rg is independently selected from the group consisting of hydrogen and methyl;
Rh and Ri are each hydrogen;
R 1 is selected from the group consisting of hydrogen and fluoro;
R 2 is selected from the group consisting of hydrogen, fluoro, chloro, —CHF 2 , —CH 2 F, —CF 3, —CN and methyl;
R 3 is selected from the group consisting of hydrogen, fluoro, chloro and bromo;
R 6 is selected from the group consisting of C 1 -C 6 alkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, said C 1 -C 6 alkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of fluoro, CN, OH and C 1 -C 3 alkyl optionally substituted with one or more fluoro; and
R 7 is hydrogen;
or a pharmaceutically acceptable salt or a solvate thereof.

2. The compound of claim 1 , wherein

3. The compound of claim 1 , wherein

4. The compound of claim 1 , wherein each of Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh and Ri is hydrogen.

5. The compound of claim 1 , wherein at least one of Ra, Rb, Rc, Rd, Re, Rf and Rg is methyl.

6. The compound of claim 1 , wherein R 1 is fluoro.

7. The compound of claim 1 , wherein R 2 is selected from the group consisting of fluoro, chloro, —CHF 2 , —CH 2 F, —CF 3 , —CN and methyl.

8. The compound of claim 1 , wherein R 3 is selected from the group consisting of fluoro, chloro and bromo.

9. The compound of claim 1 , wherein R 1 is fluoro; R 2 is selected from the group consisting of fluoro, chloro, —CHF 2 , —CH 2 F, —CF 3 , —CN and methyl; and R 3 is selected from the group consisting of fluoro, chloro and bromo.

10. The compound of claim 1 , wherein R 1 is fluoro and R 2 is methyl.

11. The compound of claim 1 , wherein R 1 is fluoro; R 2 is selected from the group consisting of fluoro and chloro; and R 3 is selected from the group consisting of hydrogen, fluoro and chloro.

12. The compound of claim 1 , wherein R 6 is a branched C 1 -C 6 alkyl optionally substituted with one or more fluoro.

13. The compound of claim 1 , wherein R 6 is selected from the group consisting of
—CH 2 (CH 3 ), —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —(CH)(CH 3 )CH 2 CH 3 , —(CH)(CH 3 )CH 2 OH, —CH(CH 3 )CF 3 , C(CH 3 ) 2 CF 3 .

14. The compound of claim 1 , wherein R 6 is —CH(CH 3 ) 2 .

15. The compound of claim 1 , wherein R 6 is —CH(CH 3 )CF 3 .

16. The compound of claim 1 , wherein R 1 is fluoro; and R 6 is —CH(CH 3 )CF 3 .

17. The compound of claim 1 , wherein R 6 is a 4-5 membered saturated ring containing one oxygen, said 4-5 membered saturated ring optionally substituted with methyl.

18. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

19. A method of treating an HBV infection in a subject comprising administering an effective amount of a compound of claim 1 .

20. The method of claim 19 , further comprising administering said compound of claim 1 in combination with at least one other anti-HBV agent.

Assignees

• Janssen Sciences Ireland Uc

Inventors

• Vandyck Koen
• Haché Geerwin Yvonne Paul
• Kesteleyn Bart Rudolf Romanie
• Raboisson Pierre Jean-Marie Bernard

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D405/12

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

• C07D211/60

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title