Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b

Patent metadata

Field	Value
Publication number	US-2018127361-A1
Application number	US-201715681309-A
Country	US
Kind code	A1
Filing date	Aug 18, 2017
Priority date	Aug 28, 2012
Publication date	May 10, 2018
Grant date	—

Abstract

Inhibitors of HBV replication of Formula (I)

including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein B, R 1 , R 2 and R 4 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

1 - 13 . (canceled)

14 . A compound of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein:
B is a monocyclic 5 membered aromatic ring containing two or more heteroatoms each independently selected from the group consisting of S and N, said 5 membered aromatic ring optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, CN, CFH 2 , CF 2 H and CF 3 ;
R 1 is hydrogen or C 1 -C 3 alkyl;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkyl-R 5 , C(═O)—R 5 , CFH 2 , CF 2 H, CF 3 , a dihydro-indenyl or tetrahydronaphthalenyl moiety optionally substituted with OH, or 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 3-7 membered saturated ring, C 1 -C 6 alkyl-R 5 or C 1 -C 6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyloxy, C 1 -C 4 alkyloxycarbonyl, oxo, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 ;
or R 1 and R 2 together with the nitrogen to which R 1 and R 2 are attached form a 6-10 membered bicyclic or bridged ring or a 5-7 membered saturated ring, said bicyclic, bridged or saturated ring moiety optionally containing one or more additional heteroatoms each independently selected from the group consisting of O, S and N, said 5-7 membered saturated ring optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyloxy, C 1 -C 4 alkyloxycarbonyl, oxo, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 ;
each R 4 is independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, OH, CN, CFH 2 , CF 2 H, CF 3 , HC≡C or a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N, said C 1 -C 4 alkyl optionally substituted with OH;
R 5 is selected from the group consisting of C 1 -C 6 alkyl, CFH 2 , CF 2 H, CF 3 , phenyl, pyridyl 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 3-7 membered saturated ring optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyloxy, C 1 -C 4 alkyloxycarbonyl, oxo, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 ;
or a pharmaceutically acceptable salt or a solvate thereof.

15 . The compound of claim 14 , wherein R 1 is hydrogen.

16 . The compound of claim 14 , wherein R 2 is a 4-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, said 4-7 membered saturated ring optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyloxy, C 1 -C 4 alkyloxycarbonyl, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 .

17 . The compound of claim 14 , wherein R 2 is C 4 -C 6 cycloalkyl.

18 . The compound of claim 14 , wherein B is imidazolyl or thiazolyl, each optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, CN, CFH 2 , CF 2 H and CF 3 .

19 . A compound of claim 14 , wherein at least one R 4 is fluoro, and one other R 4 is selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkenyl, CHF 2 and cyclopropyl.

20 . A compound of claim 14 , wherein one R 4 is fluoro and one other R 4 is selected from methyl or CHF 2 , and wherein the location of said fluoro is on the para position related to the nitrogen(*), and the location of said methyl or CHF 2 is on the meta position related to the nitrogen(*).

21 . The compound of claim 14 , wherein each R 4 is hydrogen.

22 . A compound of claim 14 , wherein the compound is selected from the group consisting of

and
pharmaceutically acceptable salts thereof.

23 . A pharmaceutical composition comprising at least one compound of claim 14 and a pharmaceutically acceptable carrier.

24 . A product containing (a) at least one compound of claim 14 , and (b) an HBV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infection.

25 . A method of preventing or treating an HBV infection in a subject in need thereof, comprising administering to said subject an effective amount of at least one compound of claim 14 .

26 . A method of preventing or treating an HBV infection in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 23 .

Assignees

• Janssen Sciences Ireland Uc

Inventors

• Vandyck Koen
• Last Stefaan Julien
• Rombouts Geert
• Verschueren Wim Gaston
• 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

• A61P31/12

  Antivirals · CPC title

• A61P1/16

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

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title