Flavone compounds for the treatment and prophylaxis of hepatitis B virus disease

Patent metadata

Field	Value
Publication number	US-12012390-B2
Application number	US-201917275502-A
Country	US
Kind code	B2
Filing date	Sep 11, 2019
Priority date	Sep 14, 2018
Publication date	Jun 18, 2024
Grant date	Jun 18, 2024

Abstract

The present invention provides flavone derivatives having the general formula (I) which are useful for the treatment of Hepatitis B Virus infection (HBV). The compounds act as cccDNA (covalently closed circular DMA) inhibitors.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
W is O or S;
A 1 is CH or CR 4 ;
A 2 is CH or CR 4 ;
A 3 is CH or CR 4 ;
A 4 is N, CH or CR 4 ;
A 5 is N, CH or CR 4 ;
A 6 is CH;
A 7 is N or CH;
R 1 is halogen, C 1-6 alkyl or C 3-7 cycloalkyl;
R 2 is H, OH, halogen, C 1-6 alkoxy, haloC 1-6 alkoxy or phenylC 1-6 alkoxy;
R 3 is carboxy or C 1-6 alkoxycarbonyl;
R 4 is halogen, OH, CN, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, oxopyrrolidinyl, morpholinyl or haloC 1-6 alkyl;
G 1 is C 1-6 alkylenyl, hydroxyC 1-6 alkylenyl or C 3-7 cycloalkylC 1-6 alkylenyl; and
G 2 is C 1-6 alkylenyl, C 3-7 cycloalkylenyl or phenylene;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

2. A compound according to claim 1 , wherein:
R 1 is Cl, Br, methyl or cyclopropyl;
R 2 is H, OH, Cl, Br, methoxy, trifluoromethoxy or benzyloxy;
R 3 is carboxy, methoxycarbonyl or ethoxycarbonyl;
R 4 is F, Cl, Br, OH, CN, methyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, oxopyrrolidinyl, morpholinyl or trifluoromethyl;
G 1 is cyclobutylmethylene, ethylenyl, hydroxypropylenyl, isopropylenyl or propylenyl; and
G 2 is cyclobutylenyl, cyclohexylenyl, cyclopentylenyl, cyclopropylenyl, isopropylenyl, ethylenyl, methylene and phenylene;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

3. A compound according to claim 1 , wherein A 1 is CH.

4. A compound according to claim 1 , wherein A 4 is CH or CR 4 .

5. A compound according to claim 1 , wherein A 5 is CH or CR 4 .

6. A compound according to claim 1 , wherein A 7 is CH.

7. A compound according to claim 1 , wherein R 1 is halogen.

8. A compound according to claim 1 , wherein R 2 is H.

9. A compound according to claim 1 , wherein R 3 is carboxy.

10. A compound according to claim 1 , wherein R 4 is halogen, C 1-6 alkyl or C 1-6 alkoxy.

11. A compound according to claim 1 , wherein G 1 is C 1-6 alkylenyl.

12. A compound according to claim 1 , wherein G 2 is C 1-6 alkylenyl or C 3-7 cycloalkylenyl.

13. A compound according to claim 1 , wherein:
R 1 is halogen;
R 2 is H;
R 3 is carboxy;
R 4 is halogen, C 1-6 alkyl or C 1-6 alkoxy;
G 1 is C 1-6 alkylenyl; and
G 2 is C 1-6 alkylenyl or C 3-7 cycloalkylenyl.

14. A compound according to claim 13 , wherein:
R 4 is F, Cl, Br, methyl, ethoxy or methoxy;
G 1 is ethylenyl or isopropylenyl; and
G 2 is cyclobutylenyl or methylene.

15. A compound according to claim 1 , selected from:
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
ethyl 3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylate;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]benzoic acid;
ethyl 2-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclopropanecarboxylate;
cis-2-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclopropanecarboxylic acid;
trans-2-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclopropanecarboxylic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclopentanecarboxylic acid;
cis-4-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclohexanecarboxylic acid;
trans-4-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclohexanecarboxylic acid;
2-[3-[[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]methyl]cyclobutoxy]acetic acid;
2-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]acetic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]propanoic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]-2,2-dimethyl-propanoic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-1-methyl-ethoxy]cyclobutanecarboxylic acid;
3-[3-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]propoxy]cyclobutanecarboxylic acid;
3-[3-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2-hydroxy-propoxy]benzoic acid;
3-[2-[4-(8-chloro-7-fluoro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-7-methoxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-6-fluoro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(7,8-dichloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-6-cyano-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-7-cyano-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-chloro-5-methoxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-chloro-5-isopropoxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(5-bromo-8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(5,8-dichloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-chloro-5-cyclopropyl-4-oxo-chromen-2-yl)phenoxy]ethoxy]-cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-chloro-5-methyl-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-bromo-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-cyclopropyl-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-methyl-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
2-[2-[4-(8-chloro-5-fluoro-4-oxo-chromen-2-yl)phenoxy]ethoxy]acetic acid;
cis-3-[2-[[5-(8-chloro-4-oxo-chromen-2-yl)-2-pyridyl]oxy]ethoxy]cyclobutanecarboxylic acid;
trans-3-[2-[[5-(8-chloro-4-oxo-chromen-2-yl)-2-pyridyl]oxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[5-(8-chloro-4-oxo-chromen-2-yl)pyrazin-2-yl]oxyethoxy]cyclobutanecarboxylic acid;
cis-methyl 3-[2-[5-(8-chloro-4-oxo-chromen-2-yl)pyrazin-2-yl]oxyethoxy]-cyclobutanecarboxylate;
cis-methyl 3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)pyridazin-3-yl]oxyethoxy]-cyclobutanecarboxylate;
cis-3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)-2-fluoro-phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[2-chloro-4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[2-bromo-4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)-2-cyclopropyl-phenoxy]ethoxy]-cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)-2-cyano-phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)-2-methyl-phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)-2-isopropyl-phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)-3-methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)-3-ethoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(3,8-dichloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-chloro-3-hydroxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
cis-3-[2-[4-(8-chloro-3-methoxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
3-[2-[4-(8-chloro-4-oxo-thiochromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;
2-[2-[4-(8-chloro-4-oxo-thiochromen-2-yl)phenoxy]ethoxy]acetic acid;
2-[2-[4-(8-chloro-3-hydroxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]acetic acid;
3-[2-[4-(8-chloro-4-oxo-chromen-2-yl)-3-morpholino-phenoxy]ethoxy]cyclobutanecarboxylic acid;
2-[2-[4-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]acetamide;
methyl 3-[2-[4-[8-chloro-6-fluoro-4-oxo-3

Assignees

• Hoffmann La Roche

Inventors

• Feng Song
• Liang Chungen
• Liu Yongfu
• Shen Hong
• Tan Xuefei
• Wu Jun
• Chen Dongdong
• Li Chao
• Wang Li

Classifications

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D335/06

  Benzothiopyrans; Hydrogenated benzothiopyrans · CPC title

• A61P31/20 Primary

  for DNA viruses · CPC title

• C07D311/30 Primary

  not hydrogenated in the hetero ring, e.g. flavones · CPC title