Pyridazones and triazinones for treatment and prophylaxis of hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-9902701-B2
Application number	US-201715432706-A
Country	US
Kind code	B2
Filing date	Feb 14, 2017
Priority date	Aug 14, 2014
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 , R 2 , R 3 , X and a are as described in the description and in the claims, as well as or pharmaceutically acceptable salts thereof. The invention also contains compositions including the compounds and methods of using the compounds.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is phenyl; or phenyl substituted once or twice by C 1-6 alkyl, halogen, trifluoromethyl, or cyano;
R 2 is C 1-6 alkyl;
R 3 is phenyl; or phenyl substituted once or twice by C 1-6 alkyl, halogen, trifluoromethyl, cyano, C 1-6 alkoxy, trifluoromethoxy, —C(O)—C 1-6 alkoxy, or —C(O)—NR 4 R 5 , wherein one of R 4 and R 5 is hydrogen or C 1-6 alkyl, and the other one is C 1-6 alkyl or C 3-7 cycloalkyl;
a is a single bond; and
X is CH 2 or NH;
or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) according to claim 1 , wherein
R 1 is phenyl; or phenyl substituted once or twice by methyl, fluoro, chloro, bromo, trifluoromethyl, or cyano;
R 2 is methyl; and
R 3 is phenyl; or phenyl substituted once or twice by methyl, fluoro, chloro, trifluoromethyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, or —C(O)—NR 4 R 5 , wherein one of R 4 and R 5 is hydrogen, methyl, or isopropyl, and the other one is isopropyl, pentyl, or cyclohexyl;
or a pharmaceutically acceptable salt thereof.

3. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted once or twice by halogen, or trifluoromethyl.

4. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted once or twice by fluoro, chloro, or trifluoromethyl.

5. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl; or phenyl substituted once or twice by halogen or trifluoromethyl.

6. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl; or phenyl substituted once or twice by fluoro, chloro, or trifluoromethyl.

7. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH 2 .

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is phenyl substituted once or twice by halogen or trifluoromethyl;
R 2 is C 1-6 alkyl;
R 3 is phenyl; or phenyl substituted once or twice by halogen or trifluoromethyl; and
X is CH 2 ;
or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is phenyl substituted once or twice by fluoro, chloro, or trifluoromethyl;
R 2 is methyl;
R 3 is phenyl; or phenyl substituted once or twice by fluoro, chloro, or trifluoromethyl; and
X is CH 2 ;
or a pharmaceutically acceptable salt thereof.

10. A compound of formula (I) according to claim 1 , selected from the group consisting of
N-(4-Chlorophenyl)-2-[3-(4-chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N-methyl-acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methyl-acetamide;
N-(4-Chloro-3-fluoro-phenyl)-2-[3-(4-chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(3-methoxyphenyl)-N-methyl-acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(4-fluorophenyl)-N-methyl-acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-(p-tolyl)acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(3,4-dichlorophenyl)-N-methyl-acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(4-cyanophenyl)-N-methyl-acetamide;
Methyl 4-[[2-[3-(4-chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]acetyl]-methyl-amino]benzoate;
4-[[2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]acetyl]-methyl-amino]-N,N-diisopropyl-benzamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(2,4-difluorophenyl)-N-methyl-acetamide;
4-[[2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]acetyl]-methyl-amino]-N-methyl-N-pentyl-benzamide;
4-[[2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]acetyl]-methyl-amino]-N-cyclohexyl-benzamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethoxy)phenyl]acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(3-fluorophenyl)-N-methyl-acetamide;
N-(3-Chlorophenyl)-2-[3-(4-chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[3-(trifluoromethyl)phenyl]acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(4-methoxyphenyl)-N-methyl-acetamide;
2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-(m-tolyl)acetamide;
2-[3-(4-Chloro-3-fluoro-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(4-fluorophenyl)-N-methyl-acetamide;
2-[3-(4-Chloro-3-fluoro-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(3-fluorophenyl)-N-methyl-acetamide;
2-[3-(4-Chloro-3-fluoro-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(3-chlorophenyl)-N-methyl-acetamide;
2-[3-(4-Chloro-3-fluoro-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]acetamide;
2-[3-(4-Chloro-2-methyl-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(4-chlorophenyl)-N-methyl-acetamide;
2-[3-(4-Chloro-2-methyl-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(3-chlorophenyl)-N-methyl-acetamide;
2-[3-(4-Chloro-2-methyl-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(3-fluorophenyl)-N-methyl-acetamide;
2-[3-(4-Chloro-2-methyl-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[3-(trifluoromethyl)phenyl]acetamide;
2-[3-(2,4-Difluorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]acetamide;
2-[3-(2, 4-Difluorophenyl)-6-oxo-4, 5-dihydropyridazin-1-yl]-N-methyl-N-[3-(trifluoromethyl)phenyl]acetamide;
2-[3-(2,4-Difluorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N-methyl-acetamide;
N-(4-Chlorophenyl)-2-[3-(2,4-difluorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-acetamide;
2-[3-(2,4-Difluorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(3-fluorophenyl)-N-methyl-acetamide;
2-[3-(4-Fluoro-3-methyl-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[3-(trifluoromethyl)phenyl]acetamide;
2-[3-(4-Fluoro-3-methyl-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]acetamide;
2-[3-(4-Fluoro-3-methyl-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N-methyl-acetamide;
2-[3-(4-Fluoro-3-methyl-phenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methyl-acetamide;
N-(3-Chlorophenyl)-N-methyl-2-[6-oxo-3-[4-(trifluoromethyl)phenyl]-4,5-dihydropyridazin-1-yl]acetamide;
N-Methyl-2-[6-oxo-3-[4-(trifluoromethyl)phenyl]-4,5-dihydropyridazin-1-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;
N-Methyl-2-[6-oxo-3-[4-(trifluoromethyl)phenyl]-4,5-dihydropyridazin-1-yl]-N-[3-(trifluoromethyl)phenyl]acetamide;
N-(3-Fluorophenyl)-N-methyl-2-[6-oxo-3-[4-(trifluoromethyl)phenyl]-4,5-dihydropyridazin-1-yl]acetamide;
N-(4-Fluorophenyl)-N-methyl-2-[6-oxo-3-[4-(trifluoromethyl)phenyl]-4,5-dihydropyridazin-1-yl]acetamide;
N-(4-Chlorophenyl)-N-methyl-2-[6-oxo-3-[4-(trifluoromethyl)phenyl]-4,5-dihydropyridazin-1-yl]acetamide;
2-[3-(3,4-Dichlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]acetamide;
N-(4-Chlorophenyl)-2-[3-(3,4-dichlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-acetamide;
2-[3-(4-Fluorophenyl)-6

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Yang Song
• Liang Chungen
• Wang Jianping
• Pan Song

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P1/16

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

• C07D237/14 Primary

  Oxygen atoms · CPC title

• C07D253/07

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

• C07D253/06

  1,2,4-Triazines · CPC title