NOVEL PYRIDAZONES AND TRIAZINONES FOR TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

• US 20170157133A1
• Filed: 02/14/2017
• Published: 06/08/2017
• Est. Priority Date: 08/14/2014
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Liang, Chungen, Pan, Song, Yang, Song, Wang, Jianping
• Granted Patent: US 9,902,701 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: C07D 237/04 having less than three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 237/14 Oxygen atoms
• CPC Class Codes: C07D 253/06 1,2,4-Triazines
• CPC Class Codes: C07D 253/07 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

Abstract

The invention provides novel compounds having the general formula:

wherein R¹, R², R³, 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.

Claims

1. A compound of formula (I)

2. A compound of formula (I) according to claim 1, wherein

R¹ is phenyl;

or phenyl substituted once or twice by methyl, fluoro, chloro, bromo, trifluoromethyl or cyano;

R² is methyl;

R³ is phenyl;

or phenyl substituted once or twice by methyl, fluoro, chloro, trifluoromethyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl or —

C(O)—

NR⁴R⁵, wherein

one of R⁴ and R⁵ is hydrogen, methyl or isopropyl, and the other one is isopropyl, pantanyl or cyclohexyl;

a is single bond when X is CH₂ or NH;

or pharmaceutically acceptable salts thereof.

3. A compound of formula (I) according to any one of claims 1 to 2, wherein R¹ is phenyl substituted once or twice by halogen or trifluoromethyl.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein R¹ is phenyl substituted once or twice by fluoro, chloro or trifluoromethyl.

5. A compound of formula (I) according to any one of claims 1 to 4, wherein R³ is phenyl, or phenyl substituted once or twice by halogen or trifluoromethyl.

6. A compound of formula (I) according to any one of claims 1 to 5, wherein R³ is phenyl, or phenyl substituted once or twice by fluoro, chloro or trifluoromethyl.

7. A compound of formula (I) according to any one of claims 1 to 6, wherein X is CH₂.

8. A compound according to claim 1 or 2, wherein

R¹ is phenyl substituted once or twice by halogen or trifluoromethyl;

R² is C_1-6alkyl;

R³ is phenyl, or phenyl substituted once or twice by halogen or trifluoromethyl;

a is single bond when X is CH₂;

or pharmaceutically acceptable salts thereof.

9. A compound according to any one of claims 1, 2 or 8, wherein

R¹ is phenyl substituted once or twice by fluoro, chloro or trifluoromethyl;

R² is methyl;

R³ is phenyl, or phenyl substituted once or twice by fluoro, chloro or trifluoromethyl;

a is single bond when X is CH₂;

or pharmaceutically acceptable salts 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-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-phenyl-acetamide;

N-(4-Chlorophenyl)-2-[3-(4-fluorophenyl)-6-oxo-4, 5-dihydropyridazin-1-yl]-N-methyl-acetamide;

2-[3-(4-Bromophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-phenyl-acetamide;

2-[3-(4-Bromophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-(4-chlorophenyl)-N-methyl-acetamide;

2-[3-(4-Bromophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]acetamide;

2-[3-(3, 4-Difluorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[3-(trifluoromethyl)phenyl]acetamide;

2-[3-(3,4-Difluorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]acetamide;

N-(4-Chlorophenyl)-2-[3-(2,4-dichlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-acetamide;

N-(4-Chlorophenyl)-2-[3-(4-cyanophenyl)-6-oxo-4, 5-di hydropyridazin-1-yl]-N-methyl-acetamide;

N-(4-Chlorophenyl)-N-methyl-2-[6-oxo-3-(p-tolyl)-4, 5-dihydropyridazin-1-yl]acetamide;

N-(4-Chlorophenyl)-2-[3-(3-chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-acetamide; and

2-[6-(4-Chlorophenyl)-3-oxo-4,5-dihydro-1,2,4-triazin-2-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]acetamide;

and pharmaceutically acceptable salts thereof.

11. A compound of formula (I) according to claim 1, selected from the group consisting of

2-[3-(4-Chlorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methyl-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-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-(2,4-Difluorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[4-(trifluoromethyl)phenyl]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-[3-(trifluoromethyl)phenyl]acetamide;

N-(3-Fluorophenyl)-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; and

2-[3-(3,4-Difluorophenyl)-6-oxo-4,5-dihydropyridazin-1-yl]-N-methyl-N-[3-(trifluoromethyl)phenyl]acetamide;

and pharmaceutically acceptable salts thereof.

12. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 11 comprising one of the following steps:

(a) the reaction of a compound of formula (A)

13. A compound according to any one of claims 1 to 11 for use as therapeutically active substance.

14. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 11 and a therapeutically inert carrier.

15. The use of a compound according to any one of claims 1 to 11 for the treatment or prophylaxis of HBV infection.

16. The use of a compound according to any one of claims 1 to 11 for the preparation of a medicament for the treatment or prophylaxis of HBV infection.

17. The use of a compound according to any one of claims 1 to 11 for the inhibition of HBsAg production or secretion.

18. A compound according to any one of claims 1 to 11 for the treatment or prophylaxis of HBV infection.

19. A compound according to any one of claims 1 to 11, when manufactured according to a process of claim 12.

20. A method for the treatment or prophylaxis of HBV infection, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 11.

21. The invention as hereinbefore described.