6,7-dihydropyrido[2,1-A]phthalazin-2-ones for the treatment and prophylaxis of hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-10150740-B2
Application number	US-201815866429-A
Country	US
Kind code	B2
Filing date	Jan 9, 2018
Priority date	Jul 28, 2015
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 to R 6 are as described herein, compositions including the compounds and methods of using the compounds.

First claim

We claim:

1. A compound of formula I,

wherein
R 1 , R 2 , R 3 and R 4 are independently selected from C 1-6 alkyl, haloC 1-6 alkyl, hydrogen, halogen, amino, cyano, pyrrolidinyl, hydroxy, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-7 cycloalkylC 1-6 alkyloxy, phenylC 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, C 1-6 alkoxyC 1-6 alkyloxy, C 1-6 alkylsulfanylC 1-6 alkyloxy, C 1-6 alkylsulfonylC 1-6 alkyloxy, cyanoC 1-6 alkyloxy, aminoC 1-6 alkyloxy, C 1-6 alkylaminoC 1-6 alkyloxy, diC 1-6 alkylaminoC 1-6 alkyloxy, C 1-6 alkylcarbonylaminoC 1-6 alkyloxy, C 1-6 alkylsulfonylaminoC 1-6 alkyloxy, C 1-6 alkoxycarbonylaminoC 1-6 alkyloxy, pyrazolylC 1-6 alkyloxy, triazolylC 1-6 alkyloxy and monocyclic heterocycloalkylC 1-6 alkyloxy, wherein monocyclic heterocycloalkyl is N-containing monocyclic heterocycloalkyl;
R 5 and R 6 are independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl or C 2-6 alkenyl;

or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof.

2. The compound of formula I according to claim 1 , wherein
R 1 is hydrogen;
R 2 is C 1-6 alkoxy;
R 3 is C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyloxy, C 1-6 alkylsulfonylC 1-6 alkoxy, cyanoC 1-6 alkoxy, carboxyC 1-6 alkoxy, aminoC 1-6 alkoxy, C 1-6 alkoxycarbonylaminoC 1-6 alkoxy, morpholinylC 1-6 alkoxy or tetrahydropyranylC 1-6 alkoxy;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen, C 1-6 alkyl or C 2-6 alkenyl;

or a pharmaceutically acceptable salt, or an enantiomer, or diastereomer thereof.

3. A compound of formula I according to claim 2 , wherein
R 2 is methoxy;
R 3 methoxy, trifluoroethoxy, hydroxydimethylpropoxy, methoxypropoxy, methylsulfonylpropoxy, cyanopropoxy, carboxybutoxy, aminopentoxy, tert-butoxycarbonylaminopentoxy, morpholinylethoxy or tetrahydropyranylmethoxy;
R 6 is hydrogen, methyl, isopropyl, isobutyl or prop-2-enyl;

or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof.

4. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof, wherein R 2 is methoxy.

5. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof, wherein R 3 is haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyloxy, cyanoC 1-6 alkoxy, C 1-6 alkoxycarbonylaminoC 1-6 alkoxy or tetrahydropyranylC 1-6 alkoxy.

6. The compound of formula I according to claim 5 , or a pharmaceutically acceptable salt, or an enantiomers, or a diastereomer thereof, wherein R 3 is trifluoroethoxy, hydroxydimethylpropoxy, methoxypropoxy, cyanopropoxy, tert-butoxycarbonylaminopentoxy, or tetrahydropyranylmethoxy.

7. The compound of formula I according to claim 1 , or pharmaceutically acceptable salts, or enantiomers, or diastereomer thereof, wherein R 6 is C 1-6 alkyl.

8. The compound of formula I according to claim 7 , or a pharmaceutically acceptable salt, or an enantiomers, or a diastereomer thereof, wherein R 6 is isobutyl.

9. The compound according to claim 1 , which compound is selected from the group consisting of:
9,10-Dimethoxy-2-oxo-6,7-dihydropyrido[2,1-a]phthalazine-3-carboxylic acid;
9,10-Dimethoxy-6-methyl-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Allyl-9,10-dimethoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Isopropyl-9,10-dimethoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Isobutyl-9,10-dimethoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Isobutyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Isobutyl-10-methoxy-2-oxo-9-(2,2,2-trifluoroethoxy)-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Isobutyl-10-methoxy-2-oxo-9-(tetrahydropyran-4-ylmethoxy)-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Isobutyl-10-methoxy-9-(3-methylsulfonylpropoxy)-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Isobutyl-10-methoxy-9-(2-morpholinoethoxy)-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
9-(3-Hydroxy-2,2-dimethyl-propoxy)-6-isobutyl-10-methoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
9-(4-Carboxybutoxy)-6-isobutyl-10-methoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
9-(3-Cyanopropoxy)-6-isobutyl-10-methoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
9-[5-(Tert-butoxycarbonylamino)pentoxy]-6-isobutyl-10-methoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid; and,
9-(5-Aminopentoxy)-6-isobutyl-10-methoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid hydrochloride; or,

a pharmaceutically acceptable salt, or an enantiomers, or a diastereomer thereof.

10. The compound according to claim 9 , which compound is selected from the group consisting of:
6-Isobutyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
6-Isobutyl-10-methoxy-2-oxo-9-(tetrahydropyran-4-ylmethoxy)-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid;
9-(3-Hydroxy-2,2-dimethyl-propoxy)-6-isobutyl-10-methoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid; and,
9-[5-(Tert-butoxycarbonylamino)pentoxy]-6-isobutyl-10-methoxy-2-oxo-7H-pyrido[2,1-a]phthalazine-3-carboxylic acid; or,

a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof.

11. A process for the preparation of a compound according to claim 1 comprising hydrolysis of a compound of formula (A) to afford a compound of formula (I)

wherein R 11 is C 1-6 alkyl.

12. The process of according to claim 11 wherein R 3 is —C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-7 cycloalkylC 1-6 alkyloxy, phenylC 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, C 1-6 alkoxyC 1-6 alkyloxy, C 1-6 alkylsulfanylC 1-6 alkyloxy, C 1-6 alkylsulfonylC 1-6 alkyloxy, cyanoC 1-6 alkyloxy, aminoC 1-6 alkyloxy, C 1-6 alkylaminoC 1-6 alkyloxy, diC 1-6 alkylaminoC 1-6 alkyloxy, C 1-6 alkylcarbonylaminoC 1-6 alkyloxy, C 1-6 alkylsulfonylaminoC 1-6 alkyloxy, C 1-6 alkoxycarbonylaminoC 1-6 alkyloxy, pyrazolylC 1-6 alkyloxy, triazolylC 1-6 alkyloxy and monocyclic heterocycloalkylC 1-6 alkyloxy, wherein monocyclic heterocycloalkyl is N-containing monocyclic heterocycloalkyl.

13. A pharmaceutical composition comprising a compound in accord with claim 1 and at least one pharmaceutically acceptable carrier, diluent or excipient.

14. The method of inhibiting HBsAg production or secretionin a cell comprising treating the cell with a therapeutically effective amount of a compound according to claim 1 .

15. A method for the treatment or prophylaxis of HBV infection, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .

Assignees

• Hoffmann La Roche

Inventors

• Cheng Zhanling
• Han Xingchun
• Wang Yongguang
• Yang Song

Classifications

• A61P31/20

  for DNA viruses · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D237/26 Primary

  condensed with carbocyclic rings or ring systems · CPC title