Dihydroquinolizinones for the treatment and prophylaxis of hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-9920049-B2
Application number	US-201615349343-A
Country	US
Kind code	B2
Filing date	Nov 11, 2016
Priority date	May 13, 2014
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as described in the description and in the claims, as well as or pharmaceutically acceptable salts, or enantiomers, or diastereomers 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
X is oxygen or N—R 7 ;
Y is CH 2 or C(O);
R 1 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;
R 2 is hydrogen; halogen; C 1-6 alkyl, which is unsubstituted or once or more times substituted by fluoro; or C 1-6 alkoxy;
R 3 is C 1-6 alkyl, which is unsubstituted or once or more times substituted by fluoro; cyano; morpholinyl; or R 8 —O—, wherein R 8 is C 1-6 alkyl, which is unsubstituted or substituted by one or more substituents each independently selected from fluoro, C 1-6 alkoxy, C 1-6 alkylsulfonyl, cyano, C 3-7 cycloalkyl, C 1-6 alkylamino, diC 1-6 alkylamino, hydroxy, phenyl, pyrrolidinyl and tetrahydropyranyl;
R 4 is hydrogen, halogen or C 1-6 alkyl;
R 5 is hydrogen; C 1-6 alkyl, which is unsubstituted or once or more times substituted by fluoro; C 1-6 alkoxy; C 3-7 cycloalkyl; or C 3-7 cycloalkyl-C x H 2x —;
R 6 is hydrogen; C 1-6 alkylsulfonyl; hydroxyl; 1H-tetrazol-5-yl; or C 1-6 alkyl, which is unsubstituted or substituted by one or more substituents each independently selected from fluoro, C 3-7 cycloalkyl, carboxyl-C x H 2x —, phenyl, hydroxy, C 1-6 alkoxy, amino, C 1-6 alkylamino and diC 1-6 alkylamino; and
R 7 is hydrogen or C 1-6 alkyl;
or R 6 and R 7 , together with the nitrogen to which they are attached, form pyrrolidinyl, piperidinyl, or morpholinyl, each of which is unsubstituted or once or two times substituted by carboxyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

2. A compound of formula I according to claim 1 , wherein
X is oxygen or N—R 7 ;
Y is CH 2 or C(O);
R 1 is hydrogen or halogen;
R 2 is hydrogen, halogen or C 1-6 alkoxy;
R 3 is R 8 —O—, wherein R 8 is C 1-6 alkyl, which is unsubstituted or substituted by one or two substituents each independently selected from C 1-6 alkoxy, C 3-7 cycloalkyl and phenyl;
R 4 is hydrogen;
R 5 is C 1-6 alkyl, which is unsubstituted or once or two times substituted by trifluoromethyl; or C 3-7 cycloalkyl;
R 6 is hydrogen; C 1-6 alkyl, which is unsubstituted or substituted by one or two substituents each independently selected from phenyl, hydroxy, C 1-6 alkoxy, carboxy, and diC 1-6 alkylamino; hydroxy; 1H-tetrazol-5-yl; or C 1-6 alkylsulfonyl; and
R 7 is hydrogen or C 1-6 alkyl;
or R 6 and R 7 , together with the nitrogen to which they are attached, form pyrrolidinyl, piperidinyl, or morpholinyl, each of which is unsubstituted or once or two times substituted by carboxyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

3. A compound of formula I according to claim 2 , wherein
X is oxygen or N—R 7 ;
Y is CH 2 or C(O);
R 1 is hydrogen or chloro;
R 2 is hydrogen, methoxy or chloro;
R 3 is R 8 —O—, wherein R 8 is methyl, ethyl, propyl or isobutyl, each of which is unsubstituted or substituted by one or two substituents each independently selected from methoxy, cyclopropyl and phenyl;
R 4 is hydrogen;
R 5 is ethyl, isopropyl, trifluoromethylmethyl, tert-butyl or cyclobutyl;
R 6 is hydrogen; methyl, ethyl, propyl, isopropyl or isobutyl, each of which is unsubstituted or substituted by one or two substituents each independently selected from phenyl, hydroxy, methoxy, carboxy, and dimethylamino; hydroxy; 1H-tetrazol-5-yl; or methylsulfonyl; and
R 7 is hydrogen or methyl;
or R 6 and R 7 , together with the nitrogen to which they are attached, form pyrrolidinyl, piperidinyl, or morpholinyl, each of which is unsubstituted or once or two times substituted by carboxyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

4. A compound of formula I according to claim 1 , wherein R 1 is hydrogen; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

5. A compound of formula I according to claim 1 , wherein R 2 is C 1-6 alkoxy or halogen; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

6. A compound of formula I according to claim 1 , wherein R 2 is methoxy or chloro; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

7. A compound of formula I according to claim 1 , wherein R 3 is R 8 —O—, wherein R 8 is C 1-6 alkyl, which is unsubstituted or substituted by one or two substituents each independently selected from C 1-6 alkoxy and phenyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

8. A compound of formula I according to claim 1 , wherein R 3 is R 8 —O—, wherein R 8 is methyl or propyl, each of which is unsubstituted or substituted by one or two substituents each independently selected from methoxy and phenyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

9. A compound of formula I according to claim 1 , wherein R 5 is C 1-6 alkyl, which is unsubstituted or once or two times substituted by fluoro; or C 3-7 cycloalkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

10. A compound of formula I according to claim 1 , wherein R 5 is ethyl or isopropyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

11. A compound of formula I according to claim 1 , wherein R 6 is hydrogen; methyl, ethyl, propyl, isopropyl or isobutyl, each of which is unsubstituted or substituted by one or two substituents each independently selected from phenyl, hydroxy, methoxy, carboxy, and dimethylamino; hydroxy; 1H-tetrazol-5-yl; or methylsulfonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

12. A compound of formula I according to claim 1 , wherein R 6 and R 7 , together with the nitrogen to which they are attached, form pyrrolidinyl, piperidinyl, morpholinyl, each of which is unsubstituted or once or two times substituted by carboxyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

13. A compound according to claim 1 , wherein
X is oxygen, NH or N(C 1-6 alkyl);
Y is CH 2 or C(O);
R 1 is hydrogen;
R 2 is C 1-6 alkoxy or halogen;
R 3 is R 8 —O—, wherein R 8 is C 1-6 alkyl, which is unsubstituted or once substituted by phenyl or C 1-6 alkoxy;
R 4 is hydrogen;
R 5 is C 1-6 alkyl or C 3-7 cycloalkyl;
R 6 is C 1-6 alkylsulfonyl; 1H-tetrazol-5-yl; or C 1-6 alkyl, which is unsubstituted or once substituted by C 1-6 alkoxy;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

14. A compound according to claim 1 , wherein
X is oxygen, NH or N(CH 3 );
Y is CH 2 or C(O);
R 1 is hydrogen;
R 2 is methoxy or chloro;
R 3 is R 8 —O—, wherein R 8 is methyl, ethyl, propyl or isobutyl, each of which is unsubstituted or once substituted by phenyl or methoxy;
R 4 is hydrogen;
R 5 is ethyl, isopropyl, tert-butyl or cyclobutyl; and
R 6 is methylsulfonyl; 1H-tetrazol-5-yl; methyl; or isopropyl, which is once substituted by methoxy;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

15. A compound of formula I according to claim 1 , selected from the group consisting of
N-benzyl-9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxamide;
9-benzyloxy-6-ethyl-10-methoxy-N-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxamide;
9-benzyloxy-6-ethyl-10-methoxy-N-(2-methoxy-1-methyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxamide;
9-benzyloxy-6-ethyl-10-methoxy-N-methylsulfonyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxamide;
9-benzyloxy-6-ethyl-10-methoxy-2-oxo-N-propyl-6,7-dihydrobenzo[a]quinolizine-3-carbox

Assignees

• Hoffmann La Roche

Inventors

• Yang Song
• Han Xingchun
• Wang Zhanguo

Classifications

• A61P31/20

  for DNA viruses · CPC title

• C07D455/06 Primary

  containing benzo [a] quinolizine ring systems · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title