2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid derivatives for the treatment and prophylaxis of hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-10093671-B2
Application number	US-201715674810-A
Country	US
Kind code	B2
Filing date	Aug 11, 2017
Priority date	Feb 11, 2015
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 , R 2 , R 3 , R 4 , R 5 and Ar are as described herein, 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 , R 2 , R 3 and R 4 are independently selected from C 1-6 alkyl, haloC 1-6 alkyl, hydrogen, halogen, cyano, amino, C 1-6 alkylamino, diC 1-6 alkylamino, pyrrolidinyl and OR 6 ;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is hydrogen; C 1-6 alkyl; haloC 1-6 alkyl; C 3-7 cycloalkylC 1-6 alkyl; phenylC 1-6 alkyl; hydroxyC 1-6 alkyl; C 1-6 alkoxyC 1-6 alkyl; carboxyC 1-6 alkyl; C 1-6 alkylsulfanylC 1-6 alkyl; C 1-6 alkylsulfonylC 1-6 alkyl; cyanoC 1-6 alkyl; aminoC 1-6 alkyl; C 1-6 alkylaminoC 1-6 alkyl; diC 1-6 alkylaminoC 1-6 alkyl; C 1-6 alkylcarbonylaminoC 1-6 alkyl; C 1-6 alkylsulfonylaminoC 1-6 alkyl; C 1-6 alkoxycarbonylaminoC 1-6 alkyl; pyrazolylC 1-6 alkyl; triazolylC 1-6 alkyl; or heterocycloalkylC 1-6 alkyl, wherein heterocycloalkyl is N-containing monocyclic heterocycloalkyl; and
Ar is phenyl; phenyl substituted by one, two or three groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen and phenylC 1-6 alkoxy; thienyl; thienyl substituted by one, two or three groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen and phenylC 1-6 alkoxy; benzothiophenyl; benzothiophenyl substituted by one, two or three groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen and phenylC 1-6 alkoxy; pyridinyl; pyridinyl substituted by one, two or three groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen and phenylC 1-6 alkoxy; pyrimidinyl; pyrimidinyl substituted by one, two or three groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen and phenylC 1-6 alkoxy; pyrrolyl; pyrrolyl substituted by one, two or three groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen and phenylC 1-6 alkoxy; pyrazolyl; pyrazolyl substituted by one, two or three groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen and phenylC 1-6 alkoxy; thiazolyl; or thiazolyl substituted by one, two or three groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen and phenylC 1-6 alkoxy;
or a pharmaceutically acceptable salt or enantiomer thereof.

2. A compound according to claim 1 , wherein
R 1 is hydrogen;
R 2 is hydrogen, halogen or C 1-6 alkoxy;
R 3 is C 1-6 alkyl, pyrrolidinyl or OR 6 ;
R 4 is C 1-6 alkyl or hydrogen;
R 5 is hydrogen;
R 6 is C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, phenylC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkylsulfanylC 1-6 alkyl, C 1-6 alkylsulfonylC 1-6 alkyl, cyanoC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, C 1-6 alkylsulfonylaminoC 1-6 alkyl, C 1-6 alkoxycarbonylaminoC 1-6 alkyl, pyrazolylC 1-6 alkyl, triazolylC 1-6 alkyl, piperidylC 1-6 alkyl, morpholinylC 1-6 alkyl or 2-oxopyrrolidinylC 1-6 alkyl; and
Ar is phenyl; phenyl substituted by C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen or phenylC 1-6 alkoxy; thienyl; thienyl substituted by C 1-6 alkyl; or benzothiophenyl;
or a pharmaceutically acceptable salt or enantiomer thereof.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt or enantiomer thereof, wherein R 1 is hydrogen, R 4 is hydrogen and R 5 is hydrogen.

4. A compound according to claim 1 , or a pharmaceutically acceptable salt or enantiomer thereof, wherein R 2 is C 1-6 alkoxy.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt or enantiomer thereof, wherein R 2 is methoxy.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt or enantiomer thereof, wherein R 3 is pyrrolidinyl or OR 6 , wherein R 6 is C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkylsulfanylC 1-6 alkyl, cyanoC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, C 1-6 alkylsulfonylaminoC 1-6 alkyl or C 1-6 alkoxycarbonylaminoC 1-6 alkyl.

7. A compound according to claim 1 , or a pharmaceutically acceptable salt or enantiomer thereof, wherein R 3 is OR 6 , wherein R 6 is methyl, isobutyl, trifluoroethyl, cyclopropylmethyl, cyanopropyl, hydroxypropyl, hydroxyhexyl, hydroxydimethylpropyl, methoxypropyl, carboxypropyl, methylsulfanylpropyl, aminohexyl, methylcarbonylaminohexyl, methylsulfonylaminohexyl or methoxycarbonylaminohexyl.

8. A compound according to claim 1 , or a pharmaceutically acceptable salt or enantiomer thereof, wherein Ar is phenyl; phenyl substituted by C 1-6 alkyl or halogen; thienyl; or thienyl substituted by C 1-6 alkyl.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt or enantiomer thereof, wherein Ar is phenyl; phenyl substituted by methyl, fluoro or chloro; thienyl; or thienyl substituted by methyl.

10. A compound according to claim 1 , wherein
R 1 is hydrogen;
R 2 is C 1-6 alkoxy;
R 3 is pyrrolidinyl or OR 6 ;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl or C 1-6 alkylsulfanylC 1-6 alkyl; and
Ar is phenyl substituted by C 1-6 alkyl; or thienyl;
or a pharmaceutically acceptable salt or enantiomer thereof.

11. A compound according to claim 1 , wherein
R 1 is hydrogen;
R 2 is methoxy;
R 3 is pyrrolidinyl or OR 6 ;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is isobutyl, trifluoroethyl, cyclopropylmethyl, hydroxydimethylpropyl, methoxypropyl or methylsulfanylpropyl; and
Ar is phenyl substituted by methyl; or thienyl;
or a pharmaceutically acceptable salt or enantiomer thereof.

12. A compound according to claim 1 , selected from
10-Methoxy-9-(3-methoxypropoxy)-2-oxo-6-phenyl-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-9-(3-methoxypropoxy)-2-oxo-6-(3-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-9-(3-methoxypropoxy)-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(4-Hydroxyphenyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(4-methoxyphenyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(4-Benzyloxyphenyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-9-(3-methoxypropoxy)-6-(4-methyl-2-thienyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(3-Chlorophenyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(4-Fluorophenyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-9-(3-methoxypropoxy)-6-(o-tolyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-Methoxy-8-methyl-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-Benzyloxy-10-methoxy-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9,10-Dimethoxy-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-Isobutoxy-10-methoxy-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(Cyclopropylmethoxy)-10-methoxy-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-2-oxo-9-(3-pyrazol-1-ylpropoxy)-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(3-Hydroxypropoxy)-10-methoxy-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-2-oxo-9-[3-(1-piperidyl)propoxy]-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(3-Cyanopropoxy)-10-methoxy-2-oxo-6-(2-thienyl)-6,7-dih

Assignees

• Hoffmann La Roche

Inventors

• Han Xingchun
• Jiang Min
• Yang Song

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P1/16

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