Tetracyclic 4-oxo-pyridine-3-carboxylic acid derivatives for the treatment and prophylaxis of hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-10053461-B2
Application number	US-201815867010-A
Country	US
Kind code	B2
Filing date	Jan 10, 2018
Priority date	Jul 27, 2015
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 to R 6 , V, W, X and Y 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 hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen, cyano, amino, C 1-6 alkylamino, diC 1-6 alkylamino, pyrrolidinyl and OR 7 ;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is hydrogen or C 1-6 alkyl;
R 7 is hydrogen; C 1-6 alkyl; haloC 1-6 alkyl; C 3-7 cycloalkylC 1-6 alkyl; phenylC 1-6 alkyl; cyanoC 1-6 alkyl; hydroxyC 1-6 alkyl; C 1-6 alkoxyC 1-6 alkyl; carboxyC 1-6 alkyl; C 1-6 alkoxycarbonylC 1-6 alkyl; C 1-6 alkylsulfanylC 1-6 alkyl; C 1-6 alkylsulfonylC 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; or heterocycloalkylC 1-6 alkyl, wherein heterocycloalkyl is N-containing monocyclic heterocycloalkyl;
One of V, W, X and Y is selected from CR 8 R 9 , O, S, SO 2 and NR 10 , the others of V, W, X and Y are independently selected from a bond and CR 8 R 9 , wherein
R 8 is hydrogen or C 1-6 alkyl;
R 9 is hydrogen or C 1-6 alkyl;
R 10 is phenylC 1-6 alkoxycarbonyl, phenylC 1-6 alkylcarbonyl, phenylC 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, or C 1-6 alkylsulfonyl;

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 halogen or C 1-6 alkoxy;
R 3 is selected from C 1-6 alkyl, pyrrolidinyl or OR 7 , wherein
R 7 is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, phenylC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkoxycarbonylC 1-6 alkyl, C 1-6 alkylsulfanylC 1-6 alkyl, C 1-6 alkylsulfonylC 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, morpholinylC 1-6 alkyl, pyrrolidinylC 1-6 alkyl or (2-oxo-pyrrolidinyl)C 1-6 alkyl;
R 4 is hydrogen;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is hydrogen or C 1-6 alkyl;
V and Y are CH 2 ;
X is selected from a bond, CH 2 , O, S, SO 2 and phenylC 1-6 alkoxycarbonylamino when W is a bond; or
X is CH 2 when W is CH 2 ;
or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof.

3. The compound of formula I according to claim 2 , wherein
R 1 is hydrogen;
R 2 is chloro or methoxy;
R 3 is selected from methyl, ethyl, propyl, pyrrolidinyl, hydroxy, methoxy, difluoroethoxy, trifluoroethoxy, cyclopropylmethoxy, benzyloxy, cyanopropoxy, hydroxypropoxy, hydroxyhexyloxy, hydroxydimethylpropoxy, methoxyethoxy, methoxypropoxy, carboxypropoxy, ethoxycarbonylpropoxy, methylsulfanylpropoxy, methylsulfonylpropoxy, aminohexyloxy, methylcarbonylaminohexyloxy, methylsulfonylaminohexyloxy, tert-butoxycarbonylaminohexyloxy, morpholinylpropoxy, pyrrolidinylpropoxy and (2-oxo-pyrrolidinyl)propoxy;
R 4 is hydrogen;
R 5 is hydrogen or methyl;
R 6 is hydrogen or methyl;
V and Y are CH 2 ;
X is selected from a bond, CH 2 , O, S, SO 2 and phenylmethoxycarbonylamino when W is a bond; or
X is CH 2 when W is CH 2 ;
or or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof.

4. The compound of formula I according to claim 1 , wherein
R 1 is hydrogen;
R 2 is C 1-6 alkoxy;
R 3 is selected from C 1-6 alkyl, pyrrolidinyl or OR 7 , wherein R 7 is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, phenylC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, carboxyC 1-6 alkyl, C 1-6 alkoxycarbonylC 1-6 alkyl, C 1-6 alkylsulfanylC 1-6 alkyl, C 1-6 alkylsulfonylC 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, morpholinylC 1-6 alkyl, pyrrolidinylC 1-6 alkyl or (2-oxo-pyrrolidinyl)C 1-6 alkyl;
R 4 is hydrogen;
R 5 is C 1-6 alkyl;
R 6 is C 1-6 alkyl;
V and Y are CH 2 ;
W is a bond;
X is a bond;
or or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof.

5. 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.

6. The compound of formula I according to claim 1 , or or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof, wherein R 3 is OR 7 , wherein R 7 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, C 1-6 alkylsulfanylC 1-6 alkyl, C 1-6 alkylsulfonylC 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 or morpholinylC 1-6 alkyl.

7. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer, wherein R 3 is selected from methoxy, difluoroethoxy, trifluoroethoxy, cyclopropylmethoxy, hydroxypropoxy, hydroxyhexyloxy, hydroxydimethylpropoxy, methoxyethoxy, methoxypropoxy, methylsulfanylpropoxy, methylsulfonylpropoxy, aminohexyloxy, methylcarbonylaminohexyloxy, methylsulfonylaminohexyloxy, tert-butoxycarbonylaminohexyloxy or morpholinylpropoxy.

8. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof, wherein R 5 is methyl and R 6 is methyl.

9. The compound of formula I according to claim 1 , wherein
R 1 is hydrogen;
R 2 is halogen or C 1-6 alkoxy;
R 3 is OR 7 ; wherein R 7 is phenylC 1-6 alkyl or C 1-6 alkoxyC 1-6 alkyl;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen;
V and Y are CH 2 ;
X is selected from CH 2 , O, S, SO 2 and phenylC 1-6 alkoxycarbonylamino when W is a bond; or
X is CH 2 when W is CH 2 ;
or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof.

10. The compound according to claim 1 , or or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof, wherein R 2 is chloro or methoxy.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof, wherein R 3 is benzyloxy or methoxypropoxy.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof, wherein X is CH 2 or S when W is a bond, or X is CH 2 when W is CH 2 .

13. The compound according to claim 2 , wherein
R 1 is hydrogen;
R 2 is halogen or C 1-6 alkoxy;
R 3 is selected from C 1-6 alkyl, pyrrolidinyl or OR 7 , wherein R 7 is haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylsulfonylC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, C 1-6 alkylsulfonylaminoC 1-6 alkyl or morpholinylC 1-6 alkyl;
R 4 is hydrogen;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is hydrogen or C 1-6 alkyl;
V and Y are CH 2 ;
X is a bond or S when W is a bond, or
X is CH 2 when W is CH 2 ;
or a pharmaceutically acceptable salt, or an enantiomer, or a diastereomer thereof.

14. The compound according to claim 13 , wherein
R 1 is hydrogen;
R 2 is chloro or methoxy;
R 3 is selected from ethyl, pyrrolidinyl, difluoroethoxy, trifluoroethoxy, hydroxydimethylpropoxy, methoxypropoxy, methylsulfonylpropoxy, methylcarbonylaminohexyloxy, methylsulfonylaminohexyloxy and morpholinylpropoxy;
R 4 is hydrogen;
R 5 is hydrogen or methyl;
R 6 is hydrogen or methyl;

Assignees

• Hoffmann La Roche

Inventors

• Han Xingchun
• Jiang Min
• Wang Yongguang
• Yang Song

Classifications

• C07D495/14

  Ortho-condensed systems · CPC title

• A61P31/20

  for DNA viruses · CPC title

• C07D471/14 Primary

  Ortho-condensed systems · CPC title

• C07D455/06

  containing benzo [a] quinolizine ring systems · CPC title

• C07D491/147

  the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom · CPC title