Substituted aminothiazolopyrimidinediones for the treatment of virus infection

Patent metadata

Field	Value
Publication number	US-10975098-B2
Application number	US-202016816940-A
Country	US
Kind code	B2
Filing date	Mar 12, 2020
Priority date	Jun 30, 2015
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The present invention relates to compounds of formula (I),

wherein R 1 to R 4 are as described herein, and their prodrugs or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.

First claim

What is claimed is:

1. A method for the treatment of hepatitis B virus infection, which method comprises:
administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I),

wherein:
R 1 is H, C 1-6 alkyl, C 3-7 cycloalkyl or phenylC 1-6 alkyl, said phenylC 1-6 alkyl being unsubstituted or substituted with one to three substituents independently selected from C 1-6 alkyl and halogen;
R 2 is H or C 1-6 alkyl;
R 3 is C 1-6 alkyl; and
R 4 is C 1-6 alkyl;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

2. A method for the treatment of hepatitis B virus infection, which method comprises:
administering to a patient in need thereof a therapeutically effective amount of a compound of formula (Ia),

wherein:
R 1 is H, C 1-6 alkyl, C 3-7 cycloalkyl or phenylC 1-6 alkyl, said phenylC 1-6 alkyl being unsubstituted or substituted with one to three substituents independently selected from C 1-6 alkyl and halogen;
R 2 is H or C 1-6 alkyl;
R 3 is C 1-6 alkyl; and
R 4 is C 1-6 alkyl;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

3. A method according to claim 1 , wherein:
R 1 is H, methyl, propyl, cyclopropyl, benzyl, fluorobenzyl, chlorobenzyl, fluorochlorobenzyl or methylbenzyl;
R 2 is H or methyl;
R 3 is methyl; and
R 4 is ethyl;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

4. A method according to claim 1 , wherein R 1 is H, C 1-6 alkyl or phenylC 1-6 alkyl; or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

5. A method according to claim 1 , wherein R 1 is H, methyl or benzyl; or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

6. A method according to claim 1 , wherein R 2 is H; or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

7. A method according to claim 1 , wherein the compound is selected from:
5-amino-3-[(2R,3S,5S)-3-[(1S)-1-aminoethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-amino-3-[(2R,3S,5S)-3-[(1R)-1-aminoethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-amino-3-[(2R,3S,5S)-5-[(1S)-1-hydroxypropyl]-3-[(1R)-1-(methylamino)ethyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-amino-3-[(2R,3S,5S)-5-[(1S)-1-hydroxypropyl]-3-[(1R)-1-(propylamino)ethyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-amino-3-[(2R,3S,5S)-3-[(1R)-1-(cyclopropylamino)ethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-amino-3-[(2R,3S,5S)-3-[(1R)-1-(benzylamino)ethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-amino-3-[(2R,3S,5S)-5-[(1S)-1-hydroxypropyl]-3-[(1S)-1-(methyl amino)ethyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-amino-3-[(2R,3S,5S)-3-[(1S)-1-(benzylamino)ethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione; and
5-amino-3-[(2R,3S,5S)-3-[(1R)-1-(dimethylamino)ethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

8. The method of claim 1 , wherein the compound, or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof is administered in a pharmaceutical composition comprising a therapeutically inert carrier.

9. A method according to claim 2 , wherein:
R 1 is H, methyl, propyl, cyclopropyl, benzyl, fluorobenzyl, chlorobenzyl, fluorochlorobenzyl or methylbenzyl;
R 2 is H or methyl;
R 3 is methyl; and
R 4 is ethyl;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

10. A method according to claim 2 , wherein R 1 is H, C 1-6 alkyl or phenylC 1-6 alkyl; or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

11. A method according to claim 2 , wherein R 1 is H, methyl or benzyl; or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

12. A method according to claim 2 , wherein R 2 is H; or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

13. The method of claim 2 , wherein the compound, or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof is administered in a pharmaceutical composition comprising a therapeutically inert carrier.

Assignees

• Hoffmann La Roche

Inventors

• Wang Lisha
• Yun Hongying
• Zheng Xiufang

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07H19/24

  Heterocyclic radicals containing oxygen or sulfur as ring hetero atom · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title