3-substituted 5-amino-6H-thiazolo[4,5-D]pyrimidine-2, 7-dione compounds for the treatment and prophylaxis of virus infection

Patent metadata

Field	Value
Publication number	US-10618929-B2
Application number	US-201816025170-A
Country	US
Kind code	B2
Filing date	Jul 2, 2018
Priority date	Dec 8, 2014
Publication date	Apr 14, 2020
Grant date	Apr 14, 2020

Abstract

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

wherein R 1 , R 2 and R 3 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

We claim:

1. A substantially diastereomerically pure compound of formula (Ia),

wherein:
R 1 is hydroxy or C 1-6 alkylcarbonyl-O—;
R 2 is C 1-6 alkyl; and
R 3 is hydrogen or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt thereof.

2. The substantially diastereomerically pure compound according to claim 1 , wherein:
R 1 is hydroxy or acetyloxy;
R 2 is ethyl or propyl; and
R 3 is hydrogen, acetyl or isobutyryl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

3. A compound that is 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-[(1R)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione, having the following structure:

or a pharmaceutically acceptable salt thereof.

4. A compound that is 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione, having the following structure:

or a pharmaceutically acceptable salt thereof.

5. A compound that is [(2R,3R,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1R)-1-hydroxypropyl]tetrahydrofuran-3-yl] acetate, having the following structure:

or a pharmaceutically acceptable salt thereof.

6. A compound that is [(2R,3R,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-3-yl] acetate, having the following structure:

or a pharmaceutically acceptable salt thereof.

7. A compound that is [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate, having the following structure:

or a pharmaceutically acceptable salt thereof.

8. A compound that is 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-[(1R)-1-hydroxybutyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione, having the following structure:

or a pharmaceutically acceptable salt thereof.

9. A compound that is 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-[(1S)-1-hydroxybutyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione, having the following structure:

or a pharmaceutically acceptable salt thereof.

10. A compound that is [(1 S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] 2-methylpropanoate, having the following structure:

or a pharmaceutically acceptable salt thereof.

11. A substantially diastereomerically pure compound of formula (IIa),

wherein:
R 4 is hydroxy or C 1-6 alkylcarbonyl-O—;
R 5 is C 1-6 alkyl or C 3-7 cycloalkyl; and
R 6 is hydrogen or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt thereof.

12. The substantially diastereomerically pure compound according to claim 11 , wherein:
R 4 is hydroxy or acetyloxy;
R 5 is ethyl or cyclopropyl; and
R 6 is hydrogen or acetyl;
or a pharmaceutically acceptable salt thereof.

13. A compound that is 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-[(1R)-1-hydroxypropyl]tetrahydrofuran-2-yl]thiazolo[4,5-d]pyrimidin-2-one, having the following structure:

or a pharmaceutically acceptable salt thereof.

14. A compound that is 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]thiazolo[4,5-d]pyrimidin-2-one, having the following structure:

or a pharmaceutically acceptable salt thereof.

15. A compound that is [(2R,3R,5S)-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1R)-1-hydroxypropyl]tetrahydrofuran-3-yl] acetate, having the following structure:

or a pharmaceutically acceptable salt thereof.

16. A compound that is [(2R,3R,5S)-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-3-yl] acetate, having the following structure:

or a pharmaceutically acceptable salt thereof.

17. A compound that is [(1R)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate, having the following structure:

or a pharmaceutically acceptable salt thereof.

18. A compound that is [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate, having the following structure:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

20. A method for treating a Hepatitis B virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof.

21. A method of activating the TLR7 receptor in a patient in need thereof comprising administering an effective amount of a compound according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof.

22. A method of stimulating production of interferon-α comprising administering to a patient in need thereof a therapeutically effective amount of a compound any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof.

Assignees

• Hoffmann La Roche

Inventors

• Chen Dongdong
• Feng Song
• Gao Lu
• Li Chao
• Wang Baoxia
• Wang Lisha
• Yun Hongying
• Zheng Xiufang

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07H19/24 Primary

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

• A61P31/12

  Antivirals · CPC title

• A61P1/16

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

• A61P31/20

  for DNA viruses · CPC title