Substituted aminothiazolopyrimidinedione for the treatment and prophylaxis of virus infection

Patent metadata

Field	Value
Publication number	US-10065973-B2
Application number	US-201715809109-A
Country	US
Kind code	B2
Filing date	Nov 10, 2017
Priority date	May 12, 2015
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

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

wherein R 1 to R 5 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

The invention claimed is:

1. A compound of formula (I),

wherein
R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, phenylC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl or phenylcarbonyl;
R 2 and R 3 are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl and pyridinyl, said phenyl and pyridinyl being unsubstituted or substituted with one to three substituents independently selected from C 1-6 alkyl, halogen and C 1-6 alkoxy;
R 4 is H or C 1-6 alkyl; and
R 5 is H or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

2. A compound of formula (Ia) according to claim 1 ,

wherein
R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, phenylC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl or phenylcarbonyl;
R 2 and R 3 are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl and pyridinyl, said phenyl and pyridinyl being unsubstituted or substituted with one to three substituents independently selected from C 1-6 alkyl, halogen and C 1-6 alkoxy;
R 4 is H or C 1-6 alkyl; and
R 5 is H or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

3. A compound according to claim 1 , wherein R 1 is H, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl or phenylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

4. A compound according to claim 1 , wherein R 1 is H, methyl, acetyl, ethoxycarbonyl or phenylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

5. A compound according to claim 1 , wherein R 2 and R 3 are independently selected from H, C 1-6 alkyl and phenyl, said phenyl being unsubstituted or substituted with one to three substituents independently selected from C 1-6 alkyl, halogen and C 1-6 alkoxy; provided that R 2 and R 3 are not H simultaneously; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

6. A compound according to claim 1 , wherein R 2 and R 3 are independently selected from H, methyl, ethyl, phenyl, chlorophenyl and methoxyphenyl; provided that R 2 and R 3 are not H simultaneously; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

7. A compound according to claim 1 , wherein
R 1 is H;
R 2 and R 3 are independently selected from H, C 1-6 alkyl and phenyl; provided that R 2 and R 3 are not H simultaneously;
R 4 is H or C 1-6 alkyl; and
R 5 is H or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

8. A compound according to claim 1 , wherein
R 1 is H;
R 2 and R 3 are independently selected from H, methyl and phenyl; provided that R 2 and R 3 are not H simultaneously;
R 4 is H or ethyl; and
R 5 is H or acetyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

9. A compound according to claim 1 selected from:
5-Amino-3-[(2R,3S,5S)-3-(1-hydroxyethyl)-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-3-[cyclopropyl(hydroxy)methyl]-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-5-(hydroxymethyl)-3-(1-hydroxypropyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-5-(hydroxymethyl)-3-[hydroxy(phenyl)methyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-3[hydroxy-(2-methoxyphenyl)methyl]-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-3-[(2-chlorophenyl)-hydroxy-methyl]-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R3S,5S)-5-(hydroxymethyl)-3-[(S)-hydroxy(2-pyridyl)methyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-5-(hydroxymethyl)-3-(1-hydroxy-1-methyl-ethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
[(1R)-1-[(2R,3S,5S)-2-(5-Amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-3-yl]ethyl]acetate;
[(1S)-1-[(2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-3-yl]ethyl]acetate;
5-Amino-3-[(2R,3S,5S)-3-[(1R)-1-hydroxyethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-3-[(1S)-1-hydroxyethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
[(1R)-1-[(2R,3S,5S)-2-(5-Amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-3-yl]ethyl]ethyl carbonate;
[(1R)-1-[(2R,3S,5S)-2-(5-Amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-3-yl]ethyl]benzoate;
5-Amino-3-[(2R,3S,5S)-5-[(1S)-1-hydroxypropyl]-3-[(1R)-1-methoxyethyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-3-[(1R)-1-benzyloxyethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
3-[(2R,3S,5S)-3-[(1R)-1-Allyloxyethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-5-amino-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-5-[(1S)-1-hydroxypropyl]-3-[(1S)-1-methoxyethyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
[(1S)-1-[(2S,4S,5R)-5-(5-Amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-[(1R)-1-hydroxyethyl]tetrahydrofuran-2-yl]propyl]acetate;
5-Amino-3-[(2R,3S,5S)-3-[hydroxy(phenyl)methyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
[1-[(2R,3S,5S)-2-(5-Amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-3-yl]-1-methyl-ethyl]acetate; and
5-Amino-3-[(2R,3S,5S)-3-(1-hydroxy-1-methyl-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.

10. A compound according to claim 1 selected from:
5-Amino-3-[(2R,3S,5S)-3-(1-hydroxyethyl)-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-5-(hydroxymethyl)-3-(1-hydroxy-1-methyl-ethyl)tetrahydrofuran-2 -yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
5-Amino-3-[(2R,3S,5S)-3-[(1R)-1-hydroxyethyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione;
[(1S)-1-[(2S,4S,5R)-5-(5-Amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-[(1R)-1-hydroxyethyl]tetrahydrofuran-2-yl]propyl]acetate;
5-Amino-3-[(2R,3S,5S)-3-[hydroxy(phenyl)methyl]-5-[(1S)-1-hydroxypropyl]tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione; and
5-Amino-3-[(2R,3S,5S)-3-(1-hydroxy-1-methyl-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.

11. A process for the preparation of a compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, comprising:
(a) the reaction of a compound of formula (IVh),

with a base, wherein
R a is C 1-6 alkylcarbonyl, phenylcarbonyl or trimethylsilyl;
R b is R 2 ;
R c is R 3 ;
R d is R 4 ; and
R e is OH;

(b) the reaction of a compound of formula (Vd),

Assignees

• Hoffmann La Roche

Inventors

• Wang Baoxia
• Wang Lisha
• Yun Hongying
• Zheng Xiufang

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• A61P31/20

  for DNA viruses · CPC title