Xanthone derivatives for the treatment of hepatitis B virus disease

Patent metadata

Field	Value
Publication number	US-10611748-B2
Application number	US-201816199534-A
Country	US
Kind code	B2
Filing date	Nov 26, 2018
Priority date	May 26, 2016
Publication date	Apr 7, 2020
Grant date	Apr 7, 2020

Abstract

The present invention provides novel compounds having the general formula:

wherein R 1 to R 6 , X, Y, A 1 and A 2 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 is halogen or haloC 1-6 alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen, halogen, C 1-6 alkyl, halo 1-6 alkyl, cyano or hydroxy;
R 4 is hydrogen;
R 5 and R 6 together with nitrogen to which they are attached form pyrrolidinyl, oxopyrrolidinyl, azepanyl, diazepanyl, piperidinyl, hydroxypiperidinyl, carboxypiperidinyl, C 1-6 alkylpiperazinyl, morpholinyl, 2,6-diazaspiro[3.4]octan-6-yl or 2,7-diazaspiro[4.4]nonan-2-yl, wherein pyrrolidinyl is unsubstituted or substituted with one, two or three substituents independently selected from: C 1-6 alkyl, C 1-6 alkoxy, hydroxy, carboxy, carboxyC 1-6 alkyl, hydroxyC 1-6 alky, amino, C 1-6 alkoxycarbonyl, halophenyl, pyridinyl, (diC 1-6 alkylamino)carbonyl and morpholinylcarbonyl;
X is —C(═O)— or —C(R 9 )(R 10 )—, wherein
R 9 and R 10 are independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, hydroxy, oxetanyl and halophenyl-CH(—O-carbonylC 1-6 alkyl)-; or
R 9 and R 10 together with carbon to which they are attached form

A 1 is N or CR 7 , wherein R 7 is hydrogen, halogen or C 1-6 alkyl;
A 2 is N or CR 8 , wherein R 8 is hydrogen or halogen; and
Y is O or S;
with the proviso that 1-[5-fluoro-9-(oxetan-3-yl)-9H-xanthen-3-yl]pyrrolidine is excluded;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

2. A compound according to claim 1 , wherein:
R 1 is halogen or haloC 1-6 alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen, halogen, C 1-6 alkyl, haloC 1-6 alkyl, cyano or hydroxy;
R 4 is hydrogen;
R 5 and R 6 together with nitrogen to which they are attached form pyrrolidinyl, oxopyrrolidinyl, azepanyl, diazepanyl, piperidinyl, hydroxypiperidinyl, carboxypiperidinyl, C 1-6 alkylpiperazinyl, morpholinyl, 2,6-diazaspiro[3.4]octan-6-yl or 2,7-diazaspiro[4.4]nonan-2-yl, wherein pyrrolidinyl is unsubstituted or substituted with one, two or three substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, carboxy, haloC 1-6 alkyl, carboxyC 1-6 alkyl, hydroxyC 1-6 alky, amino, C 1-6 alkoxycarbonyl, halophenyl, pyridinyl, (diC 1-6 alkylamino)carbonyl and morpholinylcarbonyl;
X is —C(═O)—;
A 1 is N or CR 7 , wherein R 7 is hydrogen, halogen or C 1-6 alkyl;
A 2 is N or CH; and
Y is O;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

3. A compound according to claim 2 , wherein:
R 1 is halogen or haloC 1-6 alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen, halogen, C 1-6 alkyl, haloC 1-6 alkyl, cyano or hydroxy;
R 4 is hydrogen;
R 5 and R 6 together with nitrogen to which they are attached form pyrrolidinyl unsubstituted or substituted with one, two or three substituents independently selected from: C 1-6 alkyl, C 1-6 alkoxy, hydroxy, carboxy, haloC 1-6 alkyl, carboxyC 1-6 alkyl, hydroxyC 1-6 alky, amino, C 1-6 alkoxycarbonyl, halophenyl, pyridinyl, (diC 1-6 alkylamino)carbonyl and morpholinylcarbonyl;
X is —C(═O)—;
A 1 is N or CR 7 , wherein R 7 is hydrogen, halogen or C 1-6 alkyl;
A 2 is N or CH; and
Y is O;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

4. A compound according to claim 3 , wherein:
R 1 is halogen or haloC 1-6 alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen, halogen, C 1-6 alkyl, cyano or hydroxy;
R 4 is hydrogen;
R 5 and R 6 together with nitrogen to which they are attached form pyrrolidinyl, hydroxypyrrolidinyl, C 1-6 alkoxypyrrolidinyl, carboxypyrrolidinyl or C 1-6 alkoxycarbonylpyrrolidinyl;
X is —C(═O)—;
A 1 is CR 7 , wherein R 7 is hydrogen, halogen or C 1-6 alkyl;
A 2 is CH; and
Y is O;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

5. A compound according to claim 4 , wherein:
R 1 is fluoro, chloro, bromo or trifluoromethyl;
R 2 is hydrogen, fluoro or chloro;
R 3 is hydrogen, fluoro, chloro, methyl, trifluoromethyl, cyano or hydroxy;
R 4 is hydrogen;
R 5 and R 6 together with nitrogen to which they are attached form pyrrolidinyl, hydroxypyrrolidinyl, methoxyprrolidinyl, carboxypyrrolidinyl or methoxycarbonylpyrrolidinyl;
X is —C(═O)—;
A 1 is CR 7 , wherein R 7 is hydrogen, fluoro, chloro or methyl;
A 2 is CH; and
Y is O;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

6. A compound according to claim 4 , or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein R 1 is fluoro or chloro.

7. A compound according to claim 4 , or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein, R 2 is hydrogen.

8. A compound according to claim 4 , or pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein, R 3 is hydrogen, fluoro, chloro or trifluoromethyl.

9. A compound according to claim 4 , or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein, R 5 and R 6 together with nitrogen to which they are attached form pyrrolidinyl or carboxypyrrolidinyl.

10. A compound according to claim 4 , or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein, A 1 is CH.

11. A compound according to claim 4 , wherein:
R 1 is halogen;
R 2 is hydrogen;
R 3 is hydrogen, halogen or haloC 1-6 alkyl;
R 4 is hydrogen;
R 5 and R 6 together with nitrogen to which they are attached form pyrrolidinyl or carboxypyrrolidinyl;
X is-C(═O)—;
A 1 is CH;
A 2 is CH; and
Y is O;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

12. A compound according to claim 11 , wherein:
R 1 is fluoro or chloro;
R 2 is hydrogen;
R 3 is hydrogen, fluoro, chloro or trifluoromethyl;
R 4 is hydrogen;
R 5 and R 6 together with nitrogen to which they are attached form pyrrolidinyl or carboxypyrrolidinyl;
X is-C(═O)—;
A 1 is CH;
A 2 is CH; and
Y is O;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

13. A compound according to claim 4 , selected from:
5-chloro-3-pyrrolidin-1-yl-xanthen-9-one;
1-(5-chloro-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylic acid;
(3R)-1-(5-chloro-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylic acid;
(3S)-1-(5-chloro-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylic acid;
1-(5-fluoro-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylic acid;
1-(5-bromo-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylic acid;
methyl 1-(5-chloro-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylate;
5-fluoro-3-pyrrolidin-1-yl-xanthen-9-one;
1-chloro-4-fluoro-6-pyrrolidin-1-yl-xanthen-9-one;
5-fluoro-3-(3-hydroxypyrrolidin-1-yl)xanthen-9-one;
5-fluoro-2-methyl-3-pyrrolidin-1-yl-xanthen-9-one;
1-(5,8-dichloro-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylic acid;
5-chloro-3-[(3S)-3-hydroxypyrrolidin-1-yl]xanthen-9-one;
2,5-difluoro-3-pyrrolidin-1-yl-xanthen-9-one;
5-chloro-3-[(3R)-3-hydroxypyrrolidin-1-yl]xanthen-9-one;
5-fluoro-3-[(3S)-3-hydroxypyrrolidin-1-yl]xanthen-9-one;
5-fluoro-3-[(3R)-3-hydroxypyrrolidin-1-yl]xanthen-9-one;
5-fluoro-3-(3-methoxypyrrolidin-1-yl)xanthen-9-one;
2-chloro-4-fluoro-6-pyrrolidin-1-yl-xanthen-9-one;
1-(5-chloro-9-oxo-xanthen-3-yl)pyrrolidine-2-carboxylic acid;
1-[9-oxo-5-(trifluoromethyl)xanthen-3-yl]pyrrolidine-3-carboxylic acid;
1-(5-chloro-2-methyl-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylic acid;
1-(5-chloro-8

Assignees

• Hoffmann La Roche

Inventors

• Chen Dongdong
• Chen Wenming
• Feng Song
• Gao Lu
• Shen Hong
• Tan Xuefei
• Wang Li

Classifications

• C07D493/10

  Spiro-condensed systems · CPC title

• C07D311/86 Primary

  Oxygen atoms, e.g. xanthones · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D407/04

  directly linked by a ring-member-to-ring-member bond · CPC title