Dihydropyrimidinylthiazole for the treatment and prophylaxis of hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-11447489-B2
Application number	US-201816958658-A
Country	US
Kind code	B2
Filing date	Dec 21, 2018
Priority date	Dec 28, 2017
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

The present invention provides novel compounds having the general formula: wherein R1, R2, X, Y and A 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 phenyl, which is unsubstituted or substituted one, two or three times by halogen or C 1-6 alkyl;
R 2 is C 1-6 alkyl;
X is —(Cy) 0-1 -(L 1 ) 0-1 -(L 2 ) 0-1 -; wherein:
Cy is 3-20 membered heterocyclyl;
L 1 is C 1-6 alkyl or carboxyC 1-6 alkyl; and
L 2 is O, S, —N(R 3 )— or —C(O)—NH—, wherein R 3 is H or C 1-6 alkyl;

Y is a bond, C 1-9 alkyl, C 1-6 alkoxyC 1-6 alkoxyC 1-6 alkyl or carboxyC 1-9 alkyl; and
A is formula (A1)

wherein:
R 4 is hydrogen or C 1-6 alkyl; and
R 5 is hydrogen or C 1-6 alkoxy;

or A is formula (A2)

wherein:
R 6 is hydrogen or halogen;
R 7 is hydrogen or halogen;
R 8 is hydrogen or C 1-6 alkyl;
U is a bond or O; and
W is CH or N;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein:
R 1 is phenyl, which is one or two or three times substituted by halogen;
X is —(Cy) 0-1 -(L 1 ) 0-1 -(L 2 ) 0-1 -, wherein:
Cy is 5-6 membered monocyclic heterocyclyl or 9-10 membered fused bicyclic heterocyclyl;

A is formula (A1), wherein R 4 is C 1-6 alkyl, or R 5 is C 1-6 alkoxy;
or A is formula (A2), wherein R 7 is halogen, and R 8 is C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 , wherein:
R 1 is chlorofluorophenyl;
R 2 is methyl or ethyl;
X is a bond; O; —N(CH 3 )—; piperazinyl; carboxypiperazinyl; (aminocarboxy) propylpiperazinyl; (methylamino)methylmorpholinyl; (aminocarbonyl)morpholinyl; 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazinyl or (aminocarbonyl)propyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazinyl;
Y is a bond, hexyl, pentyl, butyl, propyl, (ethoxyethoxy)ethyl or carboxyhexyl; and
A is:
formula (A1), wherein R 4 is tert-butyl, R 5 is methoxy;
or
formula (A2), wherein R 6 is hydrogen or fluoro, R 7 is fluoro, R 8 is methyl, U is a bond or O, and W is CH or N;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, which is two times substituted by halogen.

5. A compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chlorofluorophenyl.

6. A compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein X is —(Cy) 1 -(L 1 ) 0-1 -(L 2 ) 0-1 -, wherein Cy is piperazinyl, carboxypiperazinyl, morpholinyl or 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazinyl.

7. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein X is piperazinyl, carboxypiperazinyl, or (aminocarbonyl)propyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazinyl.

8. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein Y is a bond, C 1-9 alkyl or C 1-6 alkoxyC 1-6 alkoxyC 1-6 alkyl.

9. A compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein Y is a bond, hexyl, propyl, or (ethoxyethoxy)ethyl.

10. A compound according to claim 1 , selected from:
6-tert-butyl-9-[6-[4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]hexoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[5-[4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]pentoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[4-[4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]butoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[3-[4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]propoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[3-[2-carboxy-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]propoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[6-[3-carboxy-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]hexoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[6-[2-carboxy-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]hexoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[6-[7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]hexoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[6-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl-methyl-amino]hexoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[2-[2-[2-[[(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carbonyl]amino]ethoxy]ethoxy]ethoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[2-[2-[2-[2-carboxy-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[4-carboxy-6-[4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]hexoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[6-[[(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carbonyl]amino]hexoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-tert-butyl-9-[6-[[4-(2-chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methoxy]hexoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-[6-[[3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoyl]amino]hexoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-[6-[[4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3,3-dimethyl-butanoyl]amino]hexoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
methyl (4R)-6-[[(8aS)-2-[4-[6-[2,3-difluoro-5-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]phenoxy]hexylamino]-2,2-dimethyl-4-oxo-butyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;
methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(3S)-3-[6-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)phenoxy]hexylcarbamoyl]morpholin-4-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• A61P31/20

  for DNA viruses · CPC title

• C07D455/06 Primary

  containing benzo [a] quinolizine ring systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title