Dihydropyrimidinylthiazole for the treatment and prophylaxis of hepatitis B virus infection

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;

methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(3R)-3-[[6-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)phenoxy]hexyl-methyl-amino]methyl]morpholin-4-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;

methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)phenoxy]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;

(2R)-4-[4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]piperazin-1-yl]-2-[6-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)phenoxy]hexylamino]butanoic acid; and

4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-1-[4-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-2-pyridyl]piperazine-2-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

11. A process for preparing a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, the process comprising any one of the following steps:

(a) hydrolysis of a compound of formula (VI), in the presence of a base;

(b) hydrolysis of a compound of formula (V-2),

(c) de-protection and substitution of a compound of formula (X-2), with bromide (V) in the presence of a base;

(d) hydrolysis of a compound of formula (XI-3), in the presence of a base;

(e) substitution of formula (X),

with bromide (V) in the presence of a base;

wherein:

bromide (V) is

PG is Boc; and

R 9 is C 1-6 alkyl.

12. A pharmaceutical composition comprising a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

13. A compound or a pharmaceutically acceptable salt thereof, when manufactured according to the process of claim 11 .

14. A method for the treatment or prophylaxis of HBV infection, which method comprises:

administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof to a subject in need thereof.

15. A pharmaceutical composition comprising a compound in accordance with claim 10 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

16. A method for the treatment or prophylaxis of HBV infection, which method comprises:

administering an effective amount of a compound of claim 10 , or a pharmaceutically acceptable salt thereof to a subject in need thereof.