NOVEL 6-AMINO ACID HETEROARYLDIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

• US 20160237078A9
• Filed: 09/10/2013
• Published: 08/18/2016
• Est. Priority Date: 09/10/2012
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Guo, Lei, Hu, Taishan, Hu, Yimin, Kocer, Buelent, Lin, Xianfeng, Liu, Haixia, Mayweg, Alexander V, Qiu, Zongxing, Shen, Hong, Tang, Guozhi, Wang, Lisha, Wu, Guolong, Yan, Shixiang, Zhang, Weixing, Zhou, Mingwei, Zhu, Wei
• Granted Patent: US 9,447,086 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The invention provides novel compounds having the general formula:

wherein R¹, R², R³, R⁴ and A are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. A compound of formula (I)

2. A compound according to claim 1, wherein

R¹ is methyl, ethyl, propyl, isopropyl, tert-butyl or trifluoromethylmethyl;

One of R² and R³ is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo, methyl or cyano; and

the other one is hydrogen or deuterium;

R⁴ is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, tert-butyl, bifluoromethyl, trifluoromethyl, cyclopropyl, methylsulfanyl, fluoro or chloro;

A is

3. A compound according to claim 1, wherein

R¹ is C_1-6alkyl or trifluoromethyl-C_xH_2x—

, wherein x is 1-6;

One of R² and R³ is phenyl, which is once or twice or three times substituted by C_1-6alkyl, cyano or halogen; and

the other one is hydrogen or deuterium;

R⁴ is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by C_1-6alkyl, C_1-6alkylsulfanyl, halogen or cycloalkyl, where said C_1-6alkyl can be further optionally substituted with halogen;

A is

4. A compound according to claim 1, wherein

R¹ is methyl, ethyl, propyl, isopropyl or trifluoromethylmethyl;

One of R² and R³ is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo, methyl or cyano; and

the other one is hydrogen or deuterium;

R⁴ is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl, methylsulfanyl, fluoro or chloro;

A is

5. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is C_1-6alkyl or trifluoromethyl-C_xH_2x—

, wherein x is 1-6;

One of R² and R³ is phenyl, which is once or twice or three times substituted by halogen; and

the other one is hydrogen or deuterium;

R⁴ is

6. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is methyl, ethyl, propyl, isopropyl or trifluoromethylmethyl;

One of R² and R³ is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo or iodo; and

the other one is hydrogen or deuterium;

R⁴ is

7. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is C_1-6alkyl;

One of R² and R³ is phenyl, which is once or twice or three times substituted by halogen; and

the other one is hydrogen;

R⁴ is

8. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is methyl or ethyl;

One of R² and R³ is phenyl, which is once or twice or three times substituted by fluoro, chloro or bromo; and

the other one is hydrogen;

R⁴ is

9. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is methyl or ethyl;

One of R² and R³ is

10. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is C_1-6alkyl;

One of R² and R³ is

11. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is C_1-6alkyl;

One of R² and R³ is phenyl, which is substituted by halogen; and

the other one is hydrogen;

R⁴ is

12. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is methyl or ethyl;

One of R² and R³ is phenyl, which is substituted by fluoro or chloro; and

the other one is hydrogen;

R⁴ is

13. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is C_1-6alkyl;

One of R² and R³ is phenyl, which is substituted by halogen; and

the other one is hydrogen;

R⁴ is

14. A compound according to claim 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein

R¹ is methyl or ethyl;

One of R² and R³ is phenyl, which is substituted by fluoro, chloro or bromo; and

the other one is hydrogen;

R⁴ is

15. A compound according to claim 1 of formula (Ib)

16. A compound according to claim 1 of formula (Ib)

17. A compound according to claim 1 of formula (Ib)

18. A compound according to claim 1 of formula (Ib)

19. A compound according to claim 1 of formula (Ib)

20. A compound according to claim 1 of formula (Ib)

21. A compound according to claim 1, selected from

6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(3,5-difluoro-pyridin-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-2-(3,5-difluoro-pyridin-2-yl)-5-methoxycarbonyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(2-carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-methyl-pyridin-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-pyridin-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-cyclopropyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-2-(4-tert-butyl-thiazol-2-yl)-6-(S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-fluoro-thiophen-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(1-methyl-1H-imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-((R)-5-carboxy-3,3-difluoro-piperidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-methyl-oxazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-thiazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4,5-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-(S)-2-carboxy-[3,3-2H2]-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(1,4-dimethyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(2-chloro-4,5-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(3-fluoro-pyridin-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-chloro-thiophen-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(3-methyl-pyridin-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-trifluoromethyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-methyl-thiophen-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-isopropyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester

(R)-4-(4-bromo-2-chloro-phenyl)-6-(S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-cyano-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(2,4-difluoro-phenyl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(1-methyl-1H-imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(6-methyl-pyridin-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2,4-dichloro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(R)-6-(2,4-Dichloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(1-methyl-4-trifluoromethyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(S)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(3,4,5-trifluoro-phenyl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(4-Bromo-2,3-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(S)-6-(3,4-Dichloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-cyano-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2,3-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-2-thiazol-2-yl-5-(2,2,2-trifluoro-ethoxycarbonyl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(S)-6-(4-Bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(S)-5-Ethoxycarbonyl-6-(3-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(S)-5-Ethoxycarbonyl-6-(4-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-(1-methyl-1H-imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(3S)-4-[[(4R)-4-(2-chloro-4-fluorophenyl)-5-methoxycarbonyl-2-(4-methylsulfanyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;

(2S)-1-[[(4R)-4-(2-chloro-4-fluorophenyl)-5-methoxycarbonyl-2-(4-methylsulfanyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]-4,4-difluoropyrrolidine-2-carboxylic acid;

(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-4-(2-Bromo-3-fluoro-phenyl)-6-(S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2,3-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Bromo-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-4-(2-Bromo-phenyl)-6-(S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-chloro-2-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(S)-6-(4-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-methyl-morpholine-3-carboxylic acid;

(R)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-methyl-morpholine-3-carboxylic acid;

(R)-6-((R)-5-Carboxy-3,3-difluoro-piperidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Chloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(S)-6-(4-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-4-(2-Bromo-4-fluoro-phenyl)-6-(S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2,4-dichloro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

3-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-1,3-thiazinane-4-carboxylic acid;

(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-2-(4-cyclopropylthiazol-2-yl)-5-methoxycarbonyl-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;

(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-2-[4-(difluoromethyl)thiazol-2-yl]-5-methoxycarbonyl-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;

(R)-6-((S)-2-Carboxy-4,4-difluoro-3,3-dimethyl-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid;

(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]thiomorpholine-3-carboxylic acid;

(S)-4-[(S)-6-(2-Chloro-4-fluoro-phenyl)-2-(1,4-dimethyl-1H-imidazol-2-yl)-5-methoxycarbonyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(4-Bromo-2-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(4-Bromo-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-trifluoromethyl-thiazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(S)-6-(3,4-Difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-(1-methyl-1H-imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[6-(2-Chloro-4-fluoro-phenyl)-5-propoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(R)-6-(S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(5-methyl-oxazol-4-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(2R,3S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(S)-4-[5-tert-Butoxycarbonyl-6-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;

(2R,3S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(R)-4-(2-Bromo-4-fluoro-phenyl)-6-(S)-2-carboxy-5,5-difluoro-piperidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(R)-4-(2-Bromo-4-fluoro-phenyl)-6-(R)-2-carboxy-5,5-difluoro-piperidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(R)-6-((S)-2-Carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((R)-2-Carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

(R)-6-((S)-2-Carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(2-chloro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;

(2R,3S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(2R,3S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(2R,3S)-4-[(R)-5-Methoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(2R,3S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(2,3S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(2R,3S)-4-[(R)-6-(2-Chloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(2R,3S)-4-[(R)-6-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(2R,3S)-4-[(R)-6-(2-Bromo-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;

(2R,3S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-isopropyl-morpholine-3-carboxylic acid;

(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-3-methylmorpholine-3-carboxylic acid;

(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid;

(3S)-4-[[(4S)-4-(4-bromophenyl)-5-ethoxycarbonyl-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;

(3S)-4-[[(4S)-4-(3-bromo-4-chlorophenyl)-5-ethoxycarbonyl-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;

(3S)-4-[[(4S)-4-(3-chloro-5-fluorophenyl)-5-ethoxycarbonyl-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;

(3S)-4-[[(4S)-4-(4-chlorophenyl)-5-ethoxycarbonyl-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;

(S)-4-(((R)-6-(2-bromophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid;

(3S)-4-[[(4R)-4-(2-bromo-3,4-difluorophenyl)-5-ethoxycarbonyl-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;

(3S)-4-[[(4R)-5-ethoxycarbonyl-4-(2-iodophenyl)-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid; and

(3S)-1-[[(4S)-4-(4-bromophenyl)-5-ethoxycarbonyl-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]-4,4-difluoropyrrolidine-2-carboxylic acid.

22. A process for the preparation of a compound according to claim 1 comprising the reaction of

(a) a compound of formula (XZ)

23. A pharmaceutical composition comprising a compound in accordance with claim 1 and a therapeutically inert carrier.

24. A method of inhibiting hepatitis B virus in a human, which method comprises administering an effective amount to said human of a compound as defined in claim 1.

25. A compound of formula (I)

26. A method for the treatment or prophylaxis of hepatitis B virus infection in a human, which method comprises administering an effective amount to said human of a compound as defined in claim 1.

27. A method for the treatment or prophylaxis of hepatitis B virus infection in a human, which method comprises administering an effective amount to said human of a compound as defined in claim 1 together with an agent selected from the group consisting of interferon, pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, and Tenofovir disoproxil.