NOVEL 4-METHYL-DIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

• US 20130267517A1
• Filed: 03/27/2013
• Published: 10/10/2013
• Est. Priority Date: 03/31/2012
• Status: Abandoned Application

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Guo, Lei, Lin, Xianfeng, Qiu, Zongxing, Sheng, Hong, Tang, Guozhi, Wu, Guolong, Zhang, Weixing, Zhu, Wei, Liu, Haixia
• Application Number:
  US13/851,542
• Publication Number:
  US 20130267517A1
• Time in Patent Office: Days
• US Class Current: 514/235.8
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• 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, R⁵, M and X 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 C_1-2alkoxycarbonyl or cyano;

R² is phenyl, which is once or twice substituted by halogen;

R³ is (i) 2-thiazolyl which is unsubstituted or once substituted by C_1-6alkyl or halogen, (ii) 2-thienyl, (iii) 2-pyridinyl, which 2-thienyl or 2-pyridinyl are once substituted by halogen, (iv) 2-imidazolyl substituted by one C_1-6alkyl;

or (v) 3-isoxazolyl which is unsubstituted or substituted by one C_1-6alkyl;

X is oxygen or —

NR⁷;

R⁴ and R⁵ are independently selected from hydrogen, C_1-6alkyl and trifluoroC_1-6alkyl;

or

R⁴ and R⁵, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl ring;

or

when X is —

NR⁷, one of R⁴ and R⁵ is hydrogen or C_1-6alkyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form a morpholinyl, pyrrolidinyl or piperidinyl each substituted by fluoro;

M is C_1-6alkoxycarbonyl, carboxy, diC_1-6alkylamino-C_2-6alkoxycarbonyl, aminocarbonyl, C_1-6alkylaminocarbonyl, diC_1-6alkylaminocarbonyl, C_1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl, hydroxy-C_yH_2y—

,

3. A compound according to claim 2, wherein

R² is phenyl substituted by one or two fluorine atoms;

R³ is

4. A compound according to claim 1 wherein.

R¹ is C_1-2alkoxycarbonyl;

R² is phenyl substituted by one halogen;

R³ is thiazol-2-yl;

X is oxygen;

R⁴ and R⁵ are independently selected from hydrogen, C_1-6alkyl and trifluoroC_1-6alkyl;

M is C_1-6alkoxycarbonyl or carboxy.

5. A compound according to any one of claim 4, wherein;

R¹ is methoxycarbonyl;

R² is 4-fluorophenyl;

R³ is thiazol-2-yl;

X is oxygen;

R⁴ and R⁵ are independently selected from hydrogen, methyl and trifluoromethyl;

M is methoxycarbonyl or carboxy.

6. A compound according to claim 1 wherein;

R¹ is C_1-2alkoxycarbonyl;

R² is phenyl substituted by one halogen;

R³ is 2-thiazolyl;

X is —

N(C_1-6alkyl) or —

N(trifluoroC_1-6alkyl);

R⁴ is hydrogen;

R⁵ is hydrogen;

or R⁴ and R⁵, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl;

M is carboxy.

7. A compound according to any one of claim 6, wherein:

R¹ is methoxycarbonyl;

R² is 4-fluorophenyl;

R³ is thiazol-2-yl;

X is —

NCH₃ or —

NCH₂CF₃;

R⁴ is hydrogen;

R⁵ is hydrogen;

or R⁴ and R⁵, together with the carbon atom to which they are attached, form cyclopropyl;

M is carboxy.

8. A compound according to claim 1 wherein

R¹ is C_1-2alkoxycarbonyl or cyano;

R² is phenyl substituted by one kor two halogen;

R³ isthiazol-2-yl;

2-pyridin-2-yl substituted by one halogen;

or imidazol-2-yl substituted by one C_1-6alkyl;

X is —

NR⁷;

one of R⁴ and R⁵ is hydrogen, and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form a morpholinyl;

M is C_1-6alkoxycarbonyl, carboxy or hydroxy-C_yH_2y—

;

y is 1-6.

9. A compound according to any one of claim 8, wherein

R¹ is methoxycarbonyl, ethoxycarbonyl or cyano;

R² is 4-fluorophenyl or 3,4-difluorophenyl;

R³ is thiazol-2-yl, 5-fluoro-pyridin-2-yl or 1-methyl-imidiazolid-2-yl;

one of R⁴ and R⁵ is hydrogen, and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form;

10. A compound according to claim 1 or 2, wherein

R¹ is C_1-2alkoxycarbonyl or cyano;

R² is phenyl substituted by one or two halogen;

R³ is thiazol-2-yl optionally substituted by one C_1-6alkyl or one halogen;

thien-2-yl or -pyridin-2-yl said thien-2-yl or -pyridin-2-yl substituted by one halogen;

-imidazol-2-yl, which substituted by one C_1-6alkyl;

or isoxazol-3-yl optionally substituted by one C_1-6alkyl;

X is —

NR⁷;

one of R⁴ and R⁵ is hydrogen or C_1-6alkyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form a pyrrolidinyl or piperidinyl substituted by fluoro;

M is C_1-6alkoxycarbonyl, carboxy, di-C_1-6alkylaminoC_2-6alkoxycarbonyl, aminocarbonyl, C_1-6alkylaminocarbonyl, di-C_1-6alkylaminocarbonyl, C_1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl, hydroxy-C_yH_2y—

,

11. A compound according to any one of claim 1, 2, 3 or 10, wherein

R¹ is methoxycarbonyl, ethoxycarbonyl or cyano;

R² is 4-fluorophenyl or 3,4-difluorophenyl;

R³ is

12. A compound according to claim 1 of formula (I′

)

13. A compound according to claim 12, wherein

R¹ is methoxycarbonyl or cyano;

R² is phenyl substituted once or twice by fluoro;

R³ is thiazol-2-yl, 5-methyl-thiazol-2-yl or 5-fluoro-pyridin-2-yl;

or;

X is oxygen or —

NR⁷;

R⁴ and R⁵ are independently selected from hydrogen, methyl and trifluoromethyl;

or

R⁴ and R⁵ together with the carbon atom to which they are attached form cyclopropyl;

or

when X is —

NR⁷, one of R⁴ and R⁵ is hydrogen or methyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form;

14. A compound according to claim 12, wherein

R¹ is C_1-2alkoxycarbonyl or cyano;

R² is phenyl which is substituted by halogen;

R³ is thiazol-2-yl or pyridin-2-yl, which is substituted by halogen;

X is —

NR⁷;

one of R⁴ and R⁵ is hydrogen or C_1-6alkyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form a morpholinyl;

R⁶ is hydrogen or C_1-6alkyl.

15. A compound according to any one of claim 14, wherein

R¹ is methoxycarbonyl or cyano;

R² is 4-fluorophenyl or 3,4-difluorophenyl;

R³ is thiazol-2-yl or 5-fluoro-pyridin-2-yl;

one of R⁴ and R⁵ is hydrogen or methyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached formform

16. A compound according to claim 12, wherein

R¹ is C_1-2alkoxycarbonyl or cyano;

R² is phenyl which is substituted by halogen;

R³ is 2-thiazolyl optionally substituted by C_1-6alkyl or 2-pyridinylsaid pyridinyl substituted by halogen;

X is —

NR⁷;

one of R⁴ and R⁵ is hydrogen or C_1-6alkyl, and the other and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form a pyrrolidinyl substituted by fluoro;

R⁶ is hydrogen or C_1-6alkyl.

17. A compound according to any one of claims 16, wherein

R¹ is methoxycarbonyl or cyano;

R² is 4-fluorophenyl or 3,4-difluorophenyl;

R³ is thiazol-2-yl, 5-methyl-thiazol-2-yl or 5-fluoro-pyridin-2-yl;

X is —

NR⁷;

one of R⁴ and R⁵ is hydrogen or methyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form

18. A compound according to any one of claims 1 selected from 4-(4-fluoro-phenyl)-6-(1-methoxycarbonyl-1-methyl-ethoxymethyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

6-(1-carboxy-2,2,2-trifluoro-ethoxymethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

6-{[(1-carboxy-cyclopropyl)-methyl-amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(S)-1-[(S)-5-cyano-6-(4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid;

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

(S)-1-[(S)-5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid;

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

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

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

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

(S)-4-[(S)-6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-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-(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

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

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

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

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

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

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

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

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

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

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

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

(S)-6-{[carboxymethyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

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

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

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

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

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

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

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

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

4-(4-fluoro-phenyl)-6-((R)-3-hydroxymethyl-morpholin-4-ylmethyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;

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

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

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

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

(S)-6-[(S)-4,4-difluoro-2-(1H-tetrazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; and

(S)-6-[(S)-4,4-difluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester.

19. A process for the preparation of a compound according to claim 1 comprising the reaction of (a) a compound of formula (A)

20. A compound according to any one of claim 1 for use as therapeutically active substance.

21. A pharmaceutical composition comprising a compound in accordance with any one of claim 1 and at least one carrier, diluent or excipient.

22. The use of a compound according to any one of claim 1 for the treatment or prophylaxis of hepatitis B virus infection.

23. The use of a compound according to any one of claim 1 for the preparation of a medicament for the treatment or prophylaxis of hepatitis B virus infection.

24. A compound according to any one of claim 1 for the treatment or prophylaxis of hepatitis B virus infection.

25. A compound according to any one of claims 1 when manufactured according to a process of claim 19.

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