Bromo-phenyl substituted thiazolyl dihydropyrimidines

1. A compound having formula (I) or its isomer (Ia):

or an enantiomer or a salt thereof, wherein R 1 is o-bromine, R 2 is p-fluorine, R 3 is a C 1 -C 4 alkyl, R 6 is thiazolyl-2-yl, X is methylene, and Z is morpholinyl.

2. The compound of claim 1 or the enantiomer or the salt thereof, wherein R 1 is o-bromine, R 2 is p-fluorine, R 3 is methyl or ethyl, R 6 is thiazolyl-2-yl, X is methylene, and Z is morpholinyl.

3. A compound having one of the following structures or an enantiomer, tautomer or salt thereof:

4. A compound having one of the following structures or a levo isomer, tautomer or salt thereof:

5. The compound according to claim 1 or the enantiomer or the salt thereof, wherein the salt is an inorganic acid salt or an organic acid salt.

6. The compound according to claim 5 or the enantiomer or the salt thereof, wherein the inorganic acid salt is a hydrochloric acid salt, a hydrobromic acid salt, a phosphoric acid salt or a sulfuric acid salt.

7. The compound according to claim 5 or the enantiomer or the salt thereof, wherein the organic acid salt is a carboxylate or a sulfonate.

8. The compound according to claim 7 or the enantiomer or the salt thereof, wherein the carboxylate is acetate, maleate, fumarate, malate, citrate, tartarate, lactate or benzoate.

9. The compound according to claim 7 or the enantiomer or the salt thereof, wherein the sulfonate is methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate or naphthalenedisulfonate.

10. A method of preparing the compound of claim 1 , wherein the method is characterized by:

(a) reacting a benzaldehyde having formula (II) with a β-ketoester having formula (III) to produce a benzylidene compound having formula (IV):

and

(b) reacting the benzylidene compound having formula (IV) with an amidine having formula (V):

or a salt thereof

wherein R 1 is o-bromine, R 2 is p-fluorine, R 3 is a C 1 -C 4 alkyl, R 6 is thiazolyl-2-yl, X is methylene, and Z is morpholinyl.

11. A method of preparing the compound of claim 1 , wherein the method is characterized by reacting a compound having formula (III) with an aldehyde having formula (II) and an amidine having formula (V) or a salt thereof in one step,

wherein R 1 is o-bromine, R 2 is p-fluorine, R 3 is a C 1 -C 4 alkyl, R 6 is thiazolyl-2-yl, X is methylene, and Z is morpholinyl.

12. A method of preparing the compound of claim 1 , wherein X of formula (I) is methylene and the method is characterized by reacting the compound having formula (VI) with morpholine (VII) or a salt thereof:

wherein Y is a nucleophilic substituent, and R 1 is o-bromine, R 2 is p-fluorine, R 3 is a C 1 -C 4 alkyl, and R 6 is thiazolyl-2-yl.

13. A method of preparing the compound of claim 1 , which is characterized by the step of reacting a compound having formula (II) with an aldehyde having formula (X) and an amidine having formula (V) or a salt thereof:

wherein R 1 is o-bromine, R 2 is p-fluorine, R 3 is a C 1 -C 4 alkyl, R 6 is thiazolyl-2-yl, X is methylene, and Z is morpholinyl.

14. A composition comprising the following components:

A) at least one compound according to claim 1 ;

B) at least an HBV antiviral agent which is different from component A; and, when appropriate,

C) at least an immunomodulator or an interferon.

15. The composition of claim 14 , wherein the component B is an HBV polymerase inhibitor, lamivudine or a phenylpropenamide compound having the following formula:

or a salt thereof, wherein

each of R 1 and R 2 is independently C 1-4 alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms which comprise carbon and/or oxygen; and

each of R 3 to R 12 is independently hydrogen, halogen, C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, nitro, cyano or trifluoromethyl; and

X is halogen or optionally substituted C 1-4 alkyl.

16. The composition of claim 15 , wherein the component B is the phenylpropenamide compound having the following structure:

17. A medicament comprising at least one composition of claim 14 , and, when appropriate, one or more active pharmaceutical agents.

18. A method for treating hepatitis B infection or a disease caused by hepatitis B infection, which comprises administering the composition of claim 14 to a patient having the disease.

19. The method of claim 18 , wherein the method is for treating the disease caused by hepatitis B infection selected from hepatitis, cirrhosis or hepatocellular carcinoma.

20. A method for treating hepatitis B infection or a disease caused by hepatitis B infection, which comprises administering the compound of claim 1 to a patient having the disease.

21. The method of claim 20 , wherein the method is for treating the disease caused by hepatitis B infection selected from hepatitis, cirrhosis or hepatocellular carcinoma.

22. A pharmaceutical composition comprising at least one compound according to claim 1 , and, when appropriate, a pharmaceutically acceptable carrier.