4,4-DISUBSTITUTED-1,4-DIHYDROPYRIMIDINES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B

• US 20150005295A1
• Filed: 01/04/2013
• Published: 01/01/2015
• Est. Priority Date: 01/06/2012
• Status: Active Grant

• Current Assignee: Janssen Sciences Ireland UC (Johnson & Johnson)
• Original Assignee: Janssen R&D Ireland (Johnson & Johnson)
• Inventors: Vandyck, Koen, Hach, Geerwin Yvonne Paul, Raboisson, Pierre Jean-Marie, Rombouts, Geert, Verschueren, Wim Gaston
• Granted Patent: US 9,233,933 B2
• Time in Patent Office: Days
• US Class Current: 514/227.8
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/527 spiro-condensed
• 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 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/22 with hetero atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

Inhibitors of HBV replication of formula (I) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein R₁-R₅, B and Z have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.

Claims

1. A compound of Formula I

2. A compound according to claim 1 wherein B is selected from the group comprising C₁-C₃ alkyl optionally substituted with one or more Fluoro atoms;

Z is selected from H or halogen;

Or B and Z together with the carbons to which they are attached form a 4-7 membered ring, optionally containing one or more heteroatoms, wherein the 4-7 membered ring optionally is substituted with one or more substituents selected from the group comprising C₁-C₃ alkyl oxo and halogen; and

R₁ is selected from the group comprising heteroaryl and phenyl, optionally substituted with one or more halogen atoms.

3. A compound according to claim 1, wherein B and Z together with the carbons to which they are attached form a 5- or 6-membered ring, optionally substituted with one or more substituents selected from the group comprising C₁-C₃ alkyl, oxo and halogen

4. A compound according to claim 1, wherein B and Z together with the carbons to which they are attached form a 5- or 6-membered ring, optionally substituted with one or more CH₃ substituents.

5. A compound according to claim 1, wherein R₁ is selected from pyridinyl optionally substituted with one or two Fluoro, or thiazolyl.

6. A compound according to claim 1, wherein R₃ is C₁- or C₂-alkyloxycarbonyl.

7. A compound according to claim 1, wherein R₆ is CH₂ and R₇ is selected from morpholinyl or piperidinyl.

8. The compound according to claim 1, wherein formula I is formula (Ia)

9. A compound according to claim 1, wherein R₄ and R₅ independently are selected from the group H and Fluoro.

10. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.

13. A product containing (a) a compound of formula claim 1, and (b) another HBV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infections.

14. The compound according to claim 1, wherein R₂ is Cl.

16. A method of treating an HBV infection in a mammal, comprising administering to said mammal the compound of claim 1.

11-12. -12. (canceled)

15. (canceled)