RU2022105060A - DIHYDROPYRIMIDINE DERIVATIVES AND THEIR APPLICATION IN THE TREATMENT OF HBV INFECTION OR DISEASES CAUSED BY HBV - Google Patents

Claims (51)

1. Compound of formula (I) (I), including its deuterated, stereoisomeric or tautomeric forms, where: each of R ¹ , R ² and R ³ is independently selected from the group consisting of hydrogen, C _1-3 alkyl and halogen; R ⁴ is selected from the group consisting of thiazolyl, imidazolyl, oxazolyl and pyridyl, each of which may be optionally substituted with one or more substituents, each independently selected from methyl or halogen; R ⁵ represents C _1-4 alkyl; R ⁶ is selected from the group consisting of -CO ₂ R ^x , -C _1-9 alkyl-CO ₂ R ^x and -Het-CO ₂ R ^x ; Where C _1-9 alkyl may be optionally substituted with one or more substituents, each independently selected from halogen and hydroxyl; R ^x is selected from H and -C _1-6 alkyl, and Het is a 5-6 membered aromatic ring in which 1, 2, 3 or 4 ring members are a heteroatom, each independently selected from the group consisting of N, O and S, wherein said 5-6 membered aromatic the ring is optionally substituted with one or more substituents, each independently selected from C _1-4 alkyl and halogen; or a pharmaceutically acceptable salt or solvate thereof. 2. The compound of claim 1, wherein R ¹ , R ² and R ³ are each independently selected from the group consisting of H, halogen and methyl. 3. Connection according to any one of paragraphs. 1 or 2, wherein R ⁴ is selected from the group consisting of thiazolyl, oxazolyl, imidazolyl and pyridyl, each of which may be optionally substituted with one methyl substituent. 4. Connection according to any one of paragraphs. 1-3, where R ⁵ represents methyl or ethyl. 5. Connection according to any one of paragraphs. 1-4, where R ⁶ is selected from the group consisting of -CO ₂ H, -CH ₂ -CO ₂ H and -Het-CO ₂ H. 6. Connection according to any one of paragraphs. 1-5, where R ⁶ is selected from the group consisting of -CO ₂ H, -CH ₂ -CO ₂ H and -Het-CO ₂ H; where Het represents a 5-membered aromatic ring selected from the group consisting of oxazolyl, thiazolyl and imidazolyl, each of which may be optionally substituted with one or more substituents, each independently selected from C _1-4 alkyl and halogen. 7. Connection according to claim 1, where each of R ¹ , R ² and R ³ is independently selected from the group consisting of hydrogen, methyl, fluorine, bromine and chlorine; R ⁴ is selected from the group consisting of thiazolyl, oxazolyl, imidazolyl and pyridyl, each of which may be optionally substituted with one or more substituents, each independently selected from methyl or halogen; R ⁵ is methyl, ethyl, propyl or isopropyl, and R ⁶ is selected from the group consisting of -CO ₂ R ^x , -C _1-6 alkyl-CO ₂ R ^x , in particular -C _1-4 alkyl-CO ₂ R ^x and -Het-CO ₂ R ^x ; Where C _1-6 alkyl, in particular C _1-4 alkyl, may be optionally substituted with one or more substituents, each independently selected from halogen and hydroxyl; R ^x is selected from H and -C _1-6 alkyl, and Het is a 5-6 membered aromatic ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyridyl and pyrimidinyl, each of which may be optionally substituted with one or more substituents, each independently selected from C _1-4 alkyl and halogen. 8. Connection according to any one of paragraphs. 1-7 selected from the group consisting of the following compounds: 9. A pharmaceutical composition that contains a compound according to any one of paragraphs. 1-8 and which further contains at least one pharmaceutically acceptable carrier. 10. Connection according to any one of paragraphs. 1-8 or a pharmaceutical composition according to claim 9 for use as a medicine. 11. Connection according to any one of paragraphs. 1-8 or a pharmaceutical composition according to claim 9 for use in the prevention or treatment of an HBV infection or a disease caused by HBV in a mammal in need thereof. 12. A product containing a first compound and a second compound in the form of a combination preparation for simultaneous, separate or sequential use in the prevention or treatment of HBV infection or disease caused by HBV in a mammal in need thereof, wherein said first compound is different from that specified a second compound, where said first compound is represented by a compound according to any one of claims. 1-8 or the pharmaceutical composition according to claim 9. 13. A method for preparing a compound of formula (I), the method comprising carrying out the reaction of a compound of formula (IV), with a compound of formula (V), under suitable conditions for condensation to obtain the compound of formula (X), , And reacting a compound of formula (X) with a compound of formula (VI), under basic conditions to obtain the compound of formula (VII), ; or alternatively reacting the compounds of formula (IV), (V) and (VI) in the presence of a suitable base in a suitable solvent to obtain a compound of formula (VII); and optionally includes the stage separating a compound of formula (VII) into compounds of formula (VIIa) and (VIIb), through chiral separation, and step removing the protecting group from compound (VII) to obtain a compound of formula (I) or removing the protecting group from compound (VIIa) or compound (VIIb) to obtain a compound of formula (Ia) or (Ib), ; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein for a compound of formula (I), and P is a suitable protecting group. 14. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims. 1-8 or the pharmaceutical composition according to claim 9. 15. A method for producing a pharmaceutical composition according to claim 9, including mixing at least one pharmaceutically acceptable carrier with a therapeutically effective amount of a compound according to any one of claims. 1-8.