DIHYDROPYRIMIDIN COMPOUNDS AND THEIR APPLICATION IN PHARMACEUTICALS Russian patent published in 2018 - IPC C07D417/14 C07D413/14 C07D413/06 C07D403/14 A61K31/506 A61K31/5375 A61P31/12 A61P31/20 

FIELD: chemistry.

SUBSTANCE: invention relates to new isomeric forms of the dihydropyrimidin derivative represented by formula (I) or (Ia), or a pharmaceutically acceptable salt thereof. In the formula (I) or (Ia)

each A is -O-; each R is -X-Z; X is - (CR⁷R^7a)_m-; Z has the formula (II) or (IIa)

where each B is - (CR⁷R^7a)_m-; each W is N; each Y is - (CR⁷R^7a)_m- or -O-, where m has the value 0 or 1; each R¹ is phenyl or phenyl substituted with one or more substituents, which are the same or different, representing H, F, Cl, Br, nitro or trifluoromethyl, for example 3,5-bis(trifluoromethyl)phenyl; each R² is H or C_1-4alkyl; R³ has one of the following formulas:

or

each R¹⁰ is independently H, F, Cl, methyl, ethyl, cyano, hydroxy, nitro, amino, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -(CR⁷R^7a)_m-C(=O)O-R^8a, -(CR⁷R^7a)_m-C(=O)N(R^8a)₂ or trifluoromethylsulfonyl; each R¹¹ is independently H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl or -(CR⁷R^7a)_m-C(=O)O-R^8a; each p is independently 0, 1, 2 or 3; each R⁴ is H; each R^7a and R⁷ is independently H, methyl, ethyl, -(CH₂)_m-OH -(CH₂)_m-C(=O)O-R⁸ or propyl; each R⁸ and R^8a is independently H, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, 1-methylpropyl, aminomethyl, 1-amino-2-methylpropyl, 1-aminoethyl, 2-aminoethyl, 1-aminobutyl, 1-aminopropyl, 2-aminopropyl, Boc-NH-methyl, 1-Boc-NH-2-methylpropyl, 1-Boc-NH-ethyl, 2-Boc-NH- ethyl, 1-Boc-NH-butyl, 1-Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH₂)_m-OH, -(CH₂)_m-C(=O)O-(CH₂)_m-H, -(CH₂)_m-OC(=O)-(CH₂)_m-H or tert-butyl; Boc is tert-butyloxycarbonyl; each R⁹ is independently -(CR⁷R^7a)_t-OH, -(CR⁷R^7a)_m-C(=O)O-R⁸, -(CR⁷R^7a)_m-C(=O)O-(CR⁷R^7a)_m-OC(=O)O-R⁸, -(CR⁷R^7a)_m-C(=O)O-(CR⁷R^7a)_m-OC(=O)-R⁸, -(CR⁷R^7a)_m-C(=O)O-(CR⁷R^7a)_m-C(=O)O-R⁸, -(CR⁷R^7a)_t-OC(=O)-R⁸, triazolyl, tetrazolyl or -(CR⁷R^7a)_m-C(=O)N(R⁸)₂, provided that R⁹ is -(CR⁷R^7a)_t-OH, R³ is furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 or 2; each t is independently 1, 2, 3 or 4; each m is independently 0, 1, 2, 3 or 4; and arbitrarily each C_1-4alkyl, C_1-4haloalkyl, amino-C_1-4-alkyl, C_1-4alkoxy, furanil, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl and triazinyl as described above, is independently substituted by one or more substituents that are the same or different, wherein the substituent is H, F, Cl, Br, I, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, -(CR⁷R^7a)_m-C(=O)O-R^8a or -(CR⁷R^7a)_m-C(=O)N(R^8a)₂.

EFFECT: compounds possess the properties of an inhibitor of hepatitis B virus activity and can be used in the treatment of diseases caused by hepatitis B infection, which is cirrhosis or hepatocellular carcinoma.

12 cl, 3 tbl, 159 ex