URIDINE-5-DIPHOSPHATE (UDP) GLYCOSYLTRANSFERASE INHIBITORS AND METHODS OF THEIR USE Russian patent published in 2024 - IPC C07D495/04 C07D513/04 C07D519/00 A61K31/4743 A61K31/496 A61K31/5377 A61P25/00 

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, where (a) X² represents either CR² or N; (b) X⁵ represents either CR⁷ or N; (c) X⁶ represents either CR¹ or N; (d) Y represents either -C(O)NR^aR^b or -C(O)O-C_1-4 alkyl; (e) each R^a is independently either H, C_1-4 alkyl, C_1-4 haloalkyl, -C_1-4 alkyl-C_3-9 cycloalkyl or C_3-9 cycloalkyl; (f) each R^b is independently either C_1-4 alkyl, C_1-4 alkoxy, C_3-9 cycloalkyl or -C_1-4 alkyl-C_1-4 alkoxy; or, when Y represents -C(O)NR^aR^b, R^a and R^b can be taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl, which is a free non-aromatic radical having from 3 to 10 rings atoms, wherein 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen substituted with 0-3 R^x substituents; (g) R⁷ is either hydrogen, C_1-4 alkyl, C_1-4 alkoxy, -S(O)₂-NR^aR^b- or heteroaryl having from 5 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen; (h) R¹ is hydrogen, halogen, -OH, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkyl, C_1-4 haloalkoxy, -NH₂, -NH(C_1-4 alkyl) or -N(C_1-4 alkyl)₂, C_3-9 cycloalkyl or azetidinyl, wherein each -NH(C_1-4 alkyl) or cycloalkyl is substituted with 0-5 R^x substituents and where each azetidinyl is substituted with 0-5 substituents R^x; (i) R² is hydrogen, halogen, -OH, C_1-4 alkyl, C_1-4 alkoxy or C_3-9 cycloalkyl; (j) A¹ represents a chemical bond, C_1-4 alkylene, -O-, -OC_1-4 alkylene, -C_2-4 alkenylene, -C_2-4 alkynylene, -NR^a, -NR^a -C_1-4 alkylene-, -S-, -S(O)-, -S(O)₂-, -C(O)-, -C(O)-O- or -OC(O)-; (k) L represents a heteroaryl having from 5 to 10 ring atoms, wherein from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, C_{3- 12} cycloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, or 1,2,3,6-tetrahydropyridinyl, each of which may be substituted with 0-5 R^x ; (l) A² represents a chemical bond, -O-, -NR^a-, -C_1-4 -alkyl-NR^a-, -C(O)-, -C_1-4 alkyl-C(O)-, -OC(O)-, -C_1-4 alkyl-OC(O)-, -C(O)-O-, -C_1-4 alkyl-C(O)-O-, -OC(O) -O-, -S(O)₂-, -NR^a-S(O)-, -C_1-4 -alkyl-NR^a-S(O)-, -NR^a-S(O)₂-, -C_1-4 -alkyl-NR ^a -S(O)₂-, -C(O)-NR^a-, -C_1-4 alkyl-C(O)-NR^a-, -NR ^a -C( O)-, -C_1-4-alkyl-NR^a-C(O)-, -OC(O)-NR^a-, -C_1-4 -alkyl-OC(O)-NR^a-, -NR^a-C(O)-O-, -NR^a-C(O)-NR^a-, -NR^a-CH ₂ -C(O)-NR^a-, -O-CH₂-C(O)- NR^a-, -C(O)-O-CH₂-C(O)- or -C(O)-NR^a-CH₂ -C(O)-; (m) R⁴ represents -OH, C_1-6 alkyl, C_2-6 alkenyle, C_2-6 alkynyle, C_3-9 cycloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, naphthyl or heteroaryl, where the said heteroaryl is selected from the group consisting of imidazolyl, pyrimidinyl, pyridinyl, pyrazinyl, oxadiazolyl, thiadiazolyl and thiazolyl, where each alkyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl R⁴ is substituted with 0-5 substituents R⁵; (n) R⁵ represents OH, halogen, CO₂H, C_1-4 alkyl, C_2-6 alkynyle, C_1-4 alkoxy, C_1-4 haloalkyl, -O-C_1-4 haloalkyl, -C_1-4 alkyl-O-C_1-4 alkyl, -S-C_1-4 alkyl, -S(O)₂-C_1-4 alkyl, -S(O)-C_1-4 alkyl, -N(R^a)₂, -CH₂N(R^a)₂, -N(R^a)-S(O)-C_1-4 alkyl, -N(R^a)-S(O)₂-C_1-4 alkyl, -NO₂, -CN, -CH₂CN, C_3-9 cycloalkyl, -O-C_3-9 cycloalkyl, -C_1-4 alkyl-C_3-9 cycloalkyl, -O-C_1-4 alkyl-C_3-9 cycloalkyl, -C_1-4 alkyl-O-C_1-4 haloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical, having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, -C_1-4 alkyl-heterocycloalkyl, phenyl, naphthyl, -O-phenyl, -O-naphthyl, heteroaryl, where heteroaryl denotes heteroaromatic ring, having from 5 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, -O-heteroaryl, C_1-4-alkyl-heteroaryl, aralkyl or -O-aralkyl, where each alkyl, phenyl, naphthyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 substituents R^w; (o) each R^w independently represents halogen, -OH, C_1-4 alkyl, C_1-4 haloalkyl or -C_1-4 alkoxy; and (p) each R^x independently represents halogen, -OH, C_1-4 alkyl, -C_1-4 alkoxy, -C_1-4 alkyl-O-C_1-4 alkyl, -C(O)-N(R^a)₂, -O-C(O)-N(R^a)₂, -N(R^a)₂, -CH₂N(R^a)₂, heterocycloalkyl, which denotes a free non-aromatic radical, having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, -O-heterocycloalkyl, -O-phenyl, -O-naphthyl or -O-heteroaryl, where heteroaryl denotes heteroaromatic ring, having from 5 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen. The invention also relates to a pharmaceutical composition for the treatment of lysosomal storage disease based on these compounds.

EFFECT: new compounds and a pharmaceutical composition based on them have been obtained, which can be used in medicine for the treatment of lysosomal storage disease, in particular Krabbe disease (KD) and metachromatic leukodystrophy (MLD).

26 cl, 4 tbl, 858 ex