BENZO[1,3]DIOXIN DERIVATIVES AND THEIR USE AS LPAR5 ANTAGONISTS Russian patent published in 2018 - IPC C07C319/08 C07D405/12 C07D413/04 A61K31/357 A61K31/41 A61K31/4245 A61P9/00 

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), wherein A is selected from group consisting of R¹¹-O-C(O)- and Het¹; R¹, R², R³ and R⁴, independently of one another, are selected from the group consisting of hydrogen, halogen, (C₁-C₄) alkyl, Ar- (C₁-C₄) alkyl-, Ar, Het², Ar-C(O)-, R¹⁴-N(R¹⁵)-C(O)-, (C₁-C₄)alkyl-O-, Ar-O-, Ar-(C₁-C₄)alkyl-O-, Het³-S(O)₂-, (C₁-C₄)alkyl-NH- and di((C₁-C₄) alkyl)N-y or R¹ and R², or R² and R³, or R³ and R⁴, together with the carbon atoms to which they are attached, can form a carbocyclic ring which is selected from the group consisting of benzene and a 5- to 7-membered cycloalkane, wherein the benzene ring is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of halogen, (C₁-C₄) alkyl and (C₁-C₄) alkyl-O-, and cycloalkane ring is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C₁-C₄) alkyl; R⁵ is selected from the group consisting of hydrogen and (C₁-C₄) alkyl; R¹¹, R¹², R¹⁴ and R¹⁵, each independently of one another, is selected from the group consisting of hydrogen and (C₁-C₄) alkyl; one of the Z¹ and Z² groups is (C₃-C₈) cycloalkyl, and the other is selected from the group consisting of hydrogen, (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl and phenyl, wherein all cycloalkyl groups, independently of one another, are unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C₁-C₄) alkyl, and phenyl group is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of halogen and (C₁-C₄) alkyl; Ar represents a phenyl or aromatic 5-membered or 6-membered monocyclic heterocycle that contains in the ring one or two identical or different heteroatoms selected from the group consisting of N, O, and S atoms, and wherein phenyl is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of halogen, (C₁-C₄) alkyl and (C₁-C₄) alkyl-O-; Het¹ is a partially unsaturated or aromatic 5-membered or 6-membered monocyclic heterocycle that contains in the ring one to four identical or different heteroatoms selected from the group consisting of N and O atoms, which is attached via carbon atom of the ring and is unsubstituted or is substituted by one or more identical or different substituents selected from the group consisting of (C₁-C₄) alkyl and oxo groups; Het² is a saturated 4-7-membered monocyclic heterocycle, which contains in the ring one or two identical or different heteroatoms selected from the group consisting of N and O atoms which is attached via the ring carbon atom or ring nitrogen atom and is unsubstituted or substituted by one or more identical or different substituents, selected from group consisting of fluorine and (C₁-C₄) alkyl; Het³ is a saturated 4-7 membered monocyclic heterocycle that contains in the ring a nitrogen atom through which Het³ joins, and does not contain or contains in the ring one additional heteroatom selected from the group consisting of N and O atoms and which is unsubstituted or is substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C₁-C₄) alkyl; where all alkyl groups are unsubstituted or substituted by one or more fluorine-containing substituents; or a pharmaceutically acceptable salt thereof; with the proviso that the compound of formula I is not 6-chloro-4-cyclohexyl-4-phenyl-4H-benzo[1,3]dioxin-2-carboxylic acid, 6-chloro-4-cyclohexyl-4-phenyl-4H-benzo[1,3]dioxin-2-carboxylic acid methyl ester or 6-chloro-4,4-dicyclohexyl-4H-benzo [1,3] dioxin-2-carboxylic acid. Compounds of formula (I) are valuable pharmacologically active compounds for use in the treatment of various disorders, for example, cardiovascular disorders, such as thromboembolic diseases or restenoses, since they are effective antagonists of LPA receptor LPAR5 (GPR92) platelets and can be used in conditions in which undesirable activation of LPA receptor LPAR5 platelets takes place, LPA receptor LPAR5 mast cells or LPA receptor LPAR5 microgliocytes, or for the treatment or prevention of which it is desirable to inhibit the LPA receptor LPAR5 platelets, mast cells or microgliocytes.

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EFFECT: compounds of formula (I) are valuable pharmacologically active compounds for use in treatment of various disorders, for example, cardiovascular disorders.

7 cl, 3 tbl, 63 ex