NOVEL PYRIDOPYRIMIDINONE COMPOUNDS FOR MODULATION OF CATALYTIC ACTIVITY OF HISTONE LYSINE DEMETHYLASES (KDMS) Russian patent published in 2019 - IPC C07D471/04 A61K31/519 A61P35/00 

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to a novel compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In formula (I)

X is selected from a group consisting of hydrogen, benzofuranyl, dihydrobenzofuranyl, chromanyl, dihydroindenyl, tetrahydronaphthalenyl, -CH(R¹)NH-R² and -CH(R¹)OR², where R¹ is hydrogen or C_1-8alkyl; where benzofuranyl can optionally be substituted with one R³, where R³ is C(=O)-O(R⁴), where R⁴ is C_1-6alkyl, or -C(=O)-N(R⁴)(R⁵), where R⁴ is hydrogen and R⁵ is C_1-6alkyl, substituted with 5-6-member heterocyclyl, having 1 N heteroatom; Y is H or -CH₂NH-AZ; A is selected from a group consisting of a single bond, C_1-8alkylene, C_3-10cycloalkylene, 5-6-member heterocyclylene having 1 heteroatom N, -C(=O)- and -CH₂C(=O)-, where alkylene, cycloalkylene and heterocyclylene can optionally be substituted with one to three R⁴, where R⁴ is C_1-6alkyl, benzyl or amino; Z is selected from a group consisting of hydrogen, -N(R⁴)(R⁵), C_1-8alkyl, C_3-10cycloalkyl, 4-6-member heterocyclyl, having 1 or 2 heteroatoms selected from a group consisting of N and O, 5-member heterocyclyl, having 1 heteroatom N and substituted with two adjacent substitutes R³, which form 6-member heteroaryl ring having 1 N heteroatom; phenyl, benzyl and 5-6-member heteroaryl, having 1 or 2 heteroatoms selected from a group consisting of N, O and S, where alkyl, cycloalkyl, heterocyclyl, phenyl, benzyl and heteroaryl may optionally be substituted with one or two R³, where R³ is selected from a group consisting of halogen, C_1-8alkyl, C_1-4aminoalkyl, C_1-4hydroxyalkyl, C_1-4alkoxyalkyl, C_3-10cycloalkyl, benzyl, oxo, C(=O)-O(R⁴), -C(=O)-N(R⁴)(R⁵), -O(R⁴), -N(R⁴)(R⁵), methylpiperidine and 5-6-member heterocyclyl, having 1 or 2 heteroatoms selected from a group consisting of N and O; R² selected from a group consisting of phenyl, benzyl, biphenyl, tetrahydronaphthalenyl, dihydroindenyl, 5-6-member heterocyclyl, having 1 heteroatom, selected from a group consisting of N and O, and 5-9 membered heteroaryl, having one or two heteroatoms selected from a group consisting of N or O, where each of said values R² can optionally be substituted with one to three substitutes selected from halogen, C_1-8alkyl, C_3-10cycloalkyl, -CF₃, -CN, -NO₂, -C(=O)-O(R⁴), -C(=O)-N(R⁴)(R⁵), -O(R⁴), -OCF₃, -N(R⁴)(R⁵), C_1-8alkoxyS_1-8alkyl, -C_1-8alkyl-C(=O)R⁴, -C(=O)R⁴, -C_1-8alkyl-R⁴, -NH-C(=O)R⁴, -C_1-8alkyl-NR⁴R⁵ and pyridinyl; R⁴ or R⁵ is independently selected from a group consisting of hydrogen, C_1-6alkyl, C_1-4aminoalkyl, dimethylaminopropyl, dimethylaminoethyl, C_1-4fluoroalkyl, C_1-4hydroxyalkyl, C_3-10cycloalkyl group(C_3-8cycloalkyl)C_1-6alkyl, 5-6-member heterocyclyl, having 1 heteroatom O or N, phenyl, a group (5-6 membered heterocyclyl having 1 or 2 heteroatoms selected from N or CO)-C_1-8alkyl, (5-6-member heteroaryl, having 1 heteroatom N)-C_1-6alkyl and benzyl, where cycloalkyl, heterocyclyl, phenyl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl and benzyl can optionally be substituted with one or more substituents independently selected from R¹, where R¹ is selected from a group consisting of amino, C_1-8alkyl, C_1-8alkoxy, C_1-8alkoxyalkyl, C_1-4aminoalkyl, C_1-4fluoroalkyl, C_1-4hydroxyalkyl, C_3-10cycloalkyl, acetyl, benzyl, 5-6-member heterocyclyl, having one N heteroatom; or, alternatively, adjacent R⁴ and R⁵ form 5-6-member N-containing heterocyclyl which can additionally contain 1 heteroatom selected from N and O, and which is optionally substituted with R¹, where R¹ is selected from C_1-8alkyl, benzyl, C_1-8alkoxy, with the proviso that X is not hydrogen when Y is hydrogen; and when Y is H, X is -CH(R¹)OR², R¹ is H, and R² is phenyl, then such phenyl is substituted with one to three substitutes selected from C_1-8alkyl, C_3-10cycloalkyl, -CF₃, -CN, -NO₂, -C(=O)-O(R⁴), -C(=O)-N(R⁴)(R⁵), -O(R⁴), -OCF₃, -N(R⁴)(R⁵), C_1-8alkoxyS_1-8alkyl, -C_1-8alkyl-C(=O)R⁴, -C(=O)R⁴, -C_1-8alkyl-R⁴, -NH-C(=O)R⁴, pyridinyl and -C_1-8alkyl-NR⁴R⁵, and this substituted phenyl can additionally be substituted with halogen.

EFFECT: compounds have histoneLysine demethylase (KDM) inhibitor activity and can be used for treating cancer or KDM dysregulated disease, in particular for treating cancer, selected from a group consisting of prostate cancer, lung cancer, breast cancer, stomach cancer, cervical cancer, melanoma, renal cell carcinoma and leukemia.

9 cl, 2 dwg, 3 tbl, 241 ex

формула - formula