FGFR4 INHIBITORS Russian patent published in 2020 - IPC C07D413/12 C07D401/14 C07D403/12 C07D239/48 A61K31/505 A61K31/506 A61P35/00 

FIELD: medicine; pharmaceuticals.

SUBSTANCE: invention relates to a novel compound of formula I or a pharmaceutically acceptable salt thereof. Compound has FGF19 inhibitor activity and can be used to treat a disorder which has at least one altered FGF19 status and a changed FGFR4 status. In particular, the compound can be used for treating hepatocyte carcinoma, which has at least one altered status of FGF19 with high expression of FGFR4. In formula I

,

R³ is selected from a group consisting of C_1-6alkyl, C_1-6alkoxyC_1-6alkyl, NR¹⁰R¹¹C_1-6alkyl, R¹⁰heterocyclylC_1-6alkyl, where the heterocyclyl group is selected from 5–6 membered saturated heterocyclyl and 5–6 member heteroaryl containing 1–2 heteroatoms selected from i) one nitrogen atom, ii) two nitrogen atoms and iii) one nitrogen atom and one oxygen atom, R¹⁰arylC_1-6alkyl, where aryl is phenyl, and where R¹⁰ and R¹¹, each independently selected from a group consisting of hydrogen and C_1-6alkyl; E is selected from a group consisting of -NR¹³C(O)CR¹⁴=CHR¹⁵ and -NR¹³C(O)C≡CR¹⁴, where R¹³ is selected from a group consisting of hydrogen and methyl, R¹⁴ is selected from a group consisting of hydrogen, methyl and fluorine; and R¹⁵ is selected from a group consisting of hydrogen, methyl and chlorine; R¹² is selected from a group consisting of hydrogen, halogen, C_1-6alkyl, C_1-6alkoxy, hydroxyC_1-6alkyl, hydroxyC_1-6alkoxy, C_1-6alkoxyC_1-6alkoxy, C_1-6alkoxyC_1-6alkyl, R⁵R⁶heterocyclyl, -C(O)heterocyclylR⁵R⁶, R⁵R⁶heterocyclylC_1-6alkyl, NR⁵R⁶, NR⁵R⁶C_1-6alkyl, -C(O)NR⁵R⁶ and NR⁵R⁶C_1-6alkoxy, where each heterocyclyl is selected from 6-member saturated heterocycle containing 1–2 heteroatoms selected from nitrogen or nitrogen and oxygen, and R⁵ and R⁶, each independently selected from a group consisting of hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, -C(O)C_1-6alkyl and C_1-6alkylsulphonyl; and R¹ is phenyl, where said phenyl is substituted with 2, 3 or 4 substitutes independently selected from halogen or C_1-6alkoxy.

EFFECT: compound can be used for treating cholangiocarcinoma or rhabdomyosarcoma of expressing or overexpressing FGFR4.

34 cl, 2 dwg, 6 tbl, 185 ex