| 主权项 |
1. A method of inhibiting FGFR4 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein V is selected from CH2, O and CH(OH); W is selected from CH2, CH2CH2 and a bond; X is C(RX) or N; Y is C(RY) or N; Z is CH or N; with the proviso that when X is N, Y and Z are not N; with the proviso that when Y is N, X and Z are not N; with the proviso that when Z is N, X and Y are not N; RX is selected from hydrogen, halogen, haloC1-C3alkyl, cyano, C1-C6alkyl and hydroxyC1-C6alkyl; RY is selected from hydrogen, halogen, C1-C3alkyl, C1-C6alkoxy, hydroxyC1-C3alkoxy, NRY1RY2, cyano, C1-C3alkoxyC1-C3alkoxy, C1-C3alkoxy-haloC1-C3alkoxy, di(C1-C3alkyl)aminoC1-C6alkoxy, O—(CH2)0-1—RY3, CRY6RY7, S—C1-C3alkyl and haloC1-C6alkoxy optionally substituted with hydroxy; or RX and RY together with the ring to which they are attached form a bicyclic aromatic ring system optionally further comprising one or two heteroatoms selected from N, O, or S, which ring system is optionally substituted with C1-C3alkyl; RY1 is hydrogen and RY2 is selected from C1-C6alkyl; hydroxyC1-C6alkyl; haloC1-C6alkyl optionally substituted with hydroxy; C1-C4alkoxyC1-C6alkyl; haloC1-C3alkoxyC1-C6alkyl; (CH2)0-1—RY4; di(C1-C3alkyl)aminoC1-C6alkyl substituted with hydroxy; bicycloC5-C8alkyl optionally substituted with hydroxyC1-C3alkyl; phenyl substituted with S(O)2—CH(CH3)2; and C2-C3alkylsulfonic acid; or RY1 and RY2 together with the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once or twice by RY5; RY3 is selected from quinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, and a 5- or 6-membered aromatic heterocyclic ring; which saturated or aromatic heterocyclic ring of Ry3 is optionally substituted with C1-C3alkyl and/or oxo; RY4 is a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O, or S; which ring is optionally substituted with C1-C3alkyl; RY5 is independently selected from C1-C3alkyl, hydroxy and di(C1-C3alkyl)aminoC1-C3alkyl, or two RY5 attached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is substituted once or more than once with C1-C3alkyl; RY6 and RY7 together with the carbon atom to which they are attached form a 6-membered saturated or unsaturated non-aromatic heterocyclic ring comprising one heteroatom selected from N, O or S; R1 is selected from hydrogen; halogen; C1-C3alkyl; haloC1-C3alkyl; hydroxyC1-C3alkyl; C3-C6cycloalkyl; CH2NR2R3; CH(CH3)NR2R3; C1-C3alkoxyC1-C3alkyl; CH2CO2H; C(O)H; C1-C3alkoxy; and a 5- or 6-membered saturated heterocyclic or aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is optionally substituted once or more than once with a group independently selected from C1-C3alkyl, haloC1-C3alkyl, oxetanyl or oxo; R2 is selected from C1-C3alkyl and di(C1-C3alkyl)aminoC1-C3alkyl; R3 is selected from C1-C3alkyl, C(O)C1-C3alkyl, C(O)—CH2—OH, C(O)—CH2—O—CH3, C(O)—CH2—N(CH3)2 and S(O)2CH3; or R2 and R3 together with the N atom to which they are attached form a saturated 5- or 6-membered ring optionally comprising one additional heteroatom selected from N, N-oxide, O or S, which ring may be substituted once or more than once with R4; R4 is independently selected from C1-C3alkyl, di(C1-C3alkyl)amino, C(O)CH3 and hydroxy; or two R4 attached at the same carbon atom form together with the carbon atom to which they are attached a 4-, 5- or 6-membered non-aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S; or two R4 attached at the same ring atom form an oxo group; R5 is selected from hydrogen and C1-C3alkyl. |
