Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors

A method of treating cancer, comprising 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.

A compound of formula (IV) or a salt thereof

• wherein
• V is selected from CH2, O and CH(OH);
• W is selected from CH2, CH2CH2 and a bond;
• R1 is selected from halogen, C1-C3alkyl, haloC1-C3alkyl, hydroxyC1-C3alkyl, C3-C6cycloalkyl, CH2NR2R3, CH(CH3)NR2R3, C1-C3alkoxyC1-C3alkyl, CH2CO2H and C(O)H;
• 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 and 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 form a 4-, 5- or 6-membered non-aromatic heterocyclic ring comprising at least one heteroatom selected from N, O and S;
• or
• two R4 attached at the same ring atom form an oxo group;
• R5 is selected from hydrogen and C1-C3alkyl.