Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors

Patent metadata

Field	Value
Publication number	US-9266883-B2
Application number	US-201414522721-A
Country	US
Kind code	B2
Filing date	Oct 24, 2014
Priority date	Oct 25, 2013
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;

a method for manufacturing said compound, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition comprising said compound.

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein
V is selected from CH 2 , O and CH(OH);
W is selected from CH 2 , CH 2 CH 2 and a bond;
X is C(R x ) or N;
Y is C(R Y ) 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;
R x is selected from hydrogen, halogen, haloC 1 -C 3 alkyl, cyano, C 1 -C 6 alkyl and hydroxyC 1 -C 6 alkyl;
R Y is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 3 alkoxy, NR Y1 R Y2 , cyano, C 1 -C 3 alkoxyC 1 -C 3 alkoxy, C 1 -C 3 alkoxy-haloC 1 -C 3 alkoxy, di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkoxy, O—(CH 2 ) 0-1 —R Y3 , CR Y6 R Y7 , S—C 1 -C 3 allcyl and haloC 1 -C 6 alkoxy optionally substituted with hydroxy;

or
R x and R Y 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 C 1 -C 3 alkyl;
R Y1 is hydrogen and
R Y2 is selected from C 1 -C 6 alkyl; hydroxyC 1 -C 6 alkyl; haloC 1 -C 6 alkyl optionally substituted with hydroxy; C 1 -C 4 alkoxyC 1 -C 6 alkyl; haloC 1 -C 3 alkoxyC 1 -C 6 alkyl; (CH 2 ) 0-1 —R Y4 ; di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkyl substituted with hydroxy; bicycloC 5 -C 8 alkyl optionally substituted with hydroxyC 1 -C 3 alkyl; phenyl substituted with S(O) 2 —CH(CH 3 ) 2 ; and C 2 -C 3 alkylsulfonic acid;

or
R Y1 and R Y2 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 R Y5 ;
R Y3 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 R y3 is optionally substituted with C 1 -C 3 alkyl and/or oxo;
R Y4 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 C 1 -C 3 alkyl;
R Y5 is independently selected from C 1 -C 3 alkyl, hydroxy and di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl, or
two R Y5 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 C 1 -C 3 alkyl;
R Y6 and R Y7 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;
R 1 is selected from hydrogen; halogen; C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; hydroxyC 1 -C 3 alkyl; C 3 -C 6 cycloalkyl; CH 2 NR 2 R 3 ; CH(CH 3 )NR 2 R 3 ; C 1 -C 3 alkoxyC 1 -C 3 allcyl; CH 2 CO 2 H; C(O)H; C 1 -C 3 alkoxy; 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 C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, oxetanyl or oxo;
R 2 is selected from C 1 -C 3 alkyl and di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl;
R 3 is selected from C 1 -C 3 alkyl, C(O)C 1 -C 3 alkyl, C(O)—CH 2 —OH, C(O)—CH 2 —O—CH 3 , C(O)—CH 2 —N(CH 3 ) 2 and S(O) 2 CH 3 ;

or
R 2 and R 3 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 R 4 ;
R 4 is independently selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)amino, C(O)CH 3 and hydroxy;

or
two R 4 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 R 4 attached at the same ring atom form an oxo group;
R 5 is selected from hydrogen and C 1 -C 3 alkyl.

2. A compound according to claim 1 of formula (Ia) or a pharmaceutically acceptable salt thereof:

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R x is selected from halogen, haloC 1 -C 3 alkyl and cyano;
R Y is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 3 alkoxy, hydroxyC 1 -C 3 alkoxy, NR Y1 R Y2 , C 1 -C 3 alkoxyC 1 -C 3 alkoxy, C 1 -C 3 alkoxy-haloC 1 -C 3 alkoxy, di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkoxy and O—(CH 2 ) 0-1 —R Y3 ;
R 1 is selected from hydrogen, halogen, C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, hydroxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, CH 2 NR 2 R 3 and CH(CH 3 )NR 2 R 3 .

4. A compound according to claim 1 of formula (Ia-1), or a pharmaceutically acceptable salt thereof:

5. A compound of formula (Ia-1) according to claim 4 or a pharmaceutically acceptable salt thereof, wherein
R Y is selected from NR Y1 R Y2 , C 1 -C 3 alkoxyC 1 -C 3 alkoxy and O—(CH 2 ) 0-1 —R Y3 .

6. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
7-formyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(4,5-dichloropyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-chloropyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
7-formyl-N-(pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(4,5-dimethylpyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
7-formyl-N-(5-methylpyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-cyanopyrimidin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
6-formyl-N-(5-methylpyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxamide;
6-chloro-N-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
7-formyl-N-(6-methoxypyrimidin-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-cyanopyrazin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-cyano-4-methoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
6-formyl-N-(5-(trifluoromethyl)pyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxamide;
6-fluoro-7-formyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-chloro-4((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(4,5-dicyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
7-formyl-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-cyano-4-ethoxypyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
7-formyl-6-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-cyanopyridin-2-yl)-7-formyl-6-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
7-formyl-N-(5-(1-hydroxypentyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;
N-(5-cyano-4-(2-methoxyethoxy)

Assignees

• Buschmann Nicole
• Fairhurst Robin Alec
• Furet Pascal
• Knöpfel Thomas
• Leblanc Catherine
• Liao Lv
• Mah Robert
• Nimsgern Pierre
• Ripoche Sebastien
• Xiong Jing
• Han Bo
• Wang Can
• Zhao Xianglin
• Novartis Ag

Inventors

• Buschmann Nicole
• Fairhurst Robin Alec
• Furet Pascal
• Knöpfel Thomas
• Leblanc Catherine
• Liao Lv
• Mah Robert
• Nimsgern Pierre
• Ripoche Sebastien
• Xiong Jing
• Han Bo
• Wang Can
• Zhao Xianglin

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title