Formylated N-heterocyclic derivatives as FGFR4 inhibitors

Patent metadata

Field	Value
Publication number	US-10189813-B2
Application number	US-201615561189-A
Country	US
Kind code	B2
Filing date	Mar 23, 2016
Priority date	Mar 25, 2015
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

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) in free form or in pharmaceutically acceptable salt form

wherein
X is N or CH;
A is C(O) and B is NR 5 or
A and B together form part of a 5- or 6-membered aromatic ring wherein A is C and B is C or N;
R 1 is selected from hydrogen, hydroxyC 1 -C 3 alkyl, haloC 1 -C 3 alkyl, CO 2 H, CH 2 NR 2 R 3 , a 5-membered 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 C 1 -C 3 alkyl;
R 2 is C 1 -C 3 alkyl and R 3 is C(O)C 1 -C 3 alkyl
or
R 2 and R 3 together with the N to which they are attached form a saturated 5- or 6-membered ring optionally comprising one additional heteroatom selected from N, O or S, which ring is optionally substituted once or more than once with R 4 ;
R 4 is for each occurrence independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy or two R 4 attached at the same carbon atom form an oxo group;
R 5 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl, (CH 2 ) 0-1 —R 6 ;
R 6 is a 4-, 5-, or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O, or S;
R 7 is selected from cyano, haloC 1 -C 3 alkyl;
R 8 is selected from hydrogen, NR 9 R 10 , C 1 -C 6 alkoxy;
R 9 is hydrogen;
R 10 is selected from C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 4 alkoxyC 1 -C 6 alkyl.

2. A compound according to claim 1 of formula (Ia) in free form or in pharmaceutically acceptable salt form

3. A compound according to claim 1 of formula (Ib) in free form or in pharmaceutically acceptable salt form

wherein n is 0 or 1;
B is C or N;
D, E, F, G are each independently selected from CH or N, provided that when n is 0, at least one of B, E, F or G is N.

4. A compound according to claim 1 in free form or in pharmaceutically acceptable salt form wherein X is CH.

5. A compound according to claim 1 in free form or in pharmaceutically acceptable salt form which is selected from
6-((2-(6-formylpyridin-2-yl)phenyl)amino)nicotinonitrile;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-(6-formylpyridin-2-yl)-1-methylurea;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-(6-formylpyridin-2-yl)-1-(2-methoxyethyl)urea;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-(6-formylpyridin-2-yl)-1-((tetrahydrofuran-3-yl)methyl)urea;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-(6-formyl-5-(hydroxymethyl)pyridin-2-yl)-1-((tetrahydrofuran-3-yl)methyl)urea;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-ethyl-1-(6-formyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)urea;
3-(5-cyano-4-(isopropylamino)pyridin-2-yl)-1-ethyl-1-(6-formyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)urea;
3-(5-cyano-4-isopropoxypyridin-2-yl)-1-ethyl-1-(6-formyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)urea;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-methyl-1-(6-formyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-(isopropylamino)pyridin-2-yl)-1-(6-formyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-1-methylurea;
N-((6-(3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-methylureido)-2-formylpyridin-3-yl)methyl)-N-methylacetamide;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-(5-(difluoromethyl)-6-formylpyridin-2-yl)-1-methylurea;
3-(5-cyano-4-isopropoxypyridin-2-yl)-1-(6-formyl-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-isopropoxypyridin-2-yl)-1-(5-(difluoromethyl)-6-formylpyridin-2-yl)-1-methylurea;
3-(5-cyanopyridin-2-yl)-1-(6-formyl-5-((2-oxopyrrolidin-1-yl)methyl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-(6-formyl-5-((2-oxopyrrolidin-1-yl)methyl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-isopropoxypyridin-2-yl)-1-(6-formyl-5-((4-methyl-2-oxopiperazin-1-yl)methyl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)-1-(6-formyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-isopropoxypyridin-2-yl)-1-(6-formyl-5-((2-oxopyrrolidin-1-yl)methyl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-1-(6-formyl-5-((4-methyl-2-oxopiperazin-1-yl)methyl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-isopropoxypyridin-2-yl)-1-(6-formyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-1-methylurea;
3-(5-cyano-4-isopropoxypyridin-2-yl)-1-(6-formyl-5-((3-methoxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-methylurea;
6-(2-((4-((2-methoxyethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-imidazol-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)picolinaldehyde;
6-(5-((4-((2-methoxyethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)picolinaldehyde;
3-(5-cyano-4-isopropoxypyridin-2-yl)-1-(6-formyl-5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)-1-methylurea and
1-(5-cyano-4-isopropoxypyridin-2-yl)-3-(4-formylpyrimidin-2-yl) urea.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

Assignees

• Buschmann Nicole
• Fairhurst Robin Alec
• Furet Pascal
• Knoepfel Thomas
• Leblanc Catherine
• Mah Robert
• Novartis Ag

Inventors

• Buschmann Nicole
• Fairhurst Robin Alec
• Furet Pascal
• Knoepfel Thomas
• Leblanc Catherine
• Mah Robert

Classifications

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D213/85

  in position 3 · CPC title