Furane derivatives as inhibitors of ATAD2

Patent metadata

Field	Value
Publication number	US-10654818-B2
Application number	US-201615779691-A
Country	US
Kind code	B2
Filing date	Nov 30, 2016
Priority date	Dec 3, 2015
Publication date	May 19, 2020
Grant date	May 19, 2020

Abstract

The invention relates to furane derivatives of formula (I) as inhibitors of ATAD2, a process for their preparation and use thereof.

First claim

The invention claimed is:

1. A compound of general formula I

in which
R 1 represents a benzyl group wherein the α-position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group, a halogen atom, a 4-trifluoromethyl group,
R 2 represents a C 1-6 -alkyl group,
a C 1-6 -hydroxyalkyl group,
a —C 1-3 -alkylen-O—(C 1-6 -alkyl) group,
a —C 1-6 -aminoalkyl group,
a —C 1-3 -alkylen-N—(C 1-6 -alkyl) 2 group,
a —C 1-3 -alkylen-NH—(C 1-6 -alkyl) group,
a —C 1-3 -alkylen-NH—(C 1-4 -alkyl)-OH group,
a —C 1-3 -alkylen-NH—(C 3-7 -cycloalkyl)-NH 2 group,
a —C 1-3 -alkylen-NH—C 1-4 -alkylen-heterocycloalkyl group which is optionally substituted with C 1-3 -alkyl,
a —C 1-3 -alkylen-NH-heterocycloalkyl group which is optionally substituted independently from each occurrence one or more times with C 1-4 -alkyl, halogen, benzyl, C(O)R 7 ,
a —C 1-3 -alkylen-NH—(C 1-3 -alkylen)-phenyl group,
a —C 1-3 -alkylen-NH—C(O)(C 1-4 -alkyl) group,
a —C 1-3 -alkylen-NH—C(O)—C 1-4 -alkylen-heterocycloalkyl group,
a —C 1-3 -alkylen-NH—C 1-3 -alkylen-C(O)-heterocycloalkyl group,
a —C 1-3 -alkylen-NH—C(O)-heterocycloalkyl group,
a —C 1-3 -alkylen-NH—S(O) 2 -(C 1-4 -alkyl) group,
a —C 1-3 -alkylen-(4-cyano-phenyl) group, a —C 1-3 -alkylen-C(O)—NH—(C 1-6 -alkyl) group,
a —C 1-3 -alkylen-C(O)—NH—(C 1-4 -alkyl)-OH group,
a —C 1-3 -alkylen-C(O)—NR 8 R 9 group,
a —C 1-3 -alkylen-C(O)—R 7 group,
a —C 1-3 -alkylen-C(O)-heterocycloalkyl group which is optionally substituted with C 1-3 -alkyl,
a —C 1-3 -alkylen-heterocycloalkyl group which is optionally one or more times substituted with C 1-3 -alkyl,
a C(O)R 7 group,
a —C(O)—NR 8 R 9 group,
a C(O)—NH—(C 3-7 -cycloalkyl)-NH 2 group,
a —C(O)—NH-heterocycloalkyl group which is optionally substituted with C 1-3 -alkyl, a heteroaryl group,

R 3 a —C 1-3 -alkylen-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C 1-3 -alkyl, C 1-3 -alkoxy, amino, C(O)R 7 , C(O)NR 8 R 9 ,
a —C 1-4 -alkylen-heteroaryl group, or
R 2 and R 3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom of absolute configuration R

R 4 represents a hydrogen atom, a methyl group, a chlorine atom,
R 5 represents a hydrogen atom or a halogen atom,
R 6 represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-3 alkoxy group, or a cyano group,
R 7 represents a —O—C 1-4 -alkyl group,
R 8 , R 9 , represents, independently for each occurrence, a hydrogen atom or a C 1-4 -alkyl group, or the salts thereof, the solvates thereof or the solvates of the salts thereof,
with the proviso that the following compounds
2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamide
are excluded.

2. The compound according to claim 1 , in which in which
R 1 represents a benzyl group wherein the α-position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group, a halogen atom, a 4-trifluoromethyl group,
R 2 represents a C 1-3 -alkyl group,
a C 1-3 -hydroxyalkyl group,
a —C 1-3 -alkylen-O—(C 1-3 -alkyl) group,
a —C 1-3 -aminoalkyl group,
a —C 1-3 -alkylen-N—(C 1-3 -alkyl) 2 group,
a —C 1-3 -alkylen-NH—(C 1-3 -alkyl) group,
a —C 1-3 -alkylen-NH—(C 1-3 -alkyl)-OH group,
a —C 1-3 -alkylen-NH—(C 5-6 -cycloalkyl)-NH 2 group,
a —C 1-3 -alkylen-NH—C 1-3 -alkylen-heterocycloalkyl group which is optionally substituted with C 1-3 -alkyl,
a —C 1-3 -alkylen-NH-heterocycloalkyl group which is optionally substituted independently from each occurrence one or more times with C 1-4 -alkyl, halogen, benzyl, C(O)R 7 ,
a —C 1-3 -alkylen-NH—(C 1-3 -alkylen)-phenyl group,
a —C 1-3 -alkylen-NH—C(O)(C 1-3 -alkyl) group,
a —C 1-3 -alkylen-NH—C(O)—C 1-3 -alkylen-heterocycloalkyl group,
a —C 1-3 -alkylen-NH—C 1-3 -alkylen-C(O)-heterocycloalkyl group,
a —C 1-3 -alkylen-NH—C(O)-heterocycloalkyl group,
a —C 1-3 -alkylen-NH—S(O) 2 -(C 1-3 -alkyl) group,
a —C 1-3 -alkylen-(4-cyano-phenyl) group,
a —C 1-3 -alkylen-C(O)—NH—(C 1-3 -alkyl) group,
a —C 1-3 -alkylen-C(O)—NH—(C 1-3 -alkyl)-OH group,
a —C 1-3 -alkylen-C(O)—NR 8 R 9 group,
a —C 1-3 -alkylen-C(O)—R 7 group,
a —C 1-3 -alkylen-C(O)-heterocycloalkyl group which is optionally substituted with C 1-3 -alkyl,
a —C 1-3 -alkylen-heterocycloalkyl group which is optionally one or more times substituted with C 1-3 -alkyl,
a C(O)R 7 group,
a —C(O)—NR 8 R 9 group,
a C(O)—NH—(C 5-6 -cycloalkylen)-NH 2 group,
a —C(O)—NH-heterocycloalkyl group which is optionally substituted with C 1-3 -alkyl a heteroaryl group,

R 3 a —C 1-3 -alkylen-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C 1-3 -alkyl, C 1-3 -alkoxy, amino, C(O)R 7 , C(O)NR 8 R 9 ,
a —C 1-4 -alkylen-heteroaryl group, or
R 2 and R 3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom

R 4 represents a hydrogen atom, a methyl group, a chlorine atom,
R 5 represents a hydrogen atom or a halogen atom
R 6 represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-3 alkoxy group, or a cyano group,
R 7 represents a —O—C 1-4 -alkyl group
R 8 , R 9 , represents, independently for each occurrence, a hydrogen atom or a C 1-4 -alkyl group, or the salts thereof, the solvates thereof or the solvates of the salts thereof,
with the proviso that the following compounds

2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamide
are excluded.

3. The compound according to claim 1 , in which
R 1 represents a benzyl group wherein the α-position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be

Assignees

• Bayer Pharma AG

Inventors

• Berger Markus
• Hübner Jan
• Ter Laak Antonius
• Gorjanacz Matyas
• Fernandez-Montalvan Amaury Ernesto
• Rodeschini Vincent
• Roche Didier

Classifications

• C07D405/12

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

• A61K31/4525

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/341

  not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title