Substituted N-arylethyl-2-arylquinoline-4-carboxamides and use thereof

Patent metadata

Field	Value
Publication number	US-11136296-B2
Application number	US-201816603719-A
Country	US
Kind code	B2
Filing date	Apr 4, 2018
Priority date	Apr 10, 2017
Publication date	Oct 5, 2021
Grant date	Oct 5, 2021

Abstract

The present application relates to novel substituted N-arylethyl-2-arylquinoline-4-carboxamide derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of fibrotic and inflammatory disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
Ar represents phenyl or represents pyridyl,
where phenyl may be up to tetrasubstituted and pyridyl up to disubstituted, in each case identically or differently, by fluorine, chlorine, by up to tri-fluorine-substituted (C 1 -C 4 )-alkyl, up to tetra-fluorine-substituted (C 3 -C 4 )-cycloalkyl, up to tri-fluorine-substituted (C 1 -C 2 )-alkoxy, or up to tri-fluorine-substituted (C 1 -C 2 )-alkylsulfanyl, or where two substituents of the phenyl or pyridyl group, if they are attached to adjacent ring atoms, are optionally attached to one another in such a way that they together form a methylenedioxy or ethylenedioxy group,
or
where phenyl may be up to pentasubstituted by fluorine,

Y represents a bond or a group of the formula

where
# 1 represents the attachment site to the carbon atom,
# 2 represents the attachment site to the carboxyl group,
X represents a bond, —CH 2 —, —O—, —S(═O) m — or —N(R 11 )—, in which
m represents 0, 1 or 2 and
 R 11 represents hydrogen or methyl,

 R 10A and R 10B independently of one another represent hydrogen, fluorine or methyl,

or
R 10A and R 10B together with the carbon atom to which they are attached form a cyclopropyl group,

k represents 1, 2, 3 or 4,
R 1 represents halogen, up to penta-fluorine-substituted (C 1 -C 4 )-alkyl, up to tri-fluorine-substituted methoxy, (trifluoromethyl)sulfanyl, pentafluorosulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,

where cyclopropyl and cyclobutyl may be up to tetrasubstituted by fluorine,

R 2 , R 3 and R 4 independently of one another represent hydrogen, halogen or up to tri-fluorine-substituted methyl,
R 5 represents halogen, up to penta-fluorine-substituted (C 1 -C 4 )-alkyl, up to tri-fluorine-substituted methoxy, hydroxyl, methylsulfanyl, (trifluoromethyl)sulfanyl, cyano, ethenyl, cyclopropyl or cyclobutyl,
where cyclopropyl and cyclobutyl may be up to tetrasubstituted by fluorine,

R 6 represents phenyl which may be up to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine,
methyl, which is up to trisubstituted by fluorine, and methoxy, which is up to trisubstituted by fluorine, or represents thienyl which may be mono- or disubstituted by methyl or monosubstituted by chlorine or bromine, or represents thiazolyl or pyridyl,
R 7A and R 7B independently of one another represent hydrogen or methyl,
or
R 7A and R 7B together with the carbon atom to which they are attached
form a cyclopropyl group,
R 8 represents hydrogen, fluorine, methyl, trifluoromethyl, ethyl or hydroxyl,
R 9 represents hydrogen or methyl,
and/or an N-oxide, salt, solvate, salt of an N-oxide and solvate of an N-oxide and/or salt thereof.

2. The compound of formula (I) as claimed in claim 1 , in which
Ar represents phenyl or represents 2-pyridyl,
where phenyl may be up to tetrasubstituted by fluorine or up to trisubstituted by identical or different fluorine, chlorine, methyl, trifluoromethyl, difluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy substituents, or where two substituents of the phenyl group, if they are attached to adjacent ring atoms, are optionally attached to one another in such a way that they together form a methylenedioxy group, and
where 2-pyridyl may be up to disubstituted by identical or different substituents from the group consisting of chlorine and methoxy,

Y is a bond or a group of the formula
# 1 —X—(CR 10A R 10B ) k —# 2

where
# 1 represents the attachment site to the carbon atom,
# 2 represents the attachment site to the carboxyl group,
X represents a bond, —CH 2 —, —O—, —S(═O) m — or —N(R 11 )—, in which
m represents 0 or 2 and
R 11 represents hydrogen or methyl,

R 10A and R 10B are independently hydrogen, fluorine or methyl,
k represents 1, 2 or 3,

R 1 represents chlorine, bromine, iodine, methyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl)sulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,
R 2 represents hydrogen,
R 3 and R 4 independently of one another represent hydrogen, chlorine or methyl,
R 5 represents fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, methylsulfanyl or cyclopropyl,
and
R 6 represents phenyl which may be mono- or disubstituted by identical or different fluorine or chlorine substituents or monosubstituted by methyl, trifluoromethyl, methoxy or trifluoromethoxy, or represents thienyl which may be mono- or disubstituted by methyl or monosubstituted by chlorine or bromine,
R 7A represents hydrogen or methyl,
R 7B represents hydrogen,
R 8 represents hydrogen, fluorine, methyl, ethyl or hydroxy,
R 9 represents hydrogen,
and/or a salt, solvate and/or solvate of a salt thereof.

3. The compound of formula (I) as claimed in claim 1 , in which
Ar represents phenyl,
where phenyl may be up to tetrasubstituted by fluorine or up to trisubstituted by identical or different fluorine, chlorine, methyl, trifluoromethyl, difluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy substituents,

Y represents a group of the formula
# 1 —(CH 2 ) n —# 2

where
# 1 represents the attachment site to the carbon atom,
# 2 represents the attachment site to the carboxyl group,
n represents 1, 2 or 3,

R 1 represents bromine or ethynyl,
R 2 , R 3 and R 4 each represent hydrogen,
R 5 represents chlorine or methyl,
and
R 6 represents phenyl which may be monosubstituted by fluorine,
R 7A and R 7B each represent hydrogen,
R 8 represents hydrogen or methyl,
R 9 represents hydrogen,
and/or a salt, solvate and/or solvate of a salt thereof.

4. The compound of formula (I) as claimed in claim 1 , in which
Ar represents phenyl,
where phenyl may be up to tetrasubstituted by fluorine or up to trisubstituted by identical or different fluorine, chlorine, methyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy substituents,

Y represents a group of the formula
# 1 —CH 2 CH 2 —# 2

where
# 1 represents the attachment site to the carbon atom,
# 2 represents the attachment site to the carboxyl group,

R 1 represents bromine or ethynyl,
R 2 , R 3 , R 4 each represent hydrogen,
R 5 represents methyl or chlorine,
R 6 represents phenyl,
R 7A , R 7B , R 8 and R 9 are each hydrogen,
and/or a salt, solvate and/or solvate of a salt thereof.

5. A process for preparing a compound of formula (I) as defined in claim 1 , comprising:
[A] reacting a compound of formula (II)

with activation of the carboxylic acid function, with an amine compound of formula (III-A)

to obtain a compound of formula (I)

or with an amine compound of formula (III-B)

in which
T represents an ester protecting group,

to obtain a compound of formula (I

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Beck Hartmut
• Kast Raimund
• Meininghaus Mark
• Dietz Lisa
• Fuerstner Chantal
• Stellfeld Timo
• Anlauf Sonja
• Von Buehler Clemens-Jeremias
• Bairlein Michaela
• Anlahr Johanna
• Muenster Uwe
• Terjung Carsten
• Joerissen Hannah
• Hauff Peter
• Mueller Joerg
• Droebner Karoline
• Nagel Jens

Classifications

• C07D215/50 Primary

  attached in position 4 · CPC title

• C07D401/12

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

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• C07D405/12

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