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

Patent metadata

Field	Value
Publication number	US-11149018-B2
Application number	US-201816604157-A
Country	US
Kind code	B2
Filing date	Apr 4, 2018
Priority date	Apr 10, 2017
Publication date	Oct 19, 2021
Grant date	Oct 19, 2021

Abstract

The present application relates to novel substituted N-arylethyl-2-aminoquinoline-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. Compound of formula (I)

in which
Ar is phenyl or is 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 bonded to adjacent ring atoms, are optionally bonded 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 is a bond or a group of the formula
# 1 —X—(CR 10A R 10B ) k —# 2

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

R 10A and R 10B are independently hydrogen, fluorine or methyl,
or
R 10A and R 10B together with the carbon atom to which they are bonded form a cyclopropyl group,
k is 1, 2, 3 or 4,

R 1 is 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 are independently hydrogen, halogen or up to tri-fluorine-substituted methyl,
R 5 is 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 is —NR 12 R 13
in which
R 12 is hydrogen or (C 1 -C 3 )-alkyl, and
R 13 is (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,
in which (C 3 -C 7 )-cycloalkyl may be up to tetrasubstituted by fluorine and (C 1 -C 4 )-alkyl may be up to pentasubstituted by fluorine or monosubstituted by (C3-C6)-cycloalkyl, methoxy, trifluoromethoxy or phenyl,
in which phenyl may be up to trisubstituted by fluorine,

or
is a saturated or partially unsaturated, 4- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocycle which is attached via a nitrogen atom and may contain one further, identical or different heteroatom from the group consisting of N, O, S, SO and SO 2 as ring member,
where the 4- to 8-membered monocyclic and 6- to 10-membered bicyclic heterocycle may each be substituted by 1 to 3 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo, (C 1 -C 3 )-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, amino, monomethylamino, dimethylamino, aminocarbonyl, monomethylaminocarbonyl, dimethylaminocarbonyl, and additionally up to tetrasubstituted by fluorine,
in which (C 1 -C 4 )-alkyl may be up to pentasubstituted by fluorine or monosubstituted by hydroxyl or methoxy,

R 7A and R 7B are independently hydrogen or methyl,
or
R 7A and R 7B together with the carbon atom to which they are bonded form a cyclopropyl group,
R 8 is hydrogen, fluorine, methyl, trifluoromethyl, ethyl or hydroxyl,
R 9 is hydrogen or methyl,
and/or an N-oxide, salt, solvate, salt of an N-oxide and/or a solvate of an N-oxide and/or salt thereof.

2. Compound of formula (I) according to claim 1 in which
Ar is phenyl,
where phenyl may be up to tetrasubstituted by fluorine or up to trisubstituted, identically or differently, by fluorine, chlorine, methyl, trifluoromethyl, difluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,

Y is a bond or a group of the formula
# 1 —(CH 2 ) n —# 2

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

R 1 is bromine or ethynyl,
R 2 , R 3 and R 4 are each hydrogen,
R 5 is chlorine or methyl,
and
R 6 is —NR 12 R 13
in which
R 12 is hydrogen or methyl, and
R 13 is (C1-C4)-alkyl,
in which (C1-C4)-alkyl may be up to trisubstituted by fluorine or monosubstituted by phenyl,

or
is a saturated or partially unsaturated, 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocycle which is attached via a nitrogen atom and may contain one further, identical or different heteroatom from the group consisting of N, O and S as ring member,
where the 5- to 7-membered monocyclic and 7- to 10-membered bicyclic heterocycle may each be substituted by 1 or 2 substituents independently selected from the group consisting of methyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, isopropyl, and additionally up to tetrasubstituted by fluorine,

R 7A , R 7B , R 8 and R 9 are each hydrogen,
and/or a salt, solvate and/or solvate of a salt thereof.

3. Compound of formula (I) according to claim 1 in which
Ar is phenyl,
where phenyl may be up to trisubstituted, identically or differently, by fluorine, chlorine, methyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy,

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

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

R 1 is bromine,
R 2 , R 3 , R 4 are each hydrogen,
R 5 is methyl,
R 6 is a group of the formula

where
# 3 is the attachment site to the rest of the molecule,
R 14 is fluorine or methyl,
R 15 is fluorine, methyl or ethyl,

R 7A , R 7B , R 8 and R 9 are each hydrogen,
and/or a salt, solvate and/or solvate of a salt thereof.

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

in which
T is an ester protecting group,
with an amine compound of formula (III)
R 6 —H  (III),

to obtain a compound of formula (IV)

and
[B] detaching the ester radical T of the compound of formula (IV)

in which
T is an ester protecting group,
to obtain the compound of formula (I)

wherein the compound of formula (I) is optionally separated into enantiomers and/or diastereomers and/or converted with one or more appropriate (i) solvents and/or (ii) bases or acids to a solvate, salt and/or solvate of a salt thereof.

5. Compound as defined in claim 1 for treatment and/or prevention of diseases.

6. Compound as defined in claim 1 for use in a method for treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and eye disorders and fibrotic disorders of the internal organs.

7. A product comprising a compound as defined in claim 1 for production of a medicament for treatment and/or prevention of idiopathic pulmonary

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

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

Classifications

• C07D417/04

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

• C07D413/04

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

• C07D401/12

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

• C07D401/04 Primary

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

• C07D215/50 Primary

  attached in position 4 · CPC title