Substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-A]pyridine-3(2H)-ones and 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-C][1,2,4]triazol-3-ones, and use thereof

Patent metadata

Field	Value
Publication number	US-10722501-B2
Application number	US-201716300480-A
Country	US
Kind code	B2
Filing date	May 8, 2017
Priority date	May 9, 2016
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

The present application relates to novel substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-ones and 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-ones of formula (I), to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of lung inflammation disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is (C 1 -C 4 )-alkylene or CD 2 ,
wherein (C 1 -C 4 )-alkylene is optionally substituted by hydroxyl and (C 1 -C 4 )-alkoxy and optionally up to pentasubstituted by fluorine;
or

A is a group of the formula

wherein
n is 0 or 1,
P is 0 or 1,
q is 1 or 2,
wherein
# 1 marks the bond to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, and
* marks the bond to R 1 ;
X is —CR 6 R 7 —, # 2 -CR 6 R 7 —CR 8 R 9 —**, # 2 -CR 6 ═CR 8 —**, or
# 2 -CR 6 R 7 —CR 8 R 9 —CR 10 R 11 —**,
wherein # 2 marks the bond to the carbon atom of the CR 4 R 5 — group, and
wherein ** marks the bond to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring;
wherein
R 6 is hydrogen, fluorine, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, hydroxyl, mono-(C 1 -C 4 )-alkylamino, or di-(C 1 -C 4 )-alkylamino,
wherein (C 1 -C 4 )-alkyl is optionally substituted by (C 1 -C 4 )-alkoxy, hydroxyl, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and optionally up to pentasubstituted by fluorine;

R 7 is hydrogen, fluorine, or (C 1 -C 4 )-alkyl,
wherein (C 1 -C 4 )-alkyl is optionally up to pentasubstituted by fluorine;

or
R 6 and R 7 together with the carbon atom to which they are bonded form a carbonyl group;
or
R 6 and R 7 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring, or cyclopentyl ring;
or
R 6 and R 4 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring, or cyclopentyl ring;
R 8 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, fluorine, hydroxyl, mono-(C 1 -C 4 )-alkylamino, or di-(C 1 -C 4 )-alkylamino,
wherein (C 1 -C 4 )-alkyl is optionally substituted by (C 1 -C 4 )-alkoxy, hydroxyl, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and optionally up to pentasubstituted by fluorine;

R 9 is hydrogen, fluorine or (C 1 -C 4 )-alkyl,
wherein (C 1 -C 4 )-alkyl is optionally up to pentasubstituted by fluorine;

or
R 8 and R 9 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring, or cyclopentyl ring;
or
R 7 and R 9 together with the carbon atoms to which they are bonded form a cyclopropyl ring, cyclobutyl ring, or cyclopentyl ring;
R 10 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, fluorine, hydroxyl, mono-(C i —C 4 )-alkylamino, or di-(C 1 -C 4 )-alkylamino,
wherein (C 1 -C 4 )-alkyl is optionally substituted by (C 1 -C 4 )-alkoxy, hydroxyl, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and optionally up to pentasubstituted by fluorine;

R 11 is hydrogen, fluorine, or (C 1 -C 4 )-alkyl,
wherein (C 1 -C 4 )-alkyl is optionally up to pentasubstituted by fluorine;

or
R 10 and R 11 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring;
R 1 is (C 3 -C 7 )-cycloalkyl, phenyl or 5- to 6-membered heteroaryl,
wherein (C 3 -C 7 )-cycloalkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, cyano, trifluoromethyl, (C 1 -C 4 )-alkyl, and (C 1 -C 4 )-alkoxy,
wherein (C 1 -C 4 )-alkyl is optionally up to pentasubstituted by fluorine;

wherein phenyl is substituted by 1 to 4 substituents independently selected from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, (C 3 -C 5 )-cycloalkoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 3 -C 5 )-cycloalkylaminocarbonyl, (C 1 -C 4 )-alkylsulphanyl, (C 1 -C 4 )-alkylsulphonyl, (C 1 -C 4 )-alkylsulphonimidoyl, (C 1 -C 4 )-cycloalkylsulphonyl, aminosulphonyl, mono-(C 1 -C 4 )-alkylaminosulphonyl, di-(C 1 -C 4 )-alkylaminosulphonyl, (C 1 -C 4 )-alkylsulphinyl, amino, mono-(C 1 -C 4 )-alkylamino, and di-(C 1 -C 4 )-alkylamino,
or
wherein phenyl is optionally fused to (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-heterocyclyl or 5- to 6-membered heteroaryl,
wherein phenyl is optionally substituted by methyl, ethyl, chlorine, fluorine or methoxy,
wherein (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-heterocyclyl and 5- to 6-membered heteroaryl is optionally substituted by 1 or 2 (C 1 -C 4 )-alkyl substituents,
wherein (C 1 -C 4 )-alkyl is optionally substituted by (C 1 -C 4 )-alkoxy, hydroxyl, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and optionally up to pentasubstituted by fluorine,

or
wherein 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, (C 3 -C 5 )-cycloalkoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, phenyl, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 3 -C 5 )-cycloalkylaminocarbonyl, (C 1 -C 4 )-alkylsulphanyl, (C 1 -C 4 )-alkylsulphonyl, (C 1 -C 4 )-alkylsulphonimidoyl, (C 1 -C 4 )-cycloalkylsulphonyl, amino sulphonyl, mono-(C 1 -C 4 )-alkylamino sulphonyl, di-(C 1 -C 4 )-alkylaminosulphonyl, (C 1 -C 4 )-alkylsulphinyl, amino, mono-(C 1 -C 4 )-alkylamino, and di-(C 1 -C 4 )-alkylamino,
wherein phenyl is optionally substituted by methyl, ethyl, chlorine, fluorine or methoxy,

or
wherein said 5- to 6-membered heteroaryl of R 1 is optionally fused to (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-heterocyclyl, phenyl or 5- to 6-membered heteroaryl,
wherein said 5- to 6-membered heteroaryl of R 1 is optionally substituted by methyl, ethyl, chlorine, fluorine or methoxy,
wherein (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-heterocyclyl, phenyl and 5- to 6-membered heteroaryl fused to said 5- to 6-membered heteroaryl of R 1 are optionally substituted by 1 or 2 (C 1 -C 4 )-alkyl substituents,
 wherein (C 1 -C 4 )-alkyl is optionally substituted by (C 1 -C 4 )-alkoxy, hydroxyl, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and up to pentasubstituted by fluorine;

R 2 is a group of the formula

wherein

# 3 marks the bond to the carbonyl carbon atom,
r is 0 or 1,
Z is O, NR 18 , S, SO, SO 2 , or CR 14A R 14B ,
wherein
R 14A is hydrogen, halogen, cyano, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, (C 3 -C 5 )-cycloalkoxy, difluoromethoxy, trifluoromethoxy, or 2,2,2-trifluoroethoxy,
wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxyl, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino,

R 14B is hydrogen, fluorine or (C 1 -C 4 )-alkyl,
wherein (C 1 -C 4 )-alkyl is optionally up to pentasubstituted by fluorine,
or
R 14A and R 14B together with the carbon atom to which they are bonded form a carbonyl group,
R 18 is hydrogen or methyl,

R 12 is hydrogen, cyano, (C 1 -C 4 )-alkyl, acetyl,

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Biber Nicole
• Brockschnieder Damian
• Gericke Kersten Matthias
• Kölling Florian
• Lustig Klemens
• Meding Jörg
• Meier Heinrich
• Neubauer Thomas
• Schäfer Martina
• Timmermann Andreas
• Zubov Dmitry
• Terjung Carsten
• Lindner Niels
• Badock Volker
• Moosmayer Dieter
• Miyatake Ondozabal Hideki
• Moore Stephen
• Schulz Alexander

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/4709

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