3-oxo-2,6-diphenyl-2,3-dihydropyridazine-4-carboxamides

Patent metadata

Field	Value
Publication number	US-11040035-B2
Application number	US-201716303539-A
Country	US
Kind code	B2
Filing date	May 23, 2017
Priority date	May 25, 2016
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

The present invention covers 3-oxo-2,6-diphenyl-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I): in which R1, R2, R3, R4, R5 and R6 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with 10 dysregulated immune responses or other disorders associated with aberrant AHR signaling, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of formula (I):

in which
R 1 represents C 2 -C 6 -hydroxyalkyl, wherein said C 2 -C 6 -hydroxyalkyl is optionally substituted once with R 7 and optionally one to three times with halogen, or R 1 represents C 3 -C 6 -cycloalkyl substituted once with hydroxy;
R 2 represents chloro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy or difluoromethoxy;
R 3 represents hydrogen or methyl;
R 4 represents hydrogen or halogen;
R 5 represents hydrogen;
R 6 represents hydrogen or halogen;
R 7 represents C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl or monocyclic heteroaryl;

or an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, a solvate, a physiologically acceptable salt, or a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

2. The compound according to claim 1 , wherein:
R 1 represents C 2 -C 6 -hydroxyalkyl, wherein said C 2 -C 6 -hydroxyalkyl is optionally substituted once with R 7 and optionally one to three times with fluoro or chloro, or R 1 represents C 3 -C 6 -cycloalkyl substituted once with hydroxy;
R 2 represents chloro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy or difluoromethoxy;
R 3 represents hydrogen or methyl;
R 4 represents hydrogen, fluoro or chloro;
R 5 represents hydrogen;
R 6 represents hydrogen or fluoro;
R 7 represents methoxy, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl or imidazolyl;

or an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, a solvate, a physiologically acceptable salt, or a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

3. The compound according to claim 1 , wherein:
R 1 represents C 2 -C 6 -hydroxyalkyl, wherein said C 2 -C 6 -hydroxyalkyl is optionally substituted once with R 7 and optionally one to three times with fluoro;
R 2 represents chloro, methyl or difluoromethyl;
R 3 represents hydrogen or methyl;
R 4 represents hydrogen, fluoro or chloro;
R 5 represents hydrogen;
R 6 represents hydrogen or fluoro;
R 7 represents methoxy or tetrahydrofuranyl;

or an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, a solvate, a physiologically acceptable salt, or a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

4. The compound which is selected from the group consisting of:
2-(3-fluorophenyl)-N-(1-hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2R)-1-hydroxy-3-methylbutan-2-yl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-6-(4-methylphenyl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-6-(4-methylphenyl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-6-(4-methylphenyl)-3-oxo-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-(1-hydroxypropan-2-yl)-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-(2-hydroxy-3-methylbutyl)-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-2-hydroxy-3-methylbutyl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2R)-2-hydroxy-3-methylbutyl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-(2-hydroxypropyl)-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-2-hydroxypropyl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2R)-2-hydroxypropyl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-(2-hydroxy-3-methoxypropyl)-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2R)-2-hydroxy-3-methoxypropyl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-2-hydroxy-3-methoxypropyl]-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-(2-hydroxyethyl)-6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxybutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(1-hydroxypropan-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-3-oxo-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(2-hydroxy-3-methylbutyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-2-hydroxy-3-methylbutyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2R)-2-hydroxy-3-methylbutyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(2-hydroxy-3-methoxypropyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-2-hydroxy-3-methoxypropyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2R)-2-hydroxy-3-methoxypropyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(2-hydroxypropyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2R)-2-hydroxypropyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-2-hydroxypropyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[2-hydroxy-1-(-tetrahydrofuran-3-yl)ethyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-{(1S)-2-hydroxy-1-[(3R)-tetrahydrofuran-3-yl]ethyl}-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-{(1S)-2-hydroxy-1-[(3S)-tetrahydrofuran-3-yl]ethyl}-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-{(1R)-2-hydroxy-1-[(3R)-tetrahydrofuran-3-yl]ethyl}-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-{(1R)-2-hydroxy-1-[(3S)-tetrahydrofuran-3-yl]ethyl}-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-3-

Assignees

• Bayer Pharma AG
• Deutsches Krebsforschungszentrum Dkfz

Inventors

• Schmees Norbert
• Gutcher Ilona
• Irlbacher Horst
• Bader Benjamin
• Zhao Na
• Platten Michael
• Röhn Ulrike
• Zorn Ludwig
• Röse Lars
• Stöckigt Detlef

Classifications

• C07D405/12

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

• A61K31/50

  Pyridazines; Hydrogenated pyridazines · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title