2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-12522594-B2
Application number	US-201816485049-A
Country	US
Kind code	B2
Filing date	Feb 2, 2018
Priority date	Feb 9, 2017
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

The present invention covers 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I), in which X, R 1 , R 2 , R 3 , R 4 and R 5 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 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):

wherein
R 1 is C 2 -C 6 -hydroxyalkyl, wherein said C 2 -C 6 -hydroxyalkyl groups are optionally substituted once with cyano, —COOR 10 , —CONR 11 R 12 , C 1 -C 4 -alkoxy or C 3 -C 6 -cycloalkyl and optionally one to three times with halogen, or
C 3 -C 6 -cycloalkyl substituted once with hydroxy and optionally once with C 1 -C 3 -alkyl and/or one to three times with halogen, or
C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkyl substituted once with hydroxy and optionally once with C 1 -C 3 -alkyl and/or one to three times with halogen, or
(C 3 -C 6 -cycloalkyl) 2 -C 1 -C 3 -alkyl substituted once with hydroxy and optionally once with C 1 -C 3 -alkyl and/or one to three times with halogen, or
4- to 6-membered heterocycloalkyl substituted once with hydroxy and optionally once with C 1 -C 3 -alkyl and/or one to three times with halogen;

R 2 is chloro, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
R 3 is hydrogen, fluoro, chloro or methyl;
R 4 is hydrogen or fluoro;
R 5 is monocyclic heteroaryl, which is optionally substituted one to three times, independently from each other, with R 6 ;
R 6 is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, halogen or cyano;
X is CH;
R 10 is C 1 -C 4 -alkyl; and
R 11 and R 12 are the same or different and are independently hydrogen or C 1 -C 3 -alkyl, or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a C1-C4-alkyl group,
or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, a solvate, a physiologically acceptable salt, a solvate of the physiologically acceptable salt, or a mixture of the same.

2 . The compound according to claim 1 , wherein:
R 1 is C 2 -C 6 -hydroxyalkyl, wherein said C 2 -C 6 -hydroxyalkyl groups are optionally substituted once with cyano, —COOR 10 , —CONR 11 R 12 , C 1 -C 2 -alkoxy or cyclopropyl and optionally one to three times with halogen, or
C 4 -C 6 -cycloalkyl substituted once with hydroxy and optionally once with C 1 -C 3 -alkyl and/or one to three times with halogen, or
C 3 -C 6 -cycloalkyl-methyl substituted once with hydroxy and optionally once with C 1 -C 3 -alkyl and/or one to three times with halogen, or
(C 3 -C 6 -cycloalkyl) 2 -methyl substituted once with hydroxy and optionally once with C 1 -C 3 -alkyl and/or one to three times with halogen, or
5- or 6-membered heterocycloalkyl substituted once with hydroxy and optionally once with C 1 -C 3 -alkyl and/or one to three times with halogen;
R 2 is chloro, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; R 3 is hydrogen or fluoro; R 4 is hydrogen or fluoro; R 5 is monocyclic heteroaryl, which is optionally substituted one to three times, independently from each other, with R 6 ; R 6 is methyl, difluoromethyl, methoxy, halogen or cyano; X is CH; R 10 is C 1 -C 4 -alkyl; and R 11 and R 12 are the same or different and are independently hydrogen or C 1 -C 3 -alkyl, or R 11 and R 12 together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a C1-C4-alkyl group,
or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, a solvate, a physiologically acceptable salt, a solvate of the physiologically acceptable salt, or a mixture of the same.

3 . The compound according to claim 1 , wherein:
R 1 is C 2 -C 5 -hydroxyalkyl, wherein said C 2 -C 5 -hydroxyalkyl groups are optionally substituted once with cyano, —COOCH 3 , —CONH 2 , methoxy or cyclopropyl and optionally one to three times with fluoro, or
C 4 -C 6 -cycloalkyl substituted once with hydroxy and optionally once with methyl and/or one to two times with fluoro, or
C 3 -C 4 -cycloalkyl-methyl substituted once with hydroxy, or
5- or 6-membered heterocycloalkyl substituted once with hydroxy, said heterocycloalkyl contains one oxygen atom;
R 2 is chloro, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy; R 3 is hydrogen; R 4 is hydrogen or fluoro; R 5 is a group selected from:

wherein * indicates the point of attachment of said group with the rest of the molecule;

R6a is hydrogen, methyl, fluoro or chloro; and
X is CH,
or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, a solvate, a physiologically acceptable salt, a solvate of the physiologically acceptable salt, or a mixture of the same.

4 . The compound according to claim 1 , wherein the compound is selected from the group consisting of:
N-(1-hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxy-3-methylbutan-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxybutan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxybutan-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxybutan-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxypropan-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropan-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3,3-difluoro-2-hydroxypropyl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3,3-difluoro-2-hydroxypropyl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1-hydroxy-3-methylbutan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1-hydroxypropan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-t

Assignees

• Deutsches Krebsforsch

Inventors

• Gutcher Ilona
• Röhn Ulrike
• Schmees Norbert
• Zorn Ludwig
• Röse Lars
• Bader Benjamin
• Kober Christina
• Carretero Rafael
• Stöckigt Detlef
• Irlbacher Horst
• Platten Michael

Classifications

• C07D237/14

  Oxygen atoms · CPC title

• A61K45/06

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• C07D413/04

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