Sulphur substituted 3-oxo-2,3-dihydropyridazine-4-carboxamides
Disclosed are compounds of general formula (I): wherein R 1 , R 2 , A, X, Y and Z are as defined herein, methods of preparing the compounds, intermediate compounds useful for preparing the compounds, pharmaceutical compositions and combinations comprising the compounds and the use of the 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.
1. A compound of formula (I):
wherein
A is a group selected from the group consisting of
wherein * indicates the point of attachment of said group with the rest of the molecule;
X is CH;
Y is CH or N;
Z is CH;
R 1 is ethyl or propyl substituted once with R 7 , or
a group selected from the group consisting of
wherein * indicates the point of attachment of said group with the rest of the molecule;
R 2 is chloro or trifluoromethyl;
R 7 is —SR 10 , —SO—R 10 , —SO 2 —R 10 , or —SO(NR 8 )—R 10 ;
R 8 is hydrogen or trifluoroacetyl; and
R 10 is methyl; or
a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.
2. The compound according to claim 1 , which is selected from the group consisting of:
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-(methylsulfanyl)propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-(methylsulfonyl)propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-(methylsulfinyl)propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-{(2S)-1-[(R)-methylsulfinyl]propan-2-y}-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-{(2S)-1-[(S)-methylsulfinyl]propan-2-yl}-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-(S-methylsulfonimidoyl)propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-[(R)-S-methylsulfonimidoyl]propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-[(S)-S-methylsulfonimidoyl]propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-1-(methylsulfanyl)propan-2-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(cis)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
(−)-N-[(cis)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
(+)-N-[(cis)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(cis)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(3R,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(3 S,4R)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(cis)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(3R,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(3 S,4R)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[(cis)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[3R,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;
2-(3-fluorophenyl)-N-[3S,4R)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-[2S)-1-(methylsulfonyl)propan-2-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-1-(methylsulfinyl)propan-2-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-{(2S)-1-[(R)-methylsulfinyl[propan-2-yl}-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-{(2S)-1-[(S)-methylsulfinyl[propan-2-yl}-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(3R,4S)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(3S,4R)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(1S,3S,4R)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(1R,3 S,4R)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-1(1S,3R,4S)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(1R,3R,4S)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
N-[(cis)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(cis)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(1S,3 S,4R)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(1R,3S,4R)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(1S,3R,4S)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
N-[(1R,3R,4S)-4-hydroxy-1-oxidotetrahydrothiophen-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-1-(S-methylsulfonimidoyl)propan-2-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-1-[(R)-(S-methylsulfonimidoyl[propan-2-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-1-[(S)-S-methylsulfonimidoyl[propan-2-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
2-(1-methyl-1H-pyrazol-4-yl)-N-{(2S)-1-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]propan-2-yl}-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(3R,4S)-4-hydroxy-1-imino-1-oxidotetrahydro-1H-1λ 6 -thiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(3 S,4R)-4-hydroxy-1-imino-1-oxidotetrahydro-1H-1λ 6 -thiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(cis)-4-hydroxy-1-imino-1-oxidotetrahydro-1H-1λ 6 -thiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide, diatereomer 1;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(3 S,4R)-4-hydroxy-1-imino-1-oxidotetrahydro-1H-1λ 6 -thiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide, isomer 1;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(3 S,4R)-4-hydroxy-1-imino-1-oxidotetrahydro-1H-11λ 6 -thiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide, isomer 2;
N-[(cis)-4-hydroxy-1-imino-1-oxidotetrahydro-1H-1λ 6 -thiophen-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-1-(methylsulfanyl)propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-1-(methylsulfinyl)propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-[(2S)-1-(methylsulfonyl)propan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[2-(methylsulfinyl)ethyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[2-(S-methylsulfonimidoyl)ethyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-{2-[(R)-S-methylsulfonimidoyl]ethyl}-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-{2-[(R)-S-methylsulfonimidoyl]ethyl}-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(cis)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(3R,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(3S,4R)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;
6-(4-chlorophenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; and
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[2-(methylsulfonyl)ethyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; or
a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.
3. A method of preparing a compound of formula (I) according to claim 1 , said method comprising the step of reacting an intermediate compound of formula (VII):
wherein R 2 , A, X, Y and Z are as defined for the compound of formula (I) according to claim 1 ,
with a compound of formula (VIII):
H 2 N—R 1 (VIII),
wherein R 1 is as defined for the compound of formula (I) according to claim 1 , thereby giving a compound of formula (I).
4. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 , or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.
5. A pharmaceutical combination comprising:
one or more compounds of formula (I) according to claim 1 , or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing, and
one or more pharmaceutically active anti cancer compounds or
one or more pharmaceutically active immune checkpoint inhibitors.
6. A method for treatment of a disease associated with aberrant AHR signaling, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing, to a subject in need thereof.
7. The method according to claim 6 , wherein the disease is a cancer or a condition with dysregulated immune responses.
8. The method according to claim 6 , wherein the disease is a liquid tumour or a solid tumour.
9. The compound of claim 1 , or a physiologically acceptable salt thereof.
10. The pharmaceutical composition of claim 4 , comprising the compound of formula (I) or a physiologically acceptable salt thereof.
11. The pharmaceutical combination of claim 5 , comprising a compound of claim 1 the compound of formula (I) or a physiologically acceptable salt thereof.
12. The method of claim 6 , comprising administering a therapeutically effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.