2-phenylpyrimidine-4-carboxamides as AHR inhibitors
The present invention covers 2-phenylpyrimidine-4-carboxamide compounds of general formula (I): (I) 5 in which X, Y, Z, R1, R2, 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.
1. A compound of formula (I):
wherein
X is N, Y is CR 3 , and Z is CH, or
X is CH, Y is N, and Z is CH, or
X is CH, Y is CR 3 , and Z is CH, or
X is CH, Y is N, and Z is N;
R 1 is C 2 -C 8 -hydroxyalkyl, wherein said C 2 -C 8 -hydroxyalkyl groups are optionally substituted once with R 7 and optionally one to three times with halogen, or
C 3 -C 6 -cycloalkyl substituted once with hydroxy or C 1 -C 3 -hydroxyalkyl and optionally one to three times with halogen, or
(C 3 -C 6 -cycloalkyl substituted once with hydroxy)-C 1 -C 4 -alkyl, or 5- to 6-membered heterocycloalkyl optionally substituted once with hydroxy or C 1 -C 3 -hydroxyalkyl and optionally one to three times with halogen, or
(5- to 6-membered heterocycloalkyl optionally substituted once with hydroxy)-C 1 -C 4 -alkyl;
R 2 is hydrogen, chloro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or —NR 8 R 9 ;
R 3 is hydrogen, halogen, or methyl;
R 4 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, halogen, or cyano;
R 5 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;
R 6 is hydrogen or halogen;
R 7 is C 1 -C 4 -alkoxy, —CO 2 —R 10 , —CO—NR 8 R 9 , cyano, —NR 8 R 9 , C 3 -C 6 -cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl;
R 8 and R 9 are the same or different and are, independently from each other, hydrogen or C 1 -C 3 -alkyl, or
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 the group consisting of O, S, NH, and Nr a in which R a is a C 1 -C 4 -alkyl group; and
R 10 is hydrogen or C 1 -C 4 -alkyl; 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 , wherein:
X is CH;
Y is CR 3 ;
Z is CH;
R 1 is C 2 -C 6 -hydroxyalkyl, wherein said C 2 -C 6 -hydroxyalkyl groups are optionally substituted once with cyclobutyl and optionally one to three times with fluoro, or C 4 -C 6 -cycloalkyl substituted once with hydroxy and optionally one to two times with fluoro, or
(C 4 -C 6 -cycloalkyl substituted once with hydroxy)-methyl, or
4-hydroxyoxolan-3-yl;
R 2 is hydrogen, chloro, trifluoromethyl, or trifluoromethoxy;
R 3 is hydrogen or fluoro;
R 4 is hydrogen, fluoro, chloro, cyano, methyl, trifluoromethyl, or methoxy;
R 5 is hydrogen, fluoro, chloro, bromo, difluoromethyl, trifluoromethyl, methoxy, or trifluoromethoxy;
R 6 is hydrogen, fluoro, or chloro; 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. The compound according to claim 1 , which is selected from the group consisting of:
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
2,6-bis(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxamide;
6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxamide;
2-(4-chlorophenyl)-6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-[(2S)-1-hydroxypropan-2-yl]-2,6-bis[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-(2-hydroxy-2-methylpropyl)-2-(4-methoxyphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-(2-hydroxy-2-methylpropyl)-2-(3-methylphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(4-fluoro-3-methylphenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3,5-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-[3-chloro-4-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3,4-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-(2-hydroxy-2-methylpropyl)-2,6-bis[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3,5-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-[4-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-cyano-5-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(4-bromophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-[(2S)-1-hydroxypropan-2-yl]-2-(4-methoxyphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-[(2S)-1-hydroxypropan-2-yl]-2-(3-methylphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(4-fluoro-3-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-chloro-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3,5-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-cyano-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3,4-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3,5-difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluoro-5-methoxyphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluoro-5-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-[4-(difluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-cyano-5-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(4-bromophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
2,6-bis(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(4-methoxyphenyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(3-methylphenyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(4-fluoro-3-methylphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
2-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,5-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-cyano-4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-[3-chloro-4-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
2-(3-chlorophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-[3-fluoro-5-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluoro-5-methoxyphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluoro-5-methylphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-[4-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-cyano-5-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(4-methoxyphenyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(3-methylphenyl)pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(4-fluoro-3-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
2-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,5-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-cyano-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-[3-chloro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
2-(3-chlorophenyl)-6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluoro-5-methoxyphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
6-(4-chlorophenyl)-2-(3-fluoro-5-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-(3,4-dihydroxybutan-2-yl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-(3,3-difluoro-2-hydroxycyclohexyl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(1-hydroxycyclohexyl)methyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-1-hydroxy-3,3-dimethylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-(1,1,1-trifluoro-4-hydroxybutan-2-yl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
N-(1-cyclobutyl-2-hydroxyethyl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2R)-1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(3 S,4S)-4-hydroxyoxolan-3-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carb oxamide;
2-(3-fluorophenyl)-N-(1,1,1-trifluoro-3-hydroxybutan-2-yl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;
2-(3-fluorophenyl)-N-[(1S,2R)-2-hydroxycyclobutyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide; and
2-(3-fluorophenyl)-N-[(1R,2R)-2-hydroxycyclobutyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-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.
4. A method of preparing a compound of formula (I) or a physiologically acceptable salt thereof, according to claim 1 , said method comprising the step of reacting an intermediate compound of formula (VII):
in which X, Y, Z, R 2 , R 4 , R 5 and R 6 are as defined for the compound of formula (I) according to claim 1 ,
with a compound of formula
H 2 N—R 1 (VIII),
in which R 1 is as defined for the compound of formula (I) according to claim 1 ,
thereby giving a compound of formula (I):
in which X, Y, Z, R 2 , R 4 , R 5 and R 6 are as defined for the compound of formula (I) according to claim 1 , or a physiologically acceptable salt thereof.
5. 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.
6. 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.
7. A method fora treatment of a disease, wherein the disease is a disorder 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.
8. The method according to claim 7 , wherein the disease is a cancer.
9. The method according to claim 7 , wherein the disease is a liquid tumour or a solid tumour.
10. The compound of claim 1 , or a physiologically acceptable salt thereof.
11. The compound of claim 3 , or a physiologically acceptable salt thereof.