2-phenylpyrimidine-4-carboxamides as AHR inhibitors

Patent metadata

Field	Value
Publication number	US-11524944-B2
Application number	US-201816765780-A
Country	US
Kind code	B2
Filing date	Nov 16, 2018
Priority date	Nov 21, 2017
Publication date	Dec 13, 2022
Grant date	Dec 13, 2022

Abstract

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.

First claim

The invention claimed is:

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-

Assignees

• Bayer Ag
• Bayer Pharma AG
• Deutsches Krebsforsch

Inventors

• Lefranc Julien
• Schmees Norbert
• Röhn Ulrike
• Zorn Ludwig
• Günther Judith
• Gutcher Ilona
• Röse Lars
• Bader Benjamin
• Stöckigt Detlef
• Platten Michael

Classifications

• A61P35/04

  specific for metastasis · CPC title

• C07D239/28 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/12

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

• A61K45/06

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