Disubstituted 5-fluoro pyrimidine derivatives containing a sulfoximine group
View Patent ↗The present invention relates to disubstituted 5-fluoro pyrimidine derivatives containing a sulfoximine group of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).
1. A compound of general formula (I)
wherein
R 1 represents a group selected from the group consisting of C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, heteroraryl, phenyl-C 1 -C 3 -alkyl- and heteroaryl-C 1 -C 3 -alkyl-,
wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C 1 -C 3 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 3 -fluoroalkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, and cyclic amines;
R 2 represents a group selected from the group consisting of
R 3 , R 4 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, halogen atom, cyano, —SF 5 , C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(O)R 9 , —C(O)OR 9 , —S(O) 2 R 9 , —C(O)NR 10 R 11 , C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, and heteroaryl
wherein said C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 6 , R 7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, halogen atom, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 8 represents a group selected from the group consisting of
a) a C 1 -C 6 -alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy-, C 2 -C 3 -alkenyl-, C 2 -C 3 -alkynyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, and heteroaryl,
wherein said C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
b) a C 3 -C 6 -alkenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy-, C 2 -C 3 -alkenyl-, C 2 -C 3 -alkynyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, and heteroaryl,
wherein said C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
c) a C 3 -C 6 -alkynyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy-, C 2 -C 3 -alkenyl-, C 2 -C 3 -alkynyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, and heteroaryl,
wherein said C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
d) a C 3 -C 7 -cycloalkyl- group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy-, C 2 -C 3 -alkenyl-, and C 2 -C 3 -alkynyl-;
e) a heterocyclyl-group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy-, C 2 -C 3 -alkenyl-, and C 2 -C 3 -alkynyl-;
f) a phenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
g) a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
h) a phenyl-C 1 -C 3 -alkyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
i) a heteroaryl-C 1 -C 3 -alkyl- group, which heteroaryl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 alkyl-, halo C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
j) a C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkyl- group, which C 3 -C 6 -cycloalkyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
k) a heterocyclyl-C 1 -C 3 -alkyl- group, which heterocyclyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
l) phenyl-cyclopropyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, NH 2 , alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-; and
m) a heteroaryl-cyclopropyl- group, which heteroaryl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, NH 2 , alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
R 9 represents a group selected from the group consisting of C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 alkyl C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-; and
R 10 , R 11 represent, independently from each other, a group selected from the group consisting of hydrogen, C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl and heteroaryl wherein said C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C3-alkyl-, and C 1 -C 3 -fluoroalkoxy-;
or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof.
2. The compound of general formula (I) according to claim 1 , wherein
R 3 represents a group selected from the group consisting of a halogen atom, cyano, —SF 5 , C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-; and
R 4 represents hydrogen,
or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof.
3. The compound of general formula (I) according to claim 1 , wherein
R 1 represents a group selected from the group consisting of C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, heteroraryl, phenyl-C 1 -C 3 -alkyl- and heteroaryl-C 1 -C 3 -alkyl-,
wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C 1 -C 3 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 3 -fluoroalkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, and cyclic amines;
R 2 represents a group selected from the group consisting of
R 3 , R 4 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, fluoro atom, chloro atom, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(O)R 9 , —C(O)OR 9 , —S(O) 2 R 9 , —C(O)NR 10 R 11 , C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, and heteroaryl
wherein said C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 6 , R 7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, fluoro atom, chloro atom, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 8 represents a group selected from the group consisting of
a) a C 1 -C 6 -alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy-, C 2 -C 3 -alkenyl-, C 2 -C 3 -alkynyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, and heteroaryl,
wherein said C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
b) a C 3 -C 7 -cycloalkyl- group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy, C 2 -C 3 -alkenyl-, and C 2 -C 3 -alkynyl-;
c) a heterocyclyl-group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy-, C 2 -C 3 -alkenyl-, and C 2 -C 3 -alkynyl-;
d) a phenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
e) a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
f) a phenyl-C 1 -C 3 -alkyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C3-alkoxy-;
g) a heteroaryl-C 1 -C 3 -alkyl- group, which heteroaryl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
h) a C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkyl- group, which C 3 -C 6 -cycloalkyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
i) a heterocyclyl-C 1 -C 3 -alkyl- group, which heterocyclyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C 1 -C 3 alkoxy halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
j) phenyl-cyclopropyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, NH 2 , alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-; and
k) a heteroaryl-cyclopropyl- group, which heteroaryl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, NH 2 , alkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C3-alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
R 9 represents a group selected from the group consisting of C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-; and
R 10 , R 11 represent, independently from each other, a group selected from the group consisting of hydrogen, C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl and heteroaryl wherein said C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
or a salt, solvate or salt of a solvate thereof.
4. The compound of general formula (I) according to claim 1 , wherein
R 1 represents C 1 -C 6 -alkyl-, or C 3 -C 5 -cycloalkyl-, wherein said group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C 1 -C 2 -alkoxy-, halo-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-;
R 2 represents a group selected from the group consisting of
R 3 represents a hydrogen atom or fluoro atom;
R 4 represents a hydrogen atom or a fluoro atom;
R 5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(O)OR 9 , and —C(O)NR 10 R 11 ;
R 6 , R 7 represent, independently from each other, a hydrogen atom, fluoro atom, or chloro atom;
R 8 represents a group selected from the group consisting of
a) a C 1 -C 6 -alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, C 1 -C 3 -alkoxy-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, and heteroaryl,
wherein said C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
b) a phenyl-C 1 -C 3 -alkyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoro alkoxy-, and C 1 -C 3 -alkoxy-;
c) a heteroaryl-C 1 -C 3 -alkyl- group, which heteroaryl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
d) a C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkyl- group, which C 3 -C 6 -cycloalkyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
e) a heterocyclyl-C 1 -C 3 -alkyl- group, which heterocyclyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoro alkoxy-;
f) phenyl-cyclopropyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, —NH 2 , dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-; and
g) a heteroaryl-cyclopropyl- group, which heteroaryl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, —NH 2 , dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
R 9 represents a C 1 -C 3 -alkyl group; and
R 10 , R 11 represent, independently from each other, hydrogen, or C 1 -C 2 -alkyl-;
or a salt, solvate or salt of a solvate thereof.
5. The compound of general formula (1) according to claim 1 , wherein
R represents a C 1 -C 6 -alkyl-, or C 3 -C 5 -cycloalkyl- group, wherein said group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of C 1 -C 2 -alkoxy-, halo-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-;
R 2 represents
R 3 represents a hydrogen atom or a fluoro atom;
R 4 represents a hydrogen atom or a fluoro atom;
R 5 represents a hydrogen atom, cyano, —C(O)OR 9 , or —C(O)NR 10 R 11 ;
R 6 , R 7 represent, independently from each other, a hydrogen atom, or fluoro atom;
R 8 represents a group selected from the group consisting of
a) a C 1 -C 3 -alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, and halo-C 1 -C 3 -alkyl-;
b) a phenyl-C 1 -C 3 -alkyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
c) a heteroaryl-C 1 -C 3 -alkyl- group, which heteroaryl group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
d) a C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkyl- group, which C 3 -C 6 -cycloalkyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
e) a heterocyclyl-C 1 -C 3 -alkyl- group, which heterocyclyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
f) phenyl-cyclopropyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-; and
g) a heteroaryl-cyclopropyl- group, which heteroaryl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;
R 9 represents a C 1 -C 3 -alkyl group; and
R 10 , R 11 represent, independently from each other, hydrogen, or C 1 -C 2 -alkyl-;
or a salt, solvate or salt of a solvate thereof.
6. The compound of general formula (1) according to claim 1 , wherein
R 1 represents a C 1 -C 3 -alkyl- or cyclopropyl group;
R 2 represents
R 3 represents a hydrogen atom or fluoro atom;
R 4 represents a hydrogen atom or fluoro atom;
R 5 represents a hydrogen atom, cyano, —C(O)OR 9 , or —C(O)NR 10 R 11 ;
R 6 , R 7 represent, independently from each other, a hydrogen atom, or fluoro atom;
R 8 represents
a) a C 1 -C 3 -alkyl group; or
b) a phenyl-C 1 -C 3 -alkyl- group, which phenyl group is optionally substituted with one or two, identically or differently, halogen atoms;
R 9 represents a C 1 -C 2 -alkyl group; and
R 10 , R 11 represent, independently from each other, a hydrogen atom, or C 1 -C 2 -alkyl-;
or a salt, solvate or salt of a solvate thereof.
7. The compound of general formula (I) according to claim 1 , wherein
R 1 represents C 1 -C 3 -alkyl- or cyclopropyl-,
R 2 represents
R 3 , R 4 represent, independently from each other, a hydrogen atom, a fluoro, a chloro or a bromo atom, —SF 5 , C 1 -C 3 -alkyl-, C 1 -C 2 -alkoxy- or CF 3 —,
R 5 represents a hydrogen atom, cyano, —C(O)OR 9 or —C(O)NR 10 R 11 ,
R 6 , R 7 represent, independently from each other, a hydrogen atom or a fluoro atom,
R 8 represents
a) a C 1 -C 3 -alkyl group, which is optionally substituted with fluorine, or
b) a phenyl-C1-C2-alkyl- group, which phenyl group is optionally substituted with halogen,
R 9 represents a C 1 -C 6 -alkyl-, which is optionally substituted with C 1 -C 3 -alkoxy, and
R 10 , R 11 represent, independently from each other, hydrogen or a C 1 -C 6 -alkyl-,
or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof.
8. The compound of general formula (I) according to claim 1 , wherein
R 1 represents a methyl group;
R 2 represents
R 3 represents a hydrogen atom, or fluoro atom;
R 4 represents a hydrogen atom;
R 5 represents a hydrogen atom, cyano, —C(O)OR 9 , or —C(O)NR 10 R 11 ;
R 6 , R 7 represent, independently from each other, a hydrogen atom, or fluoro atom;
R 8 represents
a) a methyl group; or
b) a benzyl group;
R 9 represents an ethyl group;
R 10 represents a hydrogen atom; and
R 11 represents a methyl group;
or a salt, solvate or salt of a solvate thereof.
9. The compound according to claim 1 , which is selected from the group consisting of
(rac)-Ethyl[(3-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)(methyl) oxido sulfanylidene]carbamate;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}pyrimidin-2-amine;
(rac)-Ethyl {[3-({4-[2-(benzyloxy)-4-fluorophenyl]-5-fluoropyrimidin-2-yl}amino)benzyl](methyl)-oxido-λ 6 -sulfanylidene}carbamate;
(rac)-4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine;
(rac)-Ethyl[(3-{[4-(3,4-dihydro-2H-chromen-8-yl)-5-fluoropyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ 6 -sulfanylidene]carbamate;
(rac)-4-(3,4-dihydro-2H-chromen-8-yl)-5-fluoro-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine;
(rac)-{[3-({4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoropyrimidin-2-yl}amino)benzyl](methyl)oxido-λ 6 -sulfanylidene}cyanamide;
(rac)-1-[(3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ 6 -sulfanylidene]-3-methylurea;
(rac)-Ethyl[(3-fluoro-5-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)-(methyl)oxido-sulfanylidene]carbamate;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]-phenyl}pyrimidin-2-amine;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}pyrimidin-2-amine; enantiomer 1;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}pyrimidin-2-amine; enantiomer 2;
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}pyrimidin-2-amine; enantiomer 1;
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}pyrimidin-2-amine; enantiomer 2;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine; enantiomer 1;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine; enantiomer 2;
(rac)-[(3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ 6 -sulfanylidene]cyanamide;
[(3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ 6 -sulfanylidene]cyanamide; enantiomer 1;
[(3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ 6 -sulfanylidene]cyanamide; enantiomer 2;
(rac)-[Ethyl(3-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)oxido-λ 6 -sulfanylidene]cyanamide;
rac)-N-{3-[(S-Ethylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-amine;
N-{3-[(S-Ethylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-amine; enantiomer 1;
N-{3-[(S-Ethylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-amine; enantiomer 2;
(rac)-[(2,3-Difluoro-5-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)-(methyl)oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-N-{3,4-Difluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxy-phenyl)pyrimidin-2-amine;
N-{3,4-Difluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-pyrimidin-2-amine; enantiomer 1;
N-{3,4-Difluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-pyrimidin-2-amine; enantiomer 2;
(rac)-[(3-Bromo-5-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-N-{3-Bromo-5-[(S-methylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxy-phenyl)pyrimidin-2-amine;
N-{3-Bromo-5-[(S-methylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-pyrimidin-2-amine; enantiomer 1;
N-{3-Bromo-5-[(S-methylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-pyrimidin-2-amine; enantiomer 2;
(rac)-[(3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}-5-methoxybenzyl)(methyl)-oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-methoxy-5-[(S-methylsulfonimidoyl)methyl]-phenyl}pyrimidin-2-amine;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-methoxy-5-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine; enantiomer 1;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-methoxy-5-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine; enantiomer 2;
(rac)-[(3-{[4-(2-Ethoxy-4-fluorophenyl)-5-fluoropyrimidin-2-yl]amino}-5-fluorobenzyl)(methyl)oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-4-(2-Ethoxy-4-fluorophenyl)-5-fluoro-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine;
4-(2-Ethoxy-4-fluorophenyl)-5-fluoro-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine; enantiomer 1;
4-(2-Ethoxy-4-fluorophenyl)-5-fluoro-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-pyrimidin-2-amine; enantiomer 2;
(rac)-{[3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}-5-(trifluoromethyl)-benzyl](methyl) oxido-λ 6 -sulfanylidene}cyanamide;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]-5-(trifluoro-methyl)phenyl}pyrimidin-2-amine;
(rac)-[Ethyl(3-fluoro-5-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-N-{3-[(S-Ethylsulfonimidoyl)methyl]-5-fluorophenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-pyrimidin-2-amine;
N-{3-[(S-Ethylsulfonimidoyl)methyl]-5-fluorophenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-pyrimidin-2-amine; enantiomer 1;
N-{3-[(S-Ethylsulfonimidoyl)methyl]-5-fluorophenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-pyrimidin-2-amine; enantiomer 2;
(rac)-{[3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}-5-(pentafluoroethyl)-benzyl](methyl)oxido-λ 6 -sulfanylidene}cyanamide;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]-5-(pentafluoro-ethyl)phenyl}pyrimidin-2-amine;
(rac)-[Cyclopropyl(3-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-N-{3-[(S-Cyclopropylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-pyrimidin-2-amine;
(rac)-[Cyclopropyl(3-fluoro-5-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}-benzyl)oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-N-{3-[(S-Cyclopropylsulfonimidoyl)methyl]-5-fluorophenyl}-5-fluoro-4-(4-fluoro-2-methoxy-phenyl)pyrimidin-2-amine;
N-{3-[(S-Cyclopropylsulfonimidoyl)methyl]-5-fluorophenyl}-5-fluoro-4-(4-fluoro-2-methoxy-phenyl)pyrimidin-2-amine; enantiomer 1;
N-{3-[(S-Cyclopropylsulfonimidoyl)methyl]-5-fluorophenyl}-5-fluoro-4-(4-fluoro-2-methoxy-phenyl)pyrimidin-2-amine; enantiomer 2;
(rac)-Ethyl[(3-{[4-(2,3-dihydro-1-benzofuran-7-yl)-5-fluoropyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ 6 -sulfanylidene]carbamate;
(rac)-5-Fluoro-4-{4-fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}pyrimidin-2-amine;
(rac)-[(3-Chloro-5-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-N-{3-Chloro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxy-phenyl)pyrimidin-2-amine;
(rac)-[(3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}-5-methylbenzyl)(methyl)-oxido-λ 6 -sulfanylidene]cyanamide;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-methyl-5-[(S-methylsulfonimidoyl)methyl]-phenyl}pyrimidin-2-amine;
(rac)-{[3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}-5-(pentafluoro-λ 6 -sulfanyl)benzyl](methyl)oxido-λ 6 -sulfanylidene}-cyanamide;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]-5-(pentafluoro-λ 6 -sulfanyl)phenyl}pyrimidin-2-amine;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]-5-(pentafluoro-λ 6 -sulfanyl)phenyl}pyrimidin-2-amine; enantiomer 1;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]-5-(pentafluoro-λ 6 -sulfanyl)phenyl}pyrimidin-2-amine; enantiomer 2; and
2-Methoxyethyl[(3-fluoro-5-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)-(methyl)oxido-λ 6 -sulfanylidene]carbamate; single enantiomer,
or a salt, solvate or salt of a solvate thereof.
10. A pharmaceutical combination comprising a compound according to claim 1 in combination with at least one or more further active ingredients.
11. A pharmaceutical composition comprising a compound according to claim 1 in combination with an inert, nontoxic, pharmaceutically suitable adjuvant.
12. A method for the treatment of a disease or disorder selected from the group consisting of lung carcinomas, prostate carcinomas, cervical carcinomas, colorectal carcinomas, melanomas and ovarian carcinomas comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
13. The method according to claim 12 , wherein the disease or disorder is mediated by CDK9.