Pyrimidines as PLK inhibitors
The present invention comprises compounds of general formula (1) wherein A, X, Y, Z, R a , R b , R c , R 1 , R 2 and R 3 are defined as in claim 1 , which are suitable for the treatment of diseases characterised by excessive or anomalous cell proliferation, and the use thereof for preparing a pharmaceutical composition with the above-mentioned properties.
1. A compound of general formula (1)
wherein
X denotes —NR 1a , O or S, and
Y denotes CH and
Z denotes halogen-C 1-3 -alkyl; and
A is selected from formulae (i) or (ii)
and
Q 1 denotes mono- or bicyclic aryl group; and
Q 2 denotes mono- or bicyclic heteroaryl group; and
T denotes N, O or S, and
R 1 and R 1a denotes hydrogen or methyl, and
R 2 denotes a group selected from among —Cl, —Br, —I, —OR 6 , —C(═O)R 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen; and
R a , R b , R c , R d , R e and R f each independently of one another denote a group selected from among hydrogen, halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen;
or an optionally mono- or polysubstituted group selected from among C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among hydrogen, halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen; and
R 3 is selected from the formulae (iii)-(ix),
and
R 4 denotes a group selected from among hydrogen, —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen,
or denotes a group selected from among optionally mono- or polysubstituted C 1-8 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-8 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among C 1-8 -alkyl, halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen; and
R 5 denotes hydrogen, halogen, —CF 3 , C 1-3 -alkyl or —OR 6 ; and
R 6 , R 7 and R 8 in each case independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C 1-5 -alkyl, C 2-5 -alkenyl, C 2-5 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO 2 , —OR 10 , —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , —NR 10 C(═O)NR 11 R 12 , —NR 10 C(═O)ONR 11 R 12 , —NR 10 SO 2 R 11 , —N═CR 10 R 11 , —SR 10 , —SOR 10 , —SO 2 R 10 , —SO 2 NR 10 R 11 , —NR 10 SO 2 NR 11 R 12 , —OSO 2 NR 10 R 11 und pseudohalogen; and
L denotes a bond or a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 10 , —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , —NR 10 R 11 , —NR 10 COR 11 , —NR 10 C(═O)OR 11 , —NR 10 C(═O)NR 10 R 11 , —NR 10 C(═O)ONR 11 R 12 , —NR 10 SO 2 R 11 , —N═CR 10 R 11 , —SR 10 , —SOR 10 , —SO 2 R 10 , —SO 2 NR 10 R 11 , —NR 10 SO 2 NR 11 R 12 , —OSO 2 NR 10 R 11 and pseudohalogen; and
Q 3 and Q 4 independently of one another denote a bond or a group selected from among optionally mono- or polysubstituted mono- or bicyclic heterocyclyl while the substituent(s) may be identical or different and are selected from among methyl, ethyl, halogen, —NH 2 , —OH and pseudohalogen; and
R 9 denotes a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 10 , —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , —NR 10 R 11 , —NR 10 COR 11 , —NR 10 C(═O)OR 11 , —NR 10 C(═O)NR 11 R 12 , —NR 10 C(═O)ONR 11 R 12 , —NR 10 SO 2 R 11 , —N═CR 10 R 11 , —SR 10 , —SOR 10 , —SO 2 R 10 , —SO 2 NR 10 R 11 , —NR 10 SO 2 NR 11 R 12 , —OSO 2 NR 10 R 11 and pseudohalogen; and
R 10 , R 11 and R 12 in each case independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NH 2 , —OH and pseudohalogen;
optionally in the form of a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmacologically acceptable acid addition salt thereof.
2. The compound of general formula (1), according to claim 1 , wherein
X denotes —NR 1a or oxygen, and
A is selected from formulae (i) or (ii)
and
Q 1 denotes mono- or bicyclic aryl group; and
Q 2 denotes monocyclic heteroaryl group; and
T denotes N, O or S, and
R 1 and R 1a denotes hydrogen; and
R 3 denotes formula (iii),
and the other groups are as defined in claim 1 .
3. The compound of general formula (1), according to claim 1 , wherein
Y denotes CH; and
Q 1 denotes monocyclic aryl group
and the other groups are as defined in claim 1 .
4. The compound of general formula (1), according to claim 1 , wherein
R c denotes a group selected from among hydrogen, —F, —Cl, methyl and ethyl
and the other groups are as defined in claim 1 .
5. The compound of general formula (1), according to claim 1 , wherein
R a and R b in each case independently of one another denote hydrogen or an optionally mono- or polysubstituted group selected from among C 1-2 -alkyl, C 2 -alkenyl, C 2 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) may be identical or different and are selected from among hydrogen, halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 , —SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen
and the other groups are as defined in claim 1 .
6. The compound of general formula (1), according to claim 1 , wherein
R a and R b denotes hydrogen
and the other groups are as defined in claim 1 .
7. The compound of general formula (1), according to claim 1 , wherein
Z denotes C 1-3 -fluoroalkyl and
Y denotes CH
and the other groups are as defined in claim 1 .
8. A pharmaceutical composition comprising the compound of general formula (1), according to claim 1 or a pharmaceutically active salt thereof.
9. A pharmaceutical composition comprising as active substances one or more compounds of general formula (I) according to claim 1 , or a physiologically acceptable salt thereof, and one or more conventional excipients and/or carriers.
10. A method for the treatment of prostate cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 9 or a pharmaceutical composition according to claim 9 .
11. A pharmaceutical composition comprising a compound of general formula (1)
wherein
X denotes —NR 1a , O or S, and
Y denotes CH and
Z denotes halogen-C 1-3 -alkyl; and
A is selected from formulae (i) or (ii)
and
Q 1 denotes mono- or bicyclic aryl group; and
Q 2 denotes mono- or bicyclic heteroaryl group; and
T denotes N, O or S, and
R 1 and R 1a denote hydrogen or methyl, and
R 2 denotes a group selected from among —Cl, —Br, —I, —OR 6 , —C(═O)R 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen; and
R a , R b , R c , R d , R e and R f each independently of one another denote a group selected from among hydrogen, halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen;
or an optionally mono- or polysubstituted group selected from among C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) may be identical or different and are selected from among hydrogen, halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen; and
R 3 is selected from the formulae (iii)-(ix),
and
R 4 denotes a group selected from among hydrogen, —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen,
or denotes a group selected from among optionally mono- or polysubstituted C 1-8 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-8 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) may be identical or different and are selected from among C 1-8 -alkyl, halogen, —NO 2 , —OR 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 SO 2 R 7 , —N═CR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —NR 6 SO 2 NR 7 R 8 , —OSO 2 NR 7 R 8 and pseudohalogen; and
R 5 denotes hydrogen, halogen, —CF 3 , C 1-3 -alkyl or —OR 6 ; and
R 6 , R 7 and R 8 in each case independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C 1-5 -alkyl, C 2-5 -alkenyl, C 2-5 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) may be identical or different and are selected from among C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO 2 , —OR 10 , —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , —NR 10 C(═O)NR 11 R 12 , —NR 10 C(═O)ONR 11 R 12 , —NR 10 SO 2 R 11 , —N═CR 10 R 11 , —SR 10 , —SOR 10 , —SO 2 R 10 , —SO 2 NR 10 R 11 , —NR 10 SO 2 NR 11 R 12 , —OSO 2 NR 10 R 11 und pseudohalogen; and
L denotes a bond or a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 10 , —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , —NR 10 R 11 , —NR 10 COR 11 , —NR 10 C(═O)OR 11 , —NR 10 C(═O)NR 11 R 12 , —NR 10 C(═O)ONR 11 R 12 , —NR 10 SO 2 R 11 , —N═CR 10 R 11 , —SR 10 , —SOR 10 , —SO 2 R 10 , —SO 2 NR 10 R 11 , —NR 10 SO 2 NR 11 R 12 , —OSO 2 NR 10 R 11 and pseudohalogen; and
Q 3 and Q 4 independently of one another denote a bond or a group selected from among optionally mono- or polysubstituted mono- or bicyclic heterocyclyl while the substituent(s) may be identical or different and are selected from among methyl, ethyl, halogen, —NH 2 , —OH and pseudohalogen; and
R 9 denotes a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 10 , —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , —NR 10 R 11 , —NR 10 COR 11 , —NR 10 C(═O)OR 11 , —NR 10 C(═O)NR 11 R 12 , —NR 10 C(═O)ONR 11 R 12 , —NR 10 SO 2 R 11 , —N═CR 10 R 11 , —SR 10 , —SOR 10 , —SO 2 R 10 , —SO 2 NR 10 R 11 , —NR 10 SO 2 NR 11 R 12 , —OSO 2 NR 10 R 11 and pseudohalogen; and
R 10 , R 11 and R 12 in each case independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) may be identical or different and are selected from among halogen, —NH 2 , —OH and pseudohalogen;
optionally in the form of a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmacologically acceptable acid addition salt thereof, and
at least one other active substance selected from among cytostatic active substances, cytotoxic active substances, steroids and antibodies, optionally in the form of a tautomer, racemate, enantiomer, diastereomer, or a mixtures thereof, or a pharmacologically acceptable acid addition salt thereof.
12. The compound of general formula (1) according to claim 1 , wherein
Z denotes CF 3 .
13. The compound of general formula (1) according to claim 7 , wherein
Z denotes CF 3 .