HETEROCYCLIC COMPOUNDS AND THEIR USE AS GLYCOGEN SYNTHASE KINASE-3 INHIBITORS

摘要

The present invention relates to novel heterocyclic compounds of formula I;wherein the variables are as defined in the claims or the description, which are useful for inhibiting glycogen synthase kinase 3 (GSK-3), compositions containing the compounds, their use for preparing a medicament for the treatment of a medical disorder susceptible to the treatment with a compound that modulates, preferably inhibits, the activity of glycogen synthase kinase 3β, and methods of treatment of medical disorders susceptible to treatment with a compound that modulates glycogen synthase kinase 3β activity using the compounds.

主权项

1. A heterocyclic compound of the formula (I) the stereoisomers, N-oxides, prodrugs, tautomers and/or physiologically tolerated acid addition salts thereof, and the compounds of the general formula I, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope, wherein A is selected from the group consisting of CRA1RA2 and NRB; where
RA1 and RA2 are independently of each other selected from the group consisting of hydrogen, C1-C2-alkyl, C1-C2-haloalkyl, NH2 and OH; andRB is selected from hydrogen, C1-C4-alkyl and C1-C4-haloalkyl; X1 and X2 are independently of each other selected from the group consisting of CR2 and N; X3, X4, X5 and X6 are independently of each other selected from the group consisting of CR3, CR4 and N;
with the proviso that no more than two of X3, X4, X5 and X6 are CR4; Y1, Y2, Y3 and Y4 are independently of each other selected from the group consisting of CR4, CR5 and N;
with the proviso that at most one of Y1, Y2, Y3 and Y4 is N and with the proviso that at most one of Y1, Y2, Y3 and Y4 is CR4; andwith the proviso that one of Y1, Y2, Y3 and Y4 is CR4 or C—CF3 if none of X3, X4, X5 and X6 is CR4; R1 is selected from hydrogen, C1-C4-alkyl and C1-C4-haloalkyl; each R2 is independently selected from the group consisting of hydrogen, OH, halogen, CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy and NRaRb;
or two radicals R2 bonded at the carbon atoms of groups X1 and X2, together with the carbon atoms to which they are bonded, form a 5- or 6-membered saturated or unsaturated ring which may contain 1 or 2 heteroatoms as ring members selected from the group consisting of N, O and S and which optionally carries 1, 2 or 3 substituents R6; each R3 is independently selected from the group consisting of hydrogen, CN, NRaRb, OH, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C1-C6-alkoxy, C1-C6-haloalkoxy, formyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, C1-C6-alkyl-NRaRb and an aromatic radical Ar, which is selected from the group consisting of phenyl and a 5- or 6-membered N- or C-bound heteroaromatic radical comprising one nitrogen atom and optionally 1, 2 or 3 further heteroatoms independently selected from O, S and N as ring members, wherein Ar is unsubstituted or carries one or two radicals R7 and wherein Ar may also be bonded via a CH2 group; R4 is a C-bound saturated or partially unsaturated monocyclic 3-, 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom-containing groups selected from O, N, S, NO, SO and SO2 as ring members, where the heterocyclic ring optionally carries 1, 2 or 3 C- or N-bound substituents R8; R5 is selected from the group consisting of hydrogen, CN, NRaRb, OH, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C1-C6-alkoxy, C1-C6-haloalkoxy, formyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, C1-C6-alkyl-NRaRb and an aromatic radical Ar, which is selected from the group consisting of phenyl and a 5- or 6-membered N- or C-bound heteroaromatic radical comprising one nitrogen atom and optionally 1, 2 or 3 further heteroatoms independently selected from O, S and N as ring members, wherein Ar is unsubstituted or carries one or two radicals R7 and wherein Ar may also be bonded via a CH2 group; R6 and R8, independently of each other and independently of each occurrence, are selected from the group consisting of CN, NRaRb, OH, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C1-C6-alkoxy, C1-C6-haloalkoxy, formyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, C1-C6-alkyl-NRaRb and an aromatic radical Ar, which is selected from the group consisting of phenyl and a 5- or 6-membered N- or C-bound heteroaromatic radical comprising one nitrogen atom and optionally 1, 2 or 3 further heteroatoms independently selected from O, S and N as ring members, wherein Ar is unsubstituted or carries one or two radicals R7 and wherein Ar may also be bonded via a CH2 group; each R7 is independently selected from the group consisting of halogen, CN, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, NRaRb, a phenyl group and a 5- or 6-membered heteroaromatic radical comprising one nitrogen atom and optionally 1, 2 or 3 further heteroatoms independently selected from O, S and N as ring members, wherein phenyl and the heteroaromatic radical are, independently of each other, unsubstituted or substituted by 1, 2, 3 or 4 radicals selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and Ra and Rb are independently of each other selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl and C1-C4-haloalkylcarbonyl;
or Ra and Rb form, together with the nitrogen atom to which they are bonded, a 3-, 4-, 5-, 6- or 7-membered saturated or unsaturated aromatic or non-aromatic N-heterocyclic ring, which may contain 1 further heteroatom or heteroatom containing group selected from the group consisting of O, S, SO, SO2 and N as a ring member.