Novel heterocyclic NF-kB inhibitors

A compound of the general formula (III) or a salt or a physiologically functional derivative, or a stereoisomer thereof,

• wherein
• R1 is —C(O)R7, —C(O)CHR7R8, —C(O)NR7R8, —C(O)OR7, —R7C(O)R8, —C(S)R7, or R1 and R2 together with the Z to which they are attached form a 3 to 8 membered ring, wherein at least one ring atom is a heteroatom like O, N, S and the ring optionally has a substituent R9;
• R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, aryl or R2 is absent in the case Z forms a ring together with R1;
• R3 is H, C(O)NRaRb, halogen, alkyl, haloalkyl, aryl or heteroaryl;
• R4 is H, halogen, alkyl, —C(NR7)NR7′R8, —(CH2)paryl, —(CH2)pNR7R8, —C(O)NR7R8, —N═CR7R8, —NR7C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl;
• R5 is H, halogen, alkyl, —C(NR7)NR7′R8, —(CH2)paryl, —(CH2)pNR7R8, —C(O)NR7R8, —N═CR7R8, —NR7C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl;
• Ra is H, halogen, alkyl, —C(NR7)NR7′R8, —(CH2)paryl, —(CH2)pR7R8, —C(O)NR7R8, —N═CR7R8, —NR7C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl;
• Rb independently represents H, —CN, —OH, —SH, —CO2R4′, —C(O)R4′, —SO2NR4′, —NR4′R5′, —C(O)NR7R8, —SO2-alkyl, —SO2R4′, SO3R4′, —N═CR4′R5′, —NR4′C(O)R4″, —NR4′—CO-haloalkyl, —NO2, —NR4′—SO2-haloalkyl, —NR4′—SO2-alkyl, —NR4′—CO-alkyl, —NR4′(CH2)pheterocycle, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, —O(CH2)p[O(CH2)p]qOCH3, —C(NR4″)NR4′benzimidazolyl, —C(NR4″)NR4′benzthiazolyl, —C(NR4″)NR4′benz-oxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle;
• R7, R7′, R8 independently represent H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, —NHaryl, heteroaryl, alkylaryl, or aryl;
• A is CO or SO2;
• X is NR2′, O, S, or CR2′;
• Z is N or CR2′;
• if Z is CH then X is O or NR2′
• R2′ is H, alkyl, —C(O)NR2, —C(O)Rb, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl;
• p is 1 to 6;
• q is 1 to 6;
• r is 0, or 1;
• R9 independently represents H, —CN, —OH, —SH, —CO2R4′, —C(O)R4′, —C(O)NR7R8, —SO2NR4′, —NR4′R5′, —SO2-alkyl, —SO24′, SO3R4′, —N═CR4′R5′, —NR4′C(O)R4″, —NR4′—CO-haloalkyl, —NO2, —NR4′—SO2-haloalkyl, —NR4′—SO2-alkyl, —NR4′—CO-alkyl, —NR4′(CH2)pheterocycle, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, —O(CH2)p[O(CH2)p]qOCH3, —C(NR4″)NR4′benzimidazolyl, —C(NR4″)NR4′benzthiazolyl, —C(NR4″)NR4′benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle;
• R4′, R4″, R5′ independently represent H, halogen, alkyl, —C(NR7)NR7′R8, —(CH2)paryl, —CH2)pNR7R8, —C(O)NR7R8, —NCR7R8, —NR7C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl
• wherein
• an alkyl group, if not stated otherwise, denotes a linear or branched C1-C6-alkyl, a linear or branched C2-C6-alkenyl or a linear or, branched C2-C6-alkynyl group, which can be substituted by one or more substituents R9;
• R9 being defined as above.
• a heterocycle denotes a heterocycloalkyl group or a heteroaryl group;
• a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group R9 being as defined above;
• a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom like O, N, or S, wherein one or more of the carbon atoms in the ring can be substituted by, R9 being as defined above;
• an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above;
• an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above;
• an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above;
• a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
• an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above;
• a hydroxyalkylamino group denotes an (HO-alkyl)2-N— group or HO-alkyl-NH— group, the alkyl group being as defined above;
• an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
• a halogen group is fluorine, chlorine, bromine, or iodine;
• an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R9, where R9 is as defined above;
• a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom like O, N, S, wherein the heterocyclic group may be fused to another ring, and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R9, wherein R9 is as defined above;
• a alkylaryl or arylalkyl group denotes an alkyl group as defined above, which is bound to an aryl fragment as defined above via a single bond, wherein the linkage to the central moiety occurs through the alkyl part or the aryl part.

A compound of the general formula (II) or a salt or a physiologically functional derivative, or a stereoisomer thereof,

• wherein
• R1 is —C(O)R7, —C(O)CHR7R8, —C(O)NR7R8, —C(O)OR7, —R7C(O)R8, —C(S)R7, or R1 and R2 together with the the N-atom or the C-atom to which they are attached form a 3 to 8 membered ring, wherein at least one ring atom is a heteroatom like O, N, S and the ring optionally has a substituent R9;
• R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, aryl or R2 is absent in the case Z forms a ring together with R1;
• R3 is H, halogen, alkyl, haloalkyl, aryl or heteroaryl;
• R6 is H, halogen, —C(O)R7, —C(O)CHR7R8, —C(O)NR7R8, —C(O)OR7, —R7C(O)R8, —C(S)R7, —C(NR7)NR7′R8, —(CH2)paryl, —(CH2)pNR7R8, —C(O)NR7R8, —N═CR7R8, —NR7C(O)R7′, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl;
• R7, R7′, R8 independently represent H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, —NHaryl, heteroaryl, alkylaryl, or aryl;
• A is CO or SO2;
• X is NR2′, O, S, or CR2′;
• Y is N, O, or CR2′;
• Z is N or CR2′;
• if Z is CH then X is O or NR2′
• R2 is H, alkyl, —C(O)NR2, —C(O)Rb, cycloalkyl, heterocycloalkyl, haloalkyl hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl;
• n is 0 to 2;
• p is 1 to 6;
• q is 1 to 6;
• r is 0, or 1;
• R9 independently represents H, —CN, —OH, —SH, —CO2R4′, —C(O)R4′, —C(O)NR7R8, —SO2NR4′, —NR4′R5′, —SO2-alkyl, —SO2R4′, SO3R4′, —N═CR4′R5′, —NR4′C(O)R4″, —NR4′—CO-haloalkyl, —NO2, —NR4′—SO2-haloalkyl, —NR4′—SO2-alkyl, —NR4′—CO-alkyl, —NR4′(CH2)pheterocycle, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, O(CH2)p[O(CH2)p]qOCH3, —C(NR4″)NR4′benzimidazolyl, —C(NR4″)NR4′benzthiazolyl, —C(NR4″)NR4′benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle;
• R4′, R4″, R5′ independently are H, halogen, alkyl, —C(NR7)NR7′R8, —(CH2)paryl, —CH2)NR7R8, —C(O)NR7R8, —N═CR7R8, —NR7C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl;
• wherein
• an alkyl group, if not stated otherwise, denotes a linear or branched C1-C6-alkyl, a linear or branched C2-C6-alkenyl or a linear or branched C2-C6-alkynyl group, which can be substituted by one or more substituents R9;
• R9 being defined as above.
• a heterocycle denotes a heterocycloalkyl group or, a heteroaryl group;
• a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group R9 being as defined above;
• a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom like O, N, or S, wherein one or more of the carbon atoms in the ring can be substituted by R9 being as, defined above;
• an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above;
• an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above;
• an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above;
• a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
• an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above;
• a hydroxyalkylamino group denotes an (HO-alkyl)2-N— group or HO-alkyl-NH-group, the alkyl group being as defined above;
• an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
• a halogen group is fluorine, chlorine, bromine, or iodine;
• an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R9, where R9 is as defined above;
• a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom like O, N, S, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R9, wherein R9 is as defined above;
• a alkylaryl or arylalkyl group denotes an alkyl group as defined above, which is bound to an aryl fragment as defined above via a single bond, wherein the linkage to the central moiety occurs through the alkyl part or the aryl part.