Novel Heterocyclic NF-kB Inhibitors

Abstract

The present invention relates to compounds of the general formula (III): or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof.

1 . A compound of the general formula (III) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is —C(O)R 7a , —C(O)CHR 7 R 8 , —C(O)NR 7 R 8 , —C(O)OR 7 , —R 7 C(O)R 8 , or —C(S)R 7b , 
 R 2  is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, 
 or R 1  and R 2  together with the N-atom or the C-atom to which they are attached form a 3 to 8 membered saturated or at least partially unsaturated monocycloc or polycyclic ring system, wherein at least one or more of the carbon atoms in the ring is a heteroatom selected from O, N, and S, and the ring can be substituted by one or more R 9 ; 
 R 3  is H, —C(O)NR a R b , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR 4′ OR 5′ , NH 2 , hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, hetero-cycloalkyl, hydroxyalkyl, or haloalkyloxy; 
 R 4  is H, OH, SH, NH 2 , alkoxy, haloalkoxy, halogen, alkyl, —C(NR 7 )NR 7′ R 8 , —(CH 2 ) p aryl, —(CH 2 ) p NR 7 R 8 , —C(O)NR 7 R 8 , —N═CR 7 R 8 , —NR 7 C(O)R 8 , cycloalkyl, heterocycloalkyl, halo-alkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 
 R 5  is halogen, alkyl, —C(NR 7 )NR 7′ R 8 , —(CH 2 ) p aryl, —(CH 2 ) p NR 7 R 8 , —C(O)NR 7 R 8 , —N═CR 7 R 8 , —NR 7 C(O)R 8 , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxy-alkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 
 R a  is H, halogen, alkyl, —C(NR 7 )NR 7′ R 8 , —(CH 2 ) p aryl, —(CH 2 ) p NR 7 R 8 , aryl, —C(O)NR 7 R 8 , —N═CR 7 R 8 , —NR 7 C(O)R 8 , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, or heteroaryl; 
 R b  independently represents H, —CN, —OH, —SH, —CO 2 R 4′ , —C(O)R 4′ , —SO 2 NR 4′ , —NR 4′ R 5′ , C(O)NR 7 R 8 , —SO 2 -alkyl, —SO 2 R 4′ , SO 3 R 4′ , —N═CR 4′ R 5′ , —NR 4′ C(O)R 4″ , —NR 4′ —CO-haloalkyl, —NO 2 , —NR 4′ —SO 2 -haloalkyl, —NR 4′ —SO 2 -alkyl, —NR 4′ —CO-alkyl, NR 4′ (CH 2 ) p heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, —O(CH 2 ) p [O(CH 2 ) p ] q OCH 3 , —C(NR 4″ )NR 4′ benzimidazolyl, —C(NR 4″ )NR 4′ -benzthiazolyl, —C(NR 4″ )NR 4′ benzoxazolyl, hydroxyalkyl, hydroxy-cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl; 
 R 4′ , R 4″ , R 5′  independently are H, halogen, alkyl, —C(NR 7 )NR 7′ R 8 , —(CH 2 ) p aryl, haloalkyl, —CH 2 ) p NR 7 R 8 , —C(O)NR 7 R 8 , —N═CR 7 R 8 , —NR 7 C(O)R 8 , cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 
 R 7 , R 7′ , R 8  independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl; 
 R 7a  is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; 
 R 7b  is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; 
 A is CO or SO 2 ; 
 X is NR 2′ , O, or S; 
 Z is N or CR 2′ ; 
 R 2′  is H, alkyl, —C(O)NR 7 , —C(O)R b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 
 p is 1 to 6; 
 q is 1 to 6; 
 R 9  independently represents H, —CN, —OH, —SH, alkoxy, alkylthio, —CO 2 R 4′ , —C(O)R 4a , —C(O)NR 7 R 8 , —SO 2 NR 4′ , —NR 4′ R 5′ , —SO 2 -alkyl, —SO 2 R 4′ , SO 3 R 4′ , —N═CR 4′ R 5′ , —NR 4′ C(O)R 4″ , —NR 4′ —CO-haloalkyl, —NO 2 , —NR 4′ —SO 2 -haloalkyl, —NR 4′ —SO 2 -alkyl, —NR 4′ —CO-alkyl, —NR 4′ (CH 2 ) p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, —O(CH 2 ) p [O(CH 2 ) p ] q OCH 3 , —C(NR 4″ )NR 4′ benzimidazolyl, —C(NR 4″ )NR 4′ -benzthiazolyl, —C(NR 4″ )NR 4′ benzoxazolyl, hydroxycycloalkyl, hydroxy-alkylamino, haloalkyloxy, heterocycloalkyl, —(CH 2 ) p NR 7 COR 8 , aryl, or heteroaryl; 
 R 4a  is H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, —C(NR 7 )NR 7′ R 8 , —(CH 2 ) p aryl, —(CH 2 ) p NR 7 R 8 , —C(O)NR 7 R 8 , —N═CR 7 R 8 , —NR 7 C(O)R 8 , halogen, heteroaryl, or aryl; 
 wherein
 an C 1 -C 6 -alkyl group, if not stated otherwise, denotes a linear or branched C 1 -C 6 -alkyl, which can optionally be substituted by one or more substituents R′; 
 an C 2 -C 6 -alkenyl group, if not stated otherwise, denotes a linear or branched C 2 -C 6 -alkenyl, which can optionally be substituted by one or more substituents R′; 
 an alkyl group, if not stated otherwise, denotes a linear or branched C 1 -C 6 -alkyl, a linear or branched C 2 -C 6 -alkenyl or a linear or branched C 2 -C 6 -alkynyl group, which can be substituted by one or more substituents R′; R′ being defined as above; 
 R′ is independently H, —CO 2 R″, —CONHR″, —CR″O, —SO 2 NR″, —NR″—CO-haloalkyl, —NO 2 , —NR″—SO 2 -haloalkyl, —NR″—SO 2 -alkyl, —SO 2 -alkyl, —NR″—CO-alkyl, —CN, alkyl, cycloalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 
 R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; 
 a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by one or more substituents R′; R′ being defined as above; 
 a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom selected from O, N, and S, wherein one or more of the carbon atoms in the ring can be substituted by R 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 R′, where R′ is as defined above; 
 an arylamino group denotes an HN-aryl or N-diaryl group, the aryl group being as defined above; 
 a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from O, N, and 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 R′, wherein R′ is as defined above. 
 
 
   
   
       2 . The compound according to  claim 1 , wherein:
 X is S; and   Z is CH;   
   
   
       3 . A composition containing a compound according to  claim 1  or  claim 2  and a pharmaceutically acceptable carrier or diluent. 
   
   
       4 . A method for the treatment or prevention of a disease characterized by hyperproliferation of cells, wherein said method comprises administering a compound according to  claim 1  or  claim 2  to a patient in need thereof. 
   
   
       5 . A method for the treatment or prevention of a disease resulting from ischemia and/or reperfusion injury of organs and/or of parts of the body selected from the group comprising heart, brain, peripheral limb, kidney, liver, spleen and lung, and/or wherein the endothelial dysfunction is associated with diseases selected from a group comprising infarctions such as myocardial infarction and critical limb ischemia, and/or wherein the endothelial dysfunction is associated with diseases selected from the group comprising ischemic diseases, myocardial infarction and ischemic diseases of organs, wherein said method comprises administering a compound according to  claim 1  or  claim 2  to a patient in need thereof. 
   
   
       6 . A method for the treatment or prevention of a neurological diseases or disorders selected from the group comprising Alzheimer's disease, Parkinson's disease, Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington's Disease, Down's Syndrome, nerve deafness, and Meniere's disease, wherein said method comprises administering a compound according to  claim 1  or  claim 2  to a patient in need thereof. 
   
   
       7 . A method for the treatment or prevention of diseases that are caused by protozoal infestations in humans and animals, by bacteria, viruses or proteinaceous agents, wherein said method comprises administering a compound according to  claim 1  or  claim 2  to a patient in need thereof. 
   
   
       8 . A method for the treatment or prevention of disease characterized by hyperproliferation of cells, wherein the disease is selected from the group consisting of psoriasis, atopic dermatitis, alopecia greata, alopecia totalis, alopecia subtotalis, alopecia universalis, alopecia diffusa, lupus erythematodes of the skin, lichen planus, dermatomyostis of the skin, atopic eczema, morphea, sklerodermia, psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa, alopecia greata ophiasis-type, androgenetic alopecia, allergic contact eczema, irritative contact eczema, contact eczema, pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scarring mucosal pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitis herpetiformis duhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichen vidal, prurigo simplex, prurigo nodularis, prurigo acuta, linear IgA dermatosis, polymorphic light dermatoses, erythema solaris, lichen sclerosus et atrophicans, exanthema of the skin, drug exanthema, purpura chronica progressiva, dihidrotic ekzema, Ekzema, fixed drug exanthema, photoallergic skin reaction, lichen simplex eriorale, dermatitis and “Graft versus Host-Disease”, acne, rosacea, scarring, keloids, vitiligo, actinic keratoses, hyperkeratoses like epidermolytic hyperkeratosis, Hyperkeratosis Lenticularis Perstans, Keratosis pilaris and Ichthyoses, wherein said method comprises administering a compound according to  claim 1  or  claim 2  to a patient in need thereof. 
   
   
       9 . A method for the treatment or prevention of disease characterized by hyperproliferation of cells, wherein the disease is selected from the group consisting of hematological or solid tumors, wherein said method comprises administering a compound according to  claim 1  or  claim 2  to a patient in need thereof.