Benzazole analogues and uses thereof

Abstract

The present invention relates to compounds of the general formulas (I), (Ia) and (II) and salts and physiologically functional derivatives thereof, wherein the substituents —Y are attached to the 5- or 6-position of the benzazole.

1 . A compound of the general formula (I) or a salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 the substituent —Y—R 1  is attached to the 5- or 6-position of the benzazole; 
 X independently represents S, O, SO, or SO 2 ; 
 Y independently represents S, O, NR 2 , SO, or SO 2 ; 
 A independently represents ←CO—, ←CS—, ←SO—, ←SO 2 , ←CO 2 —, ←CONR 8 —, ←NR 8 CO—, ←NR 8 CONR 9 —, ←NR 8 COO—, ←NR 8 NR 9 CO—, ←NR 8 OCO—, ←ONR 8 CO—, or ←NR 8 SO 2 —, where ← indicates the point of attachment of R 3 ; 
 R 2  independently represents H, alkyl, cycloalkyl, —COR 6 , —SOR 6 , —SO 2 R 6 , —CN, hydroxyalkyl, haloalkyl, or haloalkyloxy; 
 R 3  independently represents H, alkyl, cycloalkyl, aryl, or heteroaryl; 
 R 4  independently represents H, —COR 6 , —CO 2 R 6 , —SOR 6 , —SO 2 R 6 , —SO 3 R 6 , —NO 2 , —CN, —CF 3 , —OCH 3 , —OCF 3 , alkyl, cycloalkyl, alkoxy, —NH 2 , alkylamino, —NR 7 COR 6 , halogen,
 —OH, —SH, alkylthio, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 
 
 R 5  independently represents H, alkyl, cycloalkyl, —COR 6 , —SOR 6 , —SO 2 R 6 , —CN, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; 
 R 6a  independently represents H, alkyl, cycloalkyl, —NR 8 NR 2 R 9 , —ONR 8 R 9 , —NR 8 OR 9 , aryl or heteroaryl; 
 R 6  independently represents H, alkyl, cycloalkyl, —NR 8 R 9 , —NR 8 NR 2 R 9 , —ONR 8 R 9 , —NR 8 OR 9 , aryl or heteroaryl; 
 R 7  independently represents H, alkyl, cycloalkyl, or alkoxy; 
 R 8  independently represents H, alkyl, cycloalkyl, —COR 6 , —SOR 6 , —SO 2 R 6 , haloalkyl, haloalkyloxy, aryl or heteroaryl; 
 R 9  independently represents H, alkyl, cycloalkyl, —COR 6 , —SOR 6 , —SO 2 R 6 , haloalkyl, haloalkyloxy, aryl or heteroaryl; 
 R 1  independently represents one of the following groups: 
 
       
         
           
           
               
               
           
         
       
       where * indicates the point of attachment
 Z independently represents O, NR 8 , or S; 
 R 12  independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, —NR 8a R 9a , or —X 2 R 16 ; 
 R 8a  independently represents H, alkyl, cycloalkyl, —COR 6a , —SOR 6 , —SO 2 R 6 , haloalkyl, haloalkyloxy, aryl, or heteroaryl; 
 R 9a  independently represents H, alkyl, cycloalkyl, —COR 6a , —SOR 6 , —SO 2 R 6 , haloalkyl, haloalkyloxy, aryl, or heteroaryl; 
 R 13  independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, —NR 8a R 9a , or —X 2 R 16 ; 
 R 14  independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, —NR 8a R 9a , or —X 2 R 16 ; 
 R 15  independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, —NR 8a R 9a , or —X 2 R 16 ; 
 R 17  independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, —NR 8a R 9a , or —X 2 R 16 ; 
 X 2  independently represents a direct bond, —O—, —CH 2 —, —OCO—, carbonyl, —S—, —SO—, —SO 2 —, —NR 8 CO—, —CONR 8 —, —SO 2 NR 8 —, —NR 8 SO 2 — or —NR 8a —; 
 R 16  independently represents H, alkyl, cycloalkyl, —SOR 6 , —SO 2 R 6 , —OCH 3 , hydroxyalkyl, haloalkyl, haloalkyloxy, or one of the following groups: 
 
       
         
           
           
               
               
           
         
         where * indicates the point of attachment 
         m independently represents an integer from 1-3; 
         L is absent or represents a divalent linkage group selected from alkylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein one or more of the (—CH 2 —) groups may be replaced by an oxygen or a NR 8 , and wherein one or more carbon atoms may be independently substituted by one or two substituents selected from halogen, hydroxy, alkoxy, haloalkyloxy, phosphonooxy, or phosphonooxyalkyl; 
         X 3  independently represents —COOH, —COOalkyl, —OH, —SH, —SO 3 H, or —SO 2 NR 8 R 9 ; 
         R 18  independently represents H, phosphonooxy, or phosphonooxyalkyl; 
         R 19  independently represents H, alkyl, cycloalkyl, alkylamino, or alkoxy; 
         with the proviso that the following compounds are excluded: 
         N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothazol-2-yl]-2-phenyl-acetamide, N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-benzothiazol-2-yl]-2-phenyl-acetamide, N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-3-phenyl-propionamide, N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acetamide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-acetamide, 2-(2-chloro-5-trifluoromethyl-phenyl)-N-[6-(6,7-dimethoxy-quinolin-4-yl-oxy)-5-fluoro-benzothiazol-2-yl]-acetamide; 
         wherein 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′; 
         wherein R′ independently represents 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, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heteroaryl; 
         wherein R″ independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl; 
         wherein 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 a group E, E being O, S, SO, SO 2 , N, or NR″, R″ being as defined above; 
         wherein an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; 
         wherein an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; 
         wherein an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; 
         wherein a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; 
         wherein a haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; 
         wherein a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N— group or HO-alkyl-NH— group, the alkyl group being as defined above; 
         wherein an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above; 
         wherein a halogen group is chlorine, bromine, fluorine or iodine; 
         wherein 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; 
         wherein a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S, wherein the heterocyclic group can be fused to another ring and can be substituted by one or more substituents R′, wherein R′ is as defined above; 
       
       wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
     
     
         2 . The compound of  claim 1  or a salt thereof, wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phosphatases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
     
     
         3 . The compound according to  claim 1  or a salt thereof, wherein X independently represents S or O; Y represents NH; A represents —CO—; R 5  represents H, wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
     
     
         4 . The compound according to  claim 1  or a salt thereof, wherein X independently represents S or O; Y represents NH; R 5  represents H; A represents ←NHCO—, where ← indicates the point of attachment to R 3 , wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
     
     
         5 . The compound according to  claim 1  or a salt thereof, wherein the —Y—R 1  substituent is attached to the 6-position of the benzazole, wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
     
     
         6 . The compound according to  claim 5  or a salt thereof, wherein R 12  and R 15  are H, and R 13  and R 14  independently represent —O-alkyl which may be substituted, wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
     
     
         7 . A compound of the general formula (Ia) or a salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 the substituent —Y a —R 1a  is attached to the 5- or 6-position of the benzazole; 
 X a  independently represents S, O, SO, or SO 2 ; 
 Y a  independently represents S, NR 2 , SO, or SO 2 ; 
 A a  independently represents ←CO—, ←CS—, ←SO—, ←SO 2 —, ←CO 2 —, ←CONR 8 —, ←NR 8 CO—, ←NR 8 CONR 9 —; ←NR 8 COO—, ←NR 8 NR 9 CO —, ←NR 8 OCO—, ←ONR 8 CO—, or ←NR 8 SO 2 —, where ← indicates the point of attachment to R 3 ; 
 R 1a  independently represents one of the following groups: 
 
       
         
           
           
               
               
           
         
       
       where * indicates the point of attachment;
 R 11  independently represents H, —NHR 8a , or one of the groups: 
 
       
         
           
           
               
               
           
         
       
       where * indicates point of attachment;
 R 13a  independently represents H, halogen, nitro, trifluoromethyl, alkyl, —NR 8a R 9a , or X 2 R 16 ; 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7 , R 8 , R 8a , R 9 , R 9a , R 12 , R 13 , R 16 , or X 2 , are as defined in  claim 1 ; 
 wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
 
     
     
         8 . A compound of the general formula (II) or a salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 the substituent —Y b — is attached to the 5- or 6-position of the benzazole; 
 X b  independently represents S, O, SO, or SO 2 ; 
 Y b  independently represents S, NR 2 , SO, or SO 2 ; 
 A b  independently represents ←CO—, ←CS—, ←SO—, ←SO 2 —, ←CO 2 —, ←CONR 8 —, ←NR 8 CO—, ←NR 8 CONR 9 —; ←NR 8 COO—, ←NR 8 NR 9 CO—, ←NR 8 OCO—, ←ONR 8 CO—, or ←NR 8 SO 2 —, where ← indicates the point of attachment to R 3 ; 
 R 4b  independently represents H, —SOR 6 , —SO 2 R 6 , —SO 3 R 6 , —NO 2 , —CN, —CF 3 , —OCH 3 , —OCF 3 , alkyl, cycloalkyl, alkoxy, oxyalkyl, alkoxyalkyl, —NH 2 , alkylamine, aminoalkyl, alkylaminoalkyl, —NR 7 COR 6 , halogen, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7 , R 8 , R 8a , R 9 , R 9a , R 11 , R 12 , R 16 , X 2  are as defined in  claim 1 ; 
 wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
 
     
     
         9 . A composition containing a compound of  claim 1  or a salt thereof and optionally an adjuvant and/or an additive, wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
     
     
         10 . A composition containing a compound of  claim 7  or a salt thereof and optionally an adjuvant and/or an additive, wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively. 
     
     
         11 . A composition containing a compound of  claim 8  or a salt thereof and optionally an adjuvant and/or an additive, wherein said compound or salt may be an ester transformed in vivo into the corresponding active alcohol, an ester transformed in vivo into the corresponding active acid, an imine transformed in vivo into the corresponding amines, an imine metabolized in vivo into the corresponding active carbonyl derivative, a 1-carboxy-amine decarboxylated in vivo into the active amine, a phosphoryloxy-compound dephosphorylated in vivo by phophateases into the active alcohols, or an amide metabolized into the corresponding amine or acid respectively.