Azole derivatives and fused bicyclic azole derivatives as therapeutic agents

Abstract

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated end products (RAGE) and its ligands, such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephrdpathy, atherosclerosis, and retinopathy, the development of Alzheimer's disease, erectile dysfunction, and tumor invasion and metastasis.

1 . A method for prevention and/or treatment of a RAGE mediated human disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is -hydrogen, -alkyl, -alkenyl, or -alkynyl, 
       A 1  is —N(R 2 )—,
 wherein
 R 2  is -phenyl, 
 
 
       R 3  is
 a) -hydrogen, 
 b)-halogen, 
 c) -hydroxyl, 
 d)-cyano, 
 e) -carbamoyl, 
 f) -carboxyl, 
 g) -aryl, 
 h) -cycloalkyl, 
 i) -alkyl, 
 j) -alkenyl, 
 k) -alkynyl, 
 l) -alkylene-aryl, 
 m) -alkylene-cycloalkyl, 
 n) -fused cycloalkylaryl, 
 o) -alkylene-fused cycloalkylaryl, 
 p) —C(O)—O-alkyl, 
 q) —C(O)—O-alkylene-aryl, 
 r) —C(O)—NH-alkyl, 
 s) —C(O)—NH-alkylene-aryl, 
 t) —SO 2 -alkyl, 
 u) —SO 2 -alkylene-aryl, 
 v) —SO 2 -aryl, 
 w) —SO 2 —NH-alkyl, 
 x) —SO 2 —NH-alkylene-aryl, 
 y) —C(O)-alkyl, 
 z) —C(O)-alkylene-aryl, 
 aa) -G 4 -G 5 -G 6 -R 7 , 
 bb) —Y 1 -alkyl, 
 cc) —Y 1 -aryl, 
 dd) —Y 1 -alkylene-aryl, 
 ee) —Y 1 -alkylene-NR 9 R 10 , or 
 ff) —Y 1 -alkylene-W 1 —R 11 , 
 wherein
 G 4  and G 6  are independently selected from the group consisting of: alkylene, alkenylene, alkynylene, cycloalkylene, arylene, -alkylene-aryl, -alkenylene-aryl, -alkenylene-heteroaryl, and a direct bond; 
 G 5  is —O—, —S—, —N(R 8 )—, —S(O)—, —S(O) 2 —, —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)N(R 8 )—, N(R 8 )C(O)—, —S(O 2 )N(R 8 )—, N(R 8 )S(O 2 )—, —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-, -alkylene-O—, alkylene, alkenylene, alkynylene, cycloalkylene, arylene, fused cycloalkylarylene, or a direct bond, wherein R 8  is -hydrogen, -aryl, -alkyl, -alkylene-aryl, or -alkylene-O-aryl; 
 R 7  is -hydrogen, -aryl, -cycloalkyl, -alkyl, -alkenyl, -alkynyl, -alkylene-aryl, -alkylene-cycloalkyl, -fused cycloalkylaryl, or -alkylene-fused cycloalkylaryl; 
 Y 1  and W 1  are independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—, 
 
 
       
         
           
           
               
               
           
         
         
           
             wherein R 12  and R 13  are independently selected from the group consisting of: -aryl, -alkyl, -alkylene-aryl, alkoxy, and -alkylene-O-aryl; and 
           
           R 9 , R 10 , and R 11  are independently selected from the group consisting of: -aryl, -alkyl, and -alkylene-aryl; 
         
       
       R 4  is
 a) -phenyl, 
 b) -phenylene-G 5 -G 6 -R 7 , 
 c) -phenylene-alkylene-G 5 -G 6 -R 7 , or 
 d) -phenylene-alkylenylene-G 5 -G 6 -R 7 , 
 wherein 
 G 6  is alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, -alkylene-aryl, -alkylene-heteroaryl, alkenylene-aryl, -alkenylene-heteroaryl, or a direct bond; 
 G 5  is —O—, —S—, —N(R 8 )—, —S(O)—, —S(O) 2 —, —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)N(R 8 )—, N(R 8 )C(O)—, —S(O 2 )N(R 8 )—, N(R 8 )S(O 2 )—, —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-, -alkylene-O—, alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, fused cycloalkylarylene, fused cycloalkylheteroarylene, fused heterocyclylarylene, fused heterocyclylheteroarylene, or a direct bond, wherein R 8  is -hydrogen, -aryl, -alkyl, -alkylene-aryl, or -alkylene-O-aryl; 
 R 7  is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, alkenyl, alkynyl, alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, fused heterocyclylheteroaryl, alkylene-fused cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl, -alkylene-fused heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl; 
 
       wherein
 the aryl and/or alkyl group(s) in R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 , may be optionally substituted 1-4 times with a substituent group, wherein said substituent group(s) are independently selected from the group consisting of:
 a) —H, 
 b) -halogen, 
 c) -hydroxyl, 
 d) -cyano, 
 e) -carbamoyl, 
 f) -carboxyl, 
 g) —Y 2 -alkyl, 
 h) —Y 2 -aryl, 
 i) —Y 2 -alkylene-aryl 
 j) —Y 2 -alkylene-W 2 —R 18 , 
 k) —Y 3 —Y 4 —NR 23 R 24 , 
 l) —Y 3 —Y 4 —NH—C(═NR 25 )NR 23 R 24 , and 
 m) —Y 3 —Y 4 —C(═NR 25 )NR 23 R 24 ,
 wherein
 Y 2  and W 2  is —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—S(O) 2 —, —O—CO—, 
 
 
 
 
       
         
           
           
               
               
           
         
         
           
             
                wherein; 
                R 19  and R 20  are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; 
               R 18  is -aryl, -alkyl, -alkylene-aryl, or -alkylene-O-aryl; 
               Y 3  is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—, 
             
           
         
       
       
         
           
           
               
               
           
         
         
           
             
                wherein R 27  and R 28  are independently selected from the group consisting of: -aryl, -alkyl, -alkylene-aryl, alkoxy, and -alkyl-O-aryl; 
               Y 4  is 
                a) -alkylene, 
                b) -alkenylene, 
                c) -alkynylene, 
                d) -arylene, 
                e) -cycloalkylene, 
                f) -alkylene-arylene, 
                g) -alkylene-cycloalkylene, 
                h)-arylene-alkylene, 
                i)-cycloalkylene-alkylene, 
                j) —O—, 
                k) —S—, 
                l) —S(O 2 )—, or 
                m) —S(O)—, 
                wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO 2  atoms; and 
               R 23 , R 24 , and R 25  are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, and -alkylene-O-aryl, 
             
           
         
       
       and 
       wherein
 R 2  may be optionally substituted 1-4 times with a substituent group, wherein said substituent group(s) are independently selected from the group consisting of:
 a) —H, 
 b) -halogen, 
 c) -hydroxyl, 
 d) -cyano, 
 e) -carbamoyl, 
 f) -carboxyl, 
 g) —Y 2 -alkyl, 
 h) —Y 2 -aryl, 
 i) —Y 2 -heteroaryl, 
 j) —Y 2 -alkylene-heteroaryl-aryl, 
 k) —Y 2 -alkylene-aryl, 
 l) —Y 2 -alkylene-W 2 —R 15 , 
 m) —Y 3 —Y 4 —NR 23 R 24 , 
 n) —Y 3 —Y 4 —NH—C(═NR 25 )NR 23 R 24 , 
 o) —Y 3 —Y 4 —C(═NR 25 )NR 23 R 24 , and 
 p) —Y 3 —Y 4 —Y 5 -A 2    
 wherein
 Y 2  and W 2  are independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—S(O) 2 —, —O—CO—, 
 
 
 
       
         
           
           
               
               
           
         
         
           
             
               wherein; 
                R 19  and R 20  are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; 
             
             R 18  is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl; 
             Y 3  and Y 5  are independently selected from the and consisting of a direct bond, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—, 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
               wherein R 27  and R 26  are independently selected from the group consisting of: -aryl, -alkyl, -alkylene-aryl, alkoxy, and -alkyl-O-aryl; 
             
             Y 4  is
 a) -alkylene, 
 b) -alkenylene, 
 c) -alkynylene, 
 d) -arylene, 
 e) -heteroarylene, 
 f) -cycloalkylene, 
 g) -heterocyclylene, 
 h) -alkylene-arylene, 
 i) -alkylene-heteroarylene, 
 j) -alkylene-cycloalkylene, 
 k) -alkylene-heterocyclylene, 
 l) -arylene-alkylene, 
 m) -heteroarylene-alkylene, 
 n) -cycloalkylene-alkylene, 
 o) -heterocyclylene-alkylene, 
 p) —O—, 
 q) —S—, 
 r) —S(O 2 )—, or 
 s) —S(O)—, 
  wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO 2  atoms; 
 
             A 2  is
 a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or 
 b) -imidazolyl, and 
 
             R 23 , R 24 , and R 25  are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R 23  and R 24  may be taken together to form a five-membered ring having the formula —(CH 2 ) s —X 3 —(CH 2 ) t — bonded to the nitrogen atom to which R 23  and R 24  are attached
 wherein 
  s and t are, independently, 1, 2, 3, or 4; 
  X 3  is a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—, 
 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
                wherein R 28  and R 29  are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl; 
             
             wherein the alkyl and/or aryl groups in the optional substituents
 a) —Y 2 -alkyl, 
 b) —Y 2 -aryl, 
 c) —Y 2 -heteroaryl, 
 d) —Y 2 -alyklene-heteroaryl, 
 e) —Y 2 -alkylene-aryl, 
 f) —Y 2 -alkylene-W 2 —R 18 , 
 g) —Y 3 —Y 4 —NR 23 R 24 , 
 h) —Y 3 —Y 4 —NH—C(═NR 25 )NR 23 R 24 , 
 i) Y 3 —Y 4 —C(═NR 25 )NR 23 R 24 , and 
 j) —Y 3 —Y 4 —Y 5 -A 2 , 
 of R 2  may be optionally substituted 1-4 times with a substitutent independently selected from the group consisting of: 
  a) halogen, 
  b) perhaloalkyl, 
  c) alkyl, 
  d) cyano, 
  e) alkyloxy, 
  f) aryl, and 
  g) aryloxy, and 
 
           
         
       
       wherein
 the aryl and/or alkyl group(s) in R 4  may be optionally substituted 1-4 times with a substituent group, wherein said substituent group(s) are independently selected from the group consisting of:
 a) —H, 
 b) -halogen, 
 c) -hydroxyl, 
 d) -cyano, 
 e) -carbamoyl, 
 f) -carboxyl, 
 g) —Y 2 -alkyl, 
 h) —Y 2 -aryl, 
 i) —Y 2 -heteroaryl, 
 j) —Y 2 -alkylene-heteroaryl-aryl, 
 k) —Y 2 -alkylene-aryl, 
 l) —Y 2 -alkylene-W 2 —R 18 , 
 m) —Y 3 —Y 4 —NR 23 R 24 , 
 n) —Y 3 —Y 4 —NH—C(═NR 25 )NR 23 R 24 , 
 o) —Y 3 —Y 4 —C(═NR 25 )NR 23 R 24 , and 
 P) —Y 3 —Y 4 —Y 5 -A 2 , 
 wherein
 Y 2  and W 2  are independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—S(O) 2 —, —O—CO—, 
 
 
 
       
         
           
           
               
               
           
         
         
           
             
               wherein 
                R 19  and R 20  are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; 
             
             R 18  is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl; 
             Y 3  and Y 5  are independently selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—, 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
               wherein R 27  and R 26  are independently selected from the group consisting of: -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkyl-O-aryl; 
             
             Y 4  is
 a) -alkylene, 
 b) -alkenylene, 
 c) -alkynylene, 
 d) -arylene, 
 e) -heteroarylene, 
 f) -cycloalkylene, 
 g) -heterocyclylene, 
 h) -alkylene-arylene, 
 i) -alkylene-heteroarylene, 
 j) -alkylene-cycloalkylene, 
 k) -alkylene-heterocyclylene, 
 l) -arylene-alkylene, 
 m) -heteroarylene-alkylene, 
 n) -cycloalkylene-alkylene, 
 o) -heterocyclylene-alkylene, 
 p) —O—, 
 q) —S—, 
 r) —S(O 2 )—, or 
 s) —S(O)—, 
  wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO 2  atoms; 
 
             A 2  is
 a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or 
 b) -imidazolyl, and 
 
             R 23 , R 24 , and R 25  are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R 23  and R 24  may be taken together to form a five-membered ring having the formula —(CH 2 ) s —X 3 —(CH 2 ) t — bonded to the nitrogen atom to which R 23  and R 24  are attached
 wherein 
  s and t are, independently, 1, 2, 3, or 4; 
  X 3  is a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—, 
 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
                wherein R 28  and R 29  are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl; 
             
             wherein the alkyl and/or aryl groups in the optional substituents
 a) —Y 2 -alkyl, 
 b) —Y 2 -aryl, 
 c) —Y 2 -heteroaryl, 
 d) —Y 2 -alkylene-heteroaryl, 
 e) —Y 2 -alkylene-aryl, 
 f) —Y 2 -alkylene-W 2 —R 18 , 
 g) —Y 3 —Y 4 —NR 23 R 24 , 
 h) —Y 3 —Y 4 —NH—C(═NR 25 )NR 23 R 24 , 
 i) —Y 3 —Y 4 —C(═NR 25 )NR 23 R 24 , and 
 j) —Y 3 —Y 4 —Y 5 -A 2 , 
 of R 2  and R 4  may be optionally substituted 1-4 times with a substitutent independently selected from the group consisting of: 
  a) halogen, 
  b) perhaloalkyl, 
  c) alkyl, 
  d) cyano, 
  e) alkyloxy, 
  f) aryl, and 
  g) aryloxy, and 
 
           
           wherein the ring or rings containing a heteroatom in the heteroaryl, heteroarylene, heterocyclyl, heterocyclene, fused arylheterocyclyl, or fused heteroarylheterocyclyl groups in R 2  or R 4  or in a substituent of R 2  or R 4  is a five-membered nitrogen containing ring, and 
         
       
       wherein
 at least one of R 2  and R 4  is substituted with at least one group of the formula
 a) —Y 3 —Y 4 —NR 23 R 24 , 
 b) —Y 3 —Y 4 —NH—C(═NR 25 )NR 23 R 24 , 
 c) Y 3 —Y 4 —C(═NR 25 )NR 23 R 24 , or 
 d) —Y 3 —Y 4 —Y 5 -A 2 , 
 with the proviso that no more than one of R 23 , R 24 , and R 25  is aryl or heteroaryl; 
 
 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
 
     
     
         2 . The method according to  claim 1  for treatment of acute and/or chronic systemic inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         3 . The method according to  claim 1  for treatment of acute and/or chronic skin inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         4 . The method according to  claim 1  for treatment of vascular permeability which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         5 . The method according to  claim 1  for treatment of nephropathy which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         6 . The method according to  claim 1  for treatment of atherosclerosis which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         7 . The method according to  claim 1  for treatment of retinopathy which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         8 . The method according to  claim 1  for treatment of asthma which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         9 . The method according to  claim 1  for treatment of chronic obstructive pulmonary disease which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         10 . A method for prevention and/or treatment of a RAGE mediated human disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is -hydrogen, -alkyl, or -alkenyl, 
 R 3  is -hydrogen or -alkyl, and 
 R 102  and R 104  are independently selected from the group consisting of:
 a) —H, 
 b) -alkyl, 
 c) -aryl, 
 d) -heteroaryl, 
 e) -alkylene-heteroaryl-aryl, 
 f) -alkylene-aryl, 
 g) -alkylene-W 2 —R 18 , 
 h) —Y 4 —NR 23 R 24 , 
 i) —Y 4 —NH—C(═NR 25 )NR 23 R 24 , 
 j) —Y 4 —C(═NR 25 )NR 23 R 24 , and 
 k) —Y 4 —Y 5 -A 2 ;
 wherein
 W 2  is —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—S(O) 2 —, —O—CO—, 
 
 
 
 
       
         
           
           
               
               
           
         
         
           
             
                wherein R 19  and R 20  are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; 
               R 18  is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl; 
               Y 5  is a direct bond, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—, 
             
           
         
       
       
         
           
           
               
               
           
         
         
           
             
                wherein R 27  and R 26  are independently selected from the group consisting of -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkyl-O-aryl; 
               Y 4  is 
                a) -alkylene, 
                b) -alkenylene, 
                c) -alkynylene, 
                d) -arylene, 
                e) -heteroarylene, 
                f) -cycloalkylene, 
                g) -heterocyclylene, 
                h) -alkylene-arylene, 
                i) -alkylene-heteroarylene, 
                j) -alkylene-cycloalkylene, 
                k)-alkylene-heterocyclylene, 
                l) -arylene-alkylene, 
                m) -heteroarylene-alkylene, 
                n) -cycloalkylene-alkylene, 
                o) -heterocyclylene-alkylene, 
                p) —O—, 
                q) —S—, 
                r) —S(O 2 )—, or 
                s) —S(O)—; 
                wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO 2  atoms; 
               A 2  is 
                a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or 
                b) -imidazolyl, 
               R 23 , R 24 , and R 25  are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R 23  and R 24  may be taken together to form a five-membered ring having the formula —(CH 2 ) s —X 3 —(CH 2 ) t — bonded to the nitrogen atom to which R 23  and R 24  are attached 
                wherein 
                a and t are, independently, 1, 2, 3, or 4; 
                X 3  is a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—, 
             
           
         
       
       
         
           
           
               
               
           
         
         
           
             
                wherein R 25  and R 29  are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl; 
             
           
         
       
       wherein
 the alkyl and/or aryl groups of R 102  and R 104  may be optionally substituted 1-4 times with a substituent group selected from the group consisting of:
 a) halogen, 
 b) perhaloalkyl, 
 c) alkyl, 
 d) cyano, 
 e) alkyloxy, 
 f) aryl, and 
 g) aryloxy 
 
 wherein the ring or rings containing a heteroatom in the heteroaryl, heterarylene, heterocyclyl, heterocyclene, fused arylheterocyclyl, or fused heteroarylheterocyclyl groups in R 102  or R 104  or in a substituent of R 102  or R 104  is a five-membered nitrogen containing ring, 
 
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         11 . The method according to  claim 10  for treatment of acute and/or chronic system inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         12 . The method according to  claim 10  for treatment of acute and/or chronic skin inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         13 . The method according to  claim 10  for treatment of vascular permeability which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         14 . The method according to  claim 10  for treatment of nephropathy which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         15 . The method according to  claim 10  for treatment of atherosclerosis which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         16 . The method according to  claim 10  for treatment of retinopathy which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         17 . The method according to  claim 10  for treatment of asthma which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         18 . The method according to  claim 10  for treatment of chronic obstructive pulmonary disease which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         19 . A method for prevention and/or treatment of a RAGE mediated human disease comprising administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         20 . The method according to  claim 19  for treatment of acute and/or chronic systemic inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         21 . The method according to  claim 19  for treatment of acute and/or chronic skin inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         22 . The method according to  claim 19  for treatment of acute vascular permeability which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         23 . The method according to  claim 19  for treatment of nephropathy which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         24 . The method according to  claim 19  for treatment of atherosclerosis which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         25 . The method according to  claim 19  for treatment of retinopathy which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         26 . The method according to  claim 19  for treatment of asthma which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         27 . The method according to  claim 19  for treatment of chronic obstructive pulmonary disease which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.