Aromatic sulfone hydroxamic acids and their use as protease inhibitors

Abstract

This invention is directed to aromatic sulfone hydroxamic acids (including hydroxamates) and salts thereof that, inter alia, inhibit matrix metalloproteinase (also known as “matrix metalloprotease” or “MMP”) activity and/or aggrecanase activity. This invention also is directed to a prevention or treatment method that comprises administering such a compound or salt in an MMP-inhibiting and/or aggrecanase-inhibiting effective amount to an animal, particularly a mammal having (or disposed to having) a pathological condition associated with MMP and/or aggrecanase activity.

1 . A compound or salt thereof, wherein: 
 the compound corresponds in structure to Formula 1 - 1:                          A 1  is selected from the group consisting of —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), wherein any member of such group optionally is substituted; and    A 2  and A 3 , together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members; and    E 1  is selected from the group consisting of —O—, —S(O) 2 —, —S(O)—, —S—, —N(R 1 )—,    —C(O)—N(R 1 )—, —N(R 1 )—C(O)—, and —C(R 1 )(R 2 )—; and    E 2  is selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of such group optionally is substituted; and    E forms a link of at least 2 carbon atoms between E 1  and E 3 ; and    E 3  is selected from the group consisting of —C(O)—, —O—(CO)—, —C(O)—O—, —C(NR 3 )—, —N(R 4 )—, —N(R 4 )—C(NR 3 )—, —C(NR 3 )—N(R 4 )—, —C(O)—N(R 4 )—, —N(R 4 )—C(O)—, —N(R 4 )—C(O)—N(R 5 )—, —S—, —S(O)—, —N(R 4 )—S(O) 2 —, —S(O) 2 —N(R 4 )—, —C(O)—N(R 4 )—N(R 5 )—C(O)—, —C(R 4 )(R 6 )—C(O)—, —C(R 7 )(R 8 )—; and    E 4  is selected from the group consisting of a bond, alkyl, and alkenyl, wherein the alkyl or alkenyl optionally is substituted; and    E 5  is selected from the group consisting of —OH, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, and heterocyclyl, wherein any member of such group optionally is substituted; and    R 1  and R 2  are independently selected from the group consisting of —H and alkyl, wherein the alkyl optionally is substituted; and    R 3 is selected from the group consisting of —H and —OH; and    R 4  and R 5  are independently selected from the group consisting of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member of such group optionally is substituted; and    R 6  is selected from the group consisting of —CN and —OH; and    R 7 is selected from the group consisting of —H, halogen, —OH, alkyl, alkoxy, and alkoxyalkyl, wherein the alkyl, alkoxy, or alkoxyalkyl optionally is substituted; and    R 8  is selected from the group consisting of —OH and alkoxy, wherein the alkoxy optionally is substituted; and    neither R 1  nor R 2  forms a ring structure with E 2 , E 3 , E 4 , or E 5 ; and    neither R 4  nor R 5  forms a ring structure with E 2 , E 4 , or E 5      
     
     
         2 . A compound or salt thereof according to  claim 1 , wherein: 
 A 1  is selected from the group consisting of —H, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, carbocyclylcarbonyl, carbocyclyl-C 1 -C 8 -alkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-C 1 -C 8 -alkylcarbonyl, carbocyclyloxycarbonyl, carbocyclyl-C 1 -C 8 -alkoxycarbonyl, N(R 9 )(R 10 )-C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkyl(thiocarbonyl), C 1 -C 8 -alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclyl-C 1 -C 8 -alkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclyl-C 1 -C 8 -alkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclyl-C 1 -C 8 -alkoxy(thiocarbonyl), and N(R 9 )(R 10 )-C 1 -C 8 -alkyl(thiocarbonyl); and    E 2  is selected from the group consisting of C 2 -C 20 -alkyl, cycloalkyl, C 1 -C 10 -alkylcycloalkyl, cycloalkyl-C 1 -C 10 -alkyl, and C 1 -C 10 -alkylcycloalkyl-C 1 -C 10 -alkyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkyl; and    E 4  is selected from the group consisting of a bond, C 1 -C 20 -alkyl, and C 2 -C 20 -alkenyl, wherein the C 1 -C 20 -alkyl or C 2 -C 20 -alkenyl optionally is substituted with one or more substituents independently selected from the group consisting of: 
 halogen, and  
 carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkoxy, halogen-substituted C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C 1 -C 8 -alkyl; and  
   E 5  is selected from the group consisting of —OH, C 2 -C 20 -alkenyl, C 2 -C 20 -alkynyl, C 1 -C 20 -alkoxy, C 1 -C 20 -alkoxy-C 1 -C 20 -alkyl, carbocyclyl, and heterocyclyl, wherein: 
 the C 2 -C 20 -alkenyl, C 2 -C 20 -alkynyl, C 1 -C 20 -alkoxy, or C 1 -C 20 -alkoxy-C 1 -C 2 0-alkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , and —CN, and  
 the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , carbocyclyl, carbocyclyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkoxy, halogen-substituted C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkylcarbocyclyl, halogen-substituted C 1 -C 8 -alkylcarbocyclyl, hydroxycarbocyclyl, and heterocyclyl; and  
   R 1  and R 2  are independently selected from the group consisting of —H, C 1 -C 8 -alkyl, and halo-C 1 -C 8 -alkyl; and    R 4  and R 5  are independently selected from the group consisting of —H, C 1 -C 8 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 8 -alkyl, heterocyclyl, and heterocyclyl-C 1 -C 8 -alkyl, wherein any member of such group optionally is substituted with one or more halogen; and    R 7  is selected from the group consisting of —H, halogen, —OH, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkoxy, and halogen-substituted C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl; and    R 8  is selected from the group consisting of —OH, C 1 -C 8 -alkoxy, and halo-C 1 -C 8 -alkoxy; and    R 9  and R 10  are independently selected from the group consisting of —H, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkylcarbonyl, carbocyclyl-C 1 -C 8 -alkyl, and carbocyclyl-C 1 -C 8 -alkoxycarbonyl; and    R 11  and R 12  are independently selected from the group consisting of —H, C 1 -C 8 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 8 -alkyl, heterocyclyl, and heterocyclyl-C 1 -C 8 -alkyl, wherein any member of such group optionally is substituted with one or more halogen; and    R 13  is selected from the group consisting of —H, C 1 -C 8 -alkyl, —O—R 14 , —N(R 14 )(R 15 ), carbocyclyl-C 1 -C 8 -alkyl, heterocyclyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, halogen-substituted carbocyclyl-C 1 -C 8 -alkyl, and halogen-substituted heterocyclyl-C 1 -C 8 -alkyl; and    R 14  and R 15  are independently selected from the group consisting of —H, C 1 -C 8 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 8 -alkyl, heterocyclyl, and heterocyclyl-C 1 -C 8 -alkyl, wherein any member of such group optionally is substituted with one or more halogen.    
     
     
         3 . A compound or salt thereof according to  claim 2 , wherein A 1  is —H.  
     
     
         4 . A compound or salt thereof according to  claim 3 , wherein: 
 E 2  is C 2 -C 6 -alkyl optionally substituted with one or more halogen; and    E 4  is selected from the group consisting of a bond, C 1 -C 3 -alkyl, and C 2 -C 3 -alkenyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of: 
 halogen, and  
 carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C 1 -C 6 -alkyl; and  
   E 5  is selected from the group consisting of —OH, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, carbocyclyl, and heterocyclyl, wherein: 
 the C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 1 -C 8 -alkoxy, or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , and —CN, and  
 the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 ) (R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 -R 11 , carbocyclyl, carbocyclyl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbocyclyl, halogen-substituted C 1 -C 6 -alkylcarbocyclyl, hydroxycarbocyclyl, and heteroaryl; and  
   R 1  and R 2  are independently selected from the group consisting of —H, C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkyl; and    R 4  and R 5  are independently selected from the group consisting of —H, C 1 -C 6 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 6 -alkyl, heterocyclyl, and heterocyclyl-C 1 -C 6 -alkyl, wherein any member of such group optionally is substituted with one or more halogen; and    R 7  is selected from the group consisting of —H, halogen, —OH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, and halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl; and    R 8  is selected from the group consisting of—OH, C 1 -C 6 -alkoxy, and halo-C 1 -C 6 -alkoxy; and    R 11  and R 12  are independently selected from the group consisting of —H, C 1 -C 6 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 6 -alkyl, heterocyclyl, and heterocyclyl-C 1 -C 6 -alkyl, wherein any member of such group optionally is substituted with one or more halogen; and    R 13  is selected from the group consisting of —H, C 1 -C 6 -alkyl, —O—R 14 , —N(R 14 )(R 15 ), carbocyclyl-C 1 -C 6 -alkyl, and heterocyclyl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halogen-substituted carbocyclyl-C 1 -C 6 -alkyl, and halogen-substituted heterocyclyl-C 1 -C 6 -alkyl; and    R 14  and R 15  are independently selected from the group consisting of —H, C 1 -C 6 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 6 -alkyl, heterocyclyl, and heterocyclyl-C 1 -C 6 -alkyl, wherein any member of such group optionally is substituted with one or more halogen.    
     
     
         5 . A compound or salt thereof according to  claim 4 , wherein A 2  and A 3 , together with the carbon atom to which they both are attached, form an optionally-substituted heterocyclyl containing either 5 or 6 ring members.  
     
     
         6 . A compound or salt thereof according to  claim 5 , wherein: 
 the compound corresponds in structure to a formula selected from the group consisting of:                          A 4  is selected from the group consisting of —H, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylcarbonyl, alkylsulfonyl, alkyliminocarbonyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, alkylsufoxidoalkyl, alkylthioalkenyl, alkylsulfoxidoalkenyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkoxyalkyl, carbocyclylcarbonyl, carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl, carbocylylthioalkyl, carbocylylsulfoxidoalkyl, carbocylylsulfonylalkyl, carbocyclylthioalkenyl, carbocyclylsulfoxidoalkenyl, carbocyclylsulfonylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxyalkyl, heterocyclylcarbonyl, heterocyclylthioalkyl, heterocyclylsulfoxidoalkyl, heterocyclylsulfonylalkyl, heterocyclylthioalkenyl, heterocyclylsulfoxidoalkenyl, heterocyclylsulfonylalkenyl, heterocyclylsulfonyl, heterocyclyliminocarbonyl, heterocyclylalkylcarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylsulfonyl, heterocyclylcarbonylalkyl, aminoalkylcarbonyl, aminocarbonyl, aminocarbonylalkylcarbonyl, aminosulfonyl, aminosulfonylalkyl, aminoalkyl, aminocarbonylalkyl, and aminoalkylsulfonyl, wherein:    any member of such group optionally is substituted.    
     
     
         7 . A compound or salt thereof according to  claim 6 , wherein: 
 A 4  is selected from the group consisting of —H, C 1 -C 8 -alkyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkylcarbonyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkylcarbonyl-C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkoxycarbonyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxycarbonyl-C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -alkyliminocarbonyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 2 -C 8 -alkenyl, C 1 -C 8 -alkylsulfoxido-C 1 -C 8 -alkyl, C 1 -C 8 -alkylsulfoxido-C 2 -C 8 -alkenyl, C 1 -C 8 -alkylsulfonyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkylsulfonyl-C 2 -C 8 -alkenyl, carbocyclyl, carbocyclyl-C 1 -C 8 -alkyl, carbocyclyl-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, carbocyclylcarbonyl, carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl, carbocyclylthio-C 1 -C 8 -alkyl, carbocyclylthio-C 2 -C 8 -alkenyl, carbocyclylsulfoxido-C 1 -C 8 -alkyl, carbocyclylsulfoxido-C 2 -C 8 -alkenyl, carbocyclylsulfonyl-C 1 -C 8 -alkyl, carbocyclylsulfonyl-C 2 -C 8 -alkenyl, heterocyclyl, heterocyclyl-C 1 -C 8 -alkyl, heterocyclyl-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, heterocyclylcarbonyl, heterocyclylthio-C 1 -C 8 -alkyl, heterocyclylsulfoxido-C 1 -C 8 -alkyl, heterocyclylsulfonyl-C 1 -C 8 -alkyl, heterocyclylthio-C 2 -C 8 -alkenyl, heterocyclylsulfoxido-C 2 -C 8 -alkenyl, heterocyclylsulfonyl-C 2 -C 8 -alkenyl, heterocyclylsulfonyl, heterocyclyliminocarbonyl, heterocyclyl-C 1 -C 8 -alkylcarbonyl, heterocyclylcarbonyl-C 1 -C 8 -alkylcarbonyl, heterocyclylsulfonyl, heterocyclylcarbonyl-C 1 -C 8 -alkyl, N(R 16 )(R 17 )-C 1 -C 8 -alkylcarbonyl, N(R 16 )(R 17 )-carbonyl, N(R 16 )(R 17 )-carbonyl-C 1 -C 8 -alkylcarbonyl, N(R 16 )(R 17 )-sulfonyl, N(R 16 )(R 17 )-sulfonyl-C 1 -C 8 -alkyl, N(R 16 )(R 17 )-C 1 -C 8 -alkyl, N(R 16 )(R 17 )-carbonyl-C 1 -C 8 -alkyl, and N(R 16 )(R 17 )-C 1 -C 8 -alkylsulfonyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —CN, —C(O)—OH, —SH, —SO 3 H, and NO 2 ; and  
   R 16  and R 17  are independently selected from the group consisting of —H, —OH, C 1 -C 8 -alkyl, C 1 -C 8 -alkyl-carbonyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 1 -C 8 -alkyl-thio-C 1 -C 8 -alkyl, C 1 -C 8 -alkyl-sulfoxido-C 1 -C 8 -alkyl, C 1 -C 8 -alkyl-sulfonyl-C 1 -C 8 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 8 -alkyl, carbocyclylcarbonyl, carbocyclyl-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, carbocyclylthio-C 1 -C 8 -alkyl, carbocyclylsulfoxido-C 1 -C 8 -alkyl, carbocyclylsulfonyl-C 1 -C 8 -alkyl, heterocyclyl, heterocyclyl-C 1 -C 8 -alkyl, heterocyclyl-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, heterocyclylcarbonyl, heterocyclylthio-C 1 -C 8 -alkyl, heterocyclylsulfoxido-C 1 -C 8 -alkyl, heterocyclylsulfonyl-C 1 -C 8 -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkyloxycarbonylamino-C 1 -C 8 -alkyl, and amino-C 1 -C 8 -alkyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —CN, —C(O)—OH, —SH, —SO 3 H, and NO 2 , and  
 the nitrogen of the amino-C 1 -C 8 -alkyl optionally is substituted with 1 or 2 substituents independently selected from the group consisting of C 1 -C 8 -alkyl, C 1 -C 8 -alkylcarbonyl, carbocyclyl, and carbocyclyl-C 1 -C 8 -alkyl, and  
 no greater than one of R 16  or R 17  is —OH.  
   
     
     
         8 . A compound or salt thereof according to  claim 7 , wherein A 4  is selected from the group consisting of —H, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, carbocyclyl, carbocyclyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylsulfonyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, wherein any member of such group optionally is substituted with halogen.  
     
     
         9 . A compound or salt thereof according to  claim 8 , wherein A 4  is selected from the group consisting of —H, C 1 -C 4 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkyl, phenyl, phenyl-C 1 -C 3 -alkyl, C 1 -C 2 -alkylsulfonyl, C 3 -C 4 -alkenyl, C 3 -C 4 -alkynyl, wherein any member of such group optionally is substituted with halogen.  
     
     
         10 . A compound or salt thereof according to  claim 9 , wherein A 4  is selected from the group consisting of —H, ethyl, methoxyethyl, cyclopropyl, cyclopropylmethyl, benzyl, methylsulfonyl, C 3 -alkenyl, and C 3 -alkynyl, wherein any member of such group optionally is substituted with halogen.  
     
     
         11 . A compound or salt thereof according to  claim 10 , wherein 
 A 4  is selected from the group consisting of —H, ethyl, methoxyethyl, cyclopropyl, cyclopropylmethyl, and benzyl, wherein any member of such group optionally is substituted with halogen.    
     
     
         12 . A compound or salt thereof according to  claim 7 , wherein the salt comprises an acid selected from the group consisting of HCl and CF 3 COOH.  
     
     
         13 . A compound or salt thereof according to  claim 7 , wherein E 3  is —N(R 4 )—C(NR 3 )—.  
     
     
         14 . A compound or salt thereof according to  claim 13 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound or salt thereof according to  claim 7 , wherein E 3  is —C(O)—.  
     
     
         16 . A compound or salt thereof according to  claim 15 , wherein E 5 is carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         17 . A compound or salt thereof according to  claim 16 , wherein E 5  is aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 -R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         18 . A compound or salt thereof according to  claim 17 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         19 . A compound or salt thereof according to  claim 18 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . A compound or salt thereof according to  claim 17 , wherein E 5  is phenyl which is: 
 substituted with one or more substituents independently selected from the group consisting of aryl, haloaryl, aryl-C 1 -C 6 -alkyl, and halogen-substituted aryl-C 1 -C 6 -alkyl; and    optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 -R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.    
     
     
         21 . A compound or salt thereof according to  claim 20 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         22 . A compound or salt thereof according to  claim 17 , wherein E  5 is naphthalenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         23 . A compound or salt thereof according to  claim 22 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . A compound or salt thereof according to  claim 16 , wherein E 5  is C 5 -C 6 -cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         25 . A compound or salt thereof according to  claim 24 , wherein the compound corresponds in structure to the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         26 . A compound or salt thereof according to  claim 15 , wherein E 5  is selected from the group consisting of —OH, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, wherein: 
 the C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, or C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , and, —CN.    
     
     
         27 . A compound or salt thereof according to  claim 26 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         28 . (canceled)  
     
     
         29 . A compound or salt thereof according to  claim 15 , wherein E  5 is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 -R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         30 . A compound or salt thereof according to  claim 29 , wherein the compound corresponds in structure to the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         31 . A compound or salt thereof according to  claim 29 , wherein E 5  is selected from the group consisting of furanyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, diazinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.    
     
     
         32 . A compound or salt thereof according to  claim 31 , wherein E 5  is thiophenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         33 . A compound or salt thereof according to  claim 32 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         34 . A compound or salt thereof according to  claim 7 , wherein E 3  is —S—.  
     
     
         35 . A compound or salt thereof according to  claim 34 , wherein E 5  is selected from the group consisting of —OH, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl C 1 -C 8 -alkoxy, and C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, wherein: 
 the C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 1 -C 8 -alkoxy, or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , and —CN.    
     
     
         36 . (canceled)  
     
     
         37 . A compound or salt thereof according to  claim 34 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         38 . A compound or salt thereof according to  claim 37 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         39 . A compound or salt thereof according to  claim 34 , wherein E 5  is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         40 . A compound or salt thereof according to  claim 39 , wherein E 5  is selected from the group consisting of furanyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, diazinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.    
     
     
         41 . A compound or salt thereof according to  claim 40 , wherein E  5 is pyrimidinyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 ,—S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         42 . A compound or salt thereof according to  claim 41 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         43 . A compound or salt thereof according to  claim 39 , wherein E 5  is 2-fused-ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         44 . A compound or salt thereof according to  claim 43 , wherein E 5  is selected from the group consisting of indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.    
     
     
         45 . A compound or salt thereof according to  claim 44 , wherein E 5  is selected from the group consisting of benzoxazolyl and benzothiazolyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         46 . A compound or salt thereof according to  claim 45 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         47 - 48 . (canceled)  
     
     
         49 . A compound or salt thereof according to  claim 7 , wherein E 3  is —N(R 4 )—C(O)—.  
     
     
         50 . A compound or salt thereof according to  claim 49 , wherein E 5  is carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         51 . A compound or salt thereof according to  claim 50 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         52 . A compound or salt thereof according to  claim 51 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         53 - 55 . (canceled)  
     
     
         56 . A compound or salt thereof according to  claim 50 , wherein E5 is naphthalenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         57 . A compound or salt thereof according to  claim 56 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         58 . A compound or salt thereof according to  claim 50 , wherein E 5  is cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         59 . A compound or salt thereof according to  claim 58 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         60 . (canceled)  
     
     
         61 . A compound or salt thereof according to  claim 58 , wherein E 5  is C 5 -C 6 -cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         62 . A compound or salt thereof according to  claim 61 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         63 . A compound or salt thereof according to  claim 49 , wherein E 5  is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         64 . A compound or salt thereof according to  claim 63 , wherein E 5  is selected from the group consisting of furanyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl,, thiodiazolyl, oxathiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, diazinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.    
     
     
         65 . A compound or salt thereof according to  claim 64 , wherein E 5  is selected from the group consisting of pyridinyl, pyrrolyl, isopyrrolyl, oxazolyl, isoxazole, thiazolyl, furanyl, morpholinyl, tetrazolyl, imidazolyl, thienyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         66 . A compound or salt thereof according to  claim 65 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         67 . (canceled)  
     
     
         68 . A compound or salt thereof according to  claim 63 , wherein E 5  is 2-fused-ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         69 . A compound or salt thereof according to  claim 68 , wherein E 5  is selected from the group consisting of indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.    
     
     
         70 . A compound or salt thereof according to  claim 69 , wherein E 5  is selected from the group consisting of benzazinyl, benzofuranyl, tetrahydroisoquinolinyl, indolyl, benzoxazolyl, benzothienyl, and benzothiazolyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         71 . A compound or salt thereof according to  claim 70 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         72 . (canceled)  
     
     
         73 . A compound or salt thereof according to  claim 49 , wherein E 5  is selected from the group consisting of —OH, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , and —CN.  
     
     
         74 . (canceled)  
     
     
         75 . A compound or salt thereof according to  claim 7 , wherein E3 is —C(O)—N(R 4 )—.  
     
     
         76 . A compound or salt thereof according to  claim 75 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         77 . A compound or salt thereof according to  claim 76 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         78 . (canceled)  
     
     
         79 . A compound or salt thereof according to  claim 75 , wherein E 5  is naphthalenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         80 . A compound or salt thereof according to  claim 79 , wherein the compound corresponds in structure to the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         81 . A compound or salt thereof according to  claim 75 , wherein E 5  is selected from the group consisting of —OH, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , and —CN.  
     
     
         82 . A compound or salt thereof according to  claim 81 , wherein the compound corresponds in structure to the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         83 . A compound or salt thereof according to  claim 7 , wherein E 3  is —N(R 4 )—C(O)—N(R 5 )—.  
     
     
         84 . A compound or salt thereof according to  claim 83 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         85 . A compound or salt thereof according to  claim 84 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         86 . A compound or salt thereof according to  claim 7 , wherein E 3  is —S(O) 2 —N(R 4 )—.  
     
     
         87 . A compound or salt thereof according to  claim 86 , wherein the compound corresponds in structure to the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         88 . A compound or salt thereof according to  claim 86 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         89 . A compound or salt thereof according to  claim 88 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         90 . A compound or salt thereof according to  claim 86 , wherein E 5  is selected from the group consisting of —OH, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , and —CN.  
     
     
         91 . (canceled)  
     
     
         92 . A compound or salt thereof according to  claim 7 , wherein E 3  is —N(R 4 )—S(O) 2 —.  
     
     
         93 . A compound or salt thereof according to  claim 92 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         94 . A compound or salt thereof according to  claim 93 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         95 . (canceled)  
     
     
         96 . A compound or salt thereof according to  claim 7 , wherein E 3  is —C(O)—N(R 4 )—N(R 5 )—C(O)—.  
     
     
         97 . A compound or salt thereof according to  claim 96 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         98 . A compound or salt thereof according to  claim 97 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         99 . A compound or salt thereof according to  claim 7 , wherein E 3  is —C(R 4 )(R 6 )—C(O)—.  
     
     
         100 . A compound or salt thereof according to  claim 99 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         101 . A compound or salt thereof according to  claim 100 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         102 - 103 . (canceled)  
     
     
         104 . A compound or salt thereof according to  claim 7 , wherein E 3  is —O—C(O)—.  
     
     
         105 . A compound or salt thereof according to  claim 104 , wherein E 5  is heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         106 . A compound or salt thereof according to  claim 105 , wherein E 5  is 2-fused-ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         107 . A compound or salt thereof according to  claim 106 , wherein E 5  is selected from the group consisting of indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.    
     
     
         108 . A compound or salt thereof according to  claim 107 , wherein E 5  is tetrahydroisoquinolinyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         109 . A compound or salt thereof according to  claim 108 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         110 . A compound or salt thereof according to  claim 7 , wherein E 3  is —N(R 4 )—.  
     
     
         111 . A compound or salt thereof according to  claim 110 , wherein E 5  is heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         112 . A compound or salt thereof according to  claim 111 , wherein E 5  is 2-fused-ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         113 . A compound or salt thereof according to  claim 112 , wherein E 5  is selected from the group consisting of indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl, wherein: 
 any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.    
     
     
         114 . A compound or salt thereof according to  claim 113 , wherein E 5  is selected from the group consisting of benzoxazolyl, benzothiazolyl, and benzimidazolyl, wherein any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         115 . A compound or salt thereof according to  claim 114 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         116 . A compound or salt thereof according to  claim 7 , wherein E 3  is —C(NR 3 )—.  
     
     
         117 . A compound or salt thereof according to  claim 116 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         118 . A compound or salt thereof according to  claim 117 , wherein the compound corresponds in structure to the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         119 . A compound or salt thereof according to  claim 7 , wherein E 3  is —C(R 7 )(R 8 )—.  
     
     
         120 . A compound or salt thereof according to  claim 119 , wherein E 5  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —N(R 11 )(R 12 ), —C(O)(R 13 ), —S—R 11 , —S(O) 2 —R 11 , aryl, aryl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen-substituted C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, haloaryl, halogen-substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaryl, halogen-substituted C 1 -C 6 -alkylaryl, hydroxyaryl, and heteroaryl.  
     
     
         121 . A compound or salt thereof according to  claim 120 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         122 - 379 . (canceled)  
     
     
         380 . A method for treating a pathological condition treatable by inhibiting matrix metalloprotease activity in a mammal, wherein: 
 the method comprises administering a compound or a pharmaceutically acceptable salt thereof in a therapeutically-effective amount to the mammal; and    the compound is selected from the group of compounds recited in  claim 1 .    
     
     
         381 . A method according to  claim 380 , wherein the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against both MMP-1 and MMP-14.  
     
     
         382 . A method according to  claim 381 , wherein the compound or salt inhibits the activity of MMP-13, while exhibiting substantially less inhibitory activity against both MMP-1 and MMP-14.  
     
     
         383 . A method according to  claim 382 , wherein the pathological condition is selected from the group consisting of arthritis and a cardiovascular condition.  
     
     
         384 . A method according to  claim 381 , wherein the compound or salt inhibits the activity of both MMP-2 and MMP-9, while exhibiting substantially less inhibitory activity against both MMP-1 and MMP-14.  
     
     
         385 . A method according to  claim 384 , wherein the pathological condition is selected from the group consisting of cancer, an opthalmologic condition, and a cardiovascular condition.  
     
     
         386 . A method for treating a pathological condition in a mammal wherein: 
 the method comprises administering a compound or a pharmaceutically acceptable salt thereof in a therapeutically-effective amount to the mammal; and    the compound is selected from the group of compounds recited in  claim 1  and    the pathological condition is selected from the group consisting of tissue destruction, a fibrotic disease, matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, a liver disease, an ophthalmologic disease, and a central nervous system disease.    
     
     
         387 . A method for treating a pathological condition in a mammal, wherein: 
 the method comprises administering a compound or a pharmaceutically acceptable salt thereof in a therapeutically-effective amount to the mammal; and    the compound is selected from the group of compounds recited in  claim 1  and    the pathological condition is selected from the group consisting of osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermal ulceration, epidermolysis bullosa, aortic aneurysm, defective injury repair, an adhesion, scarring, congestive heart failure, post myocardial infarction, coronary thrombosis, emphysema, proteinuria, Alzheimer's disease, bone disease, and chronic obstructive pulmonary disease.    
     
     
         388 . A method for treating a pathological condition treatable by inhibiting TNF-α convertase production or activity in a mammal wherein: 
 the method comprises administering a compound or a pharmaceutically acceptable salt thereof in a therapeutically-effective amount to the mammal; and    the compound is selected from the group of compounds recited in  claim 1 .    
     
     
         389 . A method according to  claim 388 , wherein the pathological condition is selected from the group consisting of inflammation, a pulmonary disease, a cardiovascular disease, an autoimmune disease, graft rejection, a fibrotic disease, multiple sclerosis, cancer, an infectious disease, fever, psoriasis, hemorrhage, coagulation, radiation damage, acute-phase responses of shock and sepsis, anorexia, and cachexia.  
     
     
         390 . A method for treating a pathological condition treatable by inhibiting aggrecanase activity in a mammal wherein: 
 the method comprises administering a compound or a pharmaceutically acceptable salt thereof in a therapeutically-effective amount to the mammal; and    the compound is selected from the group of compounds recited in  claim 1 .    
     
     
         391 . A method according to  claim 390 , wherein the condition is selected from the group consisting of an inflammation condition and cancer.  
     
     
         392 . A method according to  claim 390 , wherein the method further comprises administering the compound or salt thereof to treat a condition treatable by inhibiting matrix metalloprotease activity.  
     
     
         393 . A pharmaceutical composition comprising a therapeutically-effective amount of a compound or a pharmaceutically-acceptable salt thereof, wherein the compound is selected from the group of compounds recited in  claim 1.