Use of anthelmintic agents against dirofilaria immitis

Abstract

This invention is directed to compounds and salts that are generally useful as agents to treat an infection with Dirofilaria immitis . This invention also is directed to treatments comprising the administration of the compounds and salts to animals in need of the treatments.

1 . A method of treating an infection with  Dirofilaria immitis  comprising administering to a subject animal a compound or salt thereof, wherein:
 the compound corresponds in structure to Formula (I):   
       
         
           
           
               
               
           
         
         each of R 1 , R 2 , R 3 , R 4 , and R 5  is independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, nitro, aminosulfonyl, alkoxycarbonyl, alkylsulfanyl, aryl, aryloxy, arylalkoxy, arylsulfanyl, arylalkylsulfanyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylsulfanyl, and heteroarylalkylsulfanyl, wherein:
 the alkyl, alkoxy, aminosulfonyl, alkoxycarbonyl, alkylsulfanyl, aryl, aryloxy, aryl-alkoxy, arylsulfanyl, arylalkylsulfanyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylsulfanyl, and heteroarylalkylsulfanyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylsulfanyl, and haloalkylsulfanyl; 
 
         X 1  is selected from the group consisting of —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, and —NH—, wherein:
 the —NH— is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, and carbocyclylalkyl, wherein:
 any such substituent is optionally substituted with one or more independently selected halogen; 
 
 
         X 2  is selected from the group consisting of straight-chain C 3 -C 5 -alkyl, straight-chain C 3 -C 5 -alkenyl, straight-chain C 3 -C 5 -alkynyl, and C 4 -C 6 -carbocyclyl, wherein:
 the straight-chain C 3 -C 5 -alkyl, straight-chain C 3 -C 5 -alkenyl, straight-chain C 3 -C 5 -alkynyl, and C 4 -C 6 -carbocyclyl are optionally substituted with one or more independently selected alkyl; 
 
         X 3  is selected from the group consisting of —CH 2 —, —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, and —NH—, wherein:
 the —CH 2 — is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and carbocyclyl, and 
 the —NH— is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, and carbocyclylalkyl, wherein:
 any such substituent is optionally substituted with one or more independently selected halogen; 
 
 
         X 4  is selected from the group consisting of —CH 2 — and —NH—, wherein:
 the —CH 2 — is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, alkenyl, and haloalkyl, and 
 the —NH— is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, and carbocyclylalkyl, wherein:
 any such substituent is optionally substituted with one or more independently selected halogen; 
 
 
         X 5  is selected from the group consisting of —CH 2 —, —O—, —C(S)—, —C(O)—, —S(O)—, and —S(O) 2 —, wherein:
 the —CH 2 — is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and carbocyclyl; 
 
         X 6  is a linker, wherein:
 the linker is a hydrocarbon, wherein:
 the linker comprises one or more nitrogen atoms, and 
 one or more of the carbons in the hydrocarbon optionally are substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, oxo, and thiocarbonyl, 
 
 the linker comprises at least one chain of from 3 to 6 atoms that bridges X 5  to X 7 , 
 the linker comprises no chain of less than 3 atoms that bridges X 5  and X 7 , and 
 from 1 to 2 of the chain atoms are nitrogen; 
 
         X 7  is selected from the group consisting of a 
       
       bond, —O—, —C(O)—, —NH—, —S—, —S(O)—, —S(O) 2 —, —CH 2 —, —CH 2 CH 2 —, —C(O)—CH 2 —, —CH 2 —C(O)—, —O—CH 2 —, —CH 2 —O—, —NH—CH 2 —, —S(O)—CH 2 —, —CH 2 —S(O)—, —S(O) 2 —CH 2 —, and —CH 2 —S(O) 2 —, wherein:
 the —NH— is optionally substituted with alkyl, and 
 the —CH 2 —, —CH 2 CH 2 —, —C(O)—CH 2 —, —CH 2 —C(O)—, —O—CH 2 —, —CH 2 —O—, —NH—CH 2 —, —S(O)—CH 2 —, —CH 2 —S(O)—, —S(O) 2 —CH 2 —, and —CH 2 —S(O) 2 — are optionally substituted with one or more independently selected alkyl; 
 Z 1  is selected from the group consisting of N and CH, wherein: 
 the CH is substituted with a substituent selected from the group consisting of halogen, nitro, cyano, aminosulfonyl, alkyl, alkoxy, alkoxycarbonyl, alkylsulfanyl, alkylsulfinyl, alkyl sulfonyl, aryl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroaryl, heteroarylsulfanyl, heteroarylsulfinyl, and heteroarylsulfonyl, wherein:
 the alkyl, alkoxy, alkoxycarbonyl, alkylsulfanyl, alkylsulfinyl, alkyl sulfonyl, alkylsulfanyl, aryl, arylsulfanyl, arylsulfinyl, aryl sulfonyl, heteroaryl, heteroarylsulfanyl, heteroarylsulfinyl, and heteroarylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl, and 
 the aminosulfonyl is optionally substituted with up to two independently selected alkyl; 
 
 Z 2  is selected from the group consisting of N and CH, wherein: 
 the CH is optionally substituted with a substituent selected from the group consisting of cyano, halogen, nitro, alkyl, alkoxy, haloalkyl, and haloalkylsulfanyl; and 
 each of Z 3 , Z 4 , and Z 5  is independently selected from the group consisting of N and CH, wherein: 
 the CH is optionally substituted with a substituent selected from the group consisting of halogen, cyano, nitro, alkyl, alkoxy, alkylsulfanyl, haloalkyl, haloalkoxy, and haloalkylsulfanyl. 
 
     
     
         2 . The method of  claim 1 , wherein:
 each of R 1 , R 2 , R 3 , R 4 , and R 5  is independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, nitro, alkoxycarbonyl, alkylsulfanyl, aryl, aryloxy, arylalkoxy, arylsulfanyl, arylalkylsulfanyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylsulfanyl, and heteroarylalkylsulfanyl, wherein:
 the alkyl, alkoxy, alkoxycarbonyl, alkylsulfanyl, aryl, aryloxy, arylalkoxy, arylsulfanyl, arylalkylsulfanyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylsulfanyl, and heteroarylalkylsulfanyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylsulfanyl, and haloalkylsulfanyl; 
   X 4  is selected from the group consisting of —CH 2 — and —NH—, wherein:
 the —CH 2 — is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and alkenyl, and 
 the —NH— is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, and carbocyclylalkyl, wherein:
 any such substituent is optionally substituted with one or more independently selected halogen; and 
 
   X 6  is a linker, wherein:
 the linker is a hydrocarbon, wherein:
 the linker comprises one or more nitrogen atoms, and 
 one or more of the carbons in the hydrocarbon optionally are substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, oxo, and thiocarbonyl, 
 
 the linker comprises at least one chain of from 3 to 5 atoms that bridges X 5  to X 7 , 
 the linker comprises no chain of less than 3 atoms that bridges X 5  and X 7 , and 
 from 1 to 2 of the chain atoms are nitrogen. 
   
     
     
         3 . The method of  claim 1 , wherein:
 each of R 1 , R 2 , R 3 , R 4 , and R 5  is independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, nitro, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylsulfanyl, phenyl, phenyloxy, phenyl-C 1 -C 6 -alkoxy, phenylsulfanyl, phenyl-C 1 -C 6 -alkylsulfanyl, heteroaryl, heteroaryloxy, heteroaryl-C 1 -C 6 -alkoxy, heteroarylsulfanyl, and heteroaryl-C 1 -C 6 -alkylsulfanyl, wherein:
 the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylsulfanyl, phenyl, phenyloxy, phenyl-C 1 -C 6 -alkoxy, phenylsulfanyl, phenyl-C 1 -C 6 -alkylsulfanyl, heteroaryl, heteroaryloxy, heteroaryl-C 1 -C 6 -alkoxy, heteroarylsulfanyl, and heteroaryl-C 1 -C 6 -alkylsulfanyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkylsulfanyl, and halo-C 1 -C 6 -alkylsulfanyl; 
   X 1  is selected from the group consisting of —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, and —NH—, wherein:
 the —NH— is optionally substituted with a substituent selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 6 -carbocyclyl, and C 3 -C 6 -carbocyclyl-C 1 -C 6 -alkyl, wherein:
 any such substituent is optionally substituted with one or more independently selected halogen; 
 
   X 2  is selected from the group consisting of straight-chain C 3 -C 4 -alkyl, straight-chain C 3 -C 4 -alkenyl, straight-chain C 3 -C 4 -alkynyl, and C 4 -C 6 -carbocyclyl, wherein:
 the straight-chain C 3 -C 4 -alkyl, straight-chain C 3 -C 4 -alkenyl, straight-chain C 3 -C 4 -alkynyl, and C 3 -C 4 -carbocyclyl are optionally substituted with one or more independently selected C 1 -C 6 -alkyl; 
   X 3  is selected from the group consisting of —CH 2 —, —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, and —NH—, wherein:
 the —CH 2 — is optionally substituted with up to two substituents independently selected from the group consisting of C 1 -C 6 -alkyl and cyclopropyl, and 
 the —NH— is optionally substituted with a substituent selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 6 -carbocyclyl, and C 3 -C 6 -carbocyclyl-C 1 -C 6 -alkyl, wherein:
 any such substituent is optionally substituted with one or more independently selected halogen; 
 
   X 4  is selected from the group consisting of —CH 2 — and —NH—, wherein:
 the —CH 2 — is optionally substituted with up to two substituents independently selected from the group consisting of C 1 -C 6 -alkyl and C 2 -C 6 -alkenyl, and 
 the —NH— is optionally substituted with a substituent selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 6 -carbocyclyl, and C 3 -C 6 -carbocyclyl-C 1 -C 6 -alkyl, wherein:
 any such substituent is optionally substituted with one or more independently selected halogen; 
 
   X 5  is selected from the group consisting of —CH 2 —, —O—, —C(S)—, —C(O)—, —S(O)—, and —S(O) 2 —, wherein:
 the —CH 2 — is optionally substituted with up to two substituents independently selected from the group consisting of C 1 -C 6 -alkyl and cyclopropyl; 
   X 6  is a linker, wherein:
 the linker is a hydrocarbon, except:
 the linker comprises one or more nitrogen atoms, and 
 one or more of the carbons in the hydrocarbon optionally are substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 -alkoxy, oxo, and thiocarbonyl, 
 
 the linker comprises at least one chain of from 3 to 5 atoms that bridges X 5  to X 7 , 
 the linker comprises no chain of less than 3 atoms that bridges X 5  and X 7 , and 
 from 1 to 2 of the chain atoms are nitrogen; 
   X 7  is selected from the group consisting of a   
       bond, —O—, —C(O)—, —NH—, —S—, —S(O)—, —S(O) 2 —, —CH 2 —, —CH 2 CH 2 —, —C(O)—CH 2 —, —CH 2 —C(O)—, —O—CH 2 —, —CH 2 —O—, —NH—CH 2 —, —CH 2 —NH—, —S—CH 2 —, —CH 2 —S—, —S(O)—CH 2 —, —CH 2 —S(O)—, —S(O) 2 —CH 2 —, and —CH 2 —S(O) 2 —, wherein:
 the —NH— is optionally substituted with C 1 -C 6 -alkyl, and 
 the —CH 2 —, —CH 2 CH 2 —, —C(O)—CH 2 —, —CH 2 —C(O)—, —O—CH 2 —, —CH 2 —O—, —NH—CH 2 —, —CH 2 —NH—, —S—CH 2 —, —CH 2 —S—, —S(O)—CH 2 —, —CH 2 —S(O)—, —S(O) 2 —CH 2 —, and —CH 2 —S(O) 2 — are optionally substituted with one or more independently selected C 1 -C 6 -alkyl; 
 Z 1  is selected from the group consisting of N and CH, wherein: 
 the CH is substituted with a substituent selected from the group consisting of halogen, nitro, cyano, aminosulfonyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, phenyl, phenylsulfanyl, phenylsulfinyl, phenylsulfonyl, heteroaryl, heteroarylsulfanyl, heteroarylsulfinyl, and heteroarylsulfonyl, wherein:
 the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -alkylsulfanyl, phenyl, phenyl sulfanyl, phenylsulfinyl, phenyl sulfonyl, heteroaryl, heteroarylsulfanyl, heteroarylsulfinyl, and heteroarylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen and C 1 -C 6 -alkyl, and 
 the aminosulfonyl is optionally substituted with up to two independently selected C 1 -C 6 -alkyl; 
 
 Z 2  is selected from the group consisting of N and CH, wherein: 
 the CH is optionally substituted with a substituent selected from the group consisting of cyano, halogen, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkylsulfanyl; 
 each of Z 3 , Z 4 , and Z 5  is independently selected from the group consisting of N and CH, wherein: 
 the CH is optionally substituted with a substituent selected from the group consisting of halogen, cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl sulfanyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, and halo-C 1 -C 6 -alkyl sulfanyl; and 
 each heteroaryl is a 5- to 6-member heteroaryl. 
 
     
     
         4 . The method of  claim 1 , wherein:
 each of R 1 , R 2 , R 3 , R 4 , and R 5  is independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, phenoxy, and benzyloxy, wherein:
 the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkoxy; 
   X 2  is C 4 -C 6 -carbocyclyl optionally substituted with one or more independently selected C 1 -C 6 -alkyl;   X 4  is selected from the group consisting of —CH 2 — and —NH—, wherein:
 the —CH 2 — is optionally substituted with up to two independently selected C 1 -C 6 -alkyl, and 
 the —NH— is optionally substituted with a substituent selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 6 -carbocyclyl, and C 3 -C 6 -carbocyclyl-C 1 -C 6 -alkyl, wherein:
 any such substituent is optionally substituted with one or more independently selected halogen; and 
 
   Z 1  is selected from the group consisting of N and CH, wherein:
 the CH is substituted with a substituent selected from the group consisting of halogen, nitro, cyano, aminosulfonyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, phenylsulfonyl, and heteroaryl, wherein:
 the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -alkylsulfanyl, phenylsulfonyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen and C 1 -C 6 -alkyl, and 
 the aminosulfonyl is optionally substituted with up to two independently selected C 1 -C 6 -alkyl. 
 
   
     
     
         5 . The method of  claim 1 , wherein X 6  is selected from the group of linkers consisting of: 
       
         
           
           
               
               
           
         
       
       wherein:
 any such group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, oxo, and thiocarbonyl. 
 
     
     
         6 . The method of  claim 1 , wherein X 6  is selected from the group of linkers consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 any such group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, oxo, and thiocarbonyl. 
 
     
     
         7 . The method of  claim 1 , wherein:
 the compound corresponds in structure to Formula (I-7):   
       
         
           
           
               
               
           
         
         three of R 1 , R 2 , R 3 , R 4 , and R 5  are each independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, phenoxy, and benzyloxy, wherein:
 the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen and halo-C 1 -C 6 -alkyl; 
 
         the remaining two of R 1 , R 2 , R 3 , R 4 , and R 5  are each hydrogen; 
         X 1  is selected from the group consisting of —O— and —NH—, wherein:
 the —NH— is optionally substituted with C 1 -C 6 -alkyl; 
 
         X 2  is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl; 
         X 3  is selected from the group consisting of —CH 2 —, —O—, and —C(O)—; 
         X 4  is selected from the group consisting of —CH 2 — and —NH—, wherein:
 the —CH 2 — is optionally substituted with up to two independently selected C 1 -C 6 -alkyl, and 
 the —NH— is optionally substituted with C 1 -C 6 -alkyl; 
 
         X 5  is selected from the group consisting of —CH 2 —, —C(S)—, —C(O)—, and —S(O) 2 —; 
         X 6  is selected from the group of linkers consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein:
 any such group is optionally substituted with up to two substituents independently selected from the group consisting of C 1 -C 6 -alkyl and oxo; 
 Z 1  is CH substituted with a substituent selected from the group consisting of halogen, nitro, cyano, halo-C 1 -C 6 -alkoxy, and halo-C 1 -C 6 -alkylsulfanyl; 
 Z 2  is CH optionally substituted with halo-C 1 -C 6 -alkyl; 
 two of Z 3 , Z 4 , and Z 5  are independently selected from the group consisting of N and CH, wherein: 
 the CH is optionally substituted with C 1 -C 6 -alkyl; and 
 the remaining one of Z 3 , Z 4 , and Z 5  is CH. 
 
     
     
         8 . The method of  claim 1 , wherein:
 three of R 1 , R 2 , R 3 , R 4 , and R 5  are each independently selected from the group consisting of hydrogen, chloro, fluoro, cyano, nitro, methyl, tert-butyl, n-propyl, trifluoromethyl, ethyl, methoxy, ethoxy, trifluoromethoxy, trifluoromethylsulfanyl, iso-butoxy, phenyl, phenoxy, benzyloxy, and 4-trifluoromethylbenzyloxy;   the remaining two of R 1 , R 2 , R 3 , R 4 , and R 5  are each hydrogen;   X 1  is selected from the group consisting of —O—, —NH—, and —N(CH 3 )—;   X 4  is selected from the group consisting of —CH 2 —, —C(H)(CH 3 )—, —C(CH 3 ) 2 —, —NH—, and —N(CH 3 )—;   X 6  is selected from the group of linkers consisting of:   
       
         
           
           
               
               
           
         
       
       wherein:
 any such group is optionally substituted with up to two substituents independently selected from the group consisting of methyl and oxo; 
 Z 1  is CH substituted with a substituent selected from the group consisting of chloro, nitro, cyano, trifluoromethoxy, and trifluoromethylsulfanyl; 
 Z 2  is CH optionally substituted with trifluoromethyl; 
 two of Z 3 , Z 4 , and Z 5  are independently selected from the group consisting of N, CH, and C(CH 3 ); and 
 the remaining one of Z 3 , Z 4 , and Z 5  is CH. 
 
     
     
         9 . The method of  claim 1 , wherein:
 the compound corresponds in structure to Formula (I-9):   
       
         
           
           
               
               
           
         
         X 1  is selected from the group consisting of —NH— and —N(CH 3 )—; 
         X 5  is selected from the group consisting of —CH 2 — and —C(O)—; and 
         X 4  is selected from the group consisting of —CH 2 —, —C(H)(CH 3 )—, —C(CH 3 ) 2 —, —NH—, and —N(CH 3 )—; 
         X 6  is selected from the group of linkers consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein:
 any such group is optionally substituted with up to two methyl. 
 
     
     
         10 . The method of  claim 1 , wherein:
 the compound corresponds in structure to Formula (I-10):   
       
         
           
           
               
               
           
         
         X 1  is —NH— optionally substituted with C 1 -C 6 -alkyl; 
         X 4  is selected from the group consisting of —CH 2 — and —NH—, wherein:
 the —CH 2 — is optionally substituted with up to two independently selected C 1 -C 6 -alkyl, and 
 the —NH— is optionally substituted with C 1 -C 6 -alkyl; 
 
         X 5  is selected from the group consisting of —CH 2 — and —C(O)—; 
         X 6  is selected from the group of linkers consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein:
 any such group is optionally substituted with up to two substituents independently selected from the group consisting of C 1 -C 6 -alkyl and oxo; and 
 Z 3 , Z 4 , and Z 5  are each CH. 
 
     
     
         11 . The method of  claim 1 , wherein X 4  is —CH 2 — optionally substituted with up to two independently selected C 1 -C 6 -alkyl. 
     
     
         12 . The method of  claim 1 , wherein:
 the compound corresponds in structure selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
       and
 X 4  is —NH— optionally substituted with C 1 -C 6 -alkyl. 
 
     
     
         13 . The method of  claim 1 , wherein Z 2  is CH substituted with a substituent selected from the group consisting of cyano, halogen, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkylsulfanyl. 
     
     
         14 . The method of  claim 1 , wherein R 3  is independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, phenoxy, and benzyloxy, wherein:
 the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkoxy; and   at least two of R 1 , R 2 , R 4 , and R 5  are each hydrogen.   
     
     
         15 . The method of  claim 1 , wherein the compound corresponds in structure to a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein the compound corresponds in structure to a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 1 , wherein:
 the compound corresponds in structure to a formula selected from the group consisting of:   
       
         
           
           
               
               
           
         
         R 3  is selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, phenoxy, and benzyloxy, wherein:
 the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkoxy; and 
 
         at least two of R 1 , R 2 , R 4 , and R 5  are each hydrogen. 
       
     
     
         18 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 1 , wherein: the compound corresponds in structure to Formula (I): 
       
         
           
           
               
               
           
         
         each of R 1 , R 2 , R 3 , R 4 , and R 5  is independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, nitro, alkylsulfanyl, and heteroaryl wherein:
 the alkyl, alkoxy, alkylsulfanyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl; 
 
         X 1  is —NH— optionally substituted with an alkyl substituent; 
         X 2  is selected from the group consisting of straight-chain C 3 -alkyl and C 6 -carbocyclyl; 
         X 3  is selected from the group consisting of —O— and —C(O)—; 
         X 4  is selected from the group consisting of —CH 2 — and —NH—, wherein:
 the —CH 2 — is optionally substituted with an alkyl substituent and 
 the —NH— is optionally substituted with an alkyl substituent; 
 
         X 5  is selected from the group consisting of —CH 2 —, —C(S)— and —C(O)—; 
         X 6  is selected from the group of linkers consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein:
 any such group is optionally substituted with up to two alkyl substituents; 
 X 7  is selected from the group consisting of a bond, —O— and —NH—; 
 Z 1  is CH, wherein CH is substituted with a substituent selected from the group consisting of nitro and cyano; 
 Z 2  is CH, wherein CH is substituted with a substituent selected from the group consisting of alkyl, alkoxy and haloalkyl; and 
 each of Z 3 , Z 4 , and Z 5  is CH. 
 
     
     
         20 . The method of  claim 1 , wherein the compound or salt is active against larval worms and/or microfilariae of  Dirofilaria immitis.    
     
     
         21 . The method of  claim 1 , wherein the subject animal is a dog. 
     
     
         22 .- 24 . (canceled)