Pegylated ion channel modulating compounds

Abstract

This invention is directed to PEGlyated derivatives, drug conjugates and isotopic derivatives of certain ion channel modulating compounds. Pharmaceutical compositions and methods of use of also disclosed

1 . A PEGylated derivative of an ion channel modulating compound comprising one or more PEG moieties attached to an ion channel modulating compound. 
     
     
         2 . The derivative of  claim 1  wherein the PEG moiety is attached to the ion channel modulating compound via a linker. 
     
     
         3 . The derivative of  claim 1  wherein the ion channel modulating compound is a compound of formula (I), or solvates or pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
         wherein, independently at each occurrence, 
         X is selected from a direct bond, —C(R 6 ,R 14 )—Y— and —C(R 13 )═CH—, with the proviso that when X is a direct bond and A is formula (III), then at least one of R 7 , R 8  and R 9  is not hydrogen; 
         Y is selected from a direct bond, O, S and C 1 -C 4 alkylene; 
         R 13  is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl; 
         R 1  and R 2  are independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkoxyalkyl, C 1 -C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or 
         R 1  and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (I), form a ring denoted by formula (II): 
       
       
         
           
           
               
               
           
         
       
       wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C 1 -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C 1 -C 3 alkyl, C 2 -C 4 alkylcarboxy, C 1 -C 3 alkoxy, C 1 -C 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 acyl, C 2 -C 4 hydroxyalkyl and C 3 -C 8 alkoxyalkyl; or
 R 1  and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (I), may form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl; 
 R 3  and R 4  are independently attached to the cyclohexane ring shown in formula (I) at the 3-, 4-, 5- or 6-positions and are independently selected from hydrogen, hydroxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and, when both R 3  and R 4  are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; 
 R 5 , R 6  and R 14  are independently selected from hydrogen, C 1 -C 6 alkyl, aryl and benzyl, or R 6  and R 14 , when taken together with the carbon to which they are attached, may form a spiro C 3 -C 5 cycloalkyl; 
 A is selected from C 6 -C 12 alkyl, a C 3 -C 13 carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII): 
 
       
         
           
           
               
               
           
         
       
       where R 7 , R 8  and R 9  are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl and C 1 -C 6 alkyl; 
       
         
           
           
               
               
           
         
       
       where R 10  and R 11  are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 -C 6 alkyl; 
       
         
           
           
               
               
           
         
       
       where R 12  is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 -C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to “X” as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R 17  when Z is N, and R 17  is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl; 
       
         
           
           
               
               
           
         
         including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof. 
       
     
     
         4 . The derivative of  claim 3  wherein the compound of formula (I) is attached to a PEG moiety by the substitution of any valency of the compound of formula (I) with a bond to the PEG moiety, wherein the bond to the PEG moiety is a direct bond from the compound of formula (I) to the PEG moiety or is a bond from the compound of formula (I) to a linker that is bound to the PEG moiety. 
     
     
         5 . The derivative of  claim 1  wherein the ion channel modulating compound is a compound of formula (IA), or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof: 
       
         
           
           
               
               
           
         
         wherein, R 7 , R 8  and R 9  are independently selected from hydrogen, hydroxy and C 1 -C 6 alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R 7 , R 8  and R 9  cannot all be hydrogen. 
       
     
     
         6 . The derivative of  claim 5  wherein the compound of formula (IA) is attached to a PEG moiety by the substitution of any valency of the compound of formula (IA) with a bond to the PEG moiety, wherein the bond to the PEG moiety is a direct bond from the compound of formula (IA) to the PEG moiety or is a bond from the compound of formula (IA) to a linker that is attached to the PEG moiety. 
     
     
         7 . The derivative of  claim 5  wherein the compound of formula (IA) is the following Compound A: 
       
         
           
           
               
               
           
         
       
       or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof. 
     
     
         8 . The derivative of  claim 7  wherein Compound A is attached to the PEG moiety by the substitution of any valency of Compound A with a bond to a PEG moiety, wherein the bond to a PEG moiety is a direct bond from Compound A or is a bond from a linker that is bound to the PEG moiety. 
     
     
         9 . The derivative of  claim 8  wherein Compound A is attached to the PEG moiety by the substitution of the valency occupied by the hydrogen in the  OH moiety in Compound A with a bond to the PEG moiety. 
     
     
         10 . The derivative of  claim 9  wherein a second PEG moiety is attached to Compound A by the substitution of the valency occupied by one of the methyl groups of the —OCH 3  groups in Compound A with a bond to the second PEG moiety. 
     
     
         11 . The derivative of  claim 1  wherein the ion channel modulating compound is a compound of formula (IX), or solvates or pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
         wherein, independently at each occurrence, 
         n is selected from 1, 3 and 4; 
         Q is either O (oxygen) or —O—C(O); 
         X is selected from a direct bond, —C(R 6 ,R 14 )—Y—, and —C(R 13 )═CH—; 
         Y is selected from a direct bond, O, S, and C 1 -C 4 alkylene; 
         R 13  is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl, and benzyl; 
         R 1  and R 2  are independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkoxyalkyl, C 1 -C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or 
         R 1  and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (IX), form a ring denoted by formula (II): 
       
       
         
           
           
               
               
           
         
       
       wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C 1 -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C 1 -C 3 alkyl, C 2 -C 4 alkylcarboxy, C 1 -C 3 alkoxy, C 1 -C 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 acyl, C 2 -C 4 hydroxyalkyl and C 3 -C 8 alkoxyalkyl; or
 R 1  and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (IX), may form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl; 
 R 3  and R 4  are independently attached to the cyclohexane ring shown in formula (IX) at the 3-, 4-, 5- or 6-positions and are independently selected from hydrogen, hydroxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and, when both R 3  and R 4  are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; 
 R 5 , R 6  and R 14  are independently selected from hydrogen, C 1 -C 6 alkyl, aryl and benzyl, or R 6  and R 14 , when taken together with the carbon to which they are attached, may form a spiro C 3 -C 5 cycloalkyl; 
 A is selected from C 6 -C 12 alkyl, a C 3 -C 13 carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII): 
 
       
         
           
           
               
               
           
         
       
       where R 7 , R 8  and R 9  are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl and C 1 -C 6 alkyl; 
       
         
           
           
               
               
           
         
       
       where R 10  and R 11  are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 -C 6 alkyl; 
       
         
           
           
               
               
           
         
       
       where R 12  is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 -C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to “X” as shown in formula (IX) when Z is CH or N, or Z may be directly bonded to R 17  when Z is N, and R 17  is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl; 
       
         
           
           
               
               
           
         
         including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof. 
       
     
     
         12 . The derivative of  claim 11  wherein the compound of formula (IX) is attached to a PEG moiety by the substitution of any valency of the compound of formula (IX) with a bond to the PEG moiety, wherein the bond to the PEG moiety is a direct bond from the compound of formula (IX) to the PEG moiety or is a bond from the compound of formula (IX) to a linker that is bound to the PEG moiety. 
     
     
         13 . The derivative of  claim 1  having the formula (PEGI), or a solvate or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is selected from a direct bond, —C(R 6 ,R 14 )—Y— and —C(R 13 )═CH—; 
 Y is selected from a direct bond, O, S and C 1 -C 4 alkylene; 
 R 13  is selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl; 
 R 1  and R 2  are independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkoxyalkyl, C 1 -C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or 
 R 1  and R 2  are independently selected from C 3 -C 8 alkoxyalkyl, C 1 -C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or 
 R 1  and R 2  are taken together with the nitrogen atom to which they are directly attached in formula (PEGI), form a ring denoted by formula (PEG-Z-II): 
 
       
         
           
           
               
               
           
         
       
       wherein the ring of formula (PEG-Z-II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C 1 -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C 1 -C 3 alkyl, C 2 -C 4 alkylcarboxy, C 1 -C 3 alkoxy, C 1 -C 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 acyl, C 2 -C 4 hydroxyalkyl and C 3 -C 8 alkoxyalkyl; or
 R 1  and R 2  are taken together with the nitrogen atom to which they are directly attached in formula (PEGI), may form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl, wherein the bicyclic ring is substituted with —Z′—Z″-PEG; 
 Z′ is a linkage group; 
 Z″ is an optional linker; 
 R 3  and R 4  are independently attached to the cyclohexane ring shown in formula (PEGI) at the 3-, 4-, 5- or 6-positions and are independently selected from hydrogen, hydroxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and, when both R 3  and R 4  are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; 
 A is selected from C 6 -C 12 alkyl, a C 3 -C 13 carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII): 
 
       
         
           
           
               
               
           
         
       
       where R 7 , R 8  and R 9  are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl and C 1 -C 6 alkyl; 
       
         
           
           
               
               
           
         
       
       where R 10  and R 11  are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 -C 6 alkyl; 
       
         
           
           
               
               
           
         
       
       where R 12  is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15  and R 16  are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 -C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to “X” as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R 17  when Z is N, and R 17  is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl; 
       
         
           
           
               
               
           
         
         including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof. 
       
     
     
         14 . The derivative of  claim 1  having the formula (PEGII), or a solvate or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is selected from a direct bond, —C(R 6 ,R 11 )—Y— and —C(R 13 )═CH—; 
 Y is selected from a direct bond, O, S and C 1 -C 4 alkylene; 
 R 13  is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl; 
 R 1  and R 2  are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 alkoxyalkyl, C 1 -C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or 
 R 1  and R 2  are independently selected from C 3 -C 8 alkoxyalkyl, C 1 -C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or 
 R 1  and R 2  are taken together with the nitrogen atom to which they are directly attached in formula (PEGII), form a ring denoted by formula (II): 
 
       
         
           
           
               
               
           
         
         wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C 1 -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C 1 -C 3 alkyl, C 2 -C 4 alkylcarboxy, C 1 -C 3 alkoxy, C 1 -C 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 acyl, C 2 -C 4 hydroxyalkyl and C 3 -C 8 alkoxyalkyl; or 
         R 1  and R 2  are taken together with the nitrogen atom to which they are directly attached in formula (PEGII), may form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl; 
         A is selected from formulae (PEG-Z-A): 
       
       
         
           
           
               
               
           
         
         where R 7  and R 9  are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, 
         where R 8  is hydroxy, hydroxymethyl or carboxy; 
         Za′ is a linkage group; 
         Za″ is an optional linker; 
         including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof. 
       
     
     
         15 . The derivative of  claim 1  having the formula (PEGIII), or a solvate or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         X is selected from a direct bond, —C(R 6 ,R 14 )—Y— and —C(R 13 )═CH—; 
         Y is selected from a direct bond, O, S and C 1 -C 4 alkylene; 
         R 13  is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl; 
         R 1  and R 2  are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 alkoxyalkyl, C 1 -C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or 
         R 1  and R 2  are independently selected from C 3 -C 8 alkoxyalkyl, C 1 -C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or 
         R 1  and R 2  are taken together with the nitrogen atom to which they are directly attached in formula (PEGIII), form a ring denoted by formula (PEG-Z-II): 
       
       
         
           
           
               
               
           
         
         wherein the ring of formula (PEG-Z-II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C 1 -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C 1 -C 3 alkyl, C 2 -C 4 alkylcarboxy, C 1 -C 3 alkoxy, C 1 -C 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 acyl, C 2 -C 4 hydroxyalkyl and C 3 -C 8 alkoxyalkyl; or 
         R 1  and R 2  are taken together with the nitrogen atom to which they are directly attached in formula (PEGIII), may form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl, wherein the bicyclic ring is substituted with Z′-Z″-PEG; 
         Z′ is a linkage group; 
         Z″ is an optional linker; 
         R 3  and R 4  are independently attached to the cyclohexane ring shown in formula (PEGIII) at the 3-, 4-, 5- or 6-positions and are independently selected from hydrogen, hydroxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and, when both R 3  and R 4  are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; 
         R 5 , R 6  and R 14  are independently selected from hydrogen, C 1 -C 6 alkyl, aryl and benzyl, or R 6  and R 14 , when taken together with the carbon to which they are attached, may form a spiro C 3 -C 5 cycloalkyl; 
         A is selected from formulae (PEG-Z-A): 
       
       
         
           
           
               
               
           
         
         where R 7  and R 9  are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, and where R 8  is hydroxy, hydroxymethyl or carboxy; 
         Za′ is a linkage group; and 
         Za″ is an optional linker; 
         including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof. 
       
     
     
         16 . A pharmaceutical composition comprising a PEGylated derivative of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         17 . A method of treating or preventing arrhythmia in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a PEGylated derivative of  claim 1  or a pharmaceutical composition of  claim 16 . 
     
     
         18 . A method for modulating ion channel activity in a subject, wherein the method comprises administering to the subject an effective amount of a PEGylated derivative of  claim 1  or a pharmaceutical composition of  claim 16 . 
     
     
         19 . A method for modulating ion channel activity in vitro, wherein the method comprises utilizing a PEGylated derivative of  claim 1 . 
     
     
         20 . An isotopic ion channel modulating compound comprising an ion channel modulating compound wherein at least one atom of the ion channel modulating compound is substituted with a stable isotope thereof. 
     
     
         21 . The compound of  claim 20  wherein the stable isotope is selected from a heavy atom isotope of C, N, O or H. 
     
     
         22 . The compound of  claim 21  wherein the stable isotope is  2 H (deuterium). 
     
     
         23 . The compound of  claim 22  wherein the compound is perdeuterated. 
     
     
         24 . The compound of  claim 23  wherein the compound comprises a —CD 3  moiety. 
     
     
         25 . The compound of  claim 23  wherein the compound comprises a —OCD 3  moiety. 
     
     
         26 . The compound of  claim 21  wherein the stable isotope is  13 C. 
     
     
         27 . The compound of  claim 26  wherein the compound comprises a — 13 CH 3  moiety. 
     
     
         28 . The compound of  claim 26  wherein the compound comprises a O 13 CH 3  moiety. 
     
     
         29 . The compound of  claim 20  wherein the compound is of formula (XX): 
       
         
           
           
               
               
           
         
         or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form thereof, or mixtures thereof, 
         wherein: 
         R 21 , R 22  and R 23  are independently selected from hydrogen, deuterium, C 1 -C 6 alkoxy, and a C 1 -C 6 alkoxy comprising a heavy atom, with the proviso that R 21 , R 22  and R 23  cannot all be hydrogen, and wherein at least one of the atoms in the compound is a heavy atom isotope. 
       
     
     
         30 . The compound of  claim 29  wherein the compound comprises at least one  13 C atom. 
     
     
         31 . The compound of  claim 29  wherein the compound comprises at least one  15 N atom. 
     
     
         32 . The compound of  claim 29  wherein the compound comprises at least one  18 O atom. 
     
     
         33 . The compound of  claim 29  wherein the compound comprises at least one  2 H (deuterium) atom. 
     
     
         34 . The compound of  claim 29  wherein the compound is of the formula (ID): 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 29  wherein the compound is of the formula (IID): 
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 29  wherein the compound is of the formula (IIID): 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 29  wherein the compound is of the formula (IVD): 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound of  claim 29  wherein the compound is of the formula (VD): 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 29  wherein the compound is of the formula (VID): 
       
         
           
           
               
               
           
         
       
     
     
         40 . The compound of  claim 29  wherein the compound is of the formula (VIID): 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 29  wherein the compound is of the formula (VIIID): 
       
         
           
           
               
               
           
         
       
     
     
         42 . A pharmaceutical composition comprising a compound of  claim 20  and a pharmaceutically acceptable excipient. 
     
     
         43 . A method of treating or preventing arrhythmia in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of  claim 20  or a pharmaceutical composition of  claim 42 . 
     
     
         44 . A method for modulating ion channel activity in a subject, wherein the method comprises administering to the subject an effective amount of a compound of  claim 20  or a pharmaceutical composition of  claim 42 . 
     
     
         45 . A method for modulating ion channel activity in vitro, wherein the method comprises utilizing a compound of  claim 20 .