Conjugated antisense compounds and their use

Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the gomeric compounds are conjugated to N-Acetylgalactosamine or to N-Acetylgalactosamine anaologues.

1 - 243 . (canceled) 
     
     
         244 . A compound comprising an oligomer and a conjugate group having Formula II: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from Q 1 , CH 2 Q 1 , CH 2 OH and CH 2 N 3 ; 
 Q 1  is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; 
 R 2  is N(H)C(═O)-Q 2 ; 
 Q 2  is selected from C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; 
 wherein if R 1  is CH 2 OH, Q 2  is not CH 3 ; and 
 wherein if Q 2  is CH 3 , R 1  is not CH 2 OH; 
 Y is O; 
 L is a connecting group comprising a linear alkylene group optionally including one or more groups independently selected from O, S, NJ 7 , C(═O), a phosphorus linking group and a cleavable bond or L is a single bond between Y and T 1 ; 
 J 7  is H or a substituent group; 
 T 1  is said oligomer; and 
 each substituent group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, aryl, heterocyclic and heteroaryl wherein each substituent group can include a linear or branched alkylene group optionally including one or more groups independently selected from O, S, NH and C(═O), and wherein each substituent group may be further substituted with one or more groups independently selected from C 1 -C 6  alkyl, halogen or C 1 -C 6  alkoxy wherein each cyclic group is mono or polycyclic. 
 
     
     
         245 . The compound of  claim 244  wherein R 1  is Q 1  and Q 1  has the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 -E-X is selected from among: 
 
       
         
           
           
               
               
           
         
       
     
     
         246 . The compound of  claim 245 , wherein Q 1  has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         247 . The compound of  claim 245 , wherein Q 2  is CH 3 . 
     
     
         248 . The compound of  claim 244 , wherein R 1  is CH 2 N 3 . 
     
     
         249 . The compound of  claim 248 , wherein Q 2  is CH 3 . 
     
     
         250 . The compound of  claim 244 , wherein Q 2  is selected from among: 
       
         
           
           
               
               
           
         
       
     
     
         251 . The compound of  claim 250 , wherein Q 2  is 
       
         
           
           
               
               
           
         
       
     
     
         252 . The compound of  claim 250 , wherein R 1  is CH 2 OH. 
     
     
         253 . The compound of  claim 244 , wherein L optionally comprises one or more amides and wherein L attaches to T 1  through a group selected from among: 
       
         
           
           
               
               
           
         
       
     
     
         254 . The compound of  claim 244  wherein L comprises a phosphorus linking group, NH 2 , or N(CH 3 ) 2 . 
     
     
         255 . The compound of  claim 244  having the configuration: 
       
         
           
           
               
               
           
         
       
     
     
         256 . The compound of  claim 244 , wherein the oligomer is a modified oligonucleotide comprising at least one modified nucleoside comprising a modified base and/or a modified sugar moiety. 
     
     
         257 . The compound of  claim 256  having at least one modified nucleoside comprising a modified sugar moiety selected from a bicyclic sugar moiety and a 2′-substituted sugar moiety. 
     
     
         258 . The compound of  claim 257 , comprising at least one 4′-C(CH 3 )H—O-2′ or 4′-CH 2 —O-2′bridged bicyclic sugar moiety. 
     
     
         259 . The compound of  claim 257  comprising at least one 2′-O(CH 2 ) 2 OCH 3  substituted sugar moiety. 
     
     
         260 . The compound of  claim 244 , wherein the conjugate group is attached to the 5′-terminal nucleoside of the oligomer. 
     
     
         261 . The compound of  claim 244 , wherein the conjugate group is attached to the 3′-terminal nucleoside of the oligomer. 
     
     
         262 . The compound of  claim 244 , wherein the oligomer is an oligonucleotide and has a sugar motif comprising:
 a 5′-region consisting of 2-8 linked 5′-region nucleosides, wherein at least two 5′-region nucleosides are modified nucleosides and wherein the 3′-most 5′-region nucleoside is a modified nucleoside;   a 3′-region consisting of 2-8 linked 3′-region nucleosides, wherein at least two 3′-region nucleosides are modified nucleosides and wherein the 5′-most 3′-region nucleoside is a modified nucleoside; and   a central region between the 5′-region and the 3′-region consisting of 5-10 linked central region nucleosides, each independently selected from among: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′-most central region nucleoside is an unmodified deoxynucleoside and the 3′-most central region nucleoside is an unmodified deoxynucleoside.   
     
     
         263 . The compound of  claim 244 , wherein the oligomer has a nucleobase sequence comprising an at least 14 or 16 nucleobase portion complementary to an equal length portion of a target nucleic acid. 
     
     
         264 . The compound of  claim 244 , wherein the oligomer is an oligonucleotide and the compound consists of the oligonucleotide and the conjugate group. 
     
     
         265 . A pharmaceutical composition comprising a compound according to  claim 244  and a pharmaceutically acceptable carrier or diluent. 
     
     
         266 . A method of treating a disease associated with a target nucleic acid, comprising administering to an individual having or at risk of developing a disease associated with the target nucleic acid a therapeutically effective amount of the pharmaceutical composition according to  claim 264 .