Lipids and lipid nanoparticle formulations for delivery of nucleic acids

Abstract

Compounds are provided having the following structure:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1a, R1b, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6, R7, R8, R9, L1, L2, G1, G2, G3, a, b, c and d are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.

1 - 55 . (canceled) 
     
     
         56 . A compound having a structure of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 L 1  and L 2  are each a direct bond; 
 G 1  is —(C═O)— or a direct bond; 
 G 2  is —C(═O)— or a direct bond; 
 G 3  is saturated C 1 -C 6  alkylene; 
 R 1a  and R 1b  are, at each occurrence, independently either: (a) H or saturated C 1 -C 12  alkyl; or (b) R 1a  is H or saturated C 1 -C 12  alkyl, and R 1b  together with the carbon atom to which it is bound is taken together with an adjacent R 1b  and the carbon atom to which it is bound to form a carbon-carbon double bond, wherein for at least one occurrence of R 1a  and R 1b , R 1a  is H or saturated C 1 -C 12  alkyl, and R 1b  together with the carbon atom to which it is bound is taken together with an adjacent R 1b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 2a  and R 2b  are, at each occurrence, independently either: (a) H or saturated C 1 -C 12  alkyl; or (b) R 2a  is H or saturated C 1 -C 12  alkyl, and R 2b  together with the carbon atom to which it is bound is taken together with an adjacent R 2b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 3a  and R 3b  are, at each occurrence, independently either (a): H or saturated C 1 -C 12  alkyl; or (b) R 3a  is H or saturated C 1 -C 12  alkyl, and R 3b  together with the carbon atom to which it is bound is taken together with an adjacent R 3b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 4a  and R 4b  are, at each occurrence, independently either: (a) H or saturated C 1 -C 12  alkyl; or (b) R 4a  is H or saturated C 1 -C 12  alkyl, and R 4b  together with the carbon atom to which it is bound is taken together with an adjacent R 4b  and the carbon atom to which it is bound to form a carbon-carbon double bond, wherein for at least one occurrence of R 4a  and R 4b , R 4a  is H or saturated C 1 -C 12  alkyl, and R 4b  together with the carbon atom to which it is bound is taken together with an adjacent R 4b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 5  and R 6  are each independently H or methyl; 
 R 7  is saturated or unsaturated C 4 -C 20  alkyl; 
 R 8  and R 9  are each independently saturated C 1 -C 12  alkyl; or R 8  and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; 
 a, b, c and d are each independently an integer from 1 to 24. 
 
     
     
         57 . The compound of  claim 56 , having one of the following structures (IA) or (IB): 
       
         
           
           
               
               
           
         
       
     
     
         58 . The compound of  claim 56 , wherein for at least one occurrence of R 2a  and R 2b , R 2a  is H or saturated C 1 -C 12  alkyl, and R 2b  together with the carbon atom to which it is bound is taken together with an adjacent R 2b  and the carbon atom to which it is bound to form a carbon-carbon double bond. 
     
     
         59 . The compound of  claim 56 , wherein for at least one occurrence of R 3a  and R 3b , R 3a  is H or saturated C 1 -C 12  alkyl, and R 3b  together with the carbon atom to which it is bound is taken together with an adjacent R 3b  and the carbon atom to which it is bound to form a carbon-carbon double bond. 
     
     
         60 . The compound of  claim 56 , having one of the following structures (IC) or (ID): 
       
         
           
           
               
               
           
         
       
       wherein e, f, g and h are each independently an integer from 1 to 12. 
     
     
         61 . The compound of  claim 60 , wherein e, f, g and h are each independently an integer from 4 to 10. 
     
     
         62 . The compound of  claim 56 , wherein a, b, c and d are each independently an integer from 2 to 12. 
     
     
         63 . The compound of  claim 62 , wherein a, b, c and d are each independently an integer from 5 to 9. 
     
     
         64 . The compound of  claim 56 , wherein R 1a , R 2a , R 3a  and R 4a  are H at each occurrence. 
     
     
         65 . The compound of  claim 56 , wherein at least one of R 1a , R 2a , R 3a  and R 4a  is saturated C 1 -C 8  alkyl. 
     
     
         66 . The compound of  claim 65 , wherein saturated C 1 -C 8  alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl. 
     
     
         67 . The compound of  claim 56 , wherein at least one of R 1b , R 2b , R 3b  and R 4b  is H. 
     
     
         68 . The compound of  claim 56 , wherein one of R 5  or R 6  is methyl. 
     
     
         69 . The compound of  claim 56 , wherein each of R 5  and R 6  is methyl. 
     
     
         70 . The compound of  claim 56 , wherein R 7  is saturated or unsaturated C 6 -C 16  alkyl. 
     
     
         71 . The compound of  claim 56 , wherein R 7  is saturated or unsaturated C 6 -C 9  alkyl. 
     
     
         72 . The compound of  claim 56 , wherein R 7  is substituted with —(C═O)OR b , —O(C═O)R b , —C(═O)R b , —OR b , —S(O) x R b , —S—SR b , —C(═O)SR b , —SC(═O)R b , —NR a R b , —NR a C(═O)R b , —C(═O)NR a R b , —NR a C(═O)NR a R b , —OC(═O)NR a R b , —NR a C(═O)OR b , —NR a S(O) x NR a R b , —NR a S(O) x R b  or —S(O) x NR a R b , wherein: R a  is H or saturated C 1 -C 12  alkyl; R b  is C 1 -C 15  alkyl; and x is 0, 1 or 2. 
     
     
         73 . The compound of  claim 72 , wherein R 7  is substituted with —(C═O)OR b  or —O(C═O)R b . 
     
     
         74 . The compound of  claim 72 , wherein R b  is branched saturated C 1 -C 15  alkyl. 
     
     
         75 . The compound of  claim 74 , wherein R b  has one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         76 . The compound of  claim 56 , wherein at least one of R 8  or R 9  is methyl. 
     
     
         77 . The compound of  claim 76 , wherein each of R 8  and R 9  is methyl. 
     
     
         78 . The compound of  claim 56 , wherein R 8  and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring. 
     
     
         79 . The compound of  claim 78 , wherein the heterocyclic ring is pyrrolidinyl or piperazinyl. 
     
     
         80 . The compound of  claim 56 , wherein G 3  is saturated C 2 -C 4  alkylene. 
     
     
         81 . The compound of  claim 56 , wherein G 3  is saturated C 3  alkylene. 
     
     
         82 . The compound of  claim 56 , having one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         83 . A composition comprising the compound of  claim 56  and a therapeutic agent. 
     
     
         84 . The composition of  claim 83 , wherein the therapeutic agent comprises a nucleic acid. 
     
     
         85 . The composition of  claim 84 , wherein the nucleic acid is selected from antisense and messenger RNA. 
     
     
         86 . The composition of  claim 83 , wherein the composition comprises lipid nanoparticles. 
     
     
         87 . A lipid nanoparticle comprising the compound of  claim 56 .