Carbohydrate conjugates as delivery agents for oligonucleotides

A compound having the structure shown in formula (I):

• wherein:
• A and B are each independently for each occurrence O, N(RN), or S;
• one of X and Y is H, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, or a phosphoramidite, and the other of X and Y is a protecting group;
• R is H, alkyl, Li, or has the structure shown in formula (II)-(V)
• q2A, q2B, q3A, q3B, q4A, q4B, q5A, q5B and q5C represent independently for each occurrence 0-20 and wherein the repeating unit can be the same or different;
• Q is absent, —(P7-Q7-R7)p-T7-, or -T7-Q7-T7′-B′-T8′-Q8-T8-;
• P2A, P2B, P3A, P3B, P4A, P4B, P5A, P5B, P5C, P7, T2A, T2B, T3A, T3B, T4A, T4B, T4A, T5B, T5C, T7, T7′, T, and T8′ are each independently for each occurrence absent, CO, NH, O, S, OC(O), C(O)O, NHC(O), C(O)NH, CH2, CH2NH, NHCH2, OCH2, or CH2O;
• B′ is —CH2—N(BL)—CH2—;
• BL is -TB-QB-TB′-Rx;
• Q2A, Q2B, Q3A, Q3B, Q4A, Q4B, Q5A, Q5B, Q5C, Q7, Q8 and QB are independently for each occurrence absent, alkylene, or substituted alkylene wherein one or more methylenes can be interrupted or terminated by one or more of O, S, S(O), SO2, N(RN), C(R′)═C(R″), C≡C, or C(O);
• TB and TB′ are each independently for each occurrence absent, CO, NH, O, S, OC(O), C(O)O, NHC(O), C(O)NH, NHC(O)NH, NHC(O)O, OC(O)NH, CH2, CH2NH, NHCH2, OCH2, or CH2O;
• Rx is a lipophile, or a cationic lipid;
• R2A, R2B, R3A, R3B, R4A, R4B, R5A, R5B, R5C, and R7 are each independently for each occurrence absent, NH, O, S, CH2, C(O)O, OC(O), C(O)NH, NHC(O), NHCH(Ra)C(O), C(O)—CH(Ra)—NH, CO, CH═N—O,
• or heterocyclyl;
• L1, L2A, L2B, L3A, L3B, L4A, L4B, L5A, L5B, and L5C are each independently for each occurrence a carbohydrate or a derivative thereof having hydroxyl protecting group(s);
• R′ and R″ are each independently H, C1-C6 alkyl, OH, SH, or N(RN)2;
• RN is independently for each occurrence methyl, ethyl, propyl, isopropyl, butyl, or benzyl;
• Ra is H or amino acid side chain;
• and
• p represents independently for each occurrence 0-20.

A process of making a compound

• comprising:
• hydrolyzing the hydroxyproline compound
• to form a hydroxyproline compound
• and
• reacting the hydroxyproline compound 116 with a ligand moiety compound
• or its salt, under conditions effective to produce compound 117.