Carbohydrate conjugates as delivery agents for oligonucleotides

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

wherein:

A and B are each independently for each occurrence O, N(R N ), 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 L 1 , or has the structure shown in formula (II)-(V)

q 2A , q 2B , q 3A , q 3B , q 4A , q 4B , q 5A , q 5B , and q 5C represent independently for each occurrence 0-20 and wherein the repeating unit can be the same or different;

Q is absent, -(P 7 -Q 7 -R 7 ) p -T 7 -, or -T 7 -Q 7 -T 7′ -B′-T 8′ -Q 8 -T 8 -;

P 2A , P 2B , P 3A , P 3B , P 4A , P 4B , P 5A , P 5B , P 5C , P 7 , T 2A , T 2B , T 3A , T 3B , T 4A , T 4B , T 5A , T 5B , T 5C , T 7 , T 7′ , T 8 , and T 8′ are each independently for each occurrence absent, CO, NH, O, S, OC(O), NHC(O), CH 2 , CH 2 NH, or CH 2 O;

B′ is —CH 2 —N(B L )—CH 2 —;

B L is -T B -Q B -T B′ -R x ;

Q 2A , Q 2B , Q 3A , Q 3B , Q 4A , Q 4B , Q 5A , Q 5B , Q 5C , Q 7 , Q 8 , and Q B 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), SO 2 , N(R N ), C(R′)═C(R″), C≡C, or C(O);

T B and T B′ are each independently for each occurrence absent, CO, NH, O, S, OC(O), OC(O)O, NHC(O), NHC(O)NH, NHC(O)O, CH 2 , CH 2 NH, OCH 2 , or CH 2 O;

R x is a lipophile, or a cationic lipid;

R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R 5A , R 5B , R 5C , and R 7 are each independently for each occurrence absent, NH, O, S, CH 2 , C(O)O, C(O)NH, NHCH(R a )C(O), C(O)—CH(R a )—NH, CO, CH═N—O,

or heterocyclyl;

L 1 , L 2A , L 2B , L 3A , L 3B , L 4A , L 4B , L 5A , L 5B , and L 5C are each independently for each occurrence a carbohydrate or a derivative thereof having hydroxyl protecting group(s);

R′ and R″ are each independently H, C 1 -C 6 alkyl, OH, SH, or N(R N ) 2 ;

R N is independently for each occurrence methyl, ethyl, propyl, isopropyl, butyl, or benzyl;

R a is H or amino acid side chain; and

p represents independently for each occurrence 0-20.

2. The compound of claim 1 , wherein:

A and B are each O;

one of X and Y is H, and the other of X and Y is a hydroxyl protecting group;

R has the structure shown in formula (V)

Q is P 7 -Q 7 -T 7 ;

Q 7 is alkene; and

L 5A , L 5B , and L 5C are each independently for each occurrence a derivative of a carbohydrate, having hydroxyl protecting group(s).

3. The compound of claim 2 , wherein the carbohydrate is selected from the group consisting of galactose, galactosamine, N-acetylgalactosamine (GalNAc), D-galactosaminitol, mannose, mannosamine, mannose-6-phosphate, glucose, glucosamine, N-acetyl-glucosamine (GluNAc), glucose-6-phosphate, glucosaminitol, glucose glyceraldehyde, fucose, fucosamine, fuculose, lactose, allose, altrose, arabinose, cladinose, erythrose, erythrulose, fructose, D-fucitol, L-fucitol, L-glycero-D-mannos-heptose, glycerol, glycerone, gulose, idose, lyxose, psicose, quinovose, quinovosamine, rhamnose, rhamnitol, rhamnosamine, ribose, ribulose, sedoheptulose, sorbose, tagatose, talose, tartaric acid, threose, xylose, and xylulose.

4. The compound of claim 3 , wherein the carbohydrate is N-acetylgalactosamine (GalNAc).

5. The compound of claim 1 , wherein the compound is selected from the group consisting of:

wherein each of R′ and R″ is independently H or methyl.

6. A compound having the structure of

wherein:

n is an integer of 1 to 17,

X is H,

Y is a hydroxyl protecting group, and

R is H, methyl, or has the structure shown in formula (V)

Q is P 7 -Q 7 -T 7 ;

Q 7 is alkene; and

L 5A , L 5B , and L 5C are each independently for each occurrence a derivative of a carbohydrate, having hydroxyl protecting group(s).

7. A compound having the structure of

8. The compound of claim 6 , wherein the compound is

9. The compound of claim 2 , wherein the compound is

10. The compound of claim 2 , wherein the compound is

11. The compound of claim 1 , wherein the compound is

12. The compound of claim 2 , wherein the compound is

13. The compound of claim 1 , wherein the compound is

14. The compound of claim 1 , wherein the compound is

15. The compound of claim 1 , wherein the compound is

16. The compound of claim 1 , wherein the compound is

17. The compound of claim 1 , wherein the compound is

18. The compound of claim 1 , wherein the compound is

19. 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.

20. The process of claim 19 , wherein the hydrolyzing step is carried out in the presence of LiOH in THF/DCM/Water, followed by neutralization with acetic acid.

21. The process of claim 19 , wherein the step of reacting the hydroxyproline compound 116 with the ligand moiety compound 110 is carried out in the presence of HBTU/DIEA in DMF, or TBTU/HOBt/DIEA in DMF.

22. The process of claim 19 , further comprising:

reacting a GalNAc acid

with a branched linker compound

or its salt, under conditions effective to form a ligand moiety compound

and

hydrogenating the ligand moiety compound 109 under conditions effective to form the ligand moiety compound 110.

23. The process of claim 22 , wherein the step of reacting the GalNAc acid 103 with the branched linker compound 108 is carried out in the presence of HBTU/DIEA/HOBt in DMF.

24. The process of claim 22 , wherein the step of hydrogenating the ligand moiety compound 109 is carried out with H 2 in the presence of Pd/C, methanol, and acetic acid.

25. The process of claim 22 , further comprising:

hydrogenating a GalNAc derivative compound

under conditions effective to form the GalNAc acid compound 103.

26. The process of claim 25 , wherein the step of hydrogenating GalNAc derivative compound 102 is carried out with H 2 in the presence of Pd/C, methanol, and acetic acid.

27. The process of claim 22 , further comprising:

reacting a branched linker compound

with a linker compound

to form a branched linker compound

and

deprotecting the N protecting group of the branched linker compound 107 under conditions effective to form the branched linker compound 108.

28. The process of claim 27 , wherein the step of reacting the branched linker compound 106 with the linker compound is carried out in the presence of HBTU/DIEA in DMF.

29. The process of claim 27 , wherein the deprotecting step is carried out in the presence of TFA/DCM.