Functionalized n-acetylgalactosamine analogs
Embodiments of the present application relate to functionalized N-acetylgalactosamine-analogs, methods of making, and uses of the same. In particular, mono or trivalent N-acetylgalactosamine analogs may be prepared by utilizing a wide variety of linkers containing functional groups. These functionalized N-acetylgalactosamine-analogs may be used in the preparation of targeted delivery of oligonucleotide-based therapeutics.
1. A compound having the Formula (IId):
or a pharmaceutically acceptable salt thereof, wherein
each of L 1a , L 1b , L 1c , L 2a , L 2b , L 2c , L 3a , L 3b , and L 3c is independently a bond, —C(═O)—, —C(═S)—, —S(═O) 2 —, —C(═O)NR 9 —, —C(═S)NR 9 —, —C(═O)O—, —C(═S)O—, —NR 9 C(═O)NR 9 —, —NR 9 C(═S)NR 9 —, —OP(═O)(OH)O—, —OP(═S)(OH)O , —O—, —S—, —NR 9 —, optionally substituted C 1-10 alkylene, optionally substituted C 6-10 arylene, optionally substituted C 3-10 cycloalkylene, optionally substituted 5-10 membered hetetroarylene, optionally substituted 5 to 10 membered heterocyclylene, or optionally substituted 2 to 15 membered heteroalkylene wherein one or more carbon atoms are replaced with C(═O), O, S or N, provided that at least one of L 1a , L 1b and L 1c is not a bond, at least one of L 2a , L 2b and L 2c is not a bond, and at least one of L 3a , L 3b and L 3c is not a bond;
L 5 is absent, optionally substituted C 1-10 alkylene, or optionally substituted 2 to 15 membered heteroalkylene wherein one or more carbon atoms are replaced with C(═O), O, S or N;
each R 9 is independently hydrogen, unsubstituted C 1-6 alkyl, substituted C 1-6 alkyl, or an amino protecting group;
each of X 1 , X 2 and X 3 is —OCH 2 — or —NHCH 2 —, or each of X 1 and X 3 is —C(═O)CH 2 CH 2 —, and X 2 is —C(═O)CH 2 —;
Y 2 is NH, *NH(C═O), O or absent, the asterisk * indicates that Y 2 is connected to L 5 through the nitrogen atom of Y 2 ;
and
R 6 is —C(═O)CH 2 CH 2 C(═O)OH or
2. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
3. A solid support comprising the compound of claim 1 covalently attached thereto via R 6 of the compound of Formula (IId), wherein R 6 is —C(═O)CH 2 CH 2 C(═O)OH.
4. A method of preparing a synthetic oligonucleotide, comprising reacting a compound of claim 1 , with an oligonucleotide.
5. The compound of claim 1 , wherein Y 2 is NH.
6. The compound of claim 1 , wherein Y 2 is *NH(C═O).
7. The compound of claim 1 , wherein Y 2 is O.
8. The compound of claim 1 , wherein Y 2 is absent.
9. The compound of claim 1 , wherein L 5 is absent.
10. The compound of claim 1 , wherein L 5 is optionally substituted C 1-10 alkylene.
11. The compound of claim 1 , wherein L 5 is 2 to 15 membered heteroalkylene where one or more carbon atoms are replaced with C(═O), O or N.
12. The compound of claim 11 , wherein L 5 is —C(═O)CH 2 CH 2 C(═O)—, —C(═O)CH 2 CH 2 CH 2 C(═O)— or —C(═O)CH 2 CH 2 CH 2 CH 2 C(═O)—.
13. The compound of claim 5 , wherein L 5 is absent.
14. The compound of claim 5 , wherein L 5 is optionally substituted C 1-10 alkylene.
15. The compound of claim 5 , wherein L 5 is 2 to 15 membered heteroalkylene where one or more carbon atoms are replaced with C(═O), O or N.
16. The compound of claim 15 , wherein L 5 is —C(═O)CH 2 CH 2 C(═O)—, —C(═O)CH 2 CH 2 CH 2 C(═O)— or —C(═O)CH 2 CH 2 CH 2 CH 2 C(═O)—.
17. The compound of claim 8 , wherein L 5 is absent.
18. The compound of claim 8 , wherein L 5 is optionally substituted C 1-10 alkylene.
19. The compound of claim 8 , wherein L 5 is 2 to 15 membered heteroalkylene where one or more carbon atoms are replaced with C(═O), O or N.
20. The compound of claim 19 , wherein L 5 is —C(═O)CH 2 CH 2 C(═O)—, —C(═O)CH 2 CH 2 CH 2 C(═O)— or —C(═O)CH 2 CH 2 CH 2 CH 2 C(═O)—.
21. The compound of claim 1 , wherein each of X 1 and X 3 is —C(═O)CH 2 CH 2 —, and X 2 is —C(═O)CH 2 —.
22. The compound of claim 1 , wherein each of X 1 , X 2 and X 3 is —OCH 2 —.
23. The compound of claim 1 , wherein each of X 1 , X 2 and X 3 is —NHCH 2 —.
24. The compound of claim 1 , wherein each of L 1a , L 1b , L 1c , L 2a , L 2b , L 2c , L 3a , L 3b , and L 3c is independently a bond, C 1-10 alkylene, or 3 to 15 membered heteroalkylene where one or more carbon atoms are replaced with C(═O), O or N.
25. The compound of claim 16 , wherein the 3 to 15 membered heteroalkylene is a PEG linker comprising one to five —OCH 2 CH 2 — repeating unit.
26. The compound of claim 1 , wherein each of -L 1a -L 2a -L 3a -, -L 1b -L 2b -L 3b - and -L 1c -L 2c -L 3c - is —CH 2 CH 2 OCH 2 CH 2 NH—, —(CH 2 CH 2 O) 2 CH 2 CH 2 NH—, —(CH 2 CH 2 O) 3 CH 2 CH 2 NH—, —(CH 2 CH 2 O) 4 CH 2 CH 2 NH— or —(CH 2 CH 2 O) 5 CH 2 CH 2 NH—.
27. The compound of claim 1 , wherein each of -L 1a -L 2a -L 3a -, -L 1b -L 2b -L 3b - and -L 1c -L 2c -L 3c - is —CH 2 CH 2 O—, —(CH 2 CH 2 O) 2 —, —(CH 2 CH 2 O) 3 —, —(CH 2 CH 2 O) 4 — or —(CH 2 CH 2 O) 5 —.
28. The compound of claim 1 , wherein each of -L 1a -L 2a -L 3a -, -L 1b -L 2b -L 3b - and -L 1c -L 2c -L 3c - is —CH 2 CH 2 OCH 2 CH 2 NHC(═O)CH 2 CH 2 —, —(CH 2 CH 2 O) 2 CH 2 CH 2 NHC(═O)CH 2 CH 2 —, —(CH 2 CH 2 O) 3 CH 2 CH 2 NHC(═O)CH 2 CH 2 —, or —(CH 2 CH 2 O) 4 CH 2 CH 2 NHC(═O)CH 2 CH 2 —.
29. The compound of claim 1 , wherein each of -L 1a -L 2a -L 3a -, -L 1b -L 2b L 3b - and -L 1c -L 2c -L 3a - is 3 to 15 membered heteroalkylene where one or more —CH 2 — are replaced with C(═O) or NH.
30. The compound of claim 1 , wherein R 6 is —C(═O)CH 2 CH 2 C(═O)OH.
31. The compound of claim 1 , wherein R 6 is