Trialkyne Linking Agents and Methods of Use
Described are improved linking agents that are useful for facilitating the attachment of targeting groups, pharmacokinetic (PK) enhancers or modifiers, or other delivery agents to oligonucleotides. The described linking agents may exhibit improved reaction yields, stability, and biological activity, particularly when used in connection with oligonucleotide-based compounds, such as RNA interference (RNAi) agents.
1 - 17 . (canceled)
18 . A compound of Formula II,
or a pharmaceutically acceptable salt thereof,
wherein,
L 1 , L 2 , and L 3 are each independently linkers comprising optionally substituted alkylene;
L 4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, and optionally substituted cycloalkylene;
each instance of R 1 is optionally substituted alkyl;
R 2 is optionally substituted alkyl; and
R 4 is H or optionally substituted alkyl.
19 - 24 . (canceled)
25 . A compound of Formula III,
or a pharmaceutically acceptable salt thereof,
wherein,
L 1 , L 2 , and L 3 are each independently linkers comprising optionally substituted alkylene;
L 4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, and optionally substituted cycloalkylene;
R 4 is H or optionally substituted alkyl;
X is O or S; and
RNA comprises or consists of an RNAi agent.
26 - 31 . (canceled)
32 . The compound or pharmaceutically acceptable salt thereof of claim 25 , wherein the compound is selected from the group consisting of:
Compound
No.
Structure
1-O-III
1-S-III
2-O-III
2-S-III
3-O-III
3-S-III
4-O-III
4-S-III
5-O-III
5-S-III
6-O-III
6-S-III
7-O-III
7-S-III
8-O-III
8-S-III
9-O-III
9-S-III
10-O-III
10-S-III
11-O-III
11-S-III
12-O-III
12-S-III
13-O-III
13-S-III
14-O-III
14-S-III
or a pharmaceutically acceptable salt thereof, wherein RNA comprises or consists of an RNAi agent.
33 - 40 . (canceled)
41 . A compound of Formula V,
or a pharmaceutically acceptable salt thereof,
wherein,
L 1 , L 2 and L 3 are each independently linkers comprising optionally substituted alkylene;
L 4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
R 4 is H or optionally substituted alkyl;
TL is a targeting ligand;
Y is O or S; and
RNA comprises or consists of an RNAi agent.
42 . The compound of claim 41 , wherein L 1 , L 2 and L 3 are each
43 . The compound of claim 41 , wherein L 1 , L 2 and L 3 are each
44 . The compound of claim 41 , wherein L 1 , L 2 and L 3 are each
45 . The compound of claim 41 , wherein L 4 is selected from the group consisting of:
wherein indicates the point of attachment.
46 . The compound or pharmaceutically acceptable salt thereof of claim 41 , wherein the compound is selected from the group consisting of:
Compound
No.
Structure
1-O-V
1-S-V
2-O-V
2-S-V
3-O-V
3-S-V
4-O-V
4-S-V
5-O-V
5-S-V
6-O-V
6-S-V
7-O-V
7-S-V
8-O-V
8-S-V
9-O-V
9-S-V
10-O-V
10-S-V
11-O-V
11-S-V
12-O-V
12-S-V
13-O-V
13-S-V
14-O-V
14-S-V
or a pharmaceutically acceptable salt thereof, wherein TL is a targeting ligand and RNA comprises or consists of an RNAi agent.
47 - 66 . (canceled)
67 . A compound of Formula IX
or a pharmaceutically acceptable salt thereof,
wherein,
L 1 , L 2 and L 3 are each independently linkers comprising optionally substituted alkylene;
L 4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
TL is a targeting ligand;
each instance of R 4 is H or optionally substituted alkyl; and
RNA comprises or consists of an RNAi agent.
68 - 71 . (canceled)
72 . The compound or pharmaceutically acceptable salt thereof of claim 67 , wherein the compound is selected from the group consisting of:
Compound
No.
Structure
15-IX
16-IX
18-IX
19-IX
20-IX
21-IX
22-IX
or a pharmaceutically acceptable salt thereof, wherein TL is a targeting ligand and RNA comprises or consists of an RNAi agent.
73 - 76 . (canceled)