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US 2022/0402947 A1Published application
Trialkyne Linking Agents and Methods of Use
AssigneeArrowhead Pharmaceuticals, Inc.
InventorsZhen Li, Erich Altenhofer, Jeffrey Carlson, Matthew Fowler-Watters, Bo Chen
Life of this patent
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Abstract
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.
Claims76
A compound of Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein L1, L2, and L3 are each independently linkers comprising optionally substituted alkylene;
- Q is a tetravalent carbon, tetra-substituted phenyl or optionally substituted alkylene;
- R comprises a coupling moiety or an RNAi agent;
- and
- X is NRx or a bond, and Rx is H or optionally substituted C1-C6 alkyl.
3 more elements
A compound selected from:
- Compound
- No.
- Structure
- 1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 10
- 11
- 12
- 13
- 14
- 15
- 16
- 17
- 18
- 19
- 20
- 21
- 22
- or a pharmaceutically acceptable salt thereof.
23 more elements
A compound of Formula II,
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2, and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, and optionally substituted cycloalkylene;
- each instance of R1 is optionally substituted alkyl;
- R2 is optionally substituted alkyl;
- and
- R4 is H or optionally substituted alkyl.
5 more elements
A compound of Formula III,
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2, and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, and optionally substituted cycloalkylene;
- R4 is H or optionally substituted alkyl;
- X is O or S;
- and
- RNA comprises or consists of an RNAi agent.
5 more elements
A compound selected from:
- 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.
29 more elements
A compound of Formula IV,
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2, and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, and optionally substituted cycloalkylene;
- R1 and R2 are each independently optionally substituted alkyl;
- R4 is H or optionally substituted alkyl;
- and
- TL is a targeting ligand.
5 more elements
A compound selected from:
- Compound
- No.
- Structure
- 1-IV
- 2-IV
- 3-IV
- 4-IV
- 5-IV
- 6-IV
- 7-IV
- 8-IV
- 9-IV
- 10-IV
- 11-IV
- 12-IV
- 13-IV
- 14-IV
- or a pharmaceutically acceptable salt thereof, wherein TL comprises a targeting ligand.
15 more elements
A compound of Formula V,
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2 and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
- R4 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.
6 more elements
A compound selected from:
- 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.
29 more elements
A compound of Formula VI
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2 and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
- R3 is H, optionally substituted alkyl, or optionally substituted aryl;
- and
- R4 is H or optionally substituted alkyl.
4 more elements
A compound of Formula VII,
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2 and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
- each instance of R4 is H or optionally substituted alkyl;
- and
- RNA comprises or consists of an RNAi agent.
4 more elements
A compound selected from:
- Compound
- No.
- Structure
- 15-VII
- 16-VII
- 18-VII
- 19-VII
- 20-VII
- 21-VII
- 22-VII
- or a pharmaceutically acceptable salt thereof, wherein RNA comprises or consists of an RNAi agent.
8 more elements
A compound of Formula VIII
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2 and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
- R3 is H, optionally substituted alkyl, and optionally substituted aryl;
- R4 is H or optionally substituted alkyl;
- and
- TL is a targeting ligand.
5 more elements
A compound selected from
- Compound
- No.
- Structure
- 15-VIII
- 16-VIII
- 18-VIII
- 19-VIII
- 20-VIII
- 21-VIII
- 22-VIII
- or a pharmaceutically acceptable salt thereof, wherein TL comprises a targeting ligand.
8 more elements
A compound of Formula IX
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2 and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
- TL is a targeting ligand;
- each instance of R4 is H or optionally substituted alkyl;
- and
- RNA comprises or consists of an RNAi agent.
5 more elements
A compound selected from
- 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.
8 more elements
A method of reacting a compound of Formula II:
- with an RNAi agent to form a compound of Formula III:
- wherein,
- L1, L2, and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, and optionally substituted cycloalkylene;
- each instance of R1 is optionally substituted alkyl;
- R2 is optionally substituted alkyl;
- and
- R4 is H or optionally substituted alkyl
- X is O or S;
- and
- RNA comprises or consists of an RNAi agent.
8 more elements
A method of reacting a compound of Formula VI:
- with an RNAi agent comprising a free amine to form a compound of Formula VII:
- wherein,
- L1, L2 and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
- R3 is H, optionally substituted alkyl, or optionally substituted aryl;
- and
- each instance of R4 is H or optionally substituted alkyl;
- and
- RNA comprises or consists of an RNAi agent.
6 more elements
A method of reacting a compound of Formula III
- with a targeting ligand comprising an azide to form a compound of Formula V
- wherein,
- L1, L2, and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
- R4 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.
6 more elements
A method of reacting a compound of Formula VII
- with a targeting ligand comprising an azide to form a compound of Formula IX,
- wherein,
- L1, L2 and L3 are each independently linkers comprising optionally substituted alkylene;
- L4 is a linker comprising optionally substituted alkylene, optionally substituted arylene, or optionally substituted cycloalkylene;
- each instance of R4 is H or optionally substituted alkyl;
- and
- RNA comprises or consists of an RNAi agent.
4 more elements
Dependencies are inferred from the claim text.