Bicyclic peptide oligonucleotide conjugates

A peptide-oligonucleotide conjugate of Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• A′ is selected from —NHCH2C(O)NH2, —N(C1-6-alkyl)CH2C(O)NH2,
• wherein
• R5 is —C(O)(O-alkyl)x-OH, wherein x is 3-10 and each alkyl group is independently at each occurrence C2-6-alkyl, or R5 is selected from —C(O)C1-6-alkyl, trityl, monomethoxytrityl, —(C1-6-alkyl)R6, —(C1-6-heteroalkyl)-R6, aryl-R6, heteroaryl-R6, —C(O)O—(C1-6-alkyl)-R6, —C(O)O-aryl-R6, —C(O)O-heteroaryl-R6, and
• wherein R6 is selected from OH, SH, and NH2, or R6 is O, S, or NH, covalently linked to a solid support;
• each R1 is independently selected from OH and —NR3R4, wherein each R3 and R4 are independently at each occurrence —C1-6-alkyl;
• each R2 is independently selected from H, a nucleobase, and a nucleobase functionalized with a chemical protecting-group, wherein the nucleobase independently at each occurrence comprises a C3-6-heterocyclic ring selected from pyridine, pyrimidine, triazinane, purine, and deaza-purine;
• z is 8-40;
• and
• E′ is selected from H, —C1-6-alkyl, —C(O)C1-6-alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl,
• wherein
• Q is —C(O)(CH2)6C(O)— or —C(O)(CH2)2S2(CH2)2C(O)—, and
• R7 is —(CH2)2OC(O)N(R8)2, wherein R8 is —(CH2)6NHC(═NH)NH2, and
• wherein L is covalently linked by an amide bond to the amino-terminus of J, and L is —C(O)(CH2)1-6—C1-6-heteroaromatic-(CH2)1-6C(O);
• t is 4-16;
• each J is independently at each occurrence selected from an amino acid of the structure
• wherein:
• r and q are each independently 0, 1, 2, 3, or 4;
• and
• each R9 is independently at each occurrence selected from H, an amino acid side-chain, and an amino acid side-chain functionalized with a protecting-group,
• wherein three or four amino acid side-chains of R9 independently at each occurrence comprise a sulfur atom:
• a) wherein when the number of sulfur atoms is three, then the sulfur atoms, together with the atoms to which they are attached, form the structure
• such that the amino acids form a bicyclic structure;
• or
• b) wherein when the number of sulfur atoms is four, then the sulfur atoms, together with the atoms to which they are attached, form two occurrences of the structure
• such that the amino acids form a bicyclic structure;
• wherein d is 0 or 1, and M is selected from:
• wherein each R10 is independently at each occurrence H or a halogen;
• and
• G is covalently linked by an amide bond to the carboxy-terminus of J, and G is selected from H, —C(O)C1-6-alkyl, benzoyl, and stearoyl, and
• wherein at least one of the following conditions is true: