Peptide oligonucleotide conjugates

1. A peptide-oligonucleotide-conjugate, or a pharmaceutically acceptable salt thereof, of Formula (I):

wherein:

z is 8-40;

each R 1 is independently selected from OH and —NR 3 R 4 , wherein each R 3 and R 4 are independently at each occurrence —C 1-6 alkyl;

each R 2 is independently selected from H, a nucleobase, and a nucleobase functionalized with a chemical protecting-group, wherein the nucleobase independently at each occurrence comprises pyridine, pyrimidine, triazinane, purine, or deaza-purine;

A′ is selected from —NHCH 2 C(O)NH 2 , —N(C 1-6 -alkyl)CH 2 C(O) NH 2 ,

R 5 is —C(O)(O-alkyl) x -OH, wherein x is 3-10 and each alkyl group is independently at each occurrence C 2-6 -alkyl, or R 5 is selected from —C(O)C 1-6 alkyl, trityl, monomethoxytrityl, —(C 1-6 -alkyl)R 6 , —(C 1-6 heteroalkyl)-R 6 , aryl-R 6 , heteroaryl-R 6 , —C(O)O—(C 1-6 alkyl)-R 6 , —C(O)O-aryl-R 6 , —C(O)O-heteroaryl-R 6 , and -L-(J) t —G;

R 6 is selected from OH, SH, and NH 2 , or R 6 is O, S, or NH, covalently linked to a solid support;

E′ is selected from H, —C 1-6 alkyl, —C(O)C 1-6 alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl,

Q is —C(O)(CH 2 ) 6 C(O)— or —C(O)(CH 2 ) 2 S 2 (CH 2 ) 2 C(O)—,

R 7 is —(CH 2 ) 2 OC(O)N(R 8 ) 2 ;

R 8 is —(CH 2 ) 6 NHC(═NH)NH 2 ;

R 11 is selected from —OH and —NR 3 R 4 ;

-L-(J) t —G is selected from:

R is arginine;

d is 0 or 1; and

M is:

each R 10 is independently at each occurrence H or a halogen,

wherein at least one of the following conditions is true:

1) A′ is

2) E′ is -L-(J) t -G; or 3) E′ is

2. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E′ is selected from H, —C(O) CH 3 , trityl, 4-methoxytrityl, benzoyl, stearoyl, and -L-(J) t -G.

3. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A′ is

or

E′ is -L-(J) t -G.

4. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from —N(C 1-6 -alkyl)CH 2 C(O) NH 2 ,

5. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A′ is

and

E′ is selected from H, —C(O)CH 3 , trityl, 4-methoxytrityl, benzoyl, and stearoyl.

6. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate of Formula (I) is a peptide-oligonucleotide-conjugate selected from:

7. The peptide-oligonucleotide-conjugate of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate is of the Formula (Ia) and R 5 is —C(O)(O—CH 2 CH 2 ) 3 OH.

8. The peptide-oligonucleotide-conjugate of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate is of the Formula (Ib) and E′ is selected from H, C 1-6 alkyl, —C(O)CH 3 , benzoyl, and stearoyl.

9. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is fluorine.

10. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is:

11. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein z is 8-25.

12. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein z is 10-20.

13. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein z is 17-21.

14. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein z is about 18.

15. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is —N(CH 3 ) 2 .

16. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is a nucleobase independently at each occurrence selected from adenine, guanine, cytosine, 5-methyl-cytosine, thymine, uracil, and hypoxanthine.

17. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein d is 1.

18. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein d is 0.

19. The peptide-oligonucleotide-conjugate, of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate of Formula (I) is a peptide-oligonucleotide-conjugate of Formula (V):

wherein R 14 is selected from:

20. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 14 is:

21. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 14

and

d is 0.

22. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 14 is

M is

and

d is 1.

23. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 14 is

M is

and

d is 1.

24. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 14 is

and

d is 0.

25. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 14 is

M is

and

d is 1.

26. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 14 is

M is

and

d is 1.

27. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate is:

wherein:

M is

and

each R 2 is a nucleobase independently at each occurrence selected from adenine, guanine, cytosine, 5-methyl-cytosine, thymine, uracil, and hypoxanthine.