Lipid-based enhancement agent for RNA delivery and therapy

Abstract

The present disclosure provides a Lipid-Based Enhancement Agent being a compound of Formula (I), (II), (III), or (IV): or pharmaceutically acceptable salts thereof, and related conjugates. The present disclosure also relates to uses of the Lipid-Based Enhancement Agents and conjugates, e.g., in delivering nucleic acid and / or treating or preventing diseases.

Description

This disclosure provides a lipid-based enhancer, which is a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof; and related sustained compounds. This disclosure also relates to the use of said lipid-based enhancers and sustained compounds, for example, in the delivery of nucleic acids and / or in the treatment or prevention of diseases. Abstract

Claims

CLAIMS1. A Lipid-Based Enhancement Agent being a compound of Formula (I), (II), (III), or (IV):or a pharmaceutically acceptable salt thereof, wherein:L is a lipid moiety;B is H, C1-C6alkyl, or a nucleobase moiety;V is -O-, -NRV-, or -C(RV)2-; each Rvindependently is H or C1-C6alkyl optionally substituted with one or more halogen;X is H, halogen, or -ORX;Rxis H, C1-C6alkyl, or -( C1-C6alkyl)-(C6-C10aryl), wherein the C1-C6alkyl or -( C1-C6alkyl)-(C6-C10aryl) is optionally substituted with one or more RXa; or Rxand R4together form C1-C6alkylene; each RXaindependently is halogen, C1-C6alkyl, or -O-( C1-C6alkyl), wherein the C1-C6alkyl or -O-( C1-C6alkyl) is optionally substituted with one or more halogen;Y is H, C1-C6alkyl optionally substituted with one or more halogen, -P(RY)2, - P(ORY)(N(RY)2), -P(=O)(ORY)RY, -P(=S)(ORY)RY, -P(=O)(SRY)RY, -P(=S)(SRY)RY, - P(=O)(ORY)2, -P(=S)(ORY)2, -P(=O)(SRY)2, -P(=S)(SRY)2, or a hydroxy protecting group; each RYindependently is H or C1-C6alkyl optionally substituted with one or more halogen or cyano;Z is H, C1-C6alkyl optionally substituted with one or more halogen, -P(RZ)2, - P(ORZ)(N(RZ)2), -P(=O)(ORZ)RZ, -P(=S)(ORZ)RZ, -P(=O)(SRZ)RZ, -P(=S)(SRZ)RZ, - P(=O)(ORZ)2, -P(=S)(ORZ)2, -P(=O)(SRZ)2, -P(=S)(SRZ)2, or a hydroxy protecting group; each Rzindependently is H or C1-C6alkyl optionally substituted with one or more halogen or cyano; or Y and Z in Formula (I) or (III), together form -Si(RL)2-O-Si(RL)2-, wherein each RLindependently is H or C1-C6alkyl; each Raindependently is H, halogen, or C1-C6alkyl optionally substituted with one or more halogen; or two vicinal Raform a bond;R1is H, halogen, or C1-C6alkyl optionally substituted with one or more halogen;R2is H, halogen, or C1-C6alkyl optionally substituted with one or more halogen;R3is H, halogen, or C1-C6alkyl optionally substituted with one or more halogen;R4is H, halogen, or C1-C6alkyl optionally substituted with one or more halogen; or R4and Rxtogether form C1-C6alkylene; each R5independently is H, halogen, or C1-C6alkyl optionally substituted with one or more halogen; and n is an integer ranging from about 0 to about 10.

2. A conjugate or a pharmaceutically acceptable salt thereof, comprising:(i) one or more Nucleic Acid Agent;(ii) one or more Ligand; and(iii) one or more Lipid-Based Enhancement Unit, wherein each Lipid-Based Enhancement Unit independently is:wherein: variables L, B, V, X, R1, R2, R3, R4, R5, Ra, RY, Rz, and n are described herein; and when the Lipid-Based Enhancement Unit is at the 3 ’-terminus of the Nucleic Acid Agent,# is an attachment to the rest of the conjugate; and## is H, -P(RY)2, -P(ORY)(N(RY)2), -P(=O)(ORY)RY, -P(=S)(ORY)RY, -P(=O)(SRY)RY, - P(=S)(SRY)RY, -P(=O)(ORY)2, -P(=S)(ORY)2, -P(=O)(SRY)2, -P(=S)(SRY)2, or a hydroxy protecting group; or when the Lipid-Based Enhancement Unit is at the 5 ’-terminus of the Nucleic Acid Agent,# is H, -P(RZ)2, -P(ORZ)(N(RZ)2), -P(=O)(ORZ)RZ, -P(=S)(ORZ)RZ, -P(=O)(SRZ)RZ, - P(=S)(SRZ)RZ, -P(=O)(ORZ)2, -P(=S)(ORZ)2, -P(=O)(SRZ)2, -P(=S)(SRZ)2, or a hydroxy protecting group; and## is an attachment to the rest of the conjugate; or each of # and ## independently is an attachment to the rest of the conjugate.

3. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein L is -C(=O)RL, wherein:RLis C1-C30hydrocarbon chain or 2- to 30-membered hetero-hydrocarbon chain, wherein the C1-C30hydrocarbon chain or 2- to 30-membered hetero-hydrocarbon chain is optionally substituted with one or more RL; each RLindependently is oxo, halogen, -OH, -O(C1-C12alkyl), -NH2, -NH(C1-C12alkyl), -N(C1-C12alkyl)2, C1-C12alkyl, C2-C12alkenyl, C2-C12alkynyl, C3-C8cycloalkyl, 3- to 8- membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C2-C12alkenyl, C2-C12alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RLa; or two RL, together with the one or more intervening atoms, form C3-C8cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the C3-C8cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more RLa; and each RLaindependently is oxo, halogen, -OH, -O(C1-C12alkyl), -NH2, -NH(C1-C12alkyl), or -N(C1-C12alkyl)2.

4. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein RLis C1-C35 hydrocarbon chain optionally substituted with one or more RL.

5. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein RLis 2- to 35-membered hetero-hydrocarbon chain optionally substituted with one or more RL.

6. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLis oxo.

7. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLis halogen.

8. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLis -OH or -O(C1-C12alkyl) optionally substituted with one or more RLa.

9. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLis NH2, -NH(C1-C12alkyl), or -N(C1-C12alkyl)2, wherein the -NH(Ci- C12alkyl) or -N(C1-C12alkyl)2 is optionally substituted with one or more RLa.

10. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLis C1-C12alkyl, C2-C12alkenyl, or C2-C12alkynyl, wherein the C1-C12alkyl, C2-C12alkenyl, or C2-C12alkynyl is optionally substituted with one or more RLa.

11. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLis C3-C8cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the C3-C8cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more RLa.

12. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLis C6-C10aryl or 5- to 10-membered heteroaryl, wherein the C6-C10aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more RLa.

13. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein two RL, together with the one or more intervening atoms, form C3-C8cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the C3-C8cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more RLa.

14. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLais oxo.

15. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLais halogen.

16. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLais -OH or -O(C1-C12alkyl).

17. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein at least one RLais -NH2, -NH(C1-C12alkyl), or -N(C1-C12alkyl)2.

18. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein the nucleobase moiety is adenine (A), cytosine (C), guanine (G), thymine (T), or uracil (U).

19. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein V is -O-.

20. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein V is -NH-.

21. The Lipid-Based Enhancement Agent or conjugate of any one of the preceding claims, wherein V is -CH2-.

22. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the compound is of Formula (I’), (II’), (III’), or (IV’):

23. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the compound is of Formula (I-A), (II-A), (III-A), or (IV-A):or a pharmaceutically acceptable salt thereof.

24. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the compound is of Formula (F-A), (IF-A), (IIF-A), or (IV’-A):or a pharmaceutically acceptable salt thereof.

25. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the compound is of Formula (LB), (ILB), (III-B), or (IV-B):or a pharmaceutically acceptable salt thereof.

26. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the compound is of Formula (F-B), (II’ -B), (IIF-B), or (IV’ -B):or a pharmaceutically acceptable salt thereof.

27. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the compound is of Formula (I-C), (II- C), (III- C), (IV-C), (V-C), (VI-C), (VII-C), or (VIII-C):or a pharmaceutically acceptable salt thereof.

28. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the compound is of Formula (I-C), (II -C), (III- C ), (IV’ -C), (V’-C), (VI’-C), (VII -C), or (VIII -C ):or a pharmaceutically acceptable salt thereof.

29. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein:Y is a hydroxy protecting group, and Z is a hydroxy protecting group; orY and Z in Formula (I), (III), (I’), (III’), (I- A), (III- A), (I’ -A), (III’ -A), (LB), (III-B), (I’-B), (III’-B), (I-C), (IILC), (V-C), (VILC), (I’-C), (III’-C), (V’-C), or (VII’ -C) together form - Si(RL)2-O-Si(RL)2-, wherein each RLindependently is H or C1-C6alkyl.

30. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the Lipid-Based Enhancement Agent is:or a pharmaceutically acceptable salt thereof, wherein:— denotes a single or double bond;Y is -P(RY)2, -P(ORY)(N(RY)2), -P(=O)(ORY)RY, -P(=S)(ORY)RY, -P(=O)(SRY)RY, - P(=S)(SRY)RY, -P(=O)(ORY)2, -P(=S)(ORY)2, -P(=O)(SRY)2, -P(=S)(SRY)2, or a hydroxy protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tertbutyldiphenylsilyl, or triisopropyl silyl), triphenylmethyl (Tr), 4,4’ -dimethoxytrityl (DMTr), substituted acyl (e.g., optionally substituted acetyl), or benzyl); each RYindependently is H or C1-C6alkyl optionally substituted with one or more halogen or cyano;Z is -P(RZ)2, -P(ORZ)(N(RZ)2), -P(=O)(ORZ)RZ, -P(=S)(ORZ)RZ, -P(=O)(SRZ)RZ, - P(=S)(SRZ)RZ, -P(=O)(ORZ)2, -P(=S)(ORZ)2, -P(=O)(SRZ)2, -P(=S)(SRZ)2, or a hydroxy protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tertbutyldiphenylsilyl, or triisopropyl silyl), triphenylmethyl (Tr), 4,4’ -dimethoxytrityl (DMTr), substituted acyl (e.g., optionally substituted acetyl), or benzyl); and each Rzindependently is H or C1-C6alkyl optionally substituted with one or more halogen or cyano.

31. The Lipid-Based Enhancement Agent of any one of the preceding claims, wherein the Lipid-Based Enhancement Agent is selected from the compounds described in Table L and pharmaceutically acceptable salts thereof.

32. The conjugate of any of the preceding claims, wherein the conjugate comprises:(Nucleic Acid Agent)-[(Linker Unit)o-i-(Lipid-Based Enhancement Unit)-(Linker Unit)o- i-(Ligand)]i-3;(Nucleic Acid Agent)-[(Linker Unit)o-i-(Ligand)-(Linker Unit)o-i-(Lipid-Based Enhancement Unit)] 1-3; or[(Lipid-Based Enhancement Unit)-(Linker Unit)o-i]i-3-(Nucleic Acid Agent)- [(Linker Unit)o-i-(Ligand)]i-3; wherein each of the Linker Unit, Lipid-Based Enhancement Unit, and Ligand, when attached to the Nucleic Acid Agent (e.g., siRNA), independently is attached to a terminal position (e.g., a nucleotide at the 3’-terminus or the 5’-terminus) or an internal position (e.g., a nucleotide that is not at the 3’-terminus or the 5’-terminus) of the Nucleic Acid Agent (e.g., siRNA).

33. The conjugate of any one of the preceding claims, wherein at least one Lipid-BasedEnhancement Unit in the conjugate is:

34. The conjugate of any one of the preceding claims, wherein at least one Lipid-Based Enhancement Unit in the conjugate is selected from the structures described in Table C and Table D.

35. The conjugate of any one of the preceding claims, wherein the Nucleic Acid Agent comprises an oligonucleotide.

36. A pharmaceutical composition comprising the compound or conjugate of the any one of the preceding claims.

37. A method of modulating the expression of a target gene in a subject, delivering a Nucleic Acid Agent to a subject, or treating or preventing a disease in a subject in need thereof, comprising administering to the subject the conjugate of any one of the preceding claims.

38. The conjugate of any one of the preceding claims for modulating the expression of a target gene in a subject, delivering a Nucleic Acid Agent to a subject, treating or preventing a disease in a subject in need thereof.

39. Use of the conjugate of any one of the preceding claims in the manufacture of a medicament for modulating the expression of a target gene in a subject, delivering a Nucleic Acid Agent to a subject, or treating or preventing a disease in a subject in need thereof.

40. The method, conjugate, or use of any one of the preceding claims, wherein the subject is a human.

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