LIPID-BASED ENHANCEMENT AGENT FOR RNA DELIVERY AND THERAPY

1 . 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, C 1 -C 6 alkyl, or a nucleobase moiety;

V is —O—, —NR—, or —C(R V ) 2 —;

each R V independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen;

X is H, halogen, or —OR X ;

R X is H, C 1 -C 6 alkyl, or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), wherein the C 1 -C 6 alkyl or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl) is optionally substituted with one or more R Xa ; or R X and R 4 together form C 1 -C 6 alkylene;

each R Xa independently is halogen, C 1 -C 6 alkyl, or —O—(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl or —O—(C 1 -C 6 alkyl) is optionally substituted with one or more halogen;

Y is H, C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Y ) 2 , —P(OR Y )(N(R Y ) 2 ), —P(═O)(OR Y )R Y , —P(═S)(OR Y )R Y , —P(═O)(SR Y )R Y , —P(═S)(SR Y )R Y , —P(═O)(OR Y ) 2 , —P(═S)(OR Y ) 2 , —P(═O)(SR Y ) 2 , —P(═S)(SR Y ) 2 , or a hydroxy protecting group;

each R Y independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;

Z is H, C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Z ) 2 , —P(OR Z )(N(R Z ) 2 ), —P(═O)(OR Z )R Z , —P(═S)(OR Z )R Z , —P(═O)(SR Z )R Z , —P(═S)(SR Z )R Z , —P(═O)(OR Z ) 2 , —P(═S)(OR Z ) 2 , —P(═O)(SR Z ) 2 , —P(═S)(SR Z ) 2 , or a hydroxy protecting group;

each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;

or Y and Z in Formula (I) or (III), together form —Si(R L′ ′) 2 —O—Si(R L′ ′) 2 —, wherein each R L ″ independently is H or C 1 -C 6 alkyl;

each R a independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; or

two vicinal R a form a bond;

R 1 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 2 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 3 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 4 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; or R 4 and R X together form C 1 -C 6 alkylene;

each R 5 independently is H, halogen, or C 1 -C 6 alkyl 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:

L is a lipid moiety;

B is H, C 1 -C 6 alkyl, or a nucleobase moiety;

V is —O—, —NR V —, or —C(R V ) 2 —;

each R V independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen;

X is H, halogen, or —OR X ;

R X is H, C 1 -C 6 alkyl, or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), wherein the C 1 -C 6 alkyl or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl) is optionally substituted with one or more R Xa ; or R X and R 4 together form C 1 -C 6 alkylene;

each R Xa independently is halogen, C 1 -C 6 alkyl, or —O—(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl or —O—(C 1 -C 6 alkyl) is optionally substituted with one or more halogen;

each R a independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; or

two vicinal R a form a bond;

R′ is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 2 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 3 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 4 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; or R 4 and R X together form C 1 -C 6 alkylene;

each R 5 independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; and

n is an integer ranging from about 0 to about 10; and

when the Lipid-Based Enhancement Unit is at the 3′-terminus of a Nucleic Acid Agent,

# is an attachment to the rest of the conjugate; and

## is H, —P(R) 2 , —P(OR)(N(Re) 2 ), —P(═O)(OR)R, —P(═S)(OR)R, —P(═O)(SR)R, —P(═S)(SRe)Re, —P(═O)(OR) 2 , —P(═S)(OR) 2 , —P(═O)(SRe) 2 , —P(═S)(SRe) 2 , or a hydroxy protecting group, wherein each R independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano; or

when the Lipid-Based Enhancement Unit is at the 5′-terminus of a Nucleic Acid Agent,

# is H, —P(R Z ) 2 , —P(OR Z )(N(R Z ) 2 ), —P(═O)(OR Z )R Z , —P(═S)(OR Z )R Z , —P(═O)(SR Z )R Z , —P(═S)(SR Z )R Z , —P(═O)(OR Z ) 2 , —P(═S)(OR Z ) 2 , —P(═O)(SR Z ) 2 , —P(═S)(SR Z ) 2 , or a hydroxy protecting group, wherein each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano; 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 conjugate of claim 2 , wherein L is —C(═O)R L , wherein:

R L is C 1 -C 35 hydrocarbon chain or 2- to 35-membered hetero-hydrocarbon chain, wherein the C 1 -C 35 hydrocarbon chain or 2- to 35-membered hetero-hydrocarbon chain is optionally substituted with one or more R L′ ;

each R L′ independently is oxo, halogen, —OH, —O(C 1 -C 12 alkyl), —NH 2 , —NH(C 1 -C 12 alkyl), —N(C 1 -C 12 alkyl) 2 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein the C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R La ; or

two R L′ , together with the one or more intervening atoms, form C 3 -C 8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the C 3 -C 8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more R La ; and

each R La independently is oxo, halogen, —OH, —O(C 1 -C 12 alkyl), —NH 2 , —NH(C 1 -C 12 alkyl), or —N(C 1 -C 12 alkyl) 2 .

4 . The conjugate of claim 3 , wherein R L is C 1 -C 35 hydrocarbon chain optionally substituted with one or more R L′ .

5 . The conjugate of claim 3 , wherein R L is 2- to 35-membered hetero-hydrocarbon chain optionally substituted with one or more R L′ .

6 . The conjugate of claim 3 , wherein at least one R L′ is oxo.

7 . The conjugate of claim 3 , wherein at least one R L′ is halogen.

8 . The conjugate of claim 3 , wherein at least one R L′ is —OH or —O(C 1 -C 12 alkyl) optionally substituted with one or more R La .

9 . The conjugate of claim 3 , wherein at least one R L′ is —NH 2 , —NH(C 1 -C 12 alkyl), or —N(C 1 -C 12 alkyl) 2 , wherein the —NH(C 1 -C 12 alkyl) or —N(C 1 -C 12 alkyl) 2 is optionally substituted with one or more R La .

10 . The conjugate of claim 3 , wherein at least one R L′ is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, or C 2 -C 12 alkynyl, wherein the —C 1 -C 12 alkyl, C 2 -C 12 alkenyl, or C 2 -C 12 alkynyl is optionally substituted with one or more R La .

11 . The conjugate of claim 3 , wherein at least one R L′ is C 3 -C 8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the C 3 -C 8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more R La .

12 . The conjugate of claim 3 , wherein at least one R L′ is C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R La .

13 . The conjugate of claim 3 , wherein two R L′ , together with the one or more intervening atoms, form C 3 -C 8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the C 3 -C 8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more R La .

14 . The conjugate of claim 3 , wherein at least one R La is oxo or halogen.

15 . (canceled)

16 . The conjugate of claim 3 , wherein at least one R La is —OH or —O(C 1 -C 12 alkyl).

17 . The conjugate of claim 3 , wherein at least one R La is —NH 2 , —NH(C 1 -C 12 alkyl), or —N(C 1 -C 12 alkyl) 2 .

18 .- 33 . (canceled)

34 . The conjugate of claim 2 , 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 claim 2 , wherein each Nucleic Acid Agent independently comprises an oligonucleotide.

36 . A pharmaceutical composition comprising the conjugate of claim 2 .

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 claim 2 .

38 .- 40 . (canceled)