LIPID-BASED CONJUGATES FOR SYSTEMIC, CENTRAL NERVOUS SYSTEM, PERIPHERAL NERVOUS SYSTEM, AND OCULAR DELIVERY

1 . 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 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;

Q is —(CR a R a ) n —NH—* in which * denotes attachment to L; or Q is C 6 -C 10 arylene or 5- to 10-membered heteroarylene, wherein the C 6 -C 10 arylene or 5- to 10-membered heteroarylene is optionally substituted with one or more R Q ;

each R Q independently is halogen 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;

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 R4 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; and

(ii) one or more Lipid-Based Ligand Unit, wherein each Lipid-Based Ligand 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;

Q is —(CR a R a ) n —NH—* in which * denotes attachment to L; or Q is C 6 -C 10 arylene or 5- to 10-membered heteroarylene, wherein the C 6 -C 10 arylene or 5- to 10-membered heteroarylene is optionally substituted with one or more R Q ;

each R Q independently is halogen 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;

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; and

when the Lipid-Based Ligand 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 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, wherein each R Y independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano; or

when the Lipid-Based Ligand 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 or —C(═S)R L , wherein:

R L is C 2 -C 200 hydrocarbon chain or 2- to 200-membered hetero-hydrocarbon chain, wherein the C 2 -C 200 hydrocarbon chain or 2- to 200-membered hetero-hydrocarbon chain is optionally substituted with one or more R L′ ;

each R L′ independently is oxo, dihalocarbene, cyano, halogen, —OH, —O(C 1 -C 12 alkyl), —O(C 6 -C 10 aryl), —COOH, —COO(C 1 -C 12 alkyl), —CO(C 1 -C 30 alkyl), —NHCO(C 1 -C 30 alkyl), —CONH 2 , —CONH(C 1 -C 12 alkyl), —CON(C 1 -C 12 alkyl) 2 , —C(O)NHOH, —SO 3 H, —SO 3 (C 1 -C 12 alkyl), —NH 2 , —NH(C 1 -C 12 alkyl), —N(C 1 -C 12 alkyl) 2 , —S(C 1 -C 12 alkyl), —S(C 6 -C 10 aryl), —P(C 6 -C 10 aryl) 3 , —OP(═O)(O − )O—(C 1 -C 12 alkylene)-NMe 3 + , 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 —O(C 1 -C 12 alkyl), —O(C 6 -C 10 aryl), —COO(C 1 -C 12 alkyl), —CO(C 1 -C 30 alkyl), —NHCO(C 1 -C 30 alkyl), —CONH(C 1 -C 12 alkyl), —CON(C 1 -C 12 alkyl) 2 , —SO 3 (C 1 -C 12 alkyl), —NH(C 1 -C 12 alkyl), —N(C 1 -C 12 alkyl) 2 , —S(C 1 -C 12 alkyl), —S(C 6 -C 10 aryl), —P(C 6 -C 10 aryl) 3 , —OP(═O)(O − )O—(C 1 -C 12 alkylene)-NMe 3 + , 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 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, 3- to 8-membered heterocycloalkyl, C 6 -C 15 aryl, or 5- to 15-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 15 aryl, or 5- to 15-membered heteroaryl is optionally substituted with one or more R La ; and

each R La independently is oxo, halogen, —OH, —O(C 1 -C 12 alkyl), —SH, —S(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 optionally substituted with one or more C 1 -C 12 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl; or

two R La , together with the one or more intervening atoms, form C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl.

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

5 . (canceled)

6 . The conjugate of claim 2 , wherein at least one R L′ is oxo, dihalocarbene, cyano, or halogen.

7 .- 9 . (canceled)

10 . The conjugate of claim 2 , wherein at least one R L′ is —OH, —O(C 1 -C 12 alkyl), or —O(C 6 -C 10 aryl), wherein the —O(C 1 -C 12 alkyl) or —O(C 6 -C 10 aryl) is optionally substituted with one or more R La .

11 . The conjugate of claim 2 , wherein at least one R L′ is —COOH, —COO(C 1 -C 12 alkyl), —CO(C 1 -C 30 alkyl), —CONH 2 , —CONH(C 1 -C 12 alkyl), —CON(C 1 -C 12 alkyl) 2 , or —C(O)NHOH, wherein the —COO(C 1 -C 12 alkyl), —CO(C 1 -C 30 alkyl), —CONH(C 1 -C 12 alkyl), or —CON(C 1 -C 12 alkyl) 2 is optionally substituted with one or more R La .

12 . The conjugate of claim 2 , wherein at least one R L′ is —NHCO(C 1 -C 30 alkyl) optionally substituted with one or more R La .

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

14 . The conjugate of claim 2 , 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 .

15 . The conjugate of claim 2 , wherein at least one R L′ is —S(C 1 -C 12 alkyl) or —S(C 6 -C 10 aryl), wherein the —S(C 1 -C 12 alkyl) or —S(C 6 -C 10 aryl) is optionally substituted with one or more R La .

16 . The conjugate of claim 2 , wherein at least one R L′ is —P(C 6 -C 10 aryl) 3 or —OP(═O)(O − )O—(C 1 -C 12 alkylene)-NMe 3 + , wherein the —P(C 6 -C 10 aryl) 3 or —OP(═O)(O − )O—(C 1 -C 12 alkylene)-NMe 3 + is optionally substituted with one or more R La .

17 . The conjugate of claim 2 , 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 .

18 .- 19 . (canceled)

20 . The conjugate of claim 2 , wherein at least one R L′ is C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein the 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 .

21 .- 23 . (canceled)

24 . The conjugate of claim 2 , wherein two R L , together with the one or more intervening atoms, form C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 15 aryl, or 5- to 15-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 15 aryl, or 5- to 15-membered heteroaryl is optionally substituted with one or more R La .

25 .- 27 . (canceled)

28 . The conjugate of claim 2 , wherein at least one L is selected from the structures described in Tables X and Y.

29 .- 40 . (canceled)

41 . The conjugate of claim 2 , wherein at least one Lipid-Based Ligand Unit in the conjugate is selected from the structures described in Tables C, N, and Q.

42 . (canceled)

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

44 .- 47 . (canceled)

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

49 . 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 .

50 .- 58 . (canceled)