Lipid-based enhancers for RNA delivery and therapy

Abstract

The present disclosure provides a lipid-based enhancer which is a compound of Formula (I), (II), (III), or (IV): (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof; and related conjugates. The disclosure also relates to the use of the lipid-based enhancers and conjugates, for example, in the delivery of nucleic acids and / or the treatment or prophylaxis of disease.

Description

[0001] Related applications

[0002] This application claims priority and benefit to U.S. Application No. 63 / 515,256, filed July 24, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Efficient delivery of genetic material, such as RNA, into cells requires specific targeting and protection from the extracellular environment, particularly serum proteins. One approach to achieving specific targeting is to conjugate the targeting moiety to a nucleic acid (e.g., an oligonucleotide). The targeting moiety facilitates the guidance of the nucleic acid to the target site. Delivery can be further enhanced by receptor-mediated endocytosis. This process is initiated by the activation of cell surface or membrane receptors after the binding of a specific ligand to the receptor. Many receptor-mediated endocytosis systems are known, including those that recognize sugars (such as galactose, mannose, and mannose-6-phosphate), peptides, and proteins (such as transferrin, desialyl glycoprotein, vitamin B12, insulin, and epidermal growth factor (EGF)). The desialyl glycoprotein receptor (ASGP-R) is a high-capacity receptor and is highly enriched on hepatocytes. ASGP-R has a higher affinity for N-acetyl-D-galactosylamine (GalNAc) than for D-Gal. Recently, certain carbohydrate conjugates have proven to be valuable alternatives to liposomes for nucleic acid delivery. Furthermore, the stability of nucleic acids in the cellular environment after successful delivery to cells is important for achieving the desired therapeutic effect.

[0004] Therefore, new improvements are still needed to enhance nucleic acid delivery. This disclosure addresses this need. Summary of the Invention

[0005] In some aspects, this disclosure provides a lipid-based enhancer, which is a compound of formula (I), (II), (III) or (IV):

[0006] (I),

[0007] (II),

[0008] (III), or

[0009] (IV),

[0010] Or its pharmaceutically acceptable salt, wherein:

[0011] L represents the lipid portion;

[0012] B is H, C1-C6 alkyl, or nucleobase moiety;

[0013] V is -O-, -NR V -or-C(R) V )2-;

[0014] Each R V It is a C1-C6 alkyl group that is independently H or optionally substituted with one or more halogens;

[0015] X is H, halogen, or -OR X ;

[0016] R X It is H, C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 aryl), wherein the C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 Aryl) optionally by one or more R Xa Replace; or R X and R 4 Together they form C1-C6 alkylene groups;

[0017] Each R Xa It is independently a halogen, a C1-C6 alkyl or -O-(C1-C6 alkyl), wherein the C1-C6 alkyl or -O-(C1-C6 alkyl) is optionally substituted by one or more halogens;

[0018] Y is H, a C1-C6 alkyl group optionally substituted with one or more halogens, or -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 hydroxyl protecting group;

[0019] Each R Y It is independently an H or optionally a C1-C6 alkyl group substituted with one or more halogens or cyano groups;

[0020] Z is H, a C1-C6 alkyl group optionally substituted with one or more halogens, or -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 hydroxyl protecting group;

[0021] Each R Z It is independently an H or optionally a C1-C6 alkyl group substituted with one or more halogens or cyano groups;

[0022] Alternatively, Y and Z in equation (I) or (III) together form -Si(R) L’’ )2-O-Si(R L’’ )2-, where each R L’’ It is independently an H or C1-C6 alkyl group;

[0023] Each R a It is independently a C1-C6 alkyl group, a halogen, or optionally substituted with one or more halogens; or

[0024] Two adjacent R a Forming bonds;

[0025] R 1 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens;

[0026] R 2 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens;

[0027] R 3 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens;

[0028] R 4 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens; or R 4 and R X Together they form C1-C6 alkylene groups;

[0029] Each R 5Independently, it is a C1-C6 alkyl group, a halogen, or optionally substituted with one or more halogens; and

[0030] n is an integer ranging from approximately 0 to approximately 10.

[0031] In some aspects, this disclosure provides a conjugate or a pharmaceutically acceptable salt thereof comprising:

[0032] (i) One or more nucleic acid reagents;

[0033] (ii) one or more ligands; and

[0034] (iii) One or more lipid-based enhancement units, wherein each lipid-based enhancement unit is independently:

[0035] , ,

[0036] or ,

[0037] in:

[0038] Variables L, B, V, X, R 1 R 2 R 3 R 4 R 5 R a R Y R Z and n as described in this article; and

[0039] When the lipid-based enhancing unit is located at the 3' end of the nucleic acid agent,

[0040] # is the attachment to the rest of the conjugate; and

[0041] ## 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)(SRY )2 or hydroxyl protecting group; or

[0042] When the lipid-based enhancing unit is located at the 5' end of the nucleic acid agent,

[0043] # 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 hydroxyl protecting group; and

[0044] ## is the attachment to the rest of the conjugate; or

[0045] Each of # and ## is independently attached to the rest of the conjugate.

[0046] In some respects, this disclosure provides an isotopic derivative of a lipid-based enhancer as described herein.

[0047] In some aspects, this disclosure provides a pharmaceutical composition comprising the lipid-based enhancer or conjugate described herein.

[0048] In some aspects, this disclosure provides a method for regulating the expression of a target gene in a subject, the method comprising administering the conjugate described herein to the subject.

[0049] In some aspects, this disclosure provides a method for delivering a nucleic acid agent to a subject, the method comprising administering the conjugate described herein to the subject.

[0050] In some aspects, this disclosure provides a method for treating or preventing a disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the conjugate described herein.

[0051] In some respects, this disclosure provides a conjugate as described herein for regulating the expression of target genes in a subject.

[0052] In some respects, this disclosure provides a conjugate as described herein for delivering nucleic acid agents to a subject.

[0053] In some respects, this disclosure provides a conjugate as described herein for the treatment or prevention of disease in a subject in need.

[0054] In some respects, this disclosure provides the use of the conjugates described herein in the manufacture of medicaments for regulating the expression of target genes in a subject.

[0055] In some respects, this disclosure provides for the use of the conjugates described herein in the manufacture of medicaments for delivering nucleic acid agents to subjects.

[0056] In some respects, this disclosure provides for the use of the conjugates described herein in the manufacture of a medicament for treating or preventing a disease in a subject in need.

[0057] In some respects, this disclosure provides a compound that is an isotopic derivative of the lipid-based enhancer disclosed herein.

[0058] In some aspects, this disclosure provides a pharmaceutical composition comprising the conjugates described herein.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the specification, singular forms include plural forms unless the context clearly requires otherwise. Although similar or equivalent methods and materials described herein may be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not considered prior art to the claimed invention. In case of conflict, this specification, including the definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be restrictive. In case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures shall prevail.

[0060] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. Attached Figure Description

[0061] Figure 1 The chemical structures of ligand A-conjugated siRNA double strand 1 (“double strand 1”) and ligand A-conjugated siRNA double strands 2 and 3 (“double strand 2” and “double strand 3”, respectively) with lipid-based enhancement units are shown.

[0062] Figures 2A-2BThe study demonstrated the knockdown of human target gene mRNAs in the quadriceps femoris and heart via double strand 1, double strand 2, and double strand 3.

[0063] Figure 3 Various exemplary compositions of conjugates containing the lipid-based reinforcing units described herein are shown. Detailed Implementation

[0064] Effective delivery of genetic material, such as RNA, into cells requires specific targeting and protection from the extracellular environment, particularly serum proteins. One method to achieve specific targeting is to conjugate the targeting moiety to a nucleic acid (e.g., an oligonucleotide). The targeting moiety helps guide the nucleic acid to the target site.

[0065] It should be understood that oligonucleotides may need to overcome several extracellular and intracellular barriers to achieve effective gene knockdown in specific disease tissues or cell types. Chemical modification and conjugation with target ligands can improve the pharmacological properties of oligonucleotides and enhance tissue-specific delivery. However, previously, despite testing various conjugates with peptides, antibodies, small molecules, carbohydrates, and adaptors, oligonucleotides conjugated with a single target ligand have failed to achieve clinically relevant knockdown activity and specificity. These suboptimal delivery methods are likely due to numerous delivery obstacles, including poor pharmacokinetic and ADME characteristics of the conjugates, lack of efficient tissue accumulation and cellular uptake, and inefficient intracellular sorting and endosome escape.

[0066] This disclosure provides lipid-based enhancing units that improve targeted delivery efficiency and enhance the cellular activity of nucleic acids, for example, by improving PK, stability, cellular uptake and transport, or other mechanisms. This disclosure also provides conjugates comprising the lipid-based enhancing units described herein. This disclosure further relates to the use of lipid-based enhancers, lipid-based enhancing units, and conjugates, for example, in the delivery of nucleic acids and / or in the treatment or prevention of diseases.

[0067] In some implementations, conjugates containing lipid-based enhancement units exhibit higher targeted delivery efficiency compared to conjugates without lipid-based enhancement units.

[0068] In some aspects, this disclosure provides a universal delivery enhancement unit that can further improve the delivery efficiency, specificity, and knockdown activity of oligonucleotides in the presence or absence of a target ligand. The delivery enhancement unit can enhance the binding affinity of the conjugate to serum proteins, increase its nuclease resistance, and improve pharmacokinetic properties. The delivery enhancement unit can also promote the passage of oligonucleotides through capillary endothelium and into the interstitial tissue. The delivery enhancement unit can improve the binding of oligonucleotide conjugates to target receptors, thereby improving receptor-mediated endocytosis. The delivery enhancement unit can also promote intracellular transport and endosome escape of oligonucleotides, thereby increasing intracellular activity. The delivery enhancement unit can improve oligonucleotide delivery and gene knockdown activity through other mechanisms or pathways.

[0069] Lipid-based enhancers

[0070] In some aspects, this disclosure provides a lipid-based enhancer, which is a compound of formula (I), (II), (III) or (IV):

[0071] (I),

[0072] (II),

[0073] (III), or

[0074] (IV),

[0075] Or its pharmaceutically acceptable salt, wherein:

[0076] L represents the lipid portion;

[0077] B is H, C1-C6 alkyl, or nucleobase moiety;

[0078] V is -O-, -NR V -or-C(R) V )2-;

[0079] Each R V It is a C1-C6 alkyl group that is independently H or optionally substituted with one or more halogens;

[0080] X is H, halogen, or -OR X ;

[0081] R X It is H, C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 aryl), wherein the C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 Aryl) optionally by one or more R Xa Replace; or RX and R 4 Together they form C1-C6 alkylene groups;

[0082] Each R Xa It is independently a halogen, a C1-C6 alkyl or -O-(C1-C6 alkyl), wherein the C1-C6 alkyl or -O-(C1-C6 alkyl) is optionally substituted by one or more halogens;

[0083] Y is H, a C1-C6 alkyl group optionally substituted with one or more halogens, or -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 hydroxyl protecting group;

[0084] Each R Y It is independently an H or optionally a C1-C6 alkyl group substituted with one or more halogens or cyano groups;

[0085] Z is H, a C1-C6 alkyl group optionally substituted with one or more halogens, or -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 hydroxyl protecting group;

[0086] Each R ZIt is independently an H or optionally a C1-C6 alkyl group substituted with one or more halogens or cyano groups;

[0087] Alternatively, Y and Z in equation (I) or (III) together form -Si(R) L’’ )2-O-Si(R L’’ )2-, where each R L’’ It is independently an H or C1-C6 alkyl group;

[0088] Each R a It is independently a C1-C6 alkyl group, a halogen, or optionally substituted with one or more halogens; or

[0089] Two adjacent R a Forming bonds;

[0090] R 1 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens;

[0091] R 2 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens;

[0092] R 3 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens;

[0093] R 4 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens; or R 4 and R X Together they form C1-C6 alkylene groups;

[0094] Each R 5 Independently, it is a C1-C6 alkyl group, a halogen, or optionally substituted with one or more halogens; and

[0095] n is an integer ranging from approximately 0 to approximately 10.

[0096] It should be understood that, for the compounds of this disclosure (e.g., pharmaceuticals, units, and conjugates), the variables L and R... L R L’ R L’’ R La B, V, R V X, R X R Xa Y, R Y Z, R Z R a R 1 R 2 R 3 R 4 R 5n can each be selected from the groups described herein, where applicable, and this document refers to variables L and R. L R L’ R L’’ R La B, V, R V X, R X R Xa Y, R Y Z, R Z R a R 1 R 2 R 3 R 4 R 5 Any group described by either of the two groups, L and R, may be used in conjunction with the variables L and R described herein, where applicable. L R L’ R L’’ R La B, V, R V X, R X R Xa Y, R Y Z, R Z R a R 1 R 2 R 3 R 4 R 5 Any combination of groups described by one or more of the rest of n.

[0097] Variables L, R L R L’ and R La

[0098] In some embodiments, L is a fatty acid, glycerol, glycerophospholipid, sphingolipid, sterol, isopentenol, or glycolipid, any derivative thereof, or any part thereof.

[0099] In some implementations, L is a fatty acid, its derivatives, or a portion thereof.

[0100] In some implementations, L is a glyceride, its derivative, or a portion thereof.

[0101] In some implementations, L is a glycerophospholipid, its derivative, or a portion thereof.

[0102] In some implementations, L is a sphingolipid, its derivative, or a portion thereof.

[0103] In some implementations, L is a sterol, its derivative, or a portion thereof.

[0104] In some implementations, L is isopentenol, its derivatives, or a portion thereof.

[0105] In some implementations, L is a glycolipid, its derivative, or a portion thereof.

[0106] In some implementations, L is -C(=O)R L ;

[0107] R L It is C2-C 30 Hydrocarbon chain or 2 to 30-membered heterohydrocarbon chain, wherein the C2-C 30 Hydrocarbon chains or 2- to 30-membered heterohydrocarbon chains are optionally divided by one or more R L’ replace;

[0108] Each R L’ Independently, it is oxo, halogen, -OH, -O (C1-C) 12 Alkyl groups, -NH2, -NH (C1-C) 12 Alkyl), -N(C1-C 12 Alkyl)2, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. La Replace; or

[0109] Two Rs L’ Together with one or more intermediate atoms, it forms a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is optionally surrounded by one or more R La Replace; and

[0110] Each R La Independently, it is oxo, halogen, -OH, -O (C1-C) 12 Alkyl groups, -NH2, -NH (C1-C) 12 Alkyl) or -N (C1-C 12 Alkyl)2.

[0111] In some implementations, L is -C(=O)R L ;

[0112] R L It is C1-C30 Hydrocarbon chain or 2 to 30-membered heterohydrocarbon chain, wherein the C1-C 30 Hydrocarbon chains or 2- to 30-membered heterohydrocarbon chains are optionally divided by one or more R L’ replace;

[0113] Each R L’ Independently, it is oxo, halogen, -OH, -O (C1-C) 12 Alkyl groups, -NH2, -NH (C1-C) 12 Alkyl), -N(C1-C 12 Alkyl)2, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. La Replace; or

[0114] Two Rs L’ Together with one or more intermediate atoms, it forms a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is optionally surrounded by one or more R La Replace; and

[0115] Each R La Independently, it is oxo, halogen, -OH, -O (C1-C) 12 Alkyl groups, -NH2, -NH (C1-C) 12 Alkyl) or -N (C1-C 12 Alkyl)2.

[0116] In some implementation schemes, R L It is C2-C 29 Hydrocarbon chain, C2-C 28 Hydrocarbon chain, C2-C 27 Hydrocarbon chain, C2-C 26 Hydrocarbon chain, C2-C 25 Hydrocarbon chain, C2-C 24 Hydrocarbon chain, C2-C 23 Hydrocarbon chain, C2-C 22 Hydrocarbon chain, C2-C 21 Hydrocarbon chain, C2-C 20 Hydrocarbon chain, C2-C 19 Hydrocarbon chain, C2-C 18Hydrocarbon chain, C2-C 17 Hydrocarbon chain, C2-C 16 Hydrocarbon chain, C2-C 15 Hydrocarbon chain, C2-C 14 Hydrocarbon chain, C2-C 13 Hydrocarbon chain, C2-C 12 Hydrocarbon chain, C2-C 11 Hydrocarbon chain, C2-C 10 Hydrocarbon chain, C2-C9 hydrocarbon chain, C2-C8 hydrocarbon chain, C2-C7 hydrocarbon chain, or C2-C6 hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0117] In some implementation schemes, R L It is C3-C 30 Hydrocarbon chain, C4-C 30 Hydrocarbon chain, C5-C 30 Hydrocarbon chain, C6-C 30 Hydrocarbon chain, C7-C 30 Hydrocarbon chain, C8-C 30 Hydrocarbon chain, C9-C 30 Hydrocarbon chain, C 10 -C 30 Hydrocarbon chain, C 11 -C 30 Hydrocarbon chain, C 12 -C 30 Hydrocarbon chain, C 13 -C 30 Hydrocarbon chain, C 14 -C 30 Hydrocarbon chain, C 15 -C 30 Hydrocarbon chain, C 16 -C 30 Hydrocarbon chain, C 17 -C 30 Hydrocarbon chain, C 18 -C 30 Hydrocarbon chain, C 19 -C 30 Hydrocarbon chain, C 20 -C 30 Hydrocarbon chain, C 21 -C 30 Hydrocarbon chain, C 22 -C 30 Hydrocarbon chain, C 23 -C 30 Hydrocarbon chain or C 24 -C 30 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0118] In some implementation schemes, R L It is C3-C 29 Hydrocarbon chain, C4-C28 Hydrocarbon chain, C5-C 27 Hydrocarbon chain, C6-C 26 Hydrocarbon chain, C7-C 25 Hydrocarbon chain, C8-C 24 Hydrocarbon chain, C9-C 23 Hydrocarbon chain, C 10 -C 22 Hydrocarbon chain, C 11 -C 21 Hydrocarbon chain, C 12 -C 20 Hydrocarbon chain, C 13 -C 19 Hydrocarbon chain, C 14 -C 18 Hydrocarbon chain or C 15 -C 17 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0119] In some implementation schemes, R L It is C 14 -C 24 Hydrocarbon chain, C 14 -C 23 Hydrocarbon chain, C 14 -C 22 Hydrocarbon chain, C 14 -C 21 Hydrocarbon chain, C 14 -C 20 Hydrocarbon chain, C 14 -C 19 Hydrocarbon chain, C 14 -C 18 Hydrocarbon chain, C 14 -C 17 Hydrocarbon chain or C 14 -C 16 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0120] In some implementation schemes, R L It is C 15 -C 24 Hydrocarbon chain, C 16 -C 24 Hydrocarbon chain, C 17 -C 24 Hydrocarbon chain, C 18 -C 24 Hydrocarbon chain, C 19 -C 24 Hydrocarbon chain, C 20 -C 24 Hydrocarbon chain, C 21 -C 24 Hydrocarbon chain, C 22 -C24 Hydrocarbon chain or C 23 -C 24 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L replace.

[0121] In some implementation schemes, R L It is C 15 -C 23 Hydrocarbon chain, C 16 -C 22 Hydrocarbon chain, C 17 -C 21 Hydrocarbon chain or C 18 -C 20 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0122] In some implementation schemes, R L It is optionally controlled by one or more R L’ The C1 hydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The C2 hydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The replaced C3 hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The C4 hydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The C5 hydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The C6 hydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The C7 hydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The C8 hydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The C9 hydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 10 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 11 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C12 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 13 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 14 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 15 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 16 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 17 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 18 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 19 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 20 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 21 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 22 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 23 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 24 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 25 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 26 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’Replacement C 27 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 28 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 29 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement C 30 Hydrocarbon chain.

[0123] In some implementation schemes, R L It is saturated C2-C 29 Hydrocarbon chain, saturated C2-C 28 Hydrocarbon chain, saturated C2-C 27 Hydrocarbon chain, saturated C2-C 26 Hydrocarbon chain, saturated C2-C 25 Hydrocarbon chain, saturated C2-C 24 Hydrocarbon chain, saturated C2-C 23 Hydrocarbon chain, saturated C2-C 22 Hydrocarbon chain, saturated C2-C 21 Hydrocarbon chain, saturated C2-C 20 Hydrocarbon chain, saturated C2-C 19 Hydrocarbon chain, saturated C2-C 18 Hydrocarbon chain, saturated C2-C 17 Hydrocarbon chain, saturated C2-C 16 Hydrocarbon chain, saturated C2-C 15 Hydrocarbon chain, saturated C2-C 14 Hydrocarbon chain, saturated C2-C 13 Hydrocarbon chain, saturated C2-C 12 Hydrocarbon chain, saturated C2-C 11 Hydrocarbon chain, saturated C2-C 10 Hydrocarbon chain, saturated C2-C9 hydrocarbon chain, saturated C2-C8 hydrocarbon chain, saturated C2-C7 or saturated C2-C6 hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0124] In some implementation schemes, R L It is saturated C3-C 30 Hydrocarbon chain, saturated C4-C 30 Hydrocarbon chain, saturated C5-C 30 Hydrocarbon chain, saturated C6-C 30 Hydrocarbon chain, saturated C7-C 30 Hydrocarbon chain, saturated C8-C 30 Hydrocarbon chain, saturated C9-C 30 Hydrocarbon chain, saturated C 10-C 30 Hydrocarbon chain, saturated C 11 -C 30 Hydrocarbon chain, saturated C 12 -C 30 Hydrocarbon chain, saturated C 13 -C 30 Hydrocarbon chain, saturated C 14 -C 30 Hydrocarbon chain, saturated C 15 -C 30 Hydrocarbon chain, saturated C 16 -C 30 Hydrocarbon chain, saturated C 17 -C 30 Hydrocarbon chain, saturated C 18 -C 30 Hydrocarbon chain, saturated C 19 -C 30 Hydrocarbon chain, saturated C 20 -C 30 Hydrocarbon chain, saturated C 21 -C 30 Hydrocarbon chain, saturated C 22 -C 30 Hydrocarbon chain, saturated C 23 -C 30 Hydrocarbon chain or saturated C 24 -C 30 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0125] In some implementation schemes, R L It is saturated C3-C 29 Hydrocarbon chain, saturated C4-C 28 Hydrocarbon chain, saturated C5-C 27 Hydrocarbon chain, saturated C6-C 26 Hydrocarbon chain, saturated C7-C 25 Hydrocarbon chain, saturated C8-C 24 Hydrocarbon chain, saturated C9-C 23 Hydrocarbon chain, saturated C 10 -C 22 Hydrocarbon chain, saturated C 11 -C 21 Hydrocarbon chain, saturated C 12 -C 20 Hydrocarbon chain, saturated C 13 -C 19 Hydrocarbon chain, saturated C 14 -C 18 Hydrocarbon chain or saturated C 15 -C 17 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0126] In some implementation schemes, RL It is saturated C 14 -C 24 Hydrocarbon chain, saturated C 14 -C 23 Hydrocarbon chain, saturated C 14 -C 22 Hydrocarbon chain, saturated C 14 -C 21 Hydrocarbon chain, saturated C 14 -C 20 Hydrocarbon chain, saturated C 14 -C 19 Hydrocarbon chain, saturated C 14 -C 18 Hydrocarbon chain, saturated C 14 -C 17 Hydrocarbon chain or saturated C 14 -C 16 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0127] In some implementation schemes, R L It is saturated C 15 -C 24 Hydrocarbon chain, saturated C 16 -C 24 Hydrocarbon chain, saturated C 17 -C 24 Hydrocarbon chain, saturated C 18 -C 24 Hydrocarbon chain, saturated C 19 -C 24 Hydrocarbon chain, saturated C 20 -C 24 Hydrocarbon chain, saturated C 21 -C 24 Hydrocarbon chain, saturated C 22 -C 24 Hydrocarbon chain or saturated C 23 -C 24 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0128] In some implementation schemes, R L It is saturated C 15 -C 23 Hydrocarbon chain, saturated C 16 -C 22 Hydrocarbon chain, saturated C 17 -C 21 Hydrocarbon chain or saturated C 18 -C 20 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0129] In some implementation schemes, R LIt is optionally controlled by one or more R L’ The saturated C1 hydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated C2 hydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ Replacement of saturated C3 hydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Replacement of saturated C4 hydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Replacement of saturated C5 hydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Replacement of saturated C6 hydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Replacement of saturated C7 hydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated C8 hydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated C9 hydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ Replacement of saturated C 10 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 11 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 12 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 13 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 14 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 15 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 16 Hydrocarbon chain. In some implementations, R LIt is optionally controlled by one or more R L’ Replacement of saturated C 17 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 18 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 19 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 20 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 21 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 22 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 23 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 24 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 25 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 26 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 27 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 28 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 29 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Replacement of saturated C 30 Hydrocarbon chain.

[0130] In some implementation schemes, R L Unsaturated C2-C29 Hydrocarbon chain, unsaturated C2-C 28 Hydrocarbon chain, unsaturated C2-C 27 Hydrocarbon chain, unsaturated C2-C 26 Hydrocarbon chain, unsaturated C2-C 25 Hydrocarbon chain, unsaturated C2-C 24 Hydrocarbon chain, unsaturated C2-C 23 Hydrocarbon chain, unsaturated C2-C 22 Hydrocarbon chain, unsaturated C2-C 21 Hydrocarbon chain, unsaturated C2-C 20 Hydrocarbon chain, unsaturated C2-C 19 Hydrocarbon chain, unsaturated C2-C 18 Hydrocarbon chain, unsaturated C2-C 17 Hydrocarbon chain, unsaturated C2-C 16 Hydrocarbon chain, unsaturated C2-C 15 Hydrocarbon chain, unsaturated C2-C 14 Hydrocarbon chain, unsaturated C2-C 13 Hydrocarbon chain, unsaturated C2-C 12 Hydrocarbon chain, unsaturated C2-C 11 Hydrocarbon chain, unsaturated C2-C 10 Hydrocarbon chain, unsaturated C2-C9 hydrocarbon chain, unsaturated C2-C8 hydrocarbon chain, unsaturated C2-C7 hydrocarbon chain, or unsaturated C2-C6 hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0131] In some implementation schemes, R L Unsaturated C3-C 30 Hydrocarbon chain, unsaturated C4-C 30 Hydrocarbon chain, unsaturated C5-C 30 Hydrocarbon chain, unsaturated C6-C 30 Hydrocarbon chain, unsaturated C7-C 30 Hydrocarbon chain, unsaturated C8-C 30 Hydrocarbon chain, unsaturated C9-C 30 Hydrocarbon chain, unsaturated C 10 -C 30 Hydrocarbon chain, unsaturated C 11 -C 30 Hydrocarbon chain, unsaturated C 12 -C 30 Hydrocarbon chain, unsaturated C 13 -C 30 Hydrocarbon chain, unsaturated C 14 -C 30 Hydrocarbon chain, unsaturated C 15 -C 30 Hydrocarbon chain, unsaturated C 16 -C 30 Hydrocarbon chain, unsaturated C 17 -C30 Hydrocarbon chain, unsaturated C 18 -C 30 Hydrocarbon chain, unsaturated C 19 -C 30 Hydrocarbon chain, unsaturated C 20 -C 30 Hydrocarbon chain, unsaturated C 21 -C 30 Hydrocarbon chain, unsaturated C 22 -C 30 Hydrocarbon chain, unsaturated C 23 -C 30 Hydrocarbon chain or unsaturated C 24 -C 30 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0132] In some implementation schemes, R L Unsaturated C3-C 29 Hydrocarbon chain, unsaturated C4-C 28 Hydrocarbon chain, unsaturated C5-C 27 Hydrocarbon chain, unsaturated C6-C 26 Hydrocarbon chain, unsaturated C7-C 25 Hydrocarbon chain, unsaturated C8-C 24 Hydrocarbon chain, unsaturated C9-C 23 Hydrocarbon chain, unsaturated C 10 -C 22 Hydrocarbon chain, unsaturated C 11 -C 21 Hydrocarbon chain, unsaturated C 12 -C 20 Hydrocarbon chain, unsaturated C 13 -C 19 Hydrocarbon chain, unsaturated C 14 -C 18 Hydrocarbon chain or unsaturated C 15 -C 17 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0133] In some implementation schemes, R L Unsaturated C 14 -C 24 Hydrocarbon chain, unsaturated C 14 -C 23 Hydrocarbon chain, unsaturated C 14 -C 22 Hydrocarbon chain, unsaturated C 14 -C 21 Hydrocarbon chain, unsaturated C 14 -C 20 Hydrocarbon chain, unsaturated C 14 -C 19Hydrocarbon chain, unsaturated C 14 -C 18 Hydrocarbon chain, unsaturated C 14 -C 17 Hydrocarbon chain or unsaturated C 14 -C 16 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0134] In some implementation schemes, R L Unsaturated C 15 -C 24 Hydrocarbon chain, unsaturated C 16 -C 24 Hydrocarbon chain, unsaturated C 17 -C 24 Hydrocarbon chain, unsaturated C 18 -C 24 Hydrocarbon chain, unsaturated C 19 -C 24 Hydrocarbon chain, unsaturated C 20 -C 24 Hydrocarbon chain, unsaturated C 21 -C 24 Hydrocarbon chain, unsaturated C 22 -C 24 Hydrocarbon chain or unsaturated C 23 -C 24 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0135] In some implementation schemes, R L Unsaturated C 15 -C 23 Hydrocarbon chain, unsaturated C 16 -C 22 Hydrocarbon chain, unsaturated C 17 -C 21 Hydrocarbon chain or unsaturated C 18 -C 20 Hydrocarbon chain, wherein the hydrocarbon chain is optionally composed of one or more R L’ replace.

[0136] In some implementation schemes, R L It is optionally controlled by one or more R L’ Substituted unsaturated C1 hydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated C2 hydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated C3 hydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’Substituted unsaturated C4 hydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated C5 hydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated C6 hydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated C7 hydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated C8 hydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated C9 hydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 10 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 11 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 12 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 13 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 14 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 15 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 16 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 17 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 18 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 19Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 20 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 21 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 22 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 23 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 24 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 25 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 26 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 27 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 28 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 29 Hydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ Substituted unsaturated C 30 Hydrocarbon chain.

[0137] In some implementation schemes, R L It is optionally controlled by one or more R L’ Substituted hydrocarbon chains.

[0138] In some implementation schemes, R L It is optionally controlled by one or more R L’ Substituted saturated hydrocarbon chains.

[0139] In some implementation schemes, R L It is optionally controlled by one or more RL’ Substituted unsaturated hydrocarbon chains.

[0140] In some implementation schemes, R L It is a heterohydrocarbon chain of 2 to 29 members, 2 to 28 members, 2 to 27 members, 2 to 26 members, 2 to 25 members, 2 to 24 members, 2 to 23 members, 2 to 22 members, 2 to 21 members, 2 to 20 members, 2 to 19 members, 2 to 18 members, 2 to 17 members, 2 to 16 members, 2 to 15 members, 2 to 14 members, 2 to 13 members, 2 to 12 members, 2 to 11 members, 2 to 10 members, 2 to 9 members, 2 to 8 members, 2 to 7 members, or 2 to 6 members, wherein the heterohydrocarbon chain is optionally composed of one or more R... L’ replace.

[0141] In some implementation schemes, R L It is a 3- to 30-membered heterohydrocarbon chain, a 4- to 30-membered heterohydrocarbon chain, a 5- to 30-membered heterohydrocarbon chain, a 6- to 30-membered heterohydrocarbon chain, a 7- to 30-membered heterohydrocarbon chain, an 8- to 30-membered heterohydrocarbon chain, a 9- to 30-membered heterohydrocarbon chain, a 10- to 30-membered heterohydrocarbon chain, a 11- to 30-membered heterohydrocarbon chain, a 12- to 30-membered heterohydrocarbon chain, a 13- to 30-membered heterohydrocarbon chain, a 14- to 30-membered heterohydrocarbon chain, a 15- to 30-membered heterohydrocarbon chain, a 16- to 30-membered heterohydrocarbon chain, a 17- to 30-membered heterohydrocarbon chain, an 18- to 30-membered heterohydrocarbon chain, a 19- to 30-membered heterohydrocarbon chain, a 20- to 30-membered heterohydrocarbon chain, a 21- to 30-membered heterohydrocarbon chain, a 22- to 30-membered heterohydrocarbon chain, a 23- to 30-membered heterohydrocarbon chain, or a 24- to 30-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R... L’ replace.

[0142] In some implementation schemes, R L It is a heterohydrocarbon chain of 3 to 29 members, 4 to 28 members, 5 to 27 members, 6 to 26 members, 7 to 25 members, 8 to 24 members, 9 to 23 members, 10 to 22 members, 11 to 21 members, 12 to 20 members, 13 to 19 members, 14 to 18 members, or 15 to 17 members, wherein the heterohydrocarbon chain is optionally composed of one or more R... L’ replace.

[0143] In some implementation schemes, R L It is a 14- to 24-membered heterohydrocarbon chain, a 14- to 23-membered heterohydrocarbon chain, a 14- to 22-membered heterohydrocarbon chain, a 14- to 21-membered heterohydrocarbon chain, a 14- to 20-membered heterohydrocarbon chain, a 14- to 19-membered heterohydrocarbon chain, a 14- to 18-membered heterohydrocarbon chain, a 14- to 17-membered heterohydrocarbon chain, or a 14- to 16-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R... L’ replace.

[0144] In some implementation schemes, R L It is a 15- to 24-membered heterohydrocarbon chain, a 16- to 24-membered heterohydrocarbon chain, a 17- to 24-membered heterohydrocarbon chain, an 18- to 24-membered heterohydrocarbon chain, a 19- to 24-membered heterohydrocarbon chain, a 20- to 24-membered heterohydrocarbon chain, a 21- to 24-membered heterohydrocarbon chain, a 22- to 24-membered heterohydrocarbon chain, or a 23- to 24-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R... L’ replace.

[0145] In some implementation schemes, R L It is a 15- to 23-membered heterohydrocarbon chain, a 16- to 22-membered heterohydrocarbon chain, a 17- to 21-membered heterohydrocarbon chain, or an 18- to 20-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R... L’ replace.

[0146] In some implementation schemes, R L It is optionally controlled by one or more R L’ The substituted binary heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted 3-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted 4-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The replaced 5-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The substituted 6-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The substituted 7-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The substituted 8-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The substituted 9-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The substituted 10-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The substituted 11-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted 12-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted 13-membered heterohydrocarbon chain. In some embodiments, RL It is optionally controlled by one or more R L’ The substituted 14-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The 15-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The substituted 16-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The 17-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted 18-membered heterohydrocarbon chain. In some implementations, R L It is optionally controlled by one or more R L’ The 19-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The 20-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The substituted 21-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The 22-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The 23-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The 24-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The 25-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The 26-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The 27-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The 28-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The 29-membered heterohydrocarbon chain is replaced. In some implementations, R L It is optionally controlled by one or more R L’ The 30-membered heterohydrocarbon chain that is replaced.

[0147] In some implementation schemes, RL These are saturated heterohydrocarbon chains with 2 to 29 members, saturated heterohydrocarbon chains with 2 to 28 members, saturated heterohydrocarbon chains with 2 to 27 members, saturated heterohydrocarbon chains with 2 to 26 members, saturated heterohydrocarbon chains with 2 to 25 members, saturated heterohydrocarbon chains with 2 to 24 members, saturated heterohydrocarbon chains with 2 to 23 members, saturated heterohydrocarbon chains with 2 to 22 members, saturated heterohydrocarbon chains with 2 to 21 members, saturated heterohydrocarbon chains with 2 to 20 members, saturated heterohydrocarbon chains with 2 to 19 members, saturated heterohydrocarbon chains with 2 to 18 members, and saturated heterohydrocarbon chains with 2 to 1... 7-membered heterohydrocarbon chains, saturated 2- to 16-membered heterohydrocarbon chains, saturated 2- to 15-membered heterohydrocarbon chains, saturated 2- to 14-membered heterohydrocarbon chains, saturated 2- to 13-membered heterohydrocarbon chains, saturated 2- to 12-membered heterohydrocarbon chains, saturated 2- to 11-membered heterohydrocarbon chains, saturated 2- to 10-membered heterohydrocarbon chains, saturated 2- to 9-membered heterohydrocarbon chains, saturated 2- to 8-membered heterohydrocarbon chains, saturated 2- to 7-membered heterohydrocarbon chains, or saturated 2- to 6-membered heterohydrocarbon chains, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0148] In some implementation schemes, R L These are saturated heterohydrocarbon chains of 3 to 30 members, saturated heterohydrocarbon chains of 4 to 30 members, saturated heterohydrocarbon chains of 5 to 30 members, saturated heterohydrocarbon chains of 6 to 30 members, saturated heterohydrocarbon chains of 7 to 30 members, saturated heterohydrocarbon chains of 8 to 30 members, saturated heterohydrocarbon chains of 9 to 30 members, saturated heterohydrocarbon chains of 10 to 30 members, saturated heterohydrocarbon chains of 11 to 30 members, saturated heterohydrocarbon chains of 12 to 30 members, saturated heterohydrocarbon chains of 13 to 30 members, and saturated heterohydrocarbon chains of 14 to 30 members. Saturated heterohydrocarbon chains of 15 to 30 membered members, saturated heterohydrocarbon chains of 16 to 30 membered members, saturated heterohydrocarbon chains of 17 to 30 membered members, saturated heterohydrocarbon chains of 18 to 30 membered members, saturated heterohydrocarbon chains of 19 to 30 membered members, saturated heterohydrocarbon chains of 20 to 30 membered members, saturated heterohydrocarbon chains of 21 to 30 membered members, saturated heterohydrocarbon chains of 22 to 30 membered members, saturated heterohydrocarbon chains of 23 to 30 membered members, or saturated heterohydrocarbon chains of 24 to 30 membered members, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0149] In some implementation schemes, R L It is a saturated heterohydrocarbon chain of 3 to 29 members, saturated heterohydrocarbon chains of 4 to 28 members, saturated heterohydrocarbon chains of 5 to 27 members, saturated heterohydrocarbon chains of 6 to 26 members, saturated heterohydrocarbon chains of 7 to 25 members, saturated heterohydrocarbon chains of 8 to 24 members, saturated heterohydrocarbon chains of 9 to 23 members, saturated heterohydrocarbon chains of 10 to 22 members, saturated heterohydrocarbon chains of 11 to 21 members, saturated heterohydrocarbon chains of 12 to 20 members, saturated heterohydrocarbon chains of 13 to 19 members, saturated heterohydrocarbon chains of 14 to 18 members, or saturated heterohydrocarbon chains of 15 to 17 members, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0150] In some implementation schemes, R LIt is a saturated 14- to 24-membered heterohydrocarbon chain, a saturated 14- to 23-membered heterohydrocarbon chain, a saturated 14- to 22-membered heterohydrocarbon chain, a saturated 14- to 21-membered heterohydrocarbon chain, a saturated 14- to 20-membered heterohydrocarbon chain, a saturated 14- to 19-membered heterohydrocarbon chain, a saturated 14- to 18-membered heterohydrocarbon chain, a saturated 14- to 17-membered heterohydrocarbon chain, or a 14- to 16-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0151] In some implementation schemes, R L It is a saturated 15- to 24-membered heterohydrocarbon chain, a saturated 16- to 24-membered heterohydrocarbon chain, a saturated 17- to 24-membered heterohydrocarbon chain, a saturated 18- to 24-membered heterohydrocarbon chain, a saturated 19- to 24-membered heterohydrocarbon chain, a saturated 20- to 24-membered heterohydrocarbon chain, a saturated 21- to 24-membered heterohydrocarbon chain, a saturated 22- to 24-membered heterohydrocarbon chain, or a 23- to 24-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0152] In some implementation schemes, R L It is a saturated 15- to 23-membered heterohydrocarbon chain, a saturated 16- to 22-membered heterohydrocarbon chain, a saturated 17- to 21-membered heterohydrocarbon chain, or a saturated 18- to 20-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0153] In some implementation schemes, R L It is optionally controlled by one or more R L’ The substituted saturated binary heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated ternary heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated four-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 5-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated six-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated 7-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 8-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 9-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’The saturated 10-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated 11-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated 12-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated 13-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated 14-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 15-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated 16-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated 17-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted saturated 18-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 19-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 20-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 21-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 22-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 23-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 24-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 25-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 26-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’The saturated 27-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 28-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ The saturated 29-membered heterohydrocarbon chain is replaced. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted saturated 30-membered heterohydrocarbon chain.

[0154] In some implementation schemes, R L These are unsaturated 2-29 membered hydrocarbon chains, unsaturated 2-28 membered hydrocarbon chains, unsaturated 2-27 membered hydrocarbon chains, unsaturated 2-26 membered hydrocarbon chains, unsaturated 2-25 membered hydrocarbon chains, unsaturated 2-24 membered hydrocarbon chains, unsaturated 2-23 membered hydrocarbon chains, unsaturated 2-22 membered hydrocarbon chains, unsaturated 2-21 membered hydrocarbon chains, unsaturated 2-20 membered hydrocarbon chains, unsaturated 2-19 membered hydrocarbon chains, unsaturated 2-18 membered hydrocarbon chains, unsaturated 2 to 17-membered heterohydrocarbon chain, unsaturated 2- to 16-membered heterohydrocarbon chain, unsaturated 2- to 15-membered heterohydrocarbon chain, unsaturated 2- to 14-membered heterohydrocarbon chain, unsaturated 2- to 13-membered heterohydrocarbon chain, unsaturated 2- to 12-membered heterohydrocarbon chain, unsaturated 2- to 11-membered heterohydrocarbon chain, unsaturated 2- to 10-membered heterohydrocarbon chain, unsaturated 2- to 9-membered heterohydrocarbon chain, unsaturated 2- to 8-membered heterohydrocarbon chain, unsaturated 2- to 7-membered heterohydrocarbon chain, or unsaturated 2- to 6-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0155] In some implementation schemes, R L These are unsaturated 3- to 30-membered hydrocarbon chains, unsaturated 4- to 30-membered hydrocarbon chains, unsaturated 5- to 30-membered hydrocarbon chains, unsaturated 6- to 30-membered hydrocarbon chains, unsaturated 7- to 30-membered hydrocarbon chains, unsaturated 8- to 30-membered hydrocarbon chains, unsaturated 9- to 30-membered hydrocarbon chains, unsaturated 10- to 30-membered hydrocarbon chains, unsaturated 11- to 30-membered hydrocarbon chains, unsaturated 12- to 30-membered hydrocarbon chains, unsaturated 13- to 30-membered hydrocarbon chains, and unsaturated 14- to 30-membered hydrocarbon chains. Unsaturated heterohydrocarbon chains of 15 to 30 membered members, unsaturated heterohydrocarbon chains of 16 to 30 membered members, unsaturated heterohydrocarbon chains of 17 to 30 membered members, unsaturated heterohydrocarbon chains of 18 to 30 membered members, unsaturated heterohydrocarbon chains of 19 to 30 membered members, unsaturated heterohydrocarbon chains of 20 to 30 membered members, unsaturated heterohydrocarbon chains of 21 to 30 membered members, unsaturated heterohydrocarbon chains of 22 to 30 membered members, unsaturated heterohydrocarbon chains of 23 to 30 membered members, or unsaturated heterohydrocarbon chains of 24 to 30 membered members, wherein the heterohydrocarbon chain is optionally composed of one or more R... L’ replace.

[0156] In some implementation schemes, R LIt is an unsaturated 3- to 29-membered heterohydrocarbon chain, an unsaturated 4- to 28-membered heterohydrocarbon chain, an unsaturated 5- to 27-membered heterohydrocarbon chain, an unsaturated 6- to 26-membered heterohydrocarbon chain, an unsaturated 7- to 25-membered heterohydrocarbon chain, an unsaturated 8- to 24-membered heterohydrocarbon chain, an unsaturated 9- to 23-membered heterohydrocarbon chain, an unsaturated 10- to 22-membered heterohydrocarbon chain, an unsaturated 11- to 21-membered heterohydrocarbon chain, an unsaturated 12- to 20-membered heterohydrocarbon chain, an unsaturated 13- to 19-membered heterohydrocarbon chain, an unsaturated 14- to 18-membered heterohydrocarbon chain, or an unsaturated 15- to 17-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0157] In some implementation schemes, R L It is an unsaturated 14- to 24-membered heterohydrocarbon chain, an unsaturated 14- to 23-membered heterohydrocarbon chain, an unsaturated 14- to 22-membered heterohydrocarbon chain, an unsaturated 14- to 21-membered heterohydrocarbon chain, an unsaturated 14- to 20-membered heterohydrocarbon chain, an unsaturated 14- to 19-membered heterohydrocarbon chain, an unsaturated 14- to 18-membered heterohydrocarbon chain, an unsaturated 14- to 17-membered heterohydrocarbon chain, or a 14- to 16-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0158] In some implementation schemes, R L It is an unsaturated 15- to 24-membered heterohydrocarbon chain, an unsaturated 16- to 24-membered heterohydrocarbon chain, an unsaturated 17- to 24-membered heterohydrocarbon chain, an unsaturated 18- to 24-membered heterohydrocarbon chain, an unsaturated 19- to 24-membered heterohydrocarbon chain, an unsaturated 20- to 24-membered heterohydrocarbon chain, an unsaturated 21- to 24-membered heterohydrocarbon chain, an unsaturated 22- to 24-membered heterohydrocarbon chain, or a 23- to 24-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0159] In some implementation schemes, R L It is an unsaturated 15- to 23-membered heterohydrocarbon chain, an unsaturated 16- to 22-membered heterohydrocarbon chain, an unsaturated 17- to 21-membered heterohydrocarbon chain, or an unsaturated 18- to 20-membered heterohydrocarbon chain, wherein the heterohydrocarbon chain is optionally composed of one or more R L’ replace.

[0160] In some implementation schemes, R L It is optionally controlled by one or more R L’ Substituted unsaturated binary heterohydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 3-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated four-membered heterohydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 5-membered heterohydrocarbon chain. In some embodiments, RL It is optionally controlled by one or more R L’ Substituted unsaturated 6-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 7-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 8-membered heterohydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 9-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 10-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 11-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 12-membered heterohydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 13-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 14-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 15-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 16-membered heterohydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 17-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 18-membered heterohydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 19-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 20-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 21-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’Substituted unsaturated 22-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 23-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 24-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted unsaturated 25-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted unsaturated 26-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted unsaturated 27-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 28-membered heterohydrocarbon chains. In some embodiments, R L It is optionally controlled by one or more R L’ The substituted unsaturated 29-membered heterohydrocarbon chain. In some embodiments, R L It is optionally controlled by one or more R L’ Substituted unsaturated 30-membered heterohydrocarbon chains.

[0161] In some implementation schemes, R L It is optionally controlled by one or more R L’ Substituted heterohydrocarbon chains.

[0162] In some implementation schemes, R L It is a heterohydrocarbon chain having at least one O, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a heterohydrocarbon chain having at least one N, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a heterohydrocarbon chain having at least one S, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a heterohydrocarbon chain having at least one P, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a heterohydrocarbon chain having at least one Se, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ replace.

[0163] In some implementation schemes, R LIt is a heterohydrocarbon chain having one O, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a heterohydrocarbon chain having one N, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a heterohydrocarbon chain having one S, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a heterohydrocarbon chain having a P, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a heterohydrocarbon chain having one Se, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ replace.

[0164] In some implementation schemes, R L It is optionally controlled by one or more R L’ Substituted saturated heterohydrocarbon chains.

[0165] In some implementation schemes, R L It is a saturated heterohydrocarbon chain having at least one O, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a saturated heterohydrocarbon chain having at least one N, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a saturated heterohydrocarbon chain having at least one S, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a saturated heterohydrocarbon chain having at least one P, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a saturated heterohydrocarbon chain having at least one Se, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ replace.

[0166] In some implementation schemes, R L It is a saturated heterohydrocarbon chain having one O, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a saturated heterohydrocarbon chain with one N, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a saturated heterohydrocarbon chain having one S, wherein the heterohydrocarbon chain is optionally separated by one or more R L’Replacement. In some implementations, R L It is a saturated heterohydrocarbon chain having a P, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is a saturated heterohydrocarbon chain having one Se, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ replace.

[0167] In some implementation schemes, R L It is optionally controlled by one or more R L’ Substituted unsaturated heterohydrocarbon chains.

[0168] In some implementation schemes, R L It is an unsaturated heterohydrocarbon chain having at least one O, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is an unsaturated heterohydrocarbon chain having at least one N, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is an unsaturated heterohydrocarbon chain having at least one S, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is an unsaturated heterohydrocarbon chain having at least one P, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is an unsaturated heterohydrocarbon chain having at least one Se, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ replace.

[0169] In some implementation schemes, R L It is an unsaturated heterohydrocarbon chain having one O, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is an unsaturated heterohydrocarbon chain having one N, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is an unsaturated heterohydrocarbon chain having one S, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is an unsaturated heterohydrocarbon chain having a P, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ Replacement. In some implementations, R L It is an unsaturated heterohydrocarbon chain having one Se, wherein the heterohydrocarbon chain is optionally separated by one or more R L’ replace.

[0170] In some implementations, at least one R L’ It is oxygenation.

[0171] In some implementations, at least one R L’ It is a halogen (e.g., F, Cl or Br).

[0172] In some implementations, at least one R L’ It is -OH or optionally surrounded by one or more R La Substituted -O(C1-C) 12 alkyl).

[0173] In some implementations, at least one R L’ It is -OH.

[0174] In some implementations, at least one R L’ It is optionally controlled by one or more R La Substituted -O(C1-C) 12 alkyl).

[0175] In some implementations, at least one R L’ It is NH2, -NH(Cl-C) 12 Alkyl) or -N (C1-C 12 alkyl)2, wherein the -NH(C1-C 12 Alkyl) or -N (C1-C 12 Alkyl)2 optionally surrounded by one or more R La replace.

[0176] In some implementations, at least one R L’ It is -NH2.

[0177] In some implementations, at least one R L’ It is optionally controlled by one or more R La Substituted -NH(C1-C) 12 alkyl).

[0178] In some implementations, at least one R L’ It is optionally controlled by one or more R La Substituted -N(C1-C) 12 Alkyl)2.

[0179] In some implementations, at least one R L’ It is optionally controlled by one or more R La Replacement C1-C 12 alkyl.

[0180] In some implementations, at least one R L’ It is optionally controlled by one or more R LaReplacement C2-C 12 Alkenyl group.

[0181] In some implementations, at least one R L’ It is optionally controlled by one or more R La Replacement C2-C 12 Alkyne group.

[0182] In some implementations, at least one R L’ It is optionally controlled by one or more R La Substituted C3-C8 cycloalkyl groups.

[0183] In some implementations, at least one R L’ It is optionally controlled by one or more R La Substituted 3 to 8-membered heterocyclic alkyl groups.

[0184] In some implementations, at least one R L’ It is optionally controlled by one or more R La Replacement C6-C 10 Aryl.

[0185] In some implementations, at least one R L’ It is optionally controlled by one or more R La Replaced 5 to 10 heteroaryl groups.

[0186] In some implementations, two R L’ Together with one or more intermediate atoms, they form optionally one or more R La Substituted C3-C8 cycloalkyl groups.

[0187] In some implementations, two R L’ Together with one or more intermediate atoms, they form optionally one or more R La Substituted 3 to 8-membered heterocyclic alkyl groups.

[0188] In some implementations, at least one R La It is oxygenation.

[0189] In some implementations, at least one R La It is a halogen (e.g., F, Cl or Br).

[0190] In some implementations, at least one R La It is -OH or -O(Cl-C) 12 alkyl).

[0191] In some implementations, at least one R La It is -OH.

[0192] In some implementations, at least one RLa It is -O(C1-C 12 alkyl).

[0193] In some implementations, at least one R La It is -NH2, -NH(Cl-C 12 Alkyl) or -N (C1-C 12 Alkyl)2.

[0194] In some implementations, at least one R La It is -NH2.

[0195] In some implementations, at least one R La It is -NH(C1-C 12 alkyl).

[0196] In some implementations, at least one R La It is -N(C1-C 12 Alkyl)2.

[0197] In some implementations, L has formula (A),

[0198]

[0199] (A)

[0200] in:

[0201] E is -NR''- or -O-;

[0202] R'' is H or a C1-C6 alkyl group optionally substituted with one or more halogens;

[0203] m is 0 or 1;

[0204] R' is C1-C 30 Alkyl, C2-C 30 alkenyl or C2-C 30 Alkyne group, wherein the C1-C 30 Alkyl, C2-C 30 alkenyl or C2-C 30 The alkynyl group is optionally surrounded by one or more R' a replace;

[0205] Each R' a Independently, it is oxo, halogen, -OH, -O (C1-C) 12 Alkyl groups, -NH2, -NH (C1-C) 12 Alkyl), -N(C1-C 12 alkyl)2, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C6-C 10 Aryl or 5 to 10-membered heteroaryl;

[0206] and This indicates the attachment point to the lipid-based enhancer or the rest of the lipid-based enhancer unit.

[0207] In some implementations, E is -NR''-.

[0208] In some implementations, E is -O-.

[0209] In some implementations, R'' is H.

[0210] In some embodiments, R'' is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0211] In some embodiments, R'' is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0212] In some embodiments, R'' is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0213] In some implementations, m is 0.

[0214] In some implementations, m is 1.

[0215] In some implementations, R' is optionally defined by one or more R's. a Replacement C1-C 30 alkyl.

[0216] In some implementations, R' is C1-C 30 alkyl.

[0217] In some implementations, R' is a combination of one or more R's. a Replacement C1-C 30 alkyl.

[0218] In some implementations, R' is optionally defined by one or more R's. a Replacement C2-C 30 Alkenyl group.

[0219] In some implementations, R' is C2-C 30 Alkenyl group.

[0220] In some implementations, R' is a combination of one or more R's. aReplacement C2-C 30 Alkenyl group.

[0221] In some implementations, R' is optionally defined by one or more R's. a Replacement C2-C 30 Alkyne group.

[0222] In some implementations, R' is C2-C 30 Alkyne group.

[0223] In some implementations, R' is a combination of one or more R's. a Replacement C2-C 30 Alkyne group.

[0224] In some implementations, at least one R' a It is oxygenation on its own.

[0225] In some implementations, each R' a It is oxygenation.

[0226] In some implementations, at least one R' a It is a halogen on its own.

[0227] In some implementations, each R' a It is halogen.

[0228] In some implementations, at least one R' a It is -OH on its own.

[0229] In some implementations, each R' a It is -OH.

[0230] In some implementations, at least one R' a Independently is -O(C1-C) 12 alkyl).

[0231] In some implementations, each R' a It is -O(C1-C 12 alkyl).

[0232] In some implementations, at least one R' a It is -NH2 independently.

[0233] In some implementations, each R' a It is -NH2.

[0234] In some implementations, at least one R' a Independently is -NH(C1-C) 12 alkyl).

[0235] In some implementations, each R' a It is -NH(C1-C 12 alkyl).

[0236] In some implementations, at least one R' a Independently is -N(C1-C 12 Alkyl)2.

[0237] In some implementations, each R' a It is -N(C1-C 12 Alkyl)2.

[0238] In some implementations, at least one R' a It is independently a C3-C8 cycloalkyl group.

[0239] In some implementations, each R' a It is a C3-C8 cycloalkyl group.

[0240] In some implementations, at least one R' a It is independently a 3- to 8-membered heterocyclic alkyl group.

[0241] In some implementations, each R' a It is a 3- to 8-membered heterocyclic alkyl group.

[0242] In some implementations, at least one R' a Independently, it is C6-C 10 Aryl.

[0243] In some implementations, each R' a It is C6-C 10 Aryl.

[0244] In some implementations, at least one R' a Independently, it consists of 5 to 10 heteroaryl groups.

[0245] In some implementations, each R' a It consists of 5 to 10 heteroaryl compounds.

[0246] In some implementations, R' is C 15 H 31 .

[0247] In some implementations, R' is optionally defined by one or more R's. a Replacement C1-C 30 alkyl.

[0248] In some implementations, R' is C5-C 25 Alkyl, C 10-20 Alkyl, C1-C 25Alkyl, C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl, C5-C 30 Alkyl, C 10 -C 30 Alkyl, C 15 -C 30 Alkyl or C 20 -C 30 Alkyl group, wherein the C5-C 25 Alkyl, C 10-20 Alkyl, C1-C 25 Alkyl, C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Alkyl, C5-C 30 Alkyl, C 10 -C 30 Alkyl, C 15 -C 30 Alkyl or C 20 -C 30 Alkyl groups are optionally surrounded by one or more R' a replace.

[0249] In some implementations, R' is C 15 -C 23 Alkyl, C 16 -C 22 Alkyl, C 17 -C 21 Alkyl, C 15 -C 22 Alkyl, C 15 -C 21 Alkyl, C 15 -C 20 Alkyl, C 15 -C 19 Alkyl, C 16 -C 23 Alkyl, C 17 -C 23 Alkyl, C 18 -C 23 Alkyl or C 19 -C 23 Alkyl, wherein the C 15 -C 23 Alkyl, C 16 -C 22 Alkyl, C 17 -C 21 Alkyl, C 15 -C 22 Alkyl, C 15 -C 21 Alkyl, C15 -C 20 Alkyl, C 15 -C 19 Alkyl, C 16 -C 23 Alkyl, C 17 -C 23 Alkyl, C 18 -C 23 Alkyl or C 19 -C 23 Alkyl groups are optionally surrounded by one or more R' a replace.

[0250] In some implementations, R' is C 13 -C 23 Alkyl, C 14 -C 22 Alkyl, C 15 -C 21 Alkyl, C 13 -C 22 Alkyl, C 13 -C 21 Alkyl, C 14 -C 23 Alkyl or C 15 -C 23 Alkyl, wherein the C 13 -C 23 Alkyl, C 14 -C 22 Alkyl, C 15 -C 21 Alkyl, C 13 -C 22 Alkyl, C 13 -C 21 Alkyl, C 14 -C 23 Alkyl or C 15 -C 23 Alkyl groups are optionally surrounded by one or more R' a replace.

[0251] In some implementations, R' is optionally defined by one or more R's. a Replacement C 15 -C 21 alkyl.

[0252] In some implementations, R' is selected from C 15 Alkyl, C 16 alkyl 、 C 17 alkyl 、 C 18 alkyl 、 C 19 alkyl 、 C20 Alkyl and C 21 Alkyl, wherein the C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl, C 19 Alkyl, C 20 Alkyl or C 21 Alkyl groups are optionally surrounded by one or more R' a replace.

[0253] In some implementations, R' is selected from C 15 Alkyl, C 17 Alkyl and C 21 Alkyl, wherein the C 15 Alkyl, C 17 Alkyl or C 21 Alkyl groups are optionally surrounded by one or more R' a replace.

[0254] In some implementations, R' is optionally defined by one or more R's. a Substituted C1 alkyl group. In some embodiments, R' is optionally replaced by one or more R's. a Substituted C2 alkyl group. In some embodiments, R' is optionally replaced by one or more R's. a Substituted C3 alkyl group. In some embodiments, R' is optionally replaced by one or more R' a Substituted C4 alkyl group. In some embodiments, R' is optionally replaced by one or more R' a Substituted C5 alkyl group. In some embodiments, R' is optionally replaced by one or more R' a Substituted C6 alkyl group. In some embodiments, R' is optionally replaced by one or more R' a Substituted C7 alkyl group. In some embodiments, R' is optionally replaced by one or more R' a Substituted C8 alkyl group. In some embodiments, R' is optionally replaced by one or more R' a Substituted C9 alkyl group. In some embodiments, R' is optionally replaced by one or more R' a Replacement C 10 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 11 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 12 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 13Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 14 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 15 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 16 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 17 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 18 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 19 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 20 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 21 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 22 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 23 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 24 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 25 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 26 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 27 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 28 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 29 Alkyl group. In some embodiments, R' is optionally composed of one or more R's. a Replacement C 30 alkyl.

[0255] In some implementation schemes,

[0256] C1-C 30 Alkyl, C 15 Alkyl, C 17 Alkyl or C 21 Alkyl groups are optionally substituted (e.g., optionally substituted with one or more R groups). L’ replace).

[0257] In some implementation schemes, R L It is C 15 H 31 C1-C 30 Alkyl, C 15 Alkyl, C 17 Alkyl, C 21 Alkyl or -NH (C1-C) 30 Alkyl), wherein C 15 Alkyl, C 17 Alkyl, C 21 Alkyl, C1-C 30 Alkyl or -NH (C1-C) 30 Alkyl groups are optionally substituted (e.g., optionally substituted with one or more R groups). L’ replace).

[0258] In some implementation schemes, R L It is C 13 -C 23 Alkyl, C 14 -C 22 Alkyl, C 15 -C 21 Alkyl, C 13 -C 22 Alkyl, C 13 -C 21 Alkyl, C 14 -C 23 Alkyl or C 15 -C 23 Alkyl, wherein C 13 -C 23 Alkyl, C 14 -C 22 Alkyl, C 15 -C 21 Alkyl, C 13 -C 22 Alkyl, C 13 -C 21 Alkyl, C 14 -C 23 Alkyl or C 15 -C 23 Alkyl groups are optionally substituted (e.g., optionally substituted with one or more R groups). L’ replace).

[0259] In some implementation schemes, R L C is an optional substitute 15 -C 21 Alkyl groups (e.g., optionally composed of one or more R groups) L’ replace).

[0260] In some implementation schemes, R L Selected from C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl, C 19 Alkyl, C 20 Alkyl and C 21 Alkyl, wherein the C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl, C 19 Alkyl, C 20 Alkyl or C 21 Alkyl groups are optionally substituted (e.g., optionally substituted with one or more R groups). L’ replace).

[0261] In some implementation schemes, R L Selected from C 15 Alkyl, C 17 Alkyl and C 21 Alkyl, wherein the C 15 Alkyl, C 17 Alkyl or C 21 Alkyl groups are optionally substituted (e.g., optionally substituted with one or more R groups). L’ replace).

[0262] In some implementation schemes, R L It is C 15 -C 23 Alkyl, C 16 -C 22 Alkyl, C 17 -C 21 Alkyl, C 15 -C 22 Alkyl, C 15 -C 21 Alkyl, C 15 -C 20 Alkyl, C 15 -C 19 Alkyl, C 16 -C 23 Alkyl, C 17 -C 23 Alkyl, C 18 -C 23Alkyl or C 19 -C 23 Alkyl, wherein the C 15 -C 23 Alkyl, C 16 -C 22 Alkyl, C 17 -C 21 Alkyl, C 15 -C 22 Alkyl, C 15 -C 21 Alkyl, C 15 -C 20 Alkyl, C 15 -C 19 Alkyl, C 16 -C 23 Alkyl, C 17 -C 23 Alkyl, C 18 -C 23 Alkyl or C 19 -C 23 Alkyl groups are optionally substituted (e.g., optionally substituted with one or more R groups). L’ replace).

[0263] In some implementation schemes, R L C is an optional substitute 15 Alkyl groups (e.g., optionally composed of one or more R groups) L’ (Replace). In some implementations, R L C is an optional substitute 16 Alkyl groups (e.g., optionally composed of one or more R groups) L’ (Replace). In some implementations, R L C is an optional substitute 17 Alkyl groups (e.g., optionally composed of one or more R groups) L’ (Replace). In some implementations, R L C is an optional substitute 18 Alkyl groups (e.g., optionally composed of one or more R groups) L’ (Replace). In some implementations, R L C is an optional substitute 19 Alkyl groups (e.g., optionally composed of one or more R groups) L’ (Replace). In some implementations, R L C is an optional substitute 20 Alkyl groups (e.g., optionally composed of one or more R groups) L’ (Replace). In some implementations, R L C is an optional substitute 21 Alkyl groups (e.g., optionally composed of one or more R groups) L’ (Replace). In some implementations, RL C is an optional substitute 22 Alkyl groups (e.g., optionally composed of one or more R groups) L’ (Replace). In some implementations, R L C is an optional substitute 23 Alkyl groups (e.g., optionally composed of one or more R groups) L’ replace).

[0264] Variable B

[0265] In some implementations, B is H.

[0266] In some embodiments, B is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0267] In some implementations, B is methyl, ethyl, or propyl.

[0268] In some implementations, B is the nucleobase moiety.

[0269] As used herein, the term "nucleobase moiety" refers to, for example, a nucleobase attached to the remainder of a compound via an atom or functional group of the nucleobase.

[0270] In some implementations, the nucleobase moiety is adenine (A), cytosine (C), guanine (G), thymine (T), or uracil (U).

[0271] In some implementations, the nucleobase moiety is , , or ,in This indicates the attachment point with the rest of the lipid-based enhancer.

[0272] In some implementations, the nucleobase portion is a modified nucleobase.

[0273] In some implementations, the modified nucleobase is 5-methylcytosine.

[0274] In some implementations, the modified nucleobase is hypoxanthine, xanthine, or 7-methylguanine.

[0275] In some implementations, the modified nucleobase is 5,6-dihydrouracil, 5-methylcytosine, or 5-hydroxymethylcytosine.

[0276] In some implementations, the nucleobase portion is an artificial nucleobase.

[0277] In some implementations, the artificial nucleobase is isoguanine, isocytosine, 2-amino-6-(2-thienyl)purine, or pyrrole-2-carboxaldehyde.

[0278] Variables V and R V

[0279] In some implementations, V is -O-.

[0280] In some implementations, V is -NR V -

[0281] In some implementations, V is -NH-.

[0282] In some implementations, V is -C(R) V )2-.

[0283] In some implementations, V is -CH2-.

[0284] In some implementations, at least one R V It is H.

[0285] In some implementations, each R V It is H.

[0286] In some implementations, at least one R V It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0287] In some implementations, at least one R V It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0288] In some implementations, at least one R V It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0289] In some implementations, each R V It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0290] In some implementations, each R VIt is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0291] In some implementations, each R V It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0292] Variables X, R X R Xa R L’’ Y, R Y Z, R Z and R L

[0293] In some implementations, X is H.

[0294] In some implementations, X is a halogen (e.g., F, Cl, Br, or I).

[0295] In some implementations, X is F or Cl.

[0296] In some implementations, X is F.

[0297] In some implementations, X is -OR X .

[0298] In some implementations, X is -OH.

[0299] In some implementations, X is -O-(C1-C) 12 alkyl).

[0300] In some embodiments, X is -O-(C1-C6 alkyl) (e.g., where the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0301] In some implementations, X is -OCH3.

[0302] In some embodiments, X is -O-(C1-C6 alkyl)-O-(C1-C6 alkyl) (e.g., where the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0303] In some implementations, X is -OCH2CH2OCH3.

[0304] In some implementations, X is optionally represented by one or more R XaSubstituted -O-(C1-C6 alkyl)-(C6-C 10 Aryl).

[0305] In some embodiments, X is -O-(C1-C6 alkyl)-(C6-C 10 Aryl).

[0306] In some implementation schemes, X is .

[0307] In some implementations, X is optionally represented by one or more R Xa Replacement .

[0308] In some implementations, X is optionally replaced by one or more halogens. .

[0309] In some embodiments, X is optionally substituted with one or more C1-C6 alkyl groups or -O-(C1-C6 alkyl groups). The C1-C6 alkyl or -O-(C1-C6 alkyl) is optionally substituted with one or more halogens.

[0310] In some implementation schemes, R X It is H.

[0311] In some implementation schemes, R X It is optionally controlled by one or more R Xa Replacement C1-C 12 alkyl.

[0312] In some implementation schemes, R X It is C1-C 12 alkyl.

[0313] In some implementation schemes, R X It is optionally controlled by one or more R Xa Substituted C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0314] In some implementation schemes, R X It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or an -O-(C1-C6 alkyl group (e.g., wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens.

[0315] In some implementation schemes, R X It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0316] In some implementation schemes, R X It is methyl, ethyl, or propyl.

[0317] In some implementation schemes, R X It is a methyl group.

[0318] In some implementation schemes, R X It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0319] In some implementation schemes, R X It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more -O-(C1-C6 alkyl) (e.g., wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), wherein the -O-(C1-C6 alkyl) is optionally substituted with one or more halogens.

[0320] In some implementation schemes, R X It is optionally controlled by one or more R Xa Substituted -(C1-C6 alkyl)-(C6-C 10 Aryl).

[0321] In some implementation schemes, R X It is a -(C1-C6alkyl)-(C6-C) group optionally substituted with one or more halogens (e.g., F, Cl, Br, or I), C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), or -O-(C1-C6alkyl) (e.g., wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl). 10 Aryl), wherein the C1-C6 alkyl or -O-(C1-C6 alkyl) is optionally substituted with one or more halogens.

[0322] In some implementation schemes, R X It is -(C1-C6 alkyl)-(C6-C 10 Aryl).

[0323] In some implementation schemes, R X and R4 Together they form C1-C6 alkylene compounds (e.g., methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0324] In some implementation schemes, R X and R 4 Together they form methylene, ethylene, or propylene.

[0325] In some implementation schemes, R X and R 4 Together they form a methylene group.

[0326] In some implementation schemes, R X and R 4 Together they form ethylene.

[0327] In some implementation schemes, R X and R 4 Together they form propylidene.

[0328] In some implementations, Y is H.

[0329] In some embodiments, Y is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0330] In some embodiments, Y is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0331] In some implementations, Y is methyl, ethyl, or propyl.

[0332] In some implementations, Y is -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 or -P(=S)(SR Y )2.

[0333] In some implementations, Y is -P(R) Y )2.

[0334] In some implementations, Y is -PH2.

[0335] In some implementations, Y is -P(OR) Y )(N(R Y )2).

[0336] In some implementations, Y is -P(OH)(NH2).

[0337] In some embodiments, Y is -P(O(C1-C6 alkyl))(N(C1-C6 alkyl)2), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0338] In some implementations, Y is -P(=O)(OR) Y )R Y .

[0339] In some embodiments, Y is -P(=O)(OH)(C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0340] In some implementations, Y is -P(=S)(OR Y )R Y .

[0341] In some embodiments, Y is -P(=S)(OH)(C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0342] In some implementations, Y is -P(=O)(SR) Y )R Y .

[0343] In some embodiments, Y is -P(=O)(SH)(C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0344] In some implementations, Y is -P(=S)(SR) Y )R Y .

[0345] In some embodiments, Y is -P(=S)(SH)(C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0346] In some implementations, Y is -P(=O)(OR) Y )2.

[0347] In some implementations, Y is -P(=O)(OH)2.

[0348] In some implementations, Y is -P(=S)(OR Y )2.

[0349] In some implementations, Y is -P(=S)(OH)2.

[0350] In some implementations, Y is -P(=O)(SR) Y )2.

[0351] In some implementations, Y is -P(=O)(SH)2.

[0352] In some implementations, Y is -P(=S)(SR) Y )2.

[0353] In some implementations, Y is -P(=S)(SH)2.

[0354] In some implementations, Y is a hydroxyl protecting group.

[0355] In some embodiments, Y is a silyl group (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl).

[0356] In some embodiments, Y is triphenylmethyl (Tr) or 4,4′-dimethoxytriphenylmethyl (DMTr).

[0357] In some embodiments, Y is an optionally substituted acyl group (e.g., an optionally substituted acetyl group) or a benzyl group.

[0358] In some implementations, at least one R Y It is H.

[0359] In some implementations, each R Y It is H.

[0360] In some implementations, at least one R Y It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyano groups.

[0361] In some implementations, each R YIt is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyano groups.

[0362] In some implementations, at least one R Y It is H, and at least one R Y It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens or cyano groups.

[0363] In some implementations, when X is -OH, then Y is not an H or hydroxyl protecting group.

[0364] In some embodiments, when X is -OH, then Y is a C1-C6 alkyl group optionally substituted with one or more halogens, or a -P(R) group. 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 or -P(=S)(SR Y )2.

[0365] In some implementations, X is not -OH when Y is an H or hydroxyl protecting group.

[0366] In some implementations, when Y is an H or hydroxyl protecting group, then X is H, a halogen, or -OR. X And R X It is a C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 aryl), wherein the C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 Aryl) optionally by one or more R Xa replace.

[0367] In some implementations, Z is H.

[0368] In some embodiments, Z is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0369] In some embodiments, Z is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0370] In some implementations, Z is methyl, ethyl, or propyl.

[0371] In some implementations, Z is -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.

[0372] In some implementations, Z is -P(R) Z )2.

[0373] In some implementations, Z is -PH2.

[0374] In some implementations, Z is -P(OR) Z )(N(R Z )2).

[0375] In some implementations, Z is -P(OH)(NH2).

[0376] In some embodiments, Z is -P(O(C1-C6 alkyl))(N(C1-C6 alkyl)2), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0377] In some implementations, Z is -P(=O)(OR) Z )R Z .

[0378] In some embodiments, Z is -P(=O)(OH)(C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0379] In some implementations, Z is -P(=S)(OR Z )R Z .

[0380] In some embodiments, Z is -P(=S)(OH)(C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0381] In some implementations, Z is -P(=O)(SR) Z )R Z .

[0382] In some embodiments, Z is -P(=O)(SH)(C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0383] In some implementations, Z is -P(=S)(SR) Z )R Z .

[0384] In some embodiments, Z is -P(=S)(SH)(C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or cyano groups.

[0385] In some implementations, Z is -P(=O)(OR) Z )2.

[0386] In some implementations, Z is -P(=O)(OH)2.

[0387] In some implementations, Z is -P(=S)(OR Z )2.

[0388] In some implementations, Z is -P(=S)(OH)2.

[0389] In some implementations, Z is -P(=O)(SR) Z )2.

[0390] In some implementations, Z is -P(=O)(SH)2.

[0391] In some implementations, Z is -P(=S)(SR) Z )2.

[0392] In some implementations, Z is -P(=S)(SH)2.

[0393] In some implementations, Z is a hydroxyl protecting group.

[0394] In some embodiments, Z is a silyl group (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl).

[0395] In some embodiments, Z is triphenylmethyl (Tr) or 4,4′-dimethoxytriphenylmethyl (DMTr).

[0396] In some embodiments, Z is a substituted acyl group (e.g., an optionally substituted acetyl group) or a benzyl group.

[0397] In some implementations, at least one R Z It is H.

[0398] In some implementations, each R Z It is H.

[0399] In some implementations, at least one R Z It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyano groups.

[0400] In some implementations, each R Z It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyano groups.

[0401] In some implementations, at least one R Z It is H, and at least one R Z It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyano groups.

[0402] In some implementations, Y and Z in equation (I) together form -Si(R) L’’ )2-O-Si(R L’’ )2-.

[0403] In some embodiments, Y and Z in formula (I) together form -Si(C1-C6 alkyl)2-O-Si(C1-C6 alkyl)2-.

[0404] In some implementations, Y and Z in formula (I) together form -Si(iPr)2-O-Si(iPr)2-.

[0405] In some implementations, Y and Z in equation (III) together form -Si(R) L’’ )2-O-Si(R L’’ )2-.

[0406] In some embodiments, Y and Z in formula (III) together form -Si(C1-C6 alkyl)2-O-Si(C1-C6 alkyl)2-.

[0407] In some implementations, Y and Z in formula (III) together form -Si(iPr)2-O-Si(iPr)2-.

[0408] In some implementations, Y and Z in formulas (I), (III), (I'), (III'), (IA), (III-A), (I'-A), (III'-A), (IB), (III-B), (I'-B), (III'-B), (IC), (III-C), (VC), (VII-C), (I'-C), (III'-C), (V'-C), or (VII'-C) together form -Si(R) L’’ )2-O-Si(R L’’ )2-, where each R L’’ It is independently H or C1-C6 alkyl.

[0409] In some embodiments, Y and Z in formula (I), (III), (I'), (III'), (IA), (III-A), (I'-A), (III'-A), (IB), (III-B), (I'-B), (III'-B), (IC), (III-C), (VC), (VII-C), (I'-C), (III'-C), (V'-C), or (VII'-C) together form -Si(C1-C6 alkyl)2-O-Si(C1-C6 alkyl)2-.

[0410] In some implementations, Y and Z in formulas (I), (III), (I'), (III'), (IA), (III-A), (I'-A), (III'-A), (IB), (III-B), (I'-B), (III'-B), (IC), (III-C), (VC), (VII-C), (I'-C), (III'-C), (V'-C), or (VII'-C) together form -Si(iPr)2-O-Si(iPr)2-.

[0411] In some implementations, at least one R L’’ It is H.

[0412] In some implementations, at least one R L’’ It is a C1-C6 alkyl group.

[0413] In some implementations, at least one R L’’ It is methyl, ethyl, or propyl (e.g., iPr).

[0414] In some implementations, each R L’’ H stands alone.

[0415] In some implementations, each R L’’ It is independently a C1-C6 alkyl group.

[0416] In some implementations, each R L’’ It is independently methyl, ethyl, or propyl (e.g., iPr).

[0417] variable R a R 1 R 2 R 3 R 4 R 5 and n

[0418] In some implementations, each R a It is H.

[0419] In some implementations, at least one R a It is H.

[0420] In some implementations, at least one R a It is a halogen (e.g., F, Cl, Br or I) or a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br or I).

[0421] In some implementations, at least one R a It is a halogen (e.g., F, Cl, Br or I).

[0422] In some implementations, at least one R a It is either F or Cl.

[0423] In some implementations, at least one R a It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0424] In some implementations, at least one R a It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0425] In some implementations, at least one R a It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0426] In some implementations, two adjacent R a Forming bonds.

[0427] In some implementation schemes, R 1 It is H.

[0428] In some implementation schemes, R 1 It is H, where it is related to R 1 The bonded carbon atoms are characterized by (R) stereochemistry. In some embodiments, R... 1 It is H, where it is related to R 1 The bonded carbon atoms are characterized by (S) stereochemistry.

[0429] In some implementation schemes, R 1 It is a halogen (e.g., F, Cl, Br or I).

[0430] In some implementation schemes, R 1 It is either F or Cl.

[0431] In some implementation schemes, R 1 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0432] In some implementation schemes, R 1 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0433] In some implementation schemes, R 1 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0434] In some implementation schemes, R 2It is H.

[0435] In some implementation schemes, R 2 It is a halogen (e.g., F, Cl, Br or I).

[0436] In some implementation schemes, R 2 It is either F or Cl.

[0437] In some implementation schemes, R 2 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0438] In some implementation schemes, R 2 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0439] In some implementation schemes, R 2 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0440] In some implementation schemes, R 3 It is H.

[0441] In some implementation schemes, R 3 It is a halogen (e.g., F, Cl, Br or I).

[0442] In some implementation schemes, R 3 It is either F or Cl.

[0443] In some implementation schemes, R 3 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0444] In some implementation schemes, R 3 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0445] In some implementation schemes, R 3 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0446] In some implementation schemes, R 4 It is H.

[0447] In some implementation schemes, R 4 It is a halogen (e.g., F, Cl, Br or I).

[0448] In some implementation schemes, R 4 It is either F or Cl.

[0449] In some implementation schemes, R 4 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0450] In some implementation schemes, R 4 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0451] In some implementation schemes, R 4 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0452] In some implementation schemes, R 4 and R X Together they form C1-C6 alkylene compounds (e.g., methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0453] In some implementation schemes, R 4 and R X Together they form methylene, ethylene, or propylene.

[0454] In some implementation schemes, R 4 and R X Together they form a methylene group.

[0455] In some implementation schemes, R 4 and R X Together they form ethylene.

[0456] In some implementation schemes, R 4 and R X Together they form propylidene.

[0457] In some implementations, each R 5 It is H.

[0458] In some implementations, at least one R 5 It is H.

[0459] In some implementations, at least one R 5 It is a halogen (e.g., F, Cl, Br or I) or a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br or I).

[0460] In some implementations, at least one R 5 It is a halogen (e.g., F, Cl, Br or I).

[0461] In some implementations, at least one R 5 It is either F or Cl.

[0462] In some implementations, at least one R 5 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0463] In some implementations, at least one R 5 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0464] In some implementations, at least one R 5 It is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0465] In some implementation schemes, R a R 1 R 2 R 3 R 4 and R 5 Each of them is H.

[0466] In some implementations, n is an integer ranging from about 1 to about 10.

[0467] In some implementations, n is an integer ranging from about 2 to about 10.

[0468] In some implementations, n is an integer ranging from about 3 to about 10, from about 4 to about 10, from about 5 to about 10, or from about 6 to about 10.

[0469] In some implementations, n is an integer ranging from about 1 to about 8, from about 1 to about 7, from about 1 to about 6, from about 1 to about 5, from about 1 to about 4, or from about 1 to about 3.

[0470] In some implementations, n is an integer ranging from about 2 to about 8, from about 2 to about 7, from about 2 to about 6, from about 2 to about 5, from about 2 to about 4, or from about 2 to about 3.

[0471] In some implementations, n is 0.

[0472] In some implementations, n is 1.

[0473] In some implementations, n is 2.

[0474] In some implementations, n is 3.

[0475] In some implementations, n is 4.

[0476] In some implementations, n is 5.

[0477] In some implementations, n is 6.

[0478] In some implementations, n is 7.

[0479] In some implementations, n is 8.

[0480] In some implementations, n is 9.

[0481] In some implementations, n is 10.

[0482] Exemplary implementations of lipid-based enhancers

[0483] In some embodiments, the lipid-based enhancer has formula (I'), (II'), (III'), or (IV'):

[0484] (I'), (II'),

[0485] (III'), or (IV')

[0486] In some embodiments, the lipid-based enhancer has the formula (IA), (II-A), (III-A), or (IV-A):

[0487] (IA), (II-A), (III-A), or (IV-A).

[0488] In some embodiments, the lipid-based enhancer has the formula (I'-A), (II'-A), (III'-A), or (IV'-A):

[0489] (I'-A), (II'-A),

[0490] (III'-A), or (IV'-A).

[0491] In some embodiments, the lipid-based enhancer has the formula (IB), (II-B), (III-B), or (IV-B):

[0492] (IB), (II-B), (III-B) or (IV-B).

[0493] In some embodiments, the lipid-based enhancer has the formula (I'-B), (II'-B), (III'-B), or (IV'-B):

[0494] (I'-B), (II'-B),

[0495] (III'-B), or (IV'-B).

[0496] In some embodiments, the lipid-based enhancer has the formula (IC), (II-C), (III-C), (IV-C), (VC), (VI-C), (VII-C), or (VIII-C):

[0497] (IC), (II-C), (III-C), (IV-C),

[0498] (VC), (VI-C), (VI-C), or (VIII-C).

[0499] In some embodiments, the lipid-based enhancer has the formula (I'-C), (II'-C), (III'-C), (IV'-C), (V'-C), (VI'-C), (VII'-C), or (VIII'-C):

[0500] (I'-C), (II'-C), (III'-C), (IV'-C), (V'-C), (VI'-C), (VII'-C), or (VIII'-C).

[0501] In some implementations, the lipid-based enhancer is:

[0502] , , , , , , , , , , , , , , ,or ;

[0503] Or its pharmaceutically acceptable salt, wherein:

[0504] Indicates a single bond or a double bond;

[0505] Y is -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 hydroxyl protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl), triphenylmethyl (Tr), 4,4'-dimethoxytriphenylmethyl (DMTr), a substituted acyl group (e.g., an optionally substituted acetyl group) or benzyl);

[0506] Each R Y It is independently an H or optionally a C1-C6 alkyl group substituted with one or more halogens or cyano groups;

[0507] Z is -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 hydroxyl protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl), triphenylmethyl (Tr), 4,4'-dimethoxytriphenylmethyl (DMTr), a substituted acyl group (e.g., an optionally substituted acetyl group), or a benzyl group); and

[0508] Each R Z It is an H-based or optionally substituted C1-C6 alkyl group with one or more halogens or cyano groups.

[0509] In some implementations, the lipid-based enhancer is:

[0510] , , , , , , , , , , ,or Or, or a pharmaceutically acceptable salt thereof.

[0511] In some implementations, the lipid-based enhancer is selected from the compounds described in Table L and their pharmaceutically acceptable salts.

[0512] In some implementations, the lipid-based enhancer is selected from the compounds described in Table L.

[0513] Table L

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545] In some implementations, the lipid-based enhancer is L-1, L-2, L-4, or L-5.

[0546] In some implementations, the lipid-based enhancer is L-2 or L-5.

[0547] In some embodiments, the lipid-based enhancer is L-1. In some embodiments, the lipid-based enhancer is L-2. In some embodiments, the lipid-based enhancer is L-4. In some embodiments, the lipid-based enhancer is L-5.

[0548] In some implementations, the lipid-based enhancer is L-1, wherein C1-C 30 Alkyl is C 15 -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 15 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 16 -C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 17 -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 15 -C 22Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 15- -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 15 -C 20 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 15- -C 19 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 16 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 17 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 18 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 19 -C 23 alkyl.

[0549] In some implementations, the lipid-based enhancer is L-1, wherein C1-C 30 Alkyl is C 15 Alkyl, C 17 Alkyl or C 21 alkyl.

[0550] In some implementations, the lipid-based enhancer is L-1, wherein C1-C 30 Alkyl is C 15 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 16 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 17 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 18 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 19Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 20 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-1, wherein C1-C... 30 Alkyl is C 23 alkyl.

[0551] In some implementations, the lipid-based enhancer is L-2, wherein C1-C 30 Alkyl is C 15 -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 15 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 16 -C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 17 -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 15 -C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 15- -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 15 -C 20 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 15- -C 19 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 16 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30Alkyl is C 17 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 18 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 19 -C 23 alkyl.

[0552] In some implementations, the lipid-based enhancer is L-2, wherein C1-C 30 Alkyl is C 15 Alkyl, C 17 Alkyl or C 21 alkyl.

[0553] In some implementations, the lipid-based enhancer is L-2, wherein C1-C 30 Alkyl is C 15 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 16 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 17 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 18 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 19 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 20 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-2, wherein C1-C... 30 Alkyl is C 23 alkyl.

[0554] In some implementations, the lipid-based enhancer is L-4, wherein C1-C 30 Alkyl is C 15 -C 21Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 15 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 16 -C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 17 -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 15 -C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 15- -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 15 -C 20 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 15- -C 19 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 16 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 17 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 18 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 19 -C 23 alkyl.

[0555] In some implementations, the lipid-based enhancer is L-4, wherein C1-C 30 Alkyl is C 15 Alkyl, C 17 Alkyl or C 21 alkyl.

[0556] In some implementations, the lipid-based enhancer is L-4, wherein C1-C 30 Alkyl is C 15 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 16 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 17 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 18 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 19 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 20 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-4, wherein C1-C... 30 Alkyl is C 23 alkyl.

[0557] In some implementations, the lipid-based enhancer is L-5, wherein C1-C 30 Alkyl is C 15 -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 15 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 16 -C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 17 -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 15 -C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C15- -C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 15 -C 20 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 15- -C 19 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 16 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 17 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 18 -C 23 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 19 -C 23 alkyl.

[0558] In some implementations, the lipid-based enhancer is L-5, wherein C1-C 30 Alkyl is C 15 Alkyl, C 17 Alkyl or C 21 alkyl.

[0559] In some implementations, the lipid-based enhancer is L-5, wherein C1-C 30 Alkyl is C 15 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 16 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 17 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 18 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 19 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 20Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 21 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 22 Alkyl group. In some embodiments, the lipid-based enhancer is L-5, wherein C1-C... 30 Alkyl is C 23 alkyl.

[0560] In some respects, this disclosure provides an isotopic derivative (e.g., an isotopically labeled compound) of a lipid-based enhancer disclosed herein.

[0561] It should be understood that isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotope derivatives can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents by implementing the schemes and / or procedures disclosed in the examples herein.

[0562] In some implementations, the isotope derivative is a deuterium-labeled derivative.

[0563] As used herein, the term "isotope derivative" refers to a derivative of a chemical structure in which one or more atoms are enriched or labeled with isotopes. For example, an isotope derivative of a pharmaceutical agent is isotopically enriched or isotopically labeled with one or more isotopes compared to a corresponding pharmaceutical agent. In some embodiments, the isotope derivative is isotopically enriched or labeled with one or more isotopes selected from... 2 H, 13 C 14 C 15 N、 18 O、 29 Si、 32 P and 34 The S atom is enriched or labeled with that atom. In some embodiments, the isotopic derivative is a deuterium-labeled derivative (i.e., enriched for one or more of its atoms). 2 H). In some implementations, the derivative is 2 H-labeled derivatives. In some embodiments, the derivative is... 13 C-labeled derivatives or 14 C-labeled derivatives. In some embodiments, the derivative is... 18 F-labeled derivatives. In some embodiments, the derivative is... 123 I-labeled derivatives, 124 I-labeled derivatives, 125 I-labeled derivatives, 129 I-labeled derivatives,131 I-labeled derivatives, 135 I-labeled derivatives or any combination thereof. In some embodiments, the derivative is... 32 P-labeled derivatives or 32 P-labeled derivatives. In some embodiments, the derivative is... 33 S-labeled derivatives, 34 S-labeled derivatives, 35 S-labeled derivatives, 36 S-labeled derivatives or any combination thereof.

[0564] It should be understood that isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotope derivatives can typically be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents by implementing the schemes described herein and / or the procedures disclosed in the examples.

[0565] It should also be understood that isotope substitution can provide certain therapeutic advantages, which stem from greater metabolic stability, such as prolonged half-life or reduced dosage in vivo.

[0566] To avoid any doubt, it should be understood that in this specification, when a group is defined as “described herein”, the group encompasses each and all of the first and broadest definitions of the group, as well as the specific definitions of the group.

[0567] It should be understood that while the compounds disclosed herein may exist in a particular configuration, such particular configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regio isomer, or stereoisomer, nor preclude mixtures of isomers, tautomers, regio isomers, or stereoisomers. In some embodiments, compounds presented herein in a particular configuration are intended to cover and refer to each of the available isomers, tautomers, regio isomers, and stereoisomers of the compound, or any mixture thereof; however, this presentation is also intended to refer to a specific configuration of the compound.

[0568] It should be understood that while the compounds disclosed herein may be presented without specifying a configuration (e.g., without specifying a stereochemistry), such presentation is intended to cover all available isomers, tautomers, regioisomers, and stereoisomers of the compounds. In some embodiments, the presentation of compounds without specifying a configuration herein is intended to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0569] As used herein, the term "isomer" refers to compounds with the same molecular formula but different atomic bonding sequences or spatial arrangements. Compounds with the same molecular formula but different atomic properties, bonding sequences, or spatial arrangements are called "isomers." Isomers differing in their atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." A pair of enantiomers is possible if the compound has an asymmetry center, for example, bonded to four different groups. Enantiomers can be characterized by the absolute configuration of their asymmetry center, described by the R and S sequence rules of Cahn and Prelog; or by the way the molecule is rotated by plane-polarized light and designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as single enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0570] The compounds disclosed herein may have one or more asymmetric centers; therefore, such compounds may be produced as a single (R) or (S) stereoisomer or as a mixture thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both its single enantiomer and its racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see “Advanced Organic Chemistry”, 第 (Discussed in Chapter 4 of J. March, John Wiley and Sons, New York, 4th edition, 2001), for example, by synthesis from optically active starting materials or by resolving racemic forms. Some of the compounds disclosed herein may have geometric isomer centers (E and Z isomers). It should be understood that this disclosure covers all optical, diastereomeric, and geometric isomers, as well as mixtures thereof, having biological activity as defined herein.

[0571] As used in this article, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0572] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as a single diastereomer or as a mixture of diastereomers, the latter being referred to as a "diastereomer mixture." When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are arranged according to the Cahn, Ingold, and Prelog order. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; Errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0573] As used herein, the term “geometric isomer” refers to a diastereomeric form that exists due to hindered rotation around a double bond or cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate, according to the Cahn-Ingold-Prelog rule, that the groups are located on the same or opposite sides of the double bond in the molecule.

[0574] It should be understood that the compounds of this disclosure may be described as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any isomer, but it should be understood that not all isomers may have the same level of activity.

[0575] It should be understood that the structures and other compounds discussed in this disclosure include all their trans-isomers. It should also be understood that not all trans-isomers may have the same level of activity.

[0576] As used herein, the term "trans-isomer" refers to a class of stereoisomers in which the atoms of the two isomers are arranged differently in space. The existence of trans-isomers is attributed to rotational restriction caused by the impaired rotation of the large group around the central bond. Such trans-isomers typically exist as mixtures; however, due to recent advances in chromatographic techniques, it has become possible to separate mixtures of two trans-isomers under selected conditions.

[0577] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and readily transform from one isomer to another. This transformation results in the formal migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of tautomer groups. In solutions where tautomerism is possible, a chemical equilibrium will be reached between the tautomers. The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerism is called tautomerism. Of the various possible types of tautomerism, two are typically observed. In keto-enol tautomerism, a concerted migration of electrons and hydrogen atoms occurs. Cyclic tautomerism arises from the reaction of an aldehyde group (-CHO) in a sugar molecule with a group in a hydroxyl group (-OH) in the same molecule, resulting in a cyclic (ring-like) form, as exhibited by glucose.

[0578] It should be understood that the compounds of this disclosure may be described as different tautomers. It should also be understood that when a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer. It should be understood that some tautomers may have higher activity levels than others.

[0579] It should be understood that any compound of any formula described herein includes the compound itself, as well as its salts and solvates, where applicable. For example, salts may be formed between anions and positively charged groups (e.g., amino groups) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0580] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming pharmaceutically acceptable salts. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., a carboxyl group) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations (such as tetramethylammonium or diethylammonium ions). The substituted compounds disclosed herein also include those salts containing a quaternary nitrogen atom.

[0581] It should be understood that the compounds disclosed herein, such as salts of the compounds, may exist in hydrated or dehydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0582] As used herein, the term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcohol. Hydrates are formed by the combination of one or more water molecules with a molecule of another substance, where the water retains its molecular state as H₂O.

[0583] As used herein, the term "analogue" refers to a compound that is structurally similar to another compound but differs slightly in composition (e.g., an atom is replaced by an atom of a different element, a specific functional group is present, or a functional group is replaced by another functional group). Therefore, an analogue is a compound that is functionally and morphologically similar to or equivalent to a reference compound but differs in its structural origin.

[0584] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted by various groups as described herein.

[0585] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of an atom or group of atoms with another substantially similar atom or group of atoms. The aim of bioisostere substitution is to produce new compounds with similar biological properties to the parent compound. Bioisostere substitution can be based on physicochemical or topological principles. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0586] It should also be understood that certain compounds of any of the formulas disclosed herein may exist in both solvated and non-solvated forms, such as hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure covers all such solvated forms having the biological activity defined herein.

[0587] It should also be understood that certain compounds of any of the formulas disclosed herein may exhibit polymorphism, and this disclosure covers all such forms or mixtures thereof having the biological activity defined herein. It is well known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0588] Compounds of any of the formulas disclosed herein may exist in a variety of different tautomeric forms, and compounds mentioned in any of the formulas include all such forms. For the avoidance of doubt, when a compound may exist in one of several tautomeric forms, and only one is specifically described or shown, all others are covered by the formulas disclosed herein. Examples of tautomeric forms include keto, enol, and enolate forms, such as in, for example, the following tautomeric pairs: keto / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0589]

[0590] Compounds containing any of the formulas disclosed herein, which have an amine functional group, can also form N-oxides. Compounds containing any of the formulas herein, which have an amine functional group, also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides having a nitrogen atom in a tertiary amine or a nitrogen-containing heterocycle. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, Jerry March. 第 4th edition, Wiley Interscience, page number. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent, such as dichloromethane.

[0591] Compounds of any of the formulas disclosed herein may be administered as prodrugs, which are broken down in humans or animals to release the disclosed compounds. Prodrugs may be used to modify the physical and / or pharmacokinetic properties of the disclosed compounds. Prodrugs may be formed when the disclosed compounds contain suitable groups or substituents that can be attached to groups that modify properties.

[0592] Therefore, this disclosure includes compounds of any of the formulas disclosed herein as defined above, both when the compounds are prepared by organic synthesis and when they are produced by the lysis of their prodrugs in humans or animals. Thus, this disclosure includes compounds of any of the formulas disclosed herein produced by organic synthesis and such compounds produced in humans or animals by the metabolism of prodrug compounds; that is, compounds of any of the formulas disclosed herein can be synthetically produced or metabolically produced.

[0593] Suitable pharmaceutically acceptable prodrugs of any of the compounds disclosed herein are based on reasonable medical judgment, are suitable for administration to humans or animals without undesirable pharmacological activity and without excessive toxicity. Various forms of prodrugs have been described in the following literature, for example: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0594] The in vivo effects of compounds of any of the formulas disclosed herein may be exerted in part by one or more metabolites formed in a human or animal following administration of a compound of any of the formulas disclosed herein. As explained above, the in vivo effects of compounds of any of the formulas disclosed herein may also be exerted by the metabolism of a prodrug.

[0595] As appropriate, this disclosure excludes any single compound that does not have the biological activity defined herein.

[0596] Conjugates containing lipid-based reinforcing units

[0597] As used herein, the term "conjugate" refers to a compound or complex comprising a nucleic acid agent covalently attached to a ligand. In some embodiments, the conjugate also comprises the lipid-based enhancing unit described herein.

[0598] In some aspects, this disclosure provides a conjugate or a pharmaceutically acceptable salt thereof comprising:

[0599] (i) One or more nucleic acid reagents;

[0600] (ii) one or more ligands; and

[0601] (iii) One or more lipid-based enhancement units, wherein each lipid-based enhancement unit is independently:

[0602] ; ;

[0603] ;or ;

[0604] in:

[0605] Variables L, B, V, X, R 1 R 2 R 3 R 4 R 5 R a R Y R Z and n as described in this article; and

[0606] When the lipid-based enhancing unit is located at the 3' end of the nucleic acid agent,

[0607] # is the attachment to the rest of the conjugate; and

[0608] ## is H, -P(R) Y 2. -P(OR) Y )(N(R Y )2), -P(=O)(ORY )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 hydroxyl protecting group; or

[0609] When the lipid-based enhancing unit is located at the 5' end of the nucleic acid agent,

[0610] # 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 hydroxyl protecting group; and

[0611] ## is the attachment to the rest of the conjugate; or

[0612] Each of # and ## is independently attached to the rest of the conjugate.

[0613] It should be understood that one or more ligands and one or more lipid-based enhancing units each independently attach to a terminal position (e.g., a 3' end or a 5' end) or an internal position of one or more nucleic acid agents. Furthermore, it should be understood that when a nucleic acid agent contains more than one strand (e.g., a sense strand and an antisense strand), one or more ligands and one or more lipid-based enhancing units may attach to the same or different strands of the nucleic acid agent.

[0614] In some implementations, # represents 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 hydroxyl protecting group, and ## is attached to the rest of the conjugate.

[0615] In some implementations, # represents the attachment to the remainder of the conjugate, and ## represents 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 hydroxyl protecting group.

[0616] In some implementations, each of # and ## is independently attached to the rest of the conjugate.

[0617] In some implementations, the conjugate also includes one or more connecting units.

[0618] In some embodiments, the conjugate comprises a double-stranded RNA (e.g., double-stranded siRNA), one or more ligands, and one or more lipid-based ligand units.

[0619] In some implementations, one or more lipid-based enhancement units are directly attached to a nucleic acid agent (e.g., siRNA).

[0620] In some implementations, one or more lipid-based enhancement units are attached to a nucleic acid agent (e.g., siRNA) via one or more linker units.

[0621] In some implementations, one or more lipid-based enhancement units are attached to a nucleic acid agent (e.g., siRNA) via one or more ligands.

[0622] In some implementations, one or more lipid-based enhancement units are attached to a nucleic acid agent (e.g., siRNA) via one or more ligands and one or more linker units.

[0623] In some implementations, one or more ligands are directly attached to a nucleic acid agent (e.g., siRNA).

[0624] In some implementations, at least one ligand is attached to a nucleic acid agent (e.g., siRNA) via one or more linker units.

[0625] In some implementations, at least one ligand is attached to a nucleic acid agent (e.g., siRNA) via a lipid-based enhancement unit.

[0626] In some implementations, at least one ligand is directly attached to the lipid-based enhancement unit.

[0627] In some implementations, at least one ligand is attached to a lipid-based enhancement unit via a linker unit.

[0628] In some implementations, at least one ligand is attached to a nucleic acid agent (e.g., siRNA) via a lipid-based enhancement unit and a linker unit.

[0629] In some implementations, the conjugate comprises:

[0630] (Nucleic acid reagent) - [(Linking unit)] 0-1 -(Lipid-based enhancement unit)-(Connecting unit) 0-1 -(ligands)] 1-3 ;

[0631] (Nucleic acid reagent) - [(Linking unit)] 0-1 -(ligand)-(connector unit) 0-1 -(Lipid-based enhancement unit)] 1-3 ;or

[0632] [(Lipid-based enhancement unit) - (Connecting unit)] 0-1 ] 1-3 -(nucleic acid reagent)-[(linking unit)] 0-1 -(ligands)] 1-3 ;

[0633] When attached to a nucleic acid agent (e.g., siRNA), each of the linker unit, the lipid-based enhancement unit, and the ligand is independently attached to a terminal position (e.g., a nucleotide at the 3' or 5' end) or an internal position (e.g., a nucleotide not at the 3' or 5' end) of the nucleic acid agent (e.g., siRNA).

[0634] In some implementations, the conjugate comprises:

[0635]

[0636]

[0637]

[0638] As described herein, the nucleic acid agent may optionally be further attached to one or more linker units, one or more lipid-based enhancement units, and / or one or more ligands at one or more internal locations of the nucleic acid agent.

[0639] It should be understood that one or more links to a nucleic acid agent can be independently located at one or more internal sites within the nucleic acid agent (e.g., sense strand and / or antisense strand). ), 3' end position (e.g., ) or 5' end position (e.g., ).

[0640] In some implementations, the conjugate is selected from... Figure 3 The conjugates described in [the text].

[0641] In some embodiments, at least one lipid-based enhancing unit in the conjugate is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or Or, or a pharmaceutically acceptable salt thereof.

[0642] In some embodiments, at least one lipid-based enhancing unit in the conjugate is: , , , , , , , , , , , , , , ,or Or, or a pharmaceutically acceptable salt thereof.

[0643] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is selected from the structures described in Table C.

[0644] Table C

[0645] serial number structure C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22 C-23 C-24 C-25 C-26 C-27 C-28 C-29 C-30 C-31 C-32 C-33 C-34 C-35 C-36 C-37 C-38 C-39 C-40 C-41 C-42 C-43 C-44 C-45 C-46 C-47 C-48 C-49 C-50 C-51 C-52 C-53 C-54 C-55 C-56 C-57 C-58 C-59 C-60 C-61 C-62 C-63 C-64 C-65 C-66 C-67 C-68 C-69 C-70 C-71 C-72 C-73 C-74 C-75 C-76 C-77 C-78 C-79 C-80

[0646] Where L is -C(=O)R L R L It is an optional substitution of C1-C 30 A hydrocarbon chain or an optionally substituted 2 to 30-membered heterohydrocarbon chain, and B is adenine (A), cytosine (C), guanine (G) or uracil (U).

[0647] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is selected from C-1, C-2, C-3, and C-4.

[0648] In some embodiments, at least one lipid-based enhancing unit in the conjugate is C-1. In some embodiments, at least one lipid-based enhancing unit in the conjugate is C-2. In some embodiments, at least one lipid-based enhancing unit in the conjugate is C-3. In some embodiments, at least one lipid-based enhancing unit in the conjugate is C-4.

[0649] In some embodiments, at least one lipid-based enhancing unit in the conjugate is C-1, wherein R L C is an optional substitute 15 -C 21Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 15 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 16 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 17 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 15 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 15 -C 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 15 -C 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 16 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 17 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 18 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 19 -C 23 Hydrocarbon chain.

[0650] In some embodiments, at least one lipid-based enhancing unit in the conjugate is C-1, wherein R L It is C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 Hydrocarbon chain, wherein the C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 The hydrocarbon chain can be substituted at will.

[0651] In some embodiments, at least one lipid-based enhancing unit in the conjugate is C-1, wherein R L C is an optional substitute 15 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 16 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 17 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 18 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-1, wherein R L C is an optional substitute 23 Hydrocarbon chain.

[0652] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute15 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 16 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 17 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 15 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 15 -C 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 15 -C 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 16 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 17 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 18 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 19 -C 23 Hydrocarbon chain.

[0653] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L It is C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C21 Hydrocarbon chain, wherein the C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 The hydrocarbon chain can be substituted at will.

[0654] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 15 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 16 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 17 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 18 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-2, wherein R L C is an optional substitute 23 Hydrocarbon chain.

[0655] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 15 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute16 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 17 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 15 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 15 -C 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 15 -C 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 16 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 17 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 18 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 19 -C 23 Hydrocarbon chain.

[0656] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L It is C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 Hydrocarbon chain, wherein the C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 The hydrocarbon chain can be substituted at will.

[0657] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 15 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 16 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 17 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 18 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-3, wherein R L C is an optional substitute 23 Hydrocarbon chain.

[0658] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 15 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 16 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute17 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 15 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 15 -C 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 15 -C 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 16 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 17 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 18 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 19 -C 23 Hydrocarbon chain.

[0659] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L It is C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 Hydrocarbon chain, wherein the C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 The hydrocarbon chain can be substituted at will.

[0660] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 15Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 16 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 17 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 18 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is C-4, wherein R L C is an optional substitute 23 Hydrocarbon chain.

[0661] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is selected from the structures described in Table D.

[0662] Table D

[0663] serial number structure D-1 D-2 D-3 D-4 D-5 D-6 D-7 D-8 D-9 D-10 D-11 D-12 D-13 D-14 D-15 D-16 D-17 D-18 D-19 D-20 D-21 D-22 D-23 D-24 D-25 D-26 D-27 D-28 D-29 D-30 D-31 D-32 D-33 D-34 D-35 D-36 D-37 D-38 D-39 D-40

[0664] Where L is -C(=O)R L R L It is an optional substitution of C1-C 30 A hydrocarbon chain or an optionally substituted 2 to 30-membered heterohydrocarbon chain, and B is adenine (A), cytosine (C), guanine (G) or uracil (U).

[0665] In some embodiments, at least one lipid-based reinforcing unit in the conjugate is selected from D-1 and D-2.

[0666] In some embodiments, at least one lipid-based enhancing unit in the conjugate is D-1. In some embodiments, at least one lipid-based enhancing unit in the conjugate is D-2.

[0667] In some embodiments, at least one lipid-based enhancing unit in the conjugate is D-1, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 15 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 16 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 17 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 15 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 15 -C 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 15 -C 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 16 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 17 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 18 -C 23Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 19 -C 23 Hydrocarbon chain.

[0668] In some embodiments, at least one lipid-based enhancing unit in the conjugate is D-1, wherein R L It is C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 Hydrocarbon chain, wherein the C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 The hydrocarbon chain can be substituted at will.

[0669] In some embodiments, at least one lipid-based enhancing unit in the conjugate is D-1, wherein R L C is an optional substitute 15 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 16 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 17 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 18 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-1, wherein R L C is an optional substitute 23 Hydrocarbon chain.

[0670] In some embodiments, at least one lipid-based enhancing unit in the conjugate is D-2, wherein RL C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 15 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 16 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 17 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 15 -C 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 15 -C 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 15 -C 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 15 -C 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 16 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 17 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 18 -C 23 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 19 -C 23 Hydrocarbon chain.

[0671] In some embodiments, at least one lipid-based enhancing unit in the conjugate is D-2, wherein R L It is C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 Hydrocarbon chain, wherein the C 15 Hydrocarbon chain, C 17 Hydrocarbon chain or C 21 The hydrocarbon chain can be substituted at will.

[0672] In some embodiments, at least one lipid-based enhancing unit in the conjugate is D-2, wherein R L C is an optional substitute 15 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 16 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 17 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 18 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 19 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 20 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 21 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 22 Hydrocarbon chain. In some embodiments, at least one lipid-based reinforcing unit in the conjugate is D-2, wherein R L C is an optional substitute 23 Hydrocarbon chain.

[0673] Lipid-based enhancement unit

[0674] As used herein, "lipid-based enhancement unit" refers to a portion corresponding to a lipid-based enhancer, wherein the 5', 2' and / or 3' positions are attached to the ligand, linker and / or nucleic acid agent at the 5' end, 3' end or internal position of the nucleic acid agent.

[0675] In some implementations, the lipid-based enhancing unit corresponds to a lipid-based enhancing agent, wherein the 5' position is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0676] In some implementations, the lipid-based enhancing unit corresponds to a lipid-based enhancing agent, wherein the 3' position is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0677] In some implementations, the lipid-based enhancing unit corresponds to a lipid-based enhancing agent, wherein the 2' position is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0678] In some embodiments, the lipid-based enhancing unit corresponds to a lipid-based enhancing agent, wherein the 5' position is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and the 3' position is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0679] In some embodiments, the lipid-based enhancing unit corresponds to a lipid-based enhancing agent, wherein the 5' position is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and the 2' position is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0680] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (I), (II), (III), or (IV), wherein:

[0681] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0682] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0683] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (I), (II), (III), or (IV), wherein:

[0684] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0685] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0686] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (I'), (II'), (III'), or (IV'), wherein:

[0687] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0688] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0689] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (I'), (II'), (III'), or (IV'), wherein:

[0690] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0691] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0692] In some embodiments, at least one lipid-based enhancing unit corresponds to a lipid-based enhancing agent of formula (IA), (II-A), (III-A), or (IV-A), wherein:

[0693] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0694] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0695] In some embodiments, at least one lipid-based enhancing unit corresponds to a lipid-based enhancing agent of formula (IA), (II-A), (III-A), or (IV-A), wherein:

[0696] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0697] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0698] In some embodiments, at least one nucleotide in the lipid-based enhancing unit corresponds to a lipid-based enhancing agent of formula (I'-A), (II'-A), (III'-A), or (IV'-A), wherein:

[0699] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0700] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0701] In some embodiments, at least one nucleotide in the lipid-based enhancing unit corresponds to a lipid-based enhancing agent of formula (I'-A), (II'-A), (III'-A), or (IV'-A), wherein:

[0702] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0703] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0704] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (IB), (II-B), (III-B), or (IV-B), wherein:

[0705] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0706] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0707] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (IB), (II-B), (III-B), or (IV-B), wherein:

[0708] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0709] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0710] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (I'-B), (II'-B), (III'-B), or (IV'-B), wherein:

[0711] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0712] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0713] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (I'-B), (II'-B), (III'-B), or (IV'-B), wherein:

[0714] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0715] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0716] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (IC), (II-C), (III-C), (IV-C), (VC), (VI-C), (VII-C), or (VIII-C), wherein:

[0717] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0718] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0719] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (IC), (II-C), (III-C), (IV-C), (VC), (VI-C), (VII-C), or (VIII-C), wherein:

[0720] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0721] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0722] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (I'-C), (II'-C), (III'-C), (IV'-C), (V'-C), (VI'-C), (VII'-C), or (VIII'-C), wherein:

[0723] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0724] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0725] In some embodiments, at least one lipid-based reinforcing unit corresponds to a lipid-based reinforcing agent of formula (I'-C), (II'-C), (III'-C), (IV'-C), (V'-C), (VI'-C), (VII'-C), or (VIII'-C), wherein:

[0726] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0727] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0728] In some implementations, at least one lipid-based enhancement unit is selected from Table C, wherein:

[0729] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0730] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0731] In some implementations, at least one lipid-based enhancement unit is selected from Table C, wherein:

[0732] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0733] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0734] In some embodiments, at least one lipid-based enhancement unit is selected from Table D, wherein:

[0735] The 3' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0736] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0737] In some embodiments, at least one lipid-based enhancement unit is selected from Table D, wherein:

[0738] The 2' position of the lipid-based enhancing unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent; and / or

[0739] The 5' position of the lipid-based enhancement unit is attached to the ligand, linker unit, and / or nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0740] Connection unit

[0741] As used herein, a “connecting unit” or “connecting subunit” refers to the portion attached to a lipid-based reinforcing unit, ligand, and / or nucleic acid agent.

[0742] In some implementations, the connecting unit has attachments to a lipid-based reinforcing unit and a ligand.

[0743] In some implementations, the linker unit has attachments to ligands and nucleic acid agents.

[0744] In some implementations, the linker unit is attached to a lipid-based enhancement unit and a nucleic acid agent.

[0745] In some implementations, the linker is a ribose derivative.

[0746] In some embodiments, the linking unit is a 1'-alkyl-modified ribose derivative, for example, as described in PCT application number PCT / US2022 / 039517 (incorporated herein by reference).

[0747] In some embodiments, the linking unit is a ribose derivative modified with 2'-alkyl or 3'-alkyl, for example, as described in PCT application number PCT / US2022 / 044377 (incorporated herein by reference).

[0748] In some embodiments, the linking unit is a polyhydroxylated cyclopentane derivative, for example, as described in PCT application number PCT / US2022 / 045748 (incorporated herein by reference).

[0749] ligands

[0750] As used herein, the term "ligand" or "liganding group" refers to the portion of a nucleic acid agent (e.g., an oligonucleotide) that, when covalently attached to it, mediates its entry into or facilitates its delivery to a target site (e.g., a target cell or tissue).

[0751] In some implementations, the ligand comprises a sugar ligand moiety (e.g., N-acetylgalactosamine (GalNAc)) that directs the uptake of oligonucleotides into the liver.

[0752] In some embodiments, the ligand binds to the desialyl glycoprotein receptor (ASGPR). In some embodiments, the ligand binds to the liver (e.g., via ASGPR), such as parenchymal cells of the liver.

[0753] Suitable ligands include, but are not limited to, those disclosed in the following literature: Winkler (Ther. Deliv., 2013, 4(7): 791-809), PCT patent application publications WO / 2016 / 100401, WO / 2012 / 089352 and WO / 2009 / 082607, and U.S. patent application publications 2009 / 0239814, 2012 / 0136042, 2013 / 0158824 and 2009 / 0247608, each of which is incorporated herein by reference.

[0754] In some implementations, the ligand contains a carbohydrate portion.

[0755] As used herein, a "carbohydrate moiety" refers to a moiety comprising one or more monosaccharide units, each monosaccharide unit having at least six carbon atoms (which may be linear, branched, or cyclic) bonded to each carbon atom by an oxygen, nitrogen, or sulfur atom. In some embodiments, the carbohydrate moiety comprises a monosaccharide, disaccharide, trisaccharide, or tetrasaccharide. In some embodiments, the carbohydrate moiety comprises an oligosaccharide containing about 4-9 monosaccharide units. In some embodiments, the carbohydrate moiety comprises a polysaccharide (e.g., starch, glycogen, cellulose, or polysaccharide gum).

[0756] In some implementations, the carbohydrate portion comprises monosaccharides, disaccharides, trisaccharides, or tetrasaccharides.

[0757] In some implementations, the carbohydrate portion comprises oligosaccharides (e.g., containing about four to about nine monosaccharide units).

[0758] In some implementations, the carbohydrate portion comprises polysaccharides (e.g., starch, glycogen, cellulose, or polysaccharide gum).

[0759] In some implementations, the ligand is able to bind to human desialyl glycoprotein receptor (ASGPR), such as human desialyl glycoprotein receptor 2 (ASGPR2).

[0760] In some implementations, the carbohydrate portion contains sugar (e.g., one, two, or three sugars).

[0761] In some implementations, the carbohydrate portion comprises galactose or a derivative thereof (e.g., one, two, or three galactose or a derivative thereof).

[0762] In some embodiments, the carbohydrate portion comprises N-acetylgalactosamine or a derivative thereof (e.g., one, two, or three N-acetylgalactosamines or a derivative thereof).

[0763] In some embodiments, the carbohydrate portion comprises N-acetyl-D-galactosylamine or a derivative thereof (e.g., one, two, or three N-acetyl-D-galactosylamines or a derivative thereof).

[0764] In some implementations, the carbohydrate portion contains N-acetylgalactosamine (e.g., one, two, or three N-acetylgalactosamines).

[0765] In some embodiments, the carbohydrate portion comprises N-acetyl-D-galactosylamine (e.g., one, two, or three N-acetyl-D-galactosylamines).

[0766] In some implementations, the carbohydrate portion comprises mannose or a derivative thereof (e.g., mannose-6-phosphate).

[0767] In some embodiments, the carbohydrate portion further includes a linking portion that connects one or more sugars (e.g., N-acetyl-D-galactosylamine) to the linking unit.

[0768] In some embodiments, the linker portion comprises a thioether (e.g., thiosuccinimide or its hydrolyzed analogue), a disulfide bond, a triazole, a thiophosphate, a phosphate diester, an ester, an amide, or any combination thereof.

[0769] In some implementations, the connecting part is a three-arm connecting part.

[0770] Suitable ligands include, but are not limited to, those disclosed in the following patents: PCT application publication numbers WO / 2015 / 006740, WO / 2016 / 100401, WO / 2017 / 214112, WO / 2018 / 039364 and WO / 2018 / 045317, each of which is incorporated herein by reference.

[0771] In some implementations, the ligand contains (For example, one, two or three) ).

[0772] In some implementations, the ligand contains (For example, one, two or three) ).

[0773] In some implementations, the ligand contains (For example, one, two or three) ).

[0774] In some implementations, the ligand contains (For example, one, two or three) ).

[0775] In some implementations, the ligand contains (For example, one, two or three) ).

[0776] In some implementations, the ligand contains (For example, one, two or three) ).

[0777] In some implementations, the ligand contains (For example, one, two or three) ).

[0778] In some implementations, the ligand contains (For example, one, two or three) ).

[0779] In some implementations, the ligand contains

[0780] In some implementations, the ligand contains

[0781] In some implementations, the ligand contains

[0782] In some implementations, the ligand contains

[0783] In some implementations, the ligand is included.

[0784] In some implementations, the ligand is included.

[0785] In some implementations, the ligand is included.

[0786] In some implementations, the ligand contains

[0787] In some implementations, the ligand comprises a lipid moiety (e.g., one, two, or three lipid moieties).

[0788] In some implementations, the lipid portion comprises C8-C 24 Fatty acids, cholesterol, vitamins, sterols, phospholipids, or any combination thereof (e.g., one, two, or three of them).

[0789] In some implementations, the ligand comprises a peptide moiety (e.g., one, two, or three peptide moieties).

[0790] In some implementations, the peptide portion comprises integrin, insulin, glucagon-like peptide, or any combination thereof (e.g., one, two, or three of them).

[0791] In some implementations, the ligand comprises an antibody portion (e.g., transferrin).

[0792] In some implementations, the ligand comprises one, two, or three antibody moieties (e.g., transferrin).

[0793] In some implementations, the ligand comprises an oligonucleotide (e.g., an aptamer or CpG).

[0794] In some implementations, the ligand comprises one, two, or three oligonucleotides (e.g., aptamers or CpG).

[0795] In some implementations, the ligand comprises:

[0796] One, two, or three sugars (e.g., N-acetyl-D-galactosylamine).

[0797] One, two, or three lipid fractions;

[0798] One, two, or three peptide moieties;

[0799] One, two, or three antibody components;

[0800] One, two, or three oligonucleotides; or

[0801] Any combination of them.

[0802] Nucleic acid reagent

[0803] In some implementations, the nucleic acid agent contains oligonucleotides.

[0804] In some implementations, the nucleic acid agent (e.g., oligonucleotide) contains one or more phosphate groups or analogs of one or more phosphate groups.

[0805] In some implementations, the linker unit is attached to the nucleic acid agent (e.g., oligonucleotide) via a phosphate group or an analogue of a phosphate group in the nucleic acid agent.

[0806] In some embodiments, the oligonucleotide has a length of 1 to 40 nucleotides, 10 to 40 nucleotides, 12 to 35 nucleotides, 15 to 30 nucleotides, 18 to 25 nucleotides, or 20 to 23 nucleotides. In some embodiments, the oligonucleotide has a length of 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. In some embodiments, the oligonucleotide has a length of 20, 21, 22, or 23 nucleotides.

[0807] In some implementations, the nucleic acid agent comprises RNA, DNA, or a mixture thereof.

[0808] In some implementations, the nucleic acid agent contains RNA.

[0809] In some implementations, the oligonucleotide is siRNA (e.g., single-stranded siRNA (e.g., hairpin single-stranded siRNA) or double-stranded siRNA), microRNA, antimicroRNA, microRNA mimic, mir antagonist, dsRNA, ssRNA, aptamer, immunostimulatory oligonucleotide, decoy oligonucleotide, splice-modified oligonucleotide, triple-stranded oligonucleotide, G-quadruplex, or antisense oligonucleotide.

[0810] In some implementations, the nucleic acid agent comprises double-stranded RNA (dsRNA), wherein the double-stranded RNA comprises a sense strand and an antisense strand, as described herein.

[0811] In some implementations, the nucleic acid agent comprises double-stranded siRNA (ds-siRNA), wherein the double-stranded siRNA comprises a sense strand and an antisense strand, as described herein.

[0812] It should be understood that a meaningful chain is also called a passerby chain, and the terms “meaningful chain” and “passerby chain” are used interchangeably in this article.

[0813] It should be understood that antisense chains are also called bootstrap chains, and the terms “antisense chain” and “bootstrap chain” are used interchangeably in this document.

[0814] In some implementations, the oligonucleotide is iRNA.

[0815] The term "iRNA" refers to an RNA agent (e.g., siRNA) that downregulates the expression of a target gene (e.g., endogenous or pathogen target RNA). While not wishing to be bound by theory, iRNAs can function through one or more of a variety of mechanisms, including post-transcriptional cleavage of the target mRNA (referred to in the art as RNAi), or pre-transcriptional or pre-translational mechanisms. iRNAs may be single-stranded or may contain more than one strand; for example, they may be double-stranded iRNAs. If the iRNA is single-stranded, it may contain a 5′ modification comprising one or more phosphate groups or analogs of one or more phosphate groups. In some embodiments, the iRNA is double-stranded. In some embodiments, one or both strands of the double-stranded iRNA may be modified, for example, with a 5′ modification.

[0816] iRNAs typically include regions that are sufficiently homologous to the target gene and are of sufficient length in terms of nucleotides to mediate the downregulation of the target gene. An iRNA is or contains a region that is at least partially complementary to the target RNA and, in some embodiments, fully complementary. Perfect complementarity between the iRNA and the target is not required, but the correspondence is sufficient to enable sequence-specific silencing, for example, through RNAi cleavage of the target RNA (e.g., mRNA).

[0817] Nucleotides in iRNA may be modified (e.g., one or more nucleotides may contain 2′-F or 2′-OCH3 groups, or nucleotide substitutes). Single-stranded or double-stranded regions of iRNA may be modified or contain nucleotide substitutes, such as one or more unpaired regions of a hairpin structure (e.g., regions connecting two complementary regions) may have modifications or nucleotide substitutes. Modifications to one or more 3′ or 5′ ends of iRNA may be used to stabilize it, for example, to resist exonucleases. Modifications may include: C3 (or C6, C7, C12) amino linkers, thiol linkers, carboxyl linkers; non-nucleotide spacers (C3, C6, C9, C12, debased, triethylene glycol, hexaethylene glycol); special biotin or luciferin reagents provided in phosphoramide form and having another DMT-protected hydroxyl group, thereby allowing multiple couplings during RNA synthesis. Modifications may also include, for example, modifications at the 2′ OH group of the ribose (e.g., using deoxyribonucleotides, such as deoxythymidine, instead of ribonucleotides), and modifications at the phosphate group (e.g., thiophosphate modifications). In some embodiments, different chains will contain different modifications.

[0818] In some embodiments, the strands are selected such that the iRNA contains single-stranded or unpaired regions at one or both ends of the molecule. Double-stranded iRNA may have overhangs, such as one or two 5′ or 3′ overhangs (e.g., at least one 3′ overhang with 2-3 nucleotides). In some embodiments, the iRNA has overhangs of 1, 2, or 3 nucleotides in length at each end, such as 3′ overhangs. Overhangs may be caused by one strand being longer than the other, or by two strands of equal length being interleaved.

[0819] In some embodiments, the length of the double-stranded region between the strands of the iRNA is between 6 and 30 nucleotides. In some embodiments, the length of the double-stranded region is between 15 and 30 nucleotides, most preferably 18, 19, 20, 21, 22, and 23 nucleotides. In some embodiments, the length of the double-stranded region is between 6 and 20 nucleotides, most preferably 6, 7, 8, 9, 10, 11, and 12 nucleotides.

[0820] The oligonucleotide may be the oligonucleotide described in U.S. Patent Publications 2009 / 0239814, 2012 / 0136042, 2013 / 0158824 or 2009 / 0247608, each of which is hereby incorporated by reference.

[0821] In some implementations, the oligonucleotide is siRNA.

[0822] In some implementations, the oligonucleotide is a single-stranded siRNA.

[0823] In some implementations, the oligonucleotide is a double-stranded siRNA, such as the double-stranded siRNA described herein.

[0824] As used herein, "single-stranded siRNA" is a single-stranded siRNA that includes double-stranded regions formed by intrastrand pairing, for example, which may be or contain hairpin or handle structures. Single-stranded siRNAs may be antisense relative to target molecules.

[0825] Single-stranded siRNAs can be long enough to enter RISC and participate in RISC-mediated cleavage of target mRNAs. The length of a single-stranded siRNA is at least 14 nucleotides, and in some embodiments at least 15, 20, 25, 29, 35, 40, or 50 nucleotides. In some embodiments, its length is less than 200, 100, 80, 60, 50, 40, or 30 nucleotides.

[0826] In some embodiments, the length of the single-stranded siRNA is 10 to 40 nucleotides, 12 to 35 nucleotides, 15 to 30 nucleotides, 18 to 25 nucleotides, or 20 to 23 nucleotides. In some embodiments, the length of the single-stranded siRNA is 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. In some embodiments, the length of the single-stranded siRNA is 20, 21, 22, or 23 nucleotides.

[0827] The hairpin siRNA may have a double-stranded region of 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotide pairs. The length of the double-stranded region may be equal to or less than 200, 100, or 50 nucleotide pairs. In some embodiments, the length of the double-stranded region ranges from 15-30, 17-23, 19-23, and 19-21 nucleotide pairs. The hairpin may have a single-stranded overhang or a terminal unpaired region. In some embodiments, the overhang is 2-3 nucleotides long. In some embodiments, the overhang is located on the sense side of the hairpin, and in some embodiments, it is located on the antisense side of the hairpin.

[0828] In some implementations, the oligonucleotide is a double-stranded siRNA.

[0829] As used in this article, "double-stranded siRNA" is an siRNA containing more than one strand and, in some cases, two strands, in which interstrand hybridization can form a double-stranded structure.

[0830] In some implementations, the sense strand of the double-stranded siRNA may be equal to or at least 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 29, 40, or 60 nucleotides in length. Its length may be equal to or less than 200, 100, or 50 nucleotides. The length range may be 17 to 25, 19 to 23, 19 to 21, 21 to 23, or 20 to 22 nucleotides.

[0831] In some embodiments, the sense strand is 10 to 40 nucleotides, 12 to 35 nucleotides, 15 to 30 nucleotides, 18 to 25 nucleotides, or 20 to 23 nucleotides in length. In some embodiments, the sense strand is 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length. In some embodiments, the sense strand is 20, 21, 22, or 23 nucleotides in length.

[0832] In some implementations, the sense strand is 18, 19, 20, 21, or 22 nucleotides long.

[0833] In some implementations, the antisense strand of the double-stranded siRNA may be equal to or at least 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 29, 40, or 60 nucleotides in length. Its length may be equal to or less than 200, 100, or 50 nucleotides. The length range may be 17 to 25, 19 to 23, 19 to 21, 21 to 23, or 20 to 22 nucleotides.

[0834] In some embodiments, the antisense strand is 10 to 40 nucleotides, 12 to 35 nucleotides, 15 to 30 nucleotides, 18 to 25 nucleotides, or 20 to 23 nucleotides in length. In some embodiments, the antisense strand is 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length. In some embodiments, the antisense strand is 20, 21, 22, or 23 nucleotides in length.

[0835] In some implementations, the antisense strand is 20, 21, 22, 23, or 24 nucleotides in length.

[0836] In some implementations, the sense strand is 18, 19, 20, 21, or 22 nucleotides long, and the antisense strand is 20, 21, 22, 23, or 24 nucleotides long.

[0837] In some implementations, the sense strand is 18 nucleotides long and the antisense strand is 20 nucleotides long.

[0838] In some implementations, the sense strand is 19 nucleotides long and the antisense strand is 21 nucleotides long.

[0839] In some implementations, the sense strand is 20 nucleotides long and the antisense strand is 22 nucleotides long.

[0840] In some implementations, the sense strand is 21 nucleotides long and the antisense strand is 23 nucleotides long.

[0841] In some implementations, the sense strand is 22 nucleotides long and the antisense strand is 24 nucleotides long.

[0842] The length of the double-stranded portion of double-stranded siRNA can be equal to or at least 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 29, 40, or 60 nucleotide pairs. Its length can also be equal to or less than 200, 100, or 50 nucleotide pairs. The length range can be 15 to 30, 17 to 23, 19 to 23, and 19 to 21 nucleotide pairs.

[0843] In some implementations, the siRNA is large enough that it can be cleaved by endogenous molecules (e.g., by Dicer) to produce smaller siRNAs, such as siRNA agents.

[0844] The sense and antisense strands can be selected such that the double-stranded siRNA contains single-stranded or unpaired regions at one or both ends of the molecule. Therefore, the double-stranded siRNA may contain sense and antisense strands, paired to contain overhangs, such as one or two 5′ or 3′ overhangs, or 3′ overhangs having 1-3 nucleotides. Overhangs may result from one strand being longer than the other, or from two strands of equal length being interleaved. Some embodiments will have at least one 3′ overhang. In some embodiments, the siRNA molecule will have 3′ overhangs at both ends. In some embodiments, the overhangs are 2 nucleotides.

[0845] In some embodiments, the length of the double-stranded region is between 15 and 30 nucleotides, or 18, 19, 20, 21, 22, and 23 nucleotides, for example, within the range of ssiRNAs discussed above. The ssiRNA may be similar in length and structure to the natural Dicer processing product derived from long dsiRNAs. Embodiments in which the two strands of the ssiRNA are attached together (e.g., covalently attached) are also included. Hairpins or other single-stranded structures providing the desired double-stranded region and 3′ overhang are also considered.

[0846] The siRNAs (including double-stranded and single-stranded siRNAs) described herein mediate the silencing of target RNAs (e.g., mRNAs, such as transcripts of genes encoding proteins). For convenience, this mRNA is also referred to herein as the mRNA to be silenced. The gene is also referred to as the target gene. Typically, the RNA to be silenced is an endogenous gene or a pathogen gene. Additionally, RNAs other than mRNAs, such as tRNAs and viral RNAs, can also be targeted.

[0847] As used in this article, the phrase “mediated RNAi” refers to the ability to silence target RNA in a sequence-specific manner. While not wishing to be bound by theory, silencing is believed to be achieved using RNAi mechanisms or processes and guide RNAs (e.g., 21 to 23 nucleotide ssiRNAs).

[0848] In some embodiments, the siRNA is "sufficiently complementary" to the target RNA (e.g., target mRNA), such that the siRNA silences the production of proteins encoded by the target mRNA. In another embodiment, the siRNA is "completely complementary" to the target RNA, for example, by annealing the target RNA and siRNA, for instance, to form a hybrid consisting only of Watson-Crick base pairs in a completely complementary region. A "sufficiently complementary" target RNA may include an internal region (e.g., at least 10 nucleotides) that is completely complementary to the target RNA. Furthermore, in some embodiments, the siRNA specifically distinguishes single nucleotide differences. In this case, if complete complementarity is found in a region of single nucleotide difference (e.g., within 7 nucleotides), the siRNA mediates only RNAi.

[0849] MicroRNAs: MicroRNAs (miRNAs) are a class of highly conserved small RNA molecules that are transcribed from DNA in the genomes of plants and animals but not translated into proteins. Processed miRNAs are single-stranded RNA molecules of approximately 17–25 nucleotides (nt) incorporated into the RNA-induced silencing complex (RISC) and have been identified as key regulators of development, cell proliferation, apoptosis, and differentiation. They are believed to play a role in the regulation of gene expression by binding to the 3′ untranslated region of specific mRNAs. RISC mediates the downregulation of gene expression through translational repression, transcript cleavage, or both. RISC is also involved in transcriptional silencing in the nucleus of many eukaryotes.

[0850] The number of identified miRNA sequences is currently enormous and continues to grow. Illustrative examples can be found in the following literature: “miRBase: microRNA sequences, targets and gene nomenclature” Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright A J. NAR, 2006, 34, Database Issue, D140-D144; “The microRNA Registry” Griffiths-Jones S. NAR, 2004, 32, Database Issue, D109-D111.

[0851] Antisense oligonucleotides: In some embodiments, the nucleic acid is an antisense oligonucleotide targeting a target polynucleotide. The term "antisense oligonucleotide," or simply "antisense," means an oligonucleotide that is complementary to a target polynucleotide sequence. An antisense oligonucleotide is a single strand of DNA or RNA complementary to a selected sequence (e.g., target gene mRNA). Antisense oligonucleotides are thought to inhibit gene expression by binding to complementary mRNA. Binding to target mRNA can inhibit gene expression by either preventing the translation of the complementary mRNA strand by binding to the target mRNA or by causing the target mRNA to be degraded. Antisense DNA can be used to target-specific complementary (coding or non-coding) RNA. If binding occurs, such a DNA / RNA hybrid can be degraded by the enzyme RNase H. In some embodiments, the antisense oligonucleotide contains about 10 to about 50 nucleotides, more preferably about 15 to about 30 nucleotides. The term also covers antisense oligonucleotides that may not be perfectly complementary to the desired target gene. Therefore, it is preferred for a particular purpose to consider situations where non-target-specific activity is found in the antisense, or to contain one or more antisense sequences that are mismatched with the target sequence.

[0852] Antisense oligonucleotides have been shown to be effective and targeted inhibitors of protein synthesis and can therefore be used to specifically inhibit protein synthesis of target genes. The efficacy of antisense oligonucleotides in inhibiting protein synthesis has been well demonstrated. For example, the synthesis of polygalacturonase and muscarinic type 2 acetylcholine receptor has been inhibited by antisense oligonucleotides targeting their respective mRNA sequences (US Patent Nos. 5,739,119 and 5,759,829, each of which is incorporated herein by reference). Furthermore, instances of antisense inhibition have been observed in nucleoprotein cyclins, multidrug resistance genes (MDG1), ICAM-1, E-selectin, STK-1, striatal GABAA receptors, and human EGF (Jaskulski et al., Science. June 10, 1988; 240(4858):1544-6; Vasanthakumar and Ahmed, Cancer Commun. 1989; 1(4):225-32; Peris et al., Brain Res. June 15, 1998; 57(2):310-20; U.S. Patent Nos. 5,801,154, 5,789,573, 5,718,709, and 5,610,288, each of which is incorporated herein by reference). In addition, antisense constructs are described that inhibit and can be used to treat a variety of abnormal cell proliferations, such as cancer (US Patent Nos. 5,747,470, 5,591,317 and 5,783,683, each of which is incorporated herein by reference).

[0853] Methods for generating antisense oligonucleotides are known in the art and can be readily adapted to generate antisense oligonucleotides targeting any polynucleotide sequence. The selection of antisense oligonucleotide sequences specific to a given target sequence is based on analysis of the selected target sequence, as well as determinations of secondary structure, Tm, binding energy, and relative stability. Antisense oligonucleotides can be selected based on their relative inability to form dimers, hairpins, or other secondary structures that would reduce or prevent specific binding to target mRNA in the host cell. Highly preferred mRNA target regions include those regions at or near the AUG translation start codon and those sequences substantially complementary to the 5′ region of the mRNA. These secondary structure analyses and target selection considerations can be performed, for example, using OLIGO primer analysis software (Molecular Biology Insights) v.4 and / or BLASTN 2.0.5 algorithm software (Altschul et al., Nucleic Acids Res. 1997, 25(17):3389-402).

[0854] miRNA antagonists: miRNA antagonists are RNA-like oligonucleotides with various modifications to achieve RNA-like protective and pharmacological properties (such as enhanced tissue and cellular uptake). They differ from normal RNA in, for example, complete 2′-O-methylation of sugars, a phosphate thioester backbone, and, for example, a cholesterol moiety at the 3′ end. MiRNA antagonists can be used to effectively silence endogenous miRNAs by forming a duplex containing the miRNA antagonist and the endogenous miRNA, thereby preventing miRNA-induced gene silencing. An example of miRNA antagonist-mediated miRNA silencing is the silencing of miR-122, described in Krutzfeldt et al., Nature, 2005, 438: 685-689, which is explicitly incorporated herein by reference in its entirety. MiRNA antagonist RNAs can be synthesized using standard solid-phase oligonucleotide synthesis protocols. See U.S. Patent Application Publications 2007 / 0123482 and 2007 / 0213292 (each of which is incorporated herein by reference).

[0855] MiR antagonists may comprise a ligand-conjugated monomeric subunit and a monomer for oligonucleotide synthesis. Exemplary monomers are described in U.S. Patent Application Publication No. 2005 / 0107325, which is incorporated herein by reference in its entirety. MiR antagonists may have a ZXY structure, as described in WO 2004 / 080406, which is incorporated herein by reference in its entirety. MiR antagonists may be complexed with an amphiphilic moiety. Exemplary amphiphilic moieties for use with oligonucleotide agents are described in WO 2004 / 080406, which is incorporated herein by reference in its entirety.

[0856] Aptamers: Aptamers are nucleic acid or peptide molecules that bind to specific target molecules with high affinity and specificity (Tuerk and Gold, Science 249:505 (1990); Ellington and Szostak, Nature 346:818 (1990), each of which is incorporated herein by reference in its entirety). DNA or RNA aptamers have been successfully generated that bind to a wide variety of entities, from large proteins to small organic molecules. See Eaton, Curr. Opin. Chem. Biol. 1:10-16 (1997); Famulok, Curr. Opin. Struct. Biol. 9:324-9 (1999); and Hermann and Patel, Science 287:820-5 (2000), each of which is incorporated herein by reference in its entirety. Aptamers can be RNA- or DNA-based and may contain riboswitches. Riboswitches are parts of mRNA molecules that directly bind to small target molecules, and their binding to targets affects gene activity. Therefore, depending on the presence or absence of their target molecules, mRNAs containing riboswitches directly participate in regulating their own activity. Generally, aptamers are engineered through repeated rounds of in vitro selection or, equivalently, SELEX (exponentially enriched ligand system evolution) to bind to a variety of molecular targets, such as small molecules, proteins, nucleic acids, and even cells, tissues, and organisms. Aptamers can be prepared by any known method, including synthetic, recombinant, and purified methods, and can be used alone or in combination with other aptamers specific to the same target. Furthermore, as described more fully herein, the term "aptamer" specifically includes "secondary aptamers" containing a shared sequence derived from comparing two or more known aptamers targeting a given target.

[0857] Ribozymes: According to another embodiment, nucleic acid-lipid particles are associated with ribozymes. Ribozymes are RNA molecular complexes with specific catalytic domains possessing endonuclease activity (Kim and Cech, Proc Natl Acad Sci USA. Dec 1987; 84(24):8788-92; Forster and Symons, Cell. Apr 24 1987; 49(2):211-20). For example, many ribozymes accelerate phosphoester transfer reactions with high specificity, typically cleaving only one of several phosphate esters in an oligonucleotide substrate (Cech et al., Cell. Dec. 1981; 27(3 Part 2):487-96; Michel and Westhof, J Mol Biol. Dec. 5, 1990; 216(3):585-610; Reinhold-Hurek and Shub, Nature. May 14, 1992; 357(6374):173-6). This specificity is attributed to the requirement that the substrate binds to the ribozyme's internal guide sequence (“IGS”) via specific base-pairing interactions prior to the chemical reaction.

[0858] At least six basic types of naturally occurring enzymatic RNAs are currently known. Each can catalyze the hydrolysis of RNA phosphodiester bonds in a trans-trans manner under physiological conditions (and thus cleave other RNA molecules). Typically, enzymatic nucleic acids function by first binding to a target RNA. This binding is achieved through the target-binding moiety of the enzymatic nucleic acid, which is adjacent to the enzymatically active part of the molecule used to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds to the target RNA through complementary base pairing, and once bound to the correct site, it cleaves the target RNA through enzymatic catalysis. Strategic cleavage of such target RNAs disrupts their ability to direct the synthesis of encoded proteins. After the enzymatic nucleic acid binds to and cleaves its RNA target, it is released from that RNA to seek another target and can repeatedly bind to and cleave new targets.

[0859] For example, enzymatic nucleic acid molecules can form hammerhead, hairpin, hepatitis D virus, class I intron, or RNase P RNA motifs (which require binding to an RNA-guided sequence) or Neurospora VS RNA motifs. Specific examples of hammerhead motifs are described in Rossi et al., Nucleic Acids Res., 11 September 1992; 20(17):4559-65. Examples of hairpin motifs are described in the following literature: Hampel et al. (European Patent Application Publication No. EP 0360257); Hampel and Tritz, Biochemistry, 13 June 1989; 28(12):4929-33; Hampel et al., Nucleic Acids Res., 25 January 1990; 18(2):299-304; and U.S. Patent No. 5,631,359. Examples of hepatitis D virus type motifs are described by Perrotta and Been, Biochemistry. Dec 1, 1992; 31(47):11843-52; examples of RNase P type motifs are described by Guerrier-Takada et al., Cell. Dec 1983; 35(3 Part 2):849-57; Neurospora VS RNase type motifs are described by Collins (Saville and Collins, Cell. May 18, 1990; 61(4):685-96; Saville and Collins, Proc Natl Acad Sci USA. October 1, 1991; 88(19):8826-30; Collins and Olive, Biochemistry. March 23, 1993; As described in 32(11):2795-9); and examples of class I introns are described in U.S. Patent No. 4,987,071. An important characteristic of the enzymatic nucleic acid molecules used is that they have specific substrate-binding sites complementary to one or more regions of the target gene's DNA or RNA, and that they have nucleotide sequences within or around these substrate-binding sites that confer RNA-cleaving activity to the molecule. Therefore, ribozyme constructs are not necessarily limited to the specific motifs mentioned herein.

[0860] Methods for generating ribozymes that target any polynucleotide sequence are known in the art. Ribozymes can be designed as described in International Patent Application Publications WO 93 / 23569 and WO 94 / 02595 (each expressly incorporated herein by reference), and synthesized as described therein for in vitro and in vivo testing.

[0861] Ribozyme activity can be optimized by altering the length of the ribozyme-binding arm or by chemically synthesizing ribozymes with modifications that prevent degradation by serum ribonuclease (see, for example, International Patent Application Publications WO 92 / 07065, WO93 / 15187 and WO 91 / 03162; European Patent Application Publication 92110298.4; U.S. Patent No. 5,334,711; and International Patent Application Publication WO 94 / 13688, which describes various chemical modifications that can be made to the sugar moiety of enzymatic RNA molecules), modifications that enhance their efficacy in cells, and removal of stem II bases to shorten RNA synthesis time and reduce chemical requirements.

[0862] Immunostimulatory oligonucleotides: Nucleic acids associated with lipid particles can be immunostimulatory, including immunostimulatory oligonucleotides (ISS; single-stranded or double-stranded) that induce an immune response when administered to a subject, which may be a mammal or other patient. ISSs include, for example, certain palindromes that result in hairpin secondary structures (see Yamamoto S. et al. (1992) J. Immunol. 148: 4072-4076, which are incorporated herein by reference in their entirety) or CpG motifs, as well as other known ISS features (such as multi-G domains, see WO 96 / 11266, which are incorporated herein by reference in their entirety).

[0863] Immune responses can be innate or adaptive. The immune system is divided into the more innate immune system in vertebrates and the acquired adaptive immune system, the latter further divided into humoral / cellular components. In some implementations, the immune response can be mucosal.

[0864] In some implementations, the immunostimulatory nucleic acid is immunostimulatory only when administered in combination with lipid particles, and not when administered in its "free form". This oligonucleotide is considered to be immunostimulatory.

[0865] Immunostimulatory nucleic acids (ISNAs) are considered non-sequence-specific when they do not require specific binding to target polynucleotides and reduction of target polynucleotide expression to elicit an immune response. Therefore, some INAs may contain sequences corresponding to regions of naturally occurring genes or mRNAs, but they can still be considered non-sequence-specific INAs.

[0866] In some embodiments, the immunostimulatory nucleic acid or oligonucleotide comprises at least one CpG dinucleotide. The oligonucleotide or CpG dinucleotide may be unmethylated or methylated. In another embodiment, the immunostimulatory nucleic acid comprises at least one CpG dinucleotide having a methylated cytosine. In some embodiments, the nucleic acid comprises a single CpG dinucleotide, wherein the cytosine in the CpG dinucleotide is methylated. In an alternative embodiment, the nucleic acid comprises at least two CpG dinucleotides, wherein at least one cytosine in the CpG dinucleotide is methylated. In another embodiment, each cytosine in the CpG dinucleotides present in the sequence is methylated. In yet another embodiment, the nucleic acid comprises a plurality of CpG dinucleotides, wherein at least one of the CpG dinucleotides comprises a methylated cytosine.

[0867] Lipid-based enhancement units, linking units, and attachment between nucleic acid agents and ligands.

[0868] In some implementations, the attachment between the lipid-based reinforcing unit and the connecting unit is a bond.

[0869] In some implementations, the attachment between the lipid-based reinforcing unit and the linking unit is partial (e.g., a portion containing a cleavable group).

[0870] In some implementations, the attachment between the lipid-based reinforcing unit and the connecting unit includes -C(=O)- connected to the connecting unit.

[0871] In some implementations, the attachment between the lipid-based enhancement unit and the nucleic acid agent is a bond.

[0872] In some implementations, the attachment between the lipid-based enhancement unit and the nucleic acid agent is partial (e.g., a portion containing a cleavable group).

[0873] In some implementations, the attachment between the lipid-based enhancement unit and the ligand is a bond.

[0874] In some implementations, the attachment between the lipid-based reinforcing unit and the ligand is partial (e.g., a portion containing a cleavable group).

[0875] In some implementations, the attachment between the linker and the nucleic acid agent is a bond.

[0876] In some implementations, the attachment between the linker and the nucleic acid agent is partial (e.g., a portion containing a cleavable group).

[0877] In some implementations, the attachment between the linker and the ligand is a bond.

[0878] In some implementations, the attachment between the linker and the ligand is partial (e.g., a portion containing a cleavable group).

[0879] In some implementations, the attachment between the linker and the ligand includes -C(=O)- connected to the linker.

[0880] The attachment between lipid-based reinforcing units, linking units, nucleic acid agents, and ligands can be cleavable or non-cleavable groups. Suitable groups include, for example, -NR-, -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O)2-, -S(=O)2NH-, or atomic chains, such as, but not limited to, alkylene, alkenylene, ynylene, arylalkylene, arylalene, arylynylene, heteroarylalkylene, heteroarylalene, heteroarylynylene, heterocyclic alkylene, heterocyclic alkenylene, heterocyclic yn ... Arylene, heteroarylene, heterocyclic, cycloalkylene, cycloalkylene, alkylarylalkylene, alkylaryleneylene, alkylarylynylene, alkenylarylalkylene, alkenylarylynylene, alkenylarylynylene, alkenylarylalkylene, alkenylarylalkylene, alkenylarylynylene, alkenylarylynylene, alkenylheteroarylalkylene, alkylheteroarylynylene, alkylheteroarylalkylene, alkenylheteroarylalkylene, alkenylheteroarylalkylene, alkenylheteroarylalkylene Alkyne-aryl, alkyne-arylalkylene, alkyne-arylene, alkyne-arylalkylene, alkyl heterocyclic alkylene, alkyl heterocyclic alkylene, alkyl heterocyclic alkylene, alkyne-aryl, alkyne-aryl, alkyne-aryl, alkyne-aryl, alkyne-aryl, alkyne-aryl, alkyne-aryl, alkyl aryl, alkyne-aryl, alkyne-aryl, alkyl aryl, alkyne-aryl, alkyne-aryl, alkyl heterocyclic alkylene The aryl or alkynyl aryl group, each of which may be substituted or unsubstituted, and one or more of the methylene groups may be interrupted or terminated by: -O-, -S-, -S(=O)-, -S(=O)2-, -NR-, -C(=O)-, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic, wherein R is hydrogen, acyl, aliphatic, or substituted aliphatic.

[0881] A cleavable group is a group that is sufficiently stable outside the cell but is cleaved upon entering a target cell to release the two parts of the group that remain together. In a preferred embodiment, the cleavage rate of the cleavable group in the target cell or under a first reference condition (which may be selected, for example, to simulate or represent intracellular conditions) is at least 10 times faster, preferably at least 100 times faster, than in the subject's blood or under a second reference condition (which may be selected, for example, to simulate or represent conditions present in blood or serum).

[0882] Cleavable groups are susceptible to the effects of cleavage agents, such as pH, redox potential, or the presence of degrading molecules. Generally, cleavage agents are more prevalent or present at higher levels or with higher activity within cells than in serum or blood. Examples of such degrading agents include: substrate-selective or non-substrate-specific redox agents, including, for example, oxidases or reductases (such as thiols) present in cells that can degrade redox cleavable groups by reduction; esterases; endosomes or agents that can create acidic environments, such as those resulting in pH five or lower; enzymes that can hydrolyze or degrade acid cleavable groups by acting as generalized acids; peptidases (which may be substrate-specific); and phosphatases.

[0883] Cleavable groups (such as disulfide bonds) can be pH-sensitive. Human serum has a pH of 7.4, while the average intracellular pH is slightly lower, ranging from approximately 7.1 to 7.3. Endosomes are more acidic, with a pH in the range of 5.5 to 6.0, while lysosomes are even more acidic, with a pH of approximately 5.0. Some linkers will have cleavable groups that break down at a preferred pH, thereby releasing cationic lipids from intracellular ligands or into desired compartments of the cell.

[0884] Conjugates may contain cleavable groups that can be broken down by specific enzymes. The type of cleavable group incorporated into the conjugate may depend on the cell type to be targeted. For example, liver-targeting ligands can be attached to cationic lipids via a chemical moiety containing an ester group. Hepatocytes are rich in esterases, and therefore this group will be cleaved more efficiently in hepatocytes compared to cell types that are not rich in esterases. Other cell types rich in esterases include cells of the lung, renal cortex, and testes.

[0885] When targeting cell types rich in peptidase (such as hepatocytes and synovial cells), coupling groups containing peptide bonds can be used.

[0886] Typically, the suitability of a candidate cleavable group can be assessed by testing its ability to cleave the candidate group by a degrading agent (or condition). It is also desirable to test the candidate cleavable group's resistance to cleavage in blood or upon contact with other non-target tissues. Thus, a relative susceptibility to cleavage can be determined between a first condition and a second condition, wherein the first condition is selected to indicate cleavage in target cells, and the second condition is selected to indicate cleavage in other tissues or biological fluids (e.g., blood or serum). Evaluation can be performed in cell-free systems, in cells, in cell cultures, in organ or tissue cultures, or in a whole animal. It may be useful to perform an initial evaluation under cell-free or culture conditions and confirm this with further evaluation in a whole animal. In a preferred embodiment, the useful candidate compound exhibits a cleavage rate at least 2, 4, 10, or 100 times faster in cells (or in vitro conditions selected to simulate intracellular conditions) compared to blood or serum (or in vitro conditions selected to simulate intracellular conditions).

[0887] Redox-cleavable groups. A class of cleavable groups are redox-cleavable groups that cleave upon reduction or oxidation. Examples of reducible cleavable groups are disulfide linkers (—S—S—). To determine whether a candidate cleavable group is a suitable “reducible cleavable linker,” or, for example, whether it is suitable for use with a specific iRNA moiety and a specific target, the methods described herein can be consulted. For example, candidates can be evaluated by co-incubation with dithiothreitol (DTT) or other reducing agents using reagents known in the art, conditions that mimic the cleavage rate observed in cells (e.g., target cells). Candidates can also be evaluated under conditions selected to mimic blood or serum conditions. In a preferred embodiment, the candidate compound cleaves at most 10% in blood. In a preferred embodiment, the useful candidate compound degrades at least 2, 4, 10, or 100 times faster in cells (or under in vitro conditions selected to mimic intracellular conditions) compared to blood (or under in vitro conditions selected to mimic intracellular conditions). The cleavage rate of candidate compounds can be determined using standard enzyme kinetic assays under conditions selected to simulate intracellular media and compared with those selected to simulate extracellular media.

[0888] Phosphate-based cleavable groups. Phosphate-based cleavable groups are cleaved by agents that degrade or hydrolyze the phosphate group. Examples of agents that cleave phosphate groups in cells are enzymes, such as cellular phosphatases. In some embodiments, the phosphate-based linker is —O—P(=O)(OR) k —O—、—O—P(=S)(OR k )—O—、—O—P(=S)(SR k )—O—、—S—P(=O)(OR k—O—、—O—P(=O)(OR k )—S—、—S—P(=O)(OR k —S—、—O—P(=S)(OR k )—s—、—S—P(=S)(OR k )—O—、—O—P(=O)(R k )—O—、—O—P(=S)(R k )—O—、—S—P(=O)(R k )—O—、—S—P(=S)(R k )—O—、—S—P(=O)(R k )—S—or—O—P(=S)(R k In some embodiments, the phosphoric acid-based linking group is —O—P(=O)(OH)—O—, —O—P(=S)(OH)—O—, —O—P(=S)(SH)—O—, —S—P(=O)(OH)—O—, —O—P(=O)(OH)—S—, —S—P(=O)(OH)—S—, —O—P(=S)(OH)—S—, —S—P(=S)(OH)—O—, —O—P(=O)(H)—O—, —O—P(=S)(H)—O—, —S—P(=S)(H)—O—, —S—P(=O)(H)—S— or —O—P(=S)(H)—S—. In some embodiments, the phosphoric acid-based linking group is —O—P(=O)(OH)—O—.

[0889] Acid-cleavable groups. Acid-cleavable groups are linking groups that cleave under acidic conditions. In a preferred embodiment, the acid-cleavable group is cleaved in an acidic environment with a pH of about 6.5 or lower (e.g., about 6.0, 5.5, 5.0 or lower), or by an agent (such as an enzyme) that can act as a generalized acid. In cells, specific low-pH organelles (such as endosomes and lysosomes) can provide a cleavage environment for acid-cleavable linking groups. Examples of acid-cleavable groups include, but are not limited to, hydrazones, esters, and esters of amino acids. Acid-cleavable groups may have the general formula —C═NN—, C(O)O, or —OC(O). A preferred embodiment is when the carbon atom (alkoxy group) attached to the oxygen of the ester is aryl, substituted alkyl, or tertiary alkyl (such as dimethylpentyl or tert-butyl). These candidates can be evaluated using methods similar to those described above.

[0890] Ester-based cleavable groups. Ester-based cleavable groups are cleaved by enzymes in the cell, such as esterases and amidases. Examples of ester-based cleavable groups include, but are not limited to, esters with alkylene, alkenyl, and ynylene groups. The ester-cleavable linker has the general formula —C(O)O— or —OC(O)—. These candidates can be evaluated using methods similar to those described above.

[0891] Peptide-based cleavable groups. Peptide-based cleavable groups are cleaved by enzymes in the cell, such as peptidases and proteases. Peptide-based cleavable groups are peptide bonds formed between amino acids to produce oligopeptides (e.g., dipeptides, tripeptides, etc.) and polypeptides. Peptide-based cleavable groups do not contain an amide group (—C(O)NH—). Amide groups can form between any alkylene, alkenyl, or alkyne groups. A peptide bond is a special type of amide bond formed between amino acids to produce peptides and proteins. Peptide-based cleavable groups are generally limited to peptide bonds (i.e., amide bonds) formed between amino acids that produce peptides and proteins, and do not contain the entire amide functional group. Peptide-based cleavable linkers have the general formula —NHCHR A C(O)NHCHR B C(O)—, where R A and R B The R group consists of two adjacent amino acids. These candidates can be evaluated using methods similar to those described above. As used herein, "carbohydrate" refers to a compound that is itself composed of one or more monosaccharide units having at least six carbon atoms (which may be linear, branched, or cyclic), wherein an oxygen, nitrogen, or sulfur atom is bonded to each carbon atom; or a compound having a carbohydrate moiety as part of it, which is composed of one or more monosaccharide units, each monosaccharide unit having at least six carbon atoms (which may be linear, branched, or cyclic), wherein an oxygen, nitrogen, or sulfur atom is bonded to each carbon atom. Representative carbohydrates include sugars (monosaccharides, disaccharides, trisaccharides, and oligosaccharides containing about 4-9 monosaccharide units) and polysaccharides (such as starch, glycogen, cellulose, and polysaccharide gums). Specific monosaccharides include C5 and above (preferably C5-C8) sugars; disaccharides and trisaccharides, including sugars having two or three monosaccharide units (preferably C5-C8).

[0892] Synthesis method

[0893] In some aspects, this disclosure provides a method for preparing the compounds described herein (e.g., lipid-based enhancers).

[0894] In some aspects, this disclosure provides a compound that is obtainable or acquired by the methods described herein for preparing compounds (e.g., lipid-based enhancers).

[0895] In some aspects, this disclosure provides an intermediate as described herein, which is suitable for a method of preparing the compounds described herein (e.g., lipid-based enhancers).

[0896] The compounds disclosed herein can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[0897] In the description of the synthetic methods described herein and in any reference synthetic methods used to prepare the starting materials, it should be understood that all proposed reaction conditions (including the selection of solvents, reaction atmospheres, reaction temperatures, experimental durations and post-treatment procedures) may be selected by those skilled in the art.

[0898] Those skilled in the art of organic synthesis should understand that the functional groups present on various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0899] It should be understood that during the synthesis of the disclosed compounds in the methods defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent them from undergoing undesirable reactions. Skilled chemists will understand when such protection is needed, and how to in place such protecting groups and subsequently remove them. For examples of protecting groups, see one of the many general references on the subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to skilled chemists suitable for removing the protecting groups involved, chosen to achieve the removal of the protecting groups with minimal interference to other groups in the molecule. Therefore, if the reactants include groups such as amino, carboxyl, or hydroxyl groups, it may be necessary to protect these groups in some of the reactions mentioned herein.

[0900] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups (such as alkanoyl groups, such as acetyl), alkoxycarbonyl groups (such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl) or aryl acyl groups (such as benzoyl). Suitable protecting groups for hydroxyl or alkylhydroxyl groups may be, for example, acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytriphenylmethyl (DMT), methoxymethyl ether (MOM), methoxytriphenylmethyl (MMT), p-methoxybenzyl ether (PMB), p-methoxyphenyl ether (PMP), neopentanoyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), triphenylmethyl (triphenylmethyl, Tr), silyl ethers (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ether), methyl ethers, or ethoxyethyl ethers (EE). Suitable protecting groups for 1,2-diols may be, for example, acetals. Suitable protecting groups for 1,3-diols may be, for example, tetraisopropyl-disiloxanediol (TIPDS).

[0901] The deprotection conditions for the aforementioned protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups (such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups) can be removed, for example, by hydrolysis with a suitable base (such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide). Alternatively, acyl groups (such as tert-butoxycarbonyl groups) can be removed, for example, by treatment with a suitable acid (such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid), and arylmethoxycarbonyl groups (such as benzyloxycarbonyl groups) can be removed, for example, by hydrogenation on a catalyst (such as palladium on carbon) or by treatment with a Lewis acid (such as tri(trifluoroacetic acid)boron). Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with an alkylamine (such as dimethylaminopropylamine) or with hydrazine.

[0902] Suitable protecting groups for hydroxyl groups are, for example, acyl groups (e.g., alkanoyl groups, such as acetyl), aromatic acyl groups (e.g., benzoyl), or arylmethyl groups (e.g., benzyl). The deprotection conditions for these protecting groups will necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups (such as alkanoyl or aromatic acyl groups) can be removed, for example, by hydrolysis with a suitable base (such as an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or ammonia). Alternatively, arylmethyl groups (such as benzyl groups) can be removed, for example, by hydrogenation on a catalyst (such as palladium on carbon).

[0903] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl groups (which can be removed, for example, by hydrolysis with a base (such as sodium hydroxide), or tert-butyl groups (which can be removed, for example, by treatment with an acid (such as an organic acid, such as trifluoroacetic acid), or benzyl groups (which can be removed, for example, by hydrogenation on a catalyst (such as palladium on carbon)).

[0904] Conveniently, the reaction of the compound is carried out in the presence of a suitable solvent, which is preferably inert under the corresponding reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; and ethylene glycol ethers such as ethylene glycol. Monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketones, such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of said solvents or mixtures with water.

[0905] Depending on the reaction steps and the conditions used, the reaction temperature is suitable between approximately -100°C and 300°C.

[0906] Depending on the reactivity of the corresponding compound and the corresponding reaction conditions, the reaction time generally ranges from less than a minute to several days. A suitable reaction time can be readily determined using methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, a suitable reaction time typically ranges from 10 minutes to 48 hours.

[0907] Furthermore, other compounds disclosed herein can be readily prepared using the methods described herein, combined with ordinary skills in the art. Those skilled in the art will readily understand that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds.

[0908] As those skilled in the art of organic synthesis will understand, the compounds of this disclosure are readily obtained by a variety of synthetic routes, some of which are illustrated by way of example in the accompanying examples. Those skilled in the art will readily recognize what reagents and reaction conditions to use, and how to apply and adjust them, in any particular case, as necessary or applicable, in order to obtain the compounds of this disclosure. Furthermore, some of the compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under suitable conditions, for example, by applying standard synthetic methods, such as reduction, oxidation, addition, or substitution reactions, to convert one functional group present in a compound of this disclosure or a suitable precursor molecule into another functional group; these methods are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting groups (or protective groups) as necessary or applicable; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in PGM Wuts, TW Greene, “Greene's Protective Groups in Organic Synthesis”. 第 4th edition (2006) (John Wiley & Sons).

[0909] The general route for preparing the compounds of this application is described in Scheme A herein.

[0910] Option A

[0911]

[0912] Compounds (e.g., nucleic acid agents, nucleic acid agents containing lipid-based enhancement units, and conjugates) are prepared by solid-phase synthesis or synthesized via post-synthetic conjugation according to standard synthetic protocols.

[0913] In short, oligonucleotide synthesis was performed on a solid support to incorporate each nucleoside phosphoramidite from the 3' to the 5' end, thereby preparing oligonucleotide single chains. ETT or BTT was used as an activator for the coupling reaction. Iodine in water / pyridine / THF was used to oxidize the phosphite triester (P(III)) to obtain the phosphate backbone, and DDTT was used to prepare the thiophosphate linker. The oligonucleotides were cleaved from the solid support using an aqueous ammonium solution, and the protecting groups were removed bulk. The crude oligonucleotides were then concentrated and purified by strong anion exchange or reversed-phase HPLC. The purified fractions were combined and concentrated.

[0914] In some cases, oligonucleotide single chains are then conjugated to targeting ligands (e.g., peptides, antibodies) via synthetic post-conjugation to obtain conjugated compounds. The conjugation reaction is performed using standard conjugation methods. The crude conjugated compounds are further purified by strong anion exchange or reversed-phase HPLC. The purified fractions are combined and concentrated.

[0915] The synthesized single strands were then dialyzed against water using a MidiTrap G-25 column, concentrated, and their OD values ​​were measured. Based on equimolar amounts, the sense and antisense strands were annealed at 95°C for 5 min and cooled to room temperature to obtain conjugated dichains with a purity >90%. The solution of the dichains was lyophilized to obtain the desired conjugate, and its amount was calculated based on the molar amount of single strands consumed during annealing.

[0916] Bioassay

[0917] Once compounds (e.g., lipid-based enhancers) or conjugates designed, selected, prepared, and / or optimized using the methods described above are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compound, scaffold, or conjugate possesses biological activity. For example, the compound, scaffold, or conjugate can be characterized by conventional assays (including, but not limited to, those described below) to determine whether they possess the desired activity (e.g., target-binding activity) and / or specificity and / or stability.

[0918] Furthermore, high-throughput screening can be used to accelerate analyses using such assays. Therefore, it may be possible to rapidly screen the activity of molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. High-throughput assays may be performed using one or more different assay techniques, including but not limited to those described below.

[0919] Various in vitro or in vivo bioassays can be applied to detect the effects of the compounds, scaffolds, or conjugates disclosed herein. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility variation assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0920] In some implementations, bioassays are described in the examples herein.

[0921] In some aspects, this disclosure provides a pharmaceutical composition comprising the compounds, scaffolds, or conjugates of this disclosure as active ingredients.

[0922] As used herein, the term "composition" is intended to cover products containing specified amounts of specified ingredients, and any products directly or indirectly produced from combinations of specified amounts of specified ingredients.

[0923] Pharmaceutical compositions suitable for injectable applications include sterile aqueous solutions (in the water-soluble case) or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, etc. (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid suitable for easy syringe handling. It must be stable under manufacturing and storage conditions and must be protected against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol) and suitable mixtures thereof. Suitable flowability can be maintained, for example, by using coatings (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents in the composition, such as sugars, polyols (such as mannitol and sorbitol), and sodium chloride. Long-lasting absorption of injectable compositions can be achieved by including absorption-retarding agents, such as aluminum monostearate and gelatin, in the composition.

[0924] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound, along with one or more of the aforementioned components, into a suitable solvent, followed by filtration and sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile medium containing a base dispersion medium and other desired components from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, preparation methods include vacuum drying and freeze-drying, which produce powders of the active ingredient and any other desired components from solutions that have been previously sterile filtered.

[0925] The formulations disclosed herein may be in the form of an aqueous solution comprising an aqueous mediator. The aqueous mediator component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of: solubilizers, chelating agents, preservatives, tension agents, viscosity / suspending agents, buffers, and pH adjusters, as well as mixtures thereof.

[0926] Any suitable solubilizer may be used. Examples of solubilizers include cyclodextrins, such as those selected from the group consisting of: hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfonyl ether, branched-chain-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0927] Any suitable chelating agent may be used. Suitable chelating agents include those selected from the group consisting of: ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate and tetrasodium edetate, and mixtures thereof.

[0928] Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of: quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben, and mixtures thereof.

[0929] Aqueous mediators may also include tension agents to regulate surface tension (osmotic pressure). Tension agents may be selected from the group consisting of: glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0930] To adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically an inorganic acid or a metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, with sodium hydroxide and / or hydrochloric acid being preferred. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base simultaneously, depending on the formulation; adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0931] Aqueous mediators may also contain buffers to stabilize pH. When used, buffers are selected from the group consisting of: phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid, or salts thereof, including disodium tetraborate), citrate buffers (such as citric acid, or salts thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0932] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0933] The compositions disclosed herein may be in forms suitable for oral use (e.g., as tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as fine powders or liquid aerosols), administration by blowing (e.g., as fine powders), or for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0934] The compositions disclosed herein can be obtained using conventional procedures for conventional pharmaceutical excipients known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0935] An effective amount of the compound disclosed herein for use in therapy is sufficient to treat or prevent the inflammasome-related conditions mentioned herein, slow their progression, and / or alleviate symptoms associated with the condition.

[0936] An effective amount of the compound disclosed herein for use in therapy is sufficient to treat the inflammasome-related conditions mentioned herein, slow their progression, and / or alleviate symptoms associated with the condition.

[0937] According to well-known medical principles, the dosage of compounds of formula (I), (II), (III) or (IV) for therapeutic or preventative purposes will vary naturally depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0938] How to use

[0939] In some aspects, this disclosure provides a method for regulating (e.g., reducing or eliminating) the expression of a target gene in a subject, the method comprising administering a conjugate of this disclosure to the subject.

[0940] In some aspects, this disclosure provides a method for regulating (e.g., reducing or eliminating) the expression of a target gene in the cells or tissues of a subject, the method comprising administering a conjugate of this disclosure to the subject.

[0941] In some aspects, this disclosure provides a method for delivering a nucleic acid agent to a subject, the method comprising administering the conjugate of this disclosure to the subject.

[0942] In some aspects, this disclosure provides a method for treating or preventing a disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the conjugate of this disclosure.

[0943] In some aspects, this disclosure provides a conjugate of the present disclosure for regulating (e.g., reducing or eliminating) the expression of a target gene in a subject.

[0944] In some aspects, this disclosure provides a conjugate of the present disclosure for regulating (e.g., reducing or eliminating) the expression of a target gene in the cells or tissues of a subject.

[0945] In some aspects, this disclosure provides a conjugate for delivering a nucleic acid agent to a subject.

[0946] In some aspects, this disclosure provides a conjugate of the present disclosure for the treatment or prevention of disease in a subject in need.

[0947] In some respects, this disclosure provides for the use of the conjugates of this disclosure in the manufacture of medicaments for regulating (e.g., reducing or eliminating) the expression of target genes in a subject.

[0948] In some respects, this disclosure provides for the use of the conjugates of this disclosure in the manufacture of medicaments for regulating (e.g., reducing or eliminating) the expression of target genes in the cells or tissues of a subject.

[0949] In some respects, this disclosure provides for the use of the conjugates of this disclosure in the manufacture of medicaments for delivering nucleic acid agents to subjects.

[0950] In some respects, this disclosure provides for the use of the conjugates of this disclosure in the manufacture of a medicament for treating or preventing a disease in a subject in need.

[0951] In some implementations, the subjects are cells.

[0952] In some implementations, the subject is a tissue.

[0953] In some implementations, the subjects are humans.

[0954] In some implementations, the target genes are factor VII, Eg5, PCSK9, TPX2, apoB, SAA, TTR, HBV, HCV, RSV, PDGF β gene, Erb-B gene, Src gene, CRK gene, GRB2 gene, RAS gene, MEKK gene, JNK gene, RAF gene, Erk1 / 2 gene, PCNA (p21) gene, MYB gene, JUN gene, FOS gene, BCL-2 gene, cyclin D gene, VEGF gene, EGFR gene, cyclin A gene, cyclin E gene, WNT-1 gene, β-catenin gene, c-MET gene, PKC gene, NFKB gene, STAT3 gene, survivin gene, Her2 / Neu gene, topoisomerase I gene, and topoisomerase II gene. Mutations in α gene, p73 gene, p21 (WAF1 / CIP1) gene, p27 (KIP1) gene, PPM1D gene, RAS gene, caveolin I gene, MIB I gene, MTAI gene, M68 gene, tumor suppressor gene, p53 tumor suppressor gene, LDHA, or any combination thereof.

[0955] In some implementations, the disease is characterized by the unwanted expression of target genes.

[0956] In some implementations, administration results in a decrease or elimination of the expression of the target gene in the subject.

[0957] In some implementations, the disease is a viral infection, such as HCV, HBV, HPV, HSV, or HIV infection.

[0958] In some implementations, the disease is cancer.

[0959] In some implementation schemes, cancer includes biliary tract cancer, bladder cancer, transitional cell carcinoma, urothelial carcinoma, brain cancer, glioma, astrocytoma, breast cancer, metaplastic carcinoma, cervical cancer, cervical squamous cell carcinoma, rectal cancer, colorectal cancer, colon cancer, hereditary nonpolyposis colorectal cancer, colorectal adenocarcinoma, gastrointestinal stromal tumor (GIST), endometrial cancer, endometrial stromal sarcoma, esophageal cancer, esophageal squamous cell carcinoma, ocular melanoma, uveal melanoma, gallbladder cancer, gallbladder adenocarcinoma, renal cell carcinoma, clear cell renal cell carcinoma, transitional cell carcinoma, urothelial carcinoma, nephroblastoma, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and chronic myelomonocytic leukemia. Blood disorders (CMML), liver cancer, liver tumors, hepatocellular carcinoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, lung cancer, non-small cell lung cancer (NSCLC), mesothelioma, B-cell lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, T-cell lymphoma, non-Hodgkin lymphoma, precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, multiple myeloma, nasopharyngeal carcinoma (NPC), neuroblastoma, oropharyngeal carcinoma, oral squamous cell carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, pseudopapillary tumor, acinar cell carcinoma, prostate cancer, prostate adenocarcinoma, skin cancer, melanoma, malignant melanoma, cutaneous melanoma, small intestine cancer, gastric cancer, gastric adenocarcinoma, gastrointestinal stromal tumor (GIST), uterine cancer or uterine sarcoma.

[0960] In some implementation schemes, the cancer is liver cancer, liver cancer, hepatocellular carcinoma, hepatocellular carcinoma, cholangiocarcinoma, or hepatoblastoma.

[0961] In some implementations, the disease is a proliferative, inflammatory, autoimmune, neurological, ocular, respiratory, metabolic, dermatological, auditory, liver, kidney, or infectious disease. In some implementations, the disease is a liver disease.

[0962] definition

[0963] Unless otherwise stated, the following terms used in the specification and claims have the same meanings as stated below.

[0964] Not to be limited by this statement, it should be understood that while various options for variables are described herein, this disclosure is intended to cover feasible implementations having combinations of these options. This disclosure may be construed as excluding infeasible implementations resulting from specific combinations of these options.

[0965] As used herein, "hydrocarbon chain" refers to a straight or branched portion consisting of hydrogen and carbon, unless otherwise specified with one or more substitutions. In some embodiments, the hydrocarbon chain is a saturated hydrocarbon chain (e.g., alkyl). In some embodiments, the hydrocarbon chain is an unsaturated hydrocarbon chain (e.g., containing one or more double bonds and / or one or more triple bonds (e.g., alkenyl or ynyl)). In some embodiments, the two substituents of the hydrocarbon chain (e.g., two R groups) L’ The substituent, together with one or more intermediate atoms, forms a ring moiety (e.g., C3-C8 cycloalkyl or 3- to 8-membered heterocyclic alkyl), wherein the substituent comprises at least one ring atom. When the ring moiety is located in an inner position of the hydrocarbon chain, the carbon atoms of the hydrocarbon chain (e.g., C2-C4) 30 ) via the shortest path count across the loop (e.g., It contains two carbon atoms in a hydrocarbon chain, each of which Indicates the attachment point to the rest of the hydrocarbon chain. When the ring portion is located at the end of the hydrocarbon chain, the carbon atoms of the hydrocarbon chain (e.g., C2-C) 30 ) Count the longest path within the ring (e.g., It contains two carbon atoms in a hydrocarbon chain, of which This indicates the attachment point to the rest of the hydrocarbon chain.

[0966] As used herein, a “heterohydrocarbon chain” refers to a straight or branched portion consisting of hydrogen, carbon, and one or more heteroatoms (such as O, N, S, P, or Se) (e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 or 1-7 or 1-8 or 1-9 or 1-10 or 1-11 or 1-12 or 1-13 or 1-14 heteroatoms, or, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 heteroatoms), excluding one or more additionally specified substitutions. It should be understood that an "X-membered" heterohydrocarbon chain refers to a heterohydrocarbon chain in which the total number of carbon and heteroatoms along the longest path of the chain is "X" (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30-membered heterohydrocarbon chains), excluding one or more additionally specified substitutions. In some embodiments, the heterohydrocarbon chain is a saturated heterohydrocarbon chain. In some embodiments, the heterohydrocarbon chain is an unsaturated heterohydrocarbon chain (e.g., containing one or more double bonds and / or one or more triple bonds). In some embodiments, the two substituents of the heterohydrocarbon chain (e.g., two R groups) L’ The substituent, together with one or more intermediate atoms, forms a ring moiety (e.g., C3-C8 cycloalkyl or 3- to 8-membered heterocyclic alkyl), wherein the substituent comprises at least one ring atom. When the ring moiety is located inside the heterochain, the atoms of the heterochain (e.g., 2-30 members) are counted via the shortest path through the ring (e.g., It contains two atoms in a heterohydrocarbon chain, each of which Indicates the attachment point to the rest of the heterohydrocarbon chain. When the ring portion is at the end of the heterohydrocarbon chain, the atoms of the heterohydrocarbon chain (e.g., 2-30 members) are counted via the longest path within the ring (e.g., Two atoms comprising a heterohydrocarbon chain, wherein Indicates the attachment point with the rest of the heterohydrocarbon chain.

[0967] As used herein, “alkyl,” “C1, C2, C3, C4, C5, or C6 alkyl,” or “C1-C6 alkyl” is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include portions having one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, the straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in another embodiment, the straight-chain or branched alkyl group has four or fewer carbon atoms.

[0968] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl group or an alkyl group in which one or more hydrogen atoms on one or more carbons of a hydrocarbon skeleton are replaced by a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate, alkyl sulfinyl, sulfonate, sulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0969] As used herein, the term "alkenyl" includes an unsaturated aliphatic group of similar length and possibly substituted with alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, the straight-chain or branched alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight chains and C3-C6 for branched chains). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

[0970] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl in which one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton are replaced by a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate, alkyl sulfinyl, sulfonate, sulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0971] As used herein, the term "alkynyl" includes an unsaturated aliphatic group of similar length and possibly substituted with alkyl groups described above, but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, nonynyl, decanynyl) and branched-chain alkynyl groups. In some embodiments, the straight-chain or branched-chain alkynyl group has six or fewer carbon atoms in its skeleton (e.g., C2-C6 for straight chains and C3-C6 for branched chains). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenyl linker" or "C2-C6 alkenyl linker" is intended to include a C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon group. For example, C2-C6 imenoyl linkers are intended to include C2, C3, C4, C5, and C6 imenoyl linker groups.

[0972] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl group or an alkynyl group in which one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton are replaced by a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate, alkyl sulfinyl, sulfonate, sulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0973] Other optional substituted portions (such as optional substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted portion and the portion having one or more specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0974] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C4). 12 C3-C 10 Cycloalkyl refers to monocyclic or polycyclic (e.g., fused ring, bridged ring, or spirocyclic) systems of saturated or partially unsaturated hydrocarbons (C3-C8). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cycloalkyl groups, only one of the rings in the cycloalkyl group needs to be non-aromatic.

[0975] As used herein, the term "heterocyclic alkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spirocyclic), or 11-14 membered tricyclic (fused, bridged, or spirocyclic) system having one or more heteroatoms (such as O, N, S, P, or Se), for example 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example 1, 2, 3, 4, 5, or 6 heteroatoms, unless otherwise specified, the heteroatoms are independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heterocyclic alkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, dioxyl, tetrahydrofuranyl, isoindolinyl, indololinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, ethylene oxide, aziridine, oxazolyl, thioheptanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazaheptanyl, 1,4-oxazolylheptanyl, 2-oxa-5 -Azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1 ,5'-furano[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7, 8-Tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, 5,6-dihydro-4H-cyclopentano[b]thiophene, etc. In the case of polycyclic heterocyclic alkyl groups, only one of the rings in the heterocyclic alkyl group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0976] As used herein, the term "aryl" includes aromatic groups, including "conjugated" groups, or polycyclic systems having one or more aromatic rings and containing no heteroatoms in the ring structure. The term aryl includes both monovalent and divalent types. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. Conveniently, aryl is phenyl.

[0977] As used herein, the term "heteroaryl" is intended to include stable 5, 6, or 7-membered monocyclic or 7, 8, 9, 10, 11, or 12-membered bicyclic aromatic heterocycles composed of a carbon atom and one or more heteroatoms (e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or, for example, 1, 2, 3, 4, 5, or 6 heteroatoms), which are independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., and S(O) p (where p = 1 or 2). It should be noted that the total number of S and O atoms in an aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetraazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic groups to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isooxazolyl). In some embodiments, the heteroaryl group is thiophene or benzothiophene. In some embodiments, the heteroaryl group is thiophene. In some embodiments, the heteroaryl group is benzothiophene.

[0978] In addition, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic and bicyclic groups, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazolium, benzothiophene, quinoline, isoquinoline, naphthidine, indole, benzofuran, purine, benzofuran, denitropurine, and indene.

[0979] Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings may be substituted at one or more ring positions (e.g., the cyclic carbon or a heteroatom such as N) with substituents as described above; such substituents are, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic ester, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, etc. Aminocarbonyl, alkylthiocarbonyl, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidin, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkylsulfinyl, sulfonate, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, aralkyl, or aromatic or heteroaromatic moiety. Aryl and heteroaromatic groups may also be fused or bridged with non-aromatic alicyclic or heterocyclic groups to form polycyclic systems (e.g., tetrahydronaphthalene, methylenedioxyphenyl, such as benzo[d][1,3]dioxacyclopenten-5-yl).

[0980] As used herein, the term "substituted" means that one or more hydrogen atoms on a specified atom are replaced by a group selected from the specified group, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution produces a stable compound. When the substituent is an oxo or ketone group (i.e., =O), two hydrogen atoms on the atom are replaced. Ketone substituents are not present on aromatic moieties. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" mean a compound that is robust enough to be isolated from the reaction mixture with useful purity and formulated into an effective therapeutic agent.

[0981] When a bond pointing to a substituent intersects with a bond connecting two atoms in the ring, the substituent may bond to any atom in the ring. When a substituent is listed but not specified by which atom it bonds to the remainder of the compound in the given formula, the substituent may bond to any atom in the formula. Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds.

[0982] When any variable (e.g., R) appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for any other occurrence. Thus, for example, if a display group is substituted by 0-2 R moieties, that group may optionally be substituted by at most two R moieties, and R is independently selected from the definition of R each time it appears. Furthermore, combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds.

[0983] As used in this article, the term "adjacent" describes the relationship between two parts that are bonded to two adjacent carbon atoms.

[0984] As used herein, the term "hydroxyl" or "hydroxyl group" includes those having -OH or -O. - . group.

[0985] As used in this article, the term "halogenated" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0986] The terms “halogenated alkyl” or “halogenated alkoxy” refer to alkyl or alkoxy groups that are substituted with one or more halogen atoms.

[0987] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl in which one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton are replaced by a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate, alkyl sulfinyl, sulfonate, sulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0988] As used herein, the term "alkoxy" or "alkoxy group" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently attached to an oxygen atom. Examples of alkoxy groups or alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include haloalkoxy groups. Alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate ester, hypophosphonate ester, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amidinyl, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkyl sulfinyl, sulfonate ester, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, aralkyl, or aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0989] As used herein, the expressions “one or more of A, B or C”, “one or more of A, B or C”, “one or more of A, B and C”, “one or more of A, B and C”, “selected from the group consisting of A, B and C”, “selected from A, B and C”, etc., are used interchangeably and all refer to the group consisting of A, B and / or C, that is, one or more A, one or more B, one or more C or any combination thereof, unless otherwise indicated.

[0990] It should be understood that this disclosure provides methods for synthesizing the compounds, scaffolds, and conjugates described herein. This disclosure also provides detailed methods for synthesizing various disclosed compounds, scaffolds, and conjugates according to the schemes and examples shown herein.

[0991] It should be understood that throughout this specification, when a composition is described as having, including, or comprising specific components, it is anticipated that the composition is substantially composed of or consisting of the listed components. Similarly, when a method or process is described as having, including, or comprising specific process steps, the process is also substantially composed of or consisting of the listed processing steps. Furthermore, it should be understood that the order of steps for performing certain actions is irrelevant as long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0992] It should be understood that the synthetic process disclosed herein is compatible with a variety of functional groups, and therefore a wide range of substituted starting materials can be used. The process typically provides the desired final compound at or near the end of the process, although in some cases it may be desirable to further convert the compound into its pharmaceutically acceptable salt.

[0993] It should be understood that the compounds, scaffolds, and conjugates of this disclosure can be prepared in a variety of ways, using commercially available raw materials, compounds known in the literature, or readily prepared intermediates, through standard synthetic methods and procedures known to those skilled in the art, or synthetic schemes that are obvious to those skilled in the art based on the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as for the transformation and manipulation of functional groups, are available from relevant scientific literature or standard textbooks in the field. While not limited to any one or more sources, classic literature incorporated herein by reference, such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 第 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 第 The 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are all known and widely accepted reference books on organic synthesis in the field of organic synthesis.

[0994] Those skilled in the art will notice that the order of certain steps in the reaction sequence and synthetic scheme described herein can be altered, such as the introduction and removal of protecting groups. Those skilled in the art will recognize that certain groups may need to be protected from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis. 第3 ed., John Wiley & Sons: NewYork, 1999.

[0995] It should be understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of compounds, scaffolds, and conjugates to provide such treatment or prevention as described herein. It should be further understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of compounds, scaffolds, and conjugates to prepare a medicine for treating or preventing such conditions. Treatment or prevention includes treating or preventing human or non-human animals, including rodents and other disease models.

[0996] It should be understood that, unless otherwise stated, any description of treatment methods includes the use of compounds, scaffolds, and conjugates to provide such treatments as described herein. It should be further understood that, unless otherwise stated, any description of methods of treatment includes the use of compounds, scaffolds, and conjugates to prepare medicaments for treating such conditions. Treatments include treatment of humans or non-human animals, including rodents and other disease models.

[0997] As used herein, the term “subject” may be used interchangeably with the term “subject in need,” both referring to a subject who has a disease or an increased risk of developing it. “Subject” includes mammals. Mammals may be, for example, humans or suitable non-human mammals such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. Subjects may also be birds or poultry. In some embodiments, the mammal...

Claims

1. A lipid-based enhancer, which is a compound of formula (I), (II), (III) or (IV): (I)， (II), (III), or (IV), Or its pharmaceutically acceptable salt, wherein: L represents the lipid portion; B is H, C1-C6 alkyl, or nucleobase moiety; V is -O-, -NR V -or-C(R) V )2-; Each R V It is a C1-C6 alkyl group that is independently H or optionally substituted with one or more halogens; X is H, halogen, or -OR X ; R X It is H, C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 aryl), wherein the C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 Aryl) optionally by one or more R Xa Replace; or R X and R 4 Together they form C1-C6 alkylene groups; Each R Xa Independently, it is a halogen, a C1-C6 alkyl or -O-(C1-C6 alkyl), wherein the C1-C6 alkyl or -O-(C1-C6 alkyl) is optionally substituted with one or more halogens; Y is H, a C1-C6 alkyl group optionally substituted with one or more halogens, or -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 hydroxyl protecting group; Each R Y It is independently an H or optionally a C1-C6 alkyl group substituted with one or more halogens or cyano groups; Z is H, a C1-C6 alkyl group optionally substituted with one or more halogens, or -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 hydroxyl protecting group; Each R Z It is independently an H or optionally a C1-C6 alkyl group substituted with one or more halogens or cyano groups; Alternatively, Y and Z in equation (I) or (III) together form -Si(R) L’’ )2-O-Si(R L’’ )2-, where each R L’’ It is independently an H or C1-C6 alkyl group; Each R a It is independently a C1-C6 alkyl group, a halogen, or optionally substituted with one or more halogens; or Two adjacent R a Forming bonds; R 1 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens; R 2 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens; R 3 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens; R 4 It is H, a halogen, or a C1-C6 alkyl group optionally substituted with one or more halogens; or R 4 and R X Together they form C1-C6 alkylene groups; Each R 5 Independently, it is a C1-C6 alkyl group, a halogen, or optionally substituted with one or more halogens; and n is an integer ranging from approximately 0 to approximately 10.

2. A conjugate or a pharmaceutically acceptable salt thereof, comprising: (i) One or more nucleic acid reagents; (ii) one or more ligands; and (iii) One or more lipid-based enhancement units, wherein each lipid-based enhancement unit is independently: ; ; ;or ; in: Variables L, B, V, X, R 1 R 2 R 3 R 4 R 5 R a R Y R Z and n as described in this article; and When the lipid-based enhancing unit is located at the 3' end of the nucleic acid agent, # is the 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 hydroxyl protecting group; or When the lipid-based enhancing unit is located at the 5' end of the 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 hydroxyl protecting group; and ## is the attachment to the rest of the conjugate; or Each of # and ## is independently attached to the rest of the conjugate.

3. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein L is -C(=O)R L ,in: R L It is C1-C 30 Hydrocarbon chain or 2 to 30-membered heterohydrocarbon chain, wherein C1-C 30 Hydrocarbon chains or 2- to 30-membered heterohydrocarbon chains are optionally divided by one or more R L’ replace; Each R L’ Independently, it is oxo, halogen, -OH, -O (C1-C) 12 Alkyl groups, -NH2, -NH (C1-C) 12 Alkyl), -N(C1-C 12 Alkyl)2, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. La Replace; or Two Rs L’ Together with one or more intermediate atoms, it forms a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is optionally formed by one or more R La Replace; and Each R La Independently, it is oxo, halogen, -OH, -O (C1-C) 12 Alkyl groups, -NH2, -NH (C1-C) 12 Alkyl) or -N (C1-C 12 Alkyl)2.

4. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein R L It is optionally controlled by one or more R L’ Replacement C1-C 35 Hydrocarbon chain.

5. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein R L It is optionally controlled by one or more R L’ Replaced 2 to 35-membered heterohydrocarbon chains.

6. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R L’ It is oxygenation.

7. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R L’ It is halogen.

8. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R L’ It is -OH or optionally surrounded by one or more R La Substituted -O(C1-C) 12 alkyl).

9. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R L’ It is -NH2, -NH(Cl-C 12 Alkyl) or -N (C1-C 12 alkyl)2, wherein -NH(C1-C 12 Alkyl) or -N (C1-C 12 Alkyl)2 optionally surrounded by one or more R La replace.

10. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R L’ It is C1-C 12 Alkyl, C2-C 12 alkenyl or C2-C 12 Alkyne group, wherein the C1-C 12 Alkyl, C2-C 12 alkenyl or C2-C 12 The alkynyl group is optionally surrounded by one or more R La replace.

11. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R L’ It is a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is optionally composed of one or more R La replace.

12. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R L’ It is C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. La replace.

13. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein the two Rs L’ Together with one or more intermediate atoms, it forms a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is optionally formed by one or more R La replace.

14. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R La It is oxygenation.

15. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R La It is halogen.

16. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R La It is -OH or -O(Cl-C) 12 alkyl).

17. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein at least one R La It is -NH2, -NH(Cl-C 12 Alkyl) or -N (C1-C 12 Alkyl)2.

18. The lipid-based enhancer or conjugate as claimed in any of the preceding claims, wherein the nucleobase moiety is adenine (A), cytosine (C), guanine (G), thymine (T), or uracil (U).

19. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein V is -O-.

20. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein V is -NH-.

21. The lipid-based enhancer or conjugate as described in any of the preceding claims, wherein V is -CH2-.

22. The lipid-based enhancer as claimed in any of the preceding claims, wherein the compound is a compound of formula (I'), (II'), (III'), or (IV'): (I'), (II') (III'), or (IV'), Or its pharmaceutically acceptable salt.

23. The lipid-based enhancer as claimed in any of the preceding claims, wherein the compound is a compound of formula (IA), (II-A), (III-A), or (IV-A): (I-A), (II-A), (III-A), or (IV-A), Or its pharmaceutically acceptable salt.

24. The lipid-based enhancer as claimed in any of the preceding claims, wherein the compound is a compound of formula (I'-A), (II'-A), (III'-A), or (IV'-A): (I’-A), (II’-A), (III’-A), or (IV’-A), Or its pharmaceutically acceptable salt.

25. The lipid-based enhancer as claimed in any of the preceding claims, wherein the compound is a compound of formula (IB), (II-B), (III-B), or (IV-B): (IB), (II-B), (III-B), or (IV-B), Or its pharmaceutically acceptable salt.

26. The lipid-based enhancer as claimed in any of the preceding claims, wherein the compound is a compound of formula (I'-B), (II'-B), (III'-B), or (IV'-B): (I'-B) (II'-B) (III'-B), or (IV'-B), Or its pharmaceutically acceptable salt.

27. The lipid-based enhancer as claimed in any of the preceding claims, wherein the compound is a compound of formula (IC), (II-C), (III-C), (IV-C), (VC), (VI-C), (VII-C), or (VIII-C): (IC), (II-C), (III-C), (IV-C), (VC), (VI-C), (VI-C), or (VIII-C), Or its pharmaceutically acceptable salt.

28. The lipid-based enhancer as claimed in any one of the preceding claims, wherein the compound is a compound of formula (I'-C), (II'-C), (III'-C), (IV'-C), (V'-C), (VI'-C), (VII'-C), or (VIII'-C): (I’-C), (II’-C), (III’-C), (IV’-C), (V’-C), (VI’-C), (VII’-C), or (VIII’-C), Or its pharmaceutically acceptable salt.

29. The lipid-based enhancer as described in any of the preceding claims, wherein: Y is a hydroxyl protecting group, and Z is a hydroxyl protecting group; or Y and Z together in formulas (I), (III), (I'), (III'), (IA), (III-A), (I'-A), (III'-A), (IB), (III-B), (I'-B), (III'-B), (IC), (III-C), (VC), (VII-C), (I'-C), (III'-C), (V'-C), or (VII'-C) form -Si(R) L’’ )2-O-Si(R L’’ )2-, where each R L’’ It is independently H or C1-C6 alkyl.

30. The lipid-based enhancer as claimed in any of the preceding claims, wherein the lipid-based enhancer is: , , , , , , , , , , , , , , ,or ; Or its pharmaceutically acceptable salt, wherein: Indicates a single bond or a double bond; Y is -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 hydroxyl protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl), triphenylmethyl (Tr), 4,4'-dimethoxytriphenylmethyl (DMTr), a substituted acyl group (e.g., an optionally substituted acetyl group) or benzyl); Each R Y It is independently an H or optionally a C1-C6 alkyl group substituted with one or more halogens or cyano groups; Z is -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 hydroxyl protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl), triphenylmethyl (Tr), 4,4'-dimethoxytriphenylmethyl (DMTr), a substituted acyl group (e.g., an optionally substituted acetyl group), or a benzyl group); and Each R Z It is an H-based or optionally substituted C1-C6 alkyl group with one or more halogens or cyano groups.

31. The lipid-based enhancer as described in any of the preceding claims, wherein the lipid-based enhancer is selected from the compounds described in Table L and their pharmaceutically acceptable salts.

32. The conjugate as claimed in any of the preceding claims, wherein the conjugate comprises: (Nucleic acid reagent) - [(Linking unit)] 0-1 -(Lipid-based enhancement unit)-(Connecting unit) 0-1 -(ligands)] 1-3 ; (Nucleic acid reagent) - [(Linking unit)] 0-1 -(ligand)-(connector unit) 0-1 -(Lipid-based enhancement unit)] 1-3 ;or [(Lipid-based enhancement unit) - (Connecting unit)] 0-1 ] 1-3 -(nucleic acid reagent)-[(linking unit)] 0-1 -(ligands)] 1-3 ; When attached to the nucleic acid agent (e.g., siRNA), each of the linker, lipid-based enhancement unit, and ligand independently attaches to a terminal position (e.g., a nucleotide at the 3' or 5' end) or an internal position (e.g., a nucleotide not at the 3' or 5' end) of the nucleic acid agent (e.g., siRNA).

33. The conjugate as claimed in any of the preceding claims, wherein at least one lipid-based enhancing unit in the conjugate is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or , , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

34. The conjugate as claimed in any of the preceding claims, wherein at least one lipid-based reinforcing unit in the conjugate is selected from the structures described in Tables C and D.

35. The conjugate as claimed in any of the preceding claims, wherein the nucleic acid agent comprises an oligonucleotide.

36. A pharmaceutical composition comprising a compound or conjugate as described in any of the preceding claims.

37. A method for regulating 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, said method comprising administering to the subject a conjugate as described in any of the preceding claims.

38. The conjugate as described in any of the preceding claims, used for regulating 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.

39. Use of the conjugate as described in any of the preceding claims in the manufacture of a medicament for regulating 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.

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

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