Bis-ester and amide cationic lipids

Abstract

The present invention relates, in part, to a compound of formula (I): [Formula 1] TIFF2026500541000538.tif24170 or a pharmaceutically acceptable salt thereof, a bis-ester and amide cationic lipid compound of formula (II): [Case 2] TIFF2026500541000539.tif24170 or a pharmaceutically acceptable salt thereof, a bis-ester and amide cationic lipid compound of formula (III): [C3] TIFF2026500541000540.tif24170 or a pharmaceutically acceptable salt thereof and a bis-ester and amide cationic lipid compound of formula (IV): [C4] TIFF2026500541000541.tif26170, or pharmaceutically acceptable salts thereof. The compounds provided herein may be useful for delivery and expression of mRNA and encoded proteins, for example, as components of liposome delivery vehicles, and thus may be useful for treating various diseases, disorders, and conditions, such as those associated with deficiencies of one or more proteins.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to European Patent Application No. 22307007.9, filed December 22, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Nucleic acid delivery has been widely investigated as a potential treatment option for certain disease states, and messenger RNA (mRNA) therapy in particular has become an increasingly important option for the prevention and treatment (e.g., use of vaccines) of various diseases.

[0003] Efficient delivery of liposome-encapsulated nucleic acids remains an active area of ​​research. The cationic lipid component of the liposome encapsulating the nucleic acid plays an important role in promoting effective encapsulation of the nucleic acid during liposome loading. In addition, cationic lipids may play an important role in the efficient release of the nucleic acid cargo from the liposome into the cytoplasm of the target cell. A variety of cationic lipids suitable for in vivo use have been discovered. However, there remains a need to identify lipids that can be synthesized efficiently and inexpensively without the formation of potentially toxic by-products.

[0004] There are cationic lipids that contain a cyclic ring structure as a central core (lipidoids such as the cKK-E12-structure shown below). [ka]

[0005] The inventors of the present invention have surprisingly found that cationic lipids made from commercially available acyclic linkers (such as tartronic acid and aminomalonic acid) have high levels of peptide or protein expression when delivering mRNA encoding said peptide or protein, while reducing size and complexity.This reduction in size and complexity allows for faster development of new lipid analogs, and the claimed cationic lipids also have advantages in terms of downstream scale-up and manufacturing compared to previous lipidoid cationic lipids. Summary of the Invention [Means for solving the problem]

[0006] The present invention provides, inter alia, a new class of cationic lipid compounds for in vivo delivery of therapeutic agents, such as nucleic acids.These compounds are believed to be capable of highly effective in vivo delivery of therapeutic agents and vaccines while maintaining a favorable safety profile.Lipid nanoparticles comprising the cationic lipids of the present invention (e.g., compounds LXXIII and LXXIV) also exhibit improved thermal stability, which is beneficial for the development of corresponding therapeutic agents and vaccines.

[0007] The cationic lipids of the present invention contain cleavable groups (e.g., esters and disulfides) that are contemplated to improve biodegradability and thereby contribute to their favorable safety profile.

[0008] In one embodiment, a compound of formula (I): [ka] (Wherein A is -N(R 1 )- or -SS-; R 1 is an optionally substituted (C1-C6) alkyl; a and c are integers independently selected from 1, 2, 3, or 4; b and d are integers independently selected from 1, 2, 3, 4, 5, or 6; Z 1 is a covalent bond, [ka] or -SS-, and the left side of each depicted structure is selected from -(CH2) b - is bonded to Z 2 is a covalent bond, [ka] or -SS-, and the right side of each depicted structure is selected from -(CH2) d - is bonded to Each Y 1 are independently selected from hydrogen or —OH; Each R 8 are independently selected from hydrogen or optionally substituted (C1-C6) alkyl; R 2A , R 2B , R 2C and R 2D is optionally substituted (C5-C 25 ) alkyl, optionally substituted (C5-C 25 ) alkenyl or -W 1 -X 1 are each independently selected from Each W 1 is a covalent bond, optionally substituted (C1-C 10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and each X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, -*O-(C=O)- optionally substituted (C3-C 25 ) alkyl or -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is independently selected from W 1If is a covalent bond, W 1 or -CH(Y 1 )-bonded to) or a pharmaceutically acceptable salt thereof.

[0009] In one embodiment, a compound of formula (II): [ka] (In the formula, R 3 is selected from hydrogen or optionally substituted (C1-C6) alkyl; R 4 is selected from hydrogen, —OH, —NH2, optionally substituted (C1-C6) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C3) alkylene-optionally substituted aryl or optionally substituted (C1-C3) alkylene-optionally substituted heteroaryl; e and g are integers independently selected from 0, 1, 2, 3, or 4; f and h are integers independently selected from 1, 2, 3, 4, 5, or 6; Each Y 2 are independently selected from hydrogen or —OH; R 5A , R 5B , R 5C and R 5D is optionally substituted (C5-C 25 ) alkyl, optionally substituted (C5-C 25 ) alkenyl or -W 1 -X 1 are each independently selected from Each W 1 is a covalent bond, optionally substituted (C1-C 10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and each X 1is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, -*O-(C=O)- optionally substituted (C3-C 25 ) alkyl or -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is independently selected from W 1 If is a covalent bond, W 1 or -CH(Y 2 )-bonded to) or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment, a compound of formula (III): [ka] (In the formula, R 9 is selected from hydrogen or optionally substituted (C1-C6) alkyl; R 10 is selected from hydrogen, —OH, —NH2, optionally substituted (C1-C6) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C3) alkylene-optionally substituted aryl or optionally substituted (C1-C3) alkylene-optionally substituted heteroaryl; i and k are integers independently selected from 0, 1, 2, 3, or 4; j and l are integers independently selected from 1, 2, 3, 4, 5, or 6; Each Y 3 are independently selected from hydrogen or —OH; Each R 12 are independently selected from hydrogen or optionally substituted (C1-C6) alkyl; R 11A , R 11B , R 11C and R11D is optionally substituted (C5-C 25 ) alkyl, optionally substituted (C5-C 25 ) alkenyl or -W 1 -X 1 are each independently selected from Each W 1 is a covalent bond, optionally substituted (C1-C 10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and each X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, -*O-(C=O)- optionally substituted (C3-C 25 ) alkyl or -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is independently selected from W 1 If is a covalent bond, W 1 or -CH(Y 3 )-bonded to) or a pharmaceutically acceptable salt thereof.

[0011] In one embodiment, a compound of formula (IV): [ka] (In the formula, m and n are integers independently selected from 1, 2, 3, 4, 5, or 6; Z 3 is an aromatic amino acid residue, and the α-carbon carboxyl group (-C(=O)-O-) of the aromatic amino acid residue is -(CH2) m -, and the α-carbon aminyl group (—NH—) of an aromatic amino acid residue is bonded to Z 4 is connected to Z 4 teeth, [ka] The right side of each shown structure is selected from -(CH2) n - is bonded to Each Y 4 are independently selected from hydrogen or —OH; R 13A , R 13B , R 13C and R 13D is optionally substituted (C5-C 25 ) alkyl, optionally substituted (C5-C 25 ) alkenyl or -W 1 -X 1 are each independently selected from Each W 1 is a covalent bond, optionally substituted (C1-C 10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and each X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, -*O-(C=O)- optionally substituted (C3-C 25 ) alkyl or -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is independently selected from W 1 If is a covalent bond, W 1 or -CH(Y 4 )-bonded to) or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, provided herein is a cationic lipid that is a pharmaceutically acceptable salt of Formula (I):

[0013] In one aspect, provided herein is a cationic lipid that is a pharmaceutically acceptable salt of formula (II):

[0014] In one aspect, provided herein is a cationic lipid that is a pharmaceutically acceptable salt of formula (III):

[0015] In one aspect, provided herein is a cationic lipid that is a pharmaceutically acceptable salt of formula (IV):

[0016] In one aspect, provided herein is a composition comprising a cationic lipid of the present invention or a pharmaceutically acceptable salt thereof, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids. In one aspect, the composition is a lipid nanoparticle, optionally a liposome.

[0017] In one aspect, compositions comprising the cationic lipids of the present invention can be used in therapy. [Brief explanation of the drawings]

[0018] [Figure 1] Scheme 1, which is the reaction scheme of Example 1, is shown below. [Figure 2] Scheme 2, which is the reaction scheme of Example 2, is shown below. [Figure 3] Scheme 3, which is the reaction scheme of Example 3, is shown below. [Figure 4] Scheme 4, which is the reaction scheme of Example 4, is shown below. [Figure 5] Scheme 5, which is the reaction scheme of Example 5, is shown below. [Figure 6] Scheme 6, which is the reaction scheme of Example 6, is shown below. [Figure 7] Scheme 7, which is the reaction scheme of Example 7, is shown below. [Figure 8] Scheme 8, which is the reaction scheme of Example 8, is shown below. [Figure 9] Scheme 9, which is the reaction scheme of Example 9, is shown below. [Figure 10]Scheme 10, which is the reaction scheme of Example 10, is shown below. [Figure 11] Scheme 11, which is the reaction scheme of Example 11, is shown below. [Figure 12] Scheme 12, which is the reaction scheme for Example 12, is shown below. [Figure 13] Scheme 13, which is the reaction scheme of Example 13, is shown below. [Figure 14] Scheme 14, which is the reaction scheme for Example 14, is shown below. [Figure 15] Scheme 15, which is the reaction scheme for Example 15, is shown below. [Figure 16] Scheme 16, which is the reaction scheme for Example 16, is shown below. [Figure 17] Scheme 17, which is the reaction scheme for Example 17, is shown below. [Figure 18] Scheme 18, which is the reaction scheme for Example 18, is shown below. [Figure 19] Scheme 19, which is the reaction scheme for Example 19, is shown below. [Figure 20] Scheme 20, which is a reaction scheme for Example 20, is shown below. [Figure 21] Scheme 21, which is the reaction scheme for Example 21, is shown below. [Figure 22] Scheme 22, which is the reaction scheme for Example 22, is shown below. [Figure 23] Scheme 23, which is the reaction scheme for Example 23, is shown below. [Figure 24] Scheme 24, which is the reaction scheme for Example 24, is shown below. [Figure 25] Scheme 25, which is the reaction scheme for Example 25, is shown below. [Figure 26] Scheme 26, which is the reaction scheme for Example 26, is shown below. [Figure 27] Scheme 27, which is the reaction scheme for Example 27, is shown below. [Figure 28] Scheme 28, which is the reaction scheme for Example 28, is shown below. [Figure 29] Scheme 29, which is the reaction scheme for Example 29, is shown below. [Figure 30] Scheme 30, which is a reaction scheme for Example 30, is shown below. [Figure 31] Scheme 31, which is the reaction scheme for Example 31, is shown below. [Figure 32] Scheme 32, which is the reaction scheme for Example 32, is shown below. [Figure 33] Scheme 33, which is the reaction scheme for Example 33, is shown below. [Figure 34] Scheme 34, which is the reaction scheme for Example 34, is shown below. [Figure 35] Scheme 35, which is the reaction scheme for Example 35, is shown below. [Figure 36] Scheme 36, which is the reaction scheme for Example 36, is shown below. [Figure 37] Scheme 37, which is the reaction scheme for Example 37, is shown below. [Figure 38] Scheme 38, which is the reaction scheme for Example 38, is shown below. [Figure 39] Scheme 39, which is the reaction scheme for Example 39, is shown below. [Figure 40] Scheme 40, which is the reaction scheme for Example 40, is shown below. [Figure 41] Scheme 41, which is the reaction scheme for Example 41, is shown below. [Figure 42] Scheme 42, which is the reaction scheme for Example 42, is shown below. [Figure 43] Scheme 43, which is the reaction scheme for Example 43, is shown below. [Figure 44] Scheme 44, which is the reaction scheme for Example 44, is shown below. [Figure 45] Scheme 45, which is the reaction scheme for Example 45, is shown below. [Figure 46] Scheme 46, which is the reaction scheme for Example 46, is shown below. [Figure 47] Scheme 47, which is the reaction scheme for Example 47, is shown below. [Figure 48] Scheme 48, which is the reaction scheme for Example 48, is shown below. [Figure 49]Scheme 49, which is the reaction scheme for Example 49, is shown below. [Figure 50] Scheme 50, which is the reaction scheme for Example 50, is shown. [Figure 51] 1 shows in vivo hEPO protein production resulting from intramuscular delivery of hEPO mRNA using lipid nanoparticles containing compounds XII, XIV, XV, XXV, XXXII, and XXXVIII described herein. As shown in this figure, the use of these compounds as part of lipid nanoparticles can result in high levels of in vivo hEPO protein production after administration. DETAILED DESCRIPTION OF THE INVENTION

[0019] definition To facilitate understanding of the present invention, certain terms are first defined below. Further definitions for these and other terms are set forth throughout the specification. Publications and other reference materials mentioned herein to describe the background of the invention and to provide additional details regarding its practice are incorporated herein by reference.

[0020] Amino acid: As used herein, the term "amino acid" in its broadest sense refers to any compound and / or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure HN-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid, in some embodiments, an amino acid is a d-amino acid, and in some embodiments, an amino acid is an l-amino acid. A "standard amino acid" refers to any of the 20 standard l-amino acids commonly found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid that is not a standard amino acid, whether it is synthetically prepared or obtained from a natural source. As used herein, a "synthetic amino acid" encompasses chemically modified amino acids, including, but not limited to, salts, amino acid derivatives (such as amides), and / or substitutions. Amino acids, including the carboxy- and / or amino-terminal amino acids in a peptide, can be modified by methylation, amidation, acetylation, protecting groups, and / or substitutions with other chemical groups that can alter the circulating half-life of the peptide without adversely affecting its activity. Amino acids may participate in disulfide bonds. Amino acids may include one or more post-translational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.). The term "amino acid" is used interchangeably with "amino acid residue" and may refer to free amino acids and / or amino acid residues of peptides. Whether it refers to a free amino acid or a residue of a peptide will be clear from the context in which the term is used.

[0021] Aromatic Amino Acid or Residue: As used herein, the term "aromatic amino acid or residue" refers to a hydrophilic or hydrophobic amino acid or residue having a side chain containing at least one aromatic or heteroaromatic ring. Aromatic amino acids or residues include L-amino acids, D-amino acids, or racemates. Genetically encoded aromatic amino acids include L-Phe (F), L-Tyr (Y), L-His (H), and L-Trp (W). Although sometimes classified as a basic residue due to the pKa of its heteroaromatic nitrogen atom, L-His (H), histidine is classified herein as an aromatic residue because its side chain contains a heteroaromatic ring. Examples of aromatic amino acids include: [ka]

[0022] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human at any stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0023] Approximately or About: As used herein, the term "approximately" or "about" as applied to one or more values ​​of interest refers to a value similar to the stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction of (greater than or less than) the stated reference value, unless otherwise specified or clear from the context (except where such number would exceed 100% of possible values).

[0024] Biologically active: As used herein, the term "biologically active" refers to the characteristic of any agent that has activity in biological systems and particularly in living organisms. For example, an agent that, upon administration to an organism, has a biological effect on that organism is considered to be biologically active.

[0025] Delivery: As used herein, the term "delivery" encompasses both local and systemic delivery. For example, delivery of mRNA encompasses a situation in which the mRNA is delivered to a target tissue, the encoded protein is expressed, and the protein is retained within the target tissue (also referred to as "local distribution" or "local delivery"), and a situation in which the mRNA is delivered to a target tissue, the encoded protein is expressed, secreted into the patient's circulatory system (e.g., serum), distributed systemically, and absorbed by other tissues (also referred to as "systemic distribution" or "systemic delivery").

[0026] Expression: As used herein, "expression" of a nucleic acid sequence refers to the translation of mRNA into polypeptides, the assembly of multiple polypeptides into an intact protein (e.g., an enzyme), and / or the post-translational modification of a polypeptide or fully assembled protein (e.g., an enzyme). The terms "expression" and "production," and their grammatical equivalents, are used interchangeably herein.

[0027] Functional: As used herein, a "functional" biomolecule is a biomolecule in a form in which it exhibits a property and / or activity by which it is characterized.

[0028] Half-life: As used herein, the term "half-life" is the time required for a quantity, such as the concentration or activity of a nucleic acid or protein, to fall to half of its initially measured value over a period of time.

[0029] Helper lipid: As used herein, the term "helper lipid" refers to any neutral or zwitterionic lipid material, including cholesterol. Without wishing to be bound by theory, helper lipids may add stability, rigidity, and / or fluidity within the lipid bilayer / nanoparticle.

[0030] Improved, increased, or decreased: As used herein, the terms "improve," "increase," or "decrease," or grammatical equivalents, refer to a value relative to a baseline measurement, such as a measurement in the same individual prior to the initiation of a treatment described herein, or a measurement in a control subject (or control subjects) in the absence of a treatment described herein. A "control subject" is a subject suffering from the same form of disease as the subject under treatment, and who is approximately the same age as the subject under treatment.

[0031] In vitro: As used herein, the term "in vitro" refers to events that take place not within a multicellular organism, but in an artificial environment, such as in a test tube or reaction vessel, in cell culture, etc.

[0032] In vivo: As used herein, the term "in vivo" refers to events that occur within multicellular organisms, such as humans and non-human animals. In reference to cell-based systems, the term may be used to refer to events that occur within living cells (e.g., as opposed to in vitro systems).

[0033] Isolated: As used herein, the term "isolated" refers to a substance and / or entity that (1) has been separated from at least some of the components with which it was originally associated (whether produced in nature or in an experimental setting) and / or (2) has been produced, prepared, and / or manufactured by the hand of man. An isolated substance and / or entity can be separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% of the other components with which it was originally associated. In some embodiments, the isolated agent is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. As used herein, calculations of percent purity of an isolated substance and / or entity should not include excipients (e.g., buffers, solvents, water, etc.).

[0034] Liposome: As used herein, the term "liposome" refers to any lamellar, multilamellar, or solid nanoparticle vesicle. Typically, liposomes as used herein can be formed by mixing one or more lipids or by mixing one or more lipids with a polymer. In some embodiments, liposomes suitable for the present invention contain one or more cationic lipids and optionally one or more non-cationic lipids, optionally one or more cholesterol-based lipids, and / or optionally one or more PEG-modified lipids.

[0035] Messenger RNA (mRNA): As used herein, the term "messenger RNA (mRNA)" or "mRNA" refers to a polynucleotide that encodes at least one polypeptide. As used herein, mRNA encompasses both modified and unmodified RNA. The term "modified mRNA" refers to mRNA that contains at least one chemically modified nucleotide. mRNA can contain one or more coding and non-coding regions. mRNA can be purified from natural sources, produced using recombinant expression systems, optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, mRNA can include nucleoside analogs, such as analogs having chemically modified bases or sugars, backbone modifications, etc. The mRNA sequence is presented in the 5' to 3' direction unless otherwise indicated. In some embodiments, the mRNA is designed to contain natural nucleosides (e.g., adenosine, guanosine, cytidine, uridine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, 5-methylcytidine, C5-propynyl-cytidine, C5-propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcyt ...bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C 6-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine and 2-thiocytidine; chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose and hexose) and / or modified phosphate groups (e.g., phosphorothioate and 5'-N-phosphoramidite linkages).

[0036] Nucleic Acid: As used herein, the term "nucleic acid" in its broadest sense refers to any compound and / or substance that is or can be incorporated into a polynucleotide chain. In some embodiments, a nucleic acid is a compound and / or substance that is or can be incorporated into a polynucleotide chain by a phosphodiester bond. In some embodiments, "nucleic acid" refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, "nucleic acid" refers to a polynucleotide chain comprising individual nucleic acid residues. In some embodiments, "nucleic acid" encompasses RNA and single- and / or double-stranded DNA and / or cDNA. In some embodiments, "nucleic acid" encompasses ribonucleic acid (RNA), including, but not limited to, one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), multimeric coding nucleic acid (MCNA), polymer-coated nucleic acid (PCNA), guide RNA (gRNA), and CRISPR RNA (crRNA). In some embodiments, "nucleic acid" encompasses deoxyribonucleic acid (DNA), including, but not limited to, one or more of single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), and complementary DNA (cDNA). In some embodiments, "nucleic acid" encompasses both RNA and DNA. In embodiments, the DNA may be in the form of antisense DNA, plasmid DNA, a portion of plasmid DNA, pre-condensed DNA, a polymerase chain reaction (PCR) product, a vector (e.g., P1, PAC, BAC, YAC, artificial chromosome), an expression cassette, a chimeric sequence, chromosomal DNA, or derivatives of these groups.In embodiments, the RNA may be a messenger RNA (mRNA), ribosomal RNA (rRNA), signal recognition particle RNA (7 SL RNA or SRP RNA), transcribed RNA (tRNA), transcribed messenger RNA (tmRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), SmY RNA, small Cajal body specific RNA (scaRNA), guide RNA (gRNA), ribonuclease P (RNase P), Y RNA, telomerase RNA component (TERC), spliced ​​leader RNA (SL RNA), antisense RNA (aRNA or asRNA), cis-naturally occurring antisense transcript (cis-NAT), CRISPR RNA (crRNA), long non-coding RNA (lncRNA), microRNA (miRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), transactional siRNA (tasiRNA), repeat-associated siRNA (rasiRNA), 73K It may be in the form of RNA, retrotransposons, viral genomes, viroids, satellite RNA or derivatives of these groups, hi some embodiments, the nucleic acid is an mRNA that encodes a protein such as an enzyme.

[0037] Patient: As used herein, the term "patient" or "subject" refers to any organism to which provided compositions can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include prenatal and postnatal forms.

[0038] Pharmaceutically acceptable: The term "pharmaceutically acceptable," as used herein, refers to a material that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk / benefit ratio.

[0039] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, and arylsulfonates. Further pharmaceutically acceptable salts include salts formed from the quaternization of amines with electrophiles, e.g., alkyl halides, suitable for forming quaternized alkylated amino salts.

[0040] Systemic distribution or delivery: As used herein, the term "systemic distribution" or "systemic delivery" or grammatical equivalents refer to a mechanism or method of delivery or distribution that affects the entire body or organ. Typically, systemic distribution or delivery is achieved via the body's circulatory system, e.g., the bloodstream. Compare the definition of "local distribution or delivery."

[0041] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, a subject is a human being. A subject may be a patient, which refers to a human who visits a health care provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may be one who is suffering from or susceptible to a disease or disorder, which may or may not be symptomatic.

[0042] Substantially: As used herein, the term "substantially" refers to the qualitative condition of exhibiting the entire or nearly entire extent or degree of a desired characteristic or property. Those skilled in the biological arts will understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or perfection or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of integrity inherent in many biological and chemical phenomena.

[0043] Target tissue: As used herein, the term "target tissue" refers to any tissue affected by the disease to be treated. In some embodiments, the target tissue includes tissue that exhibits a pathological condition, symptom, or characteristic associated with the disease.

[0044] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount sufficient to treat, diagnose, prevent symptoms of, and / or delay the onset of, a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition. Those skilled in the art will understand that a therapeutically effective amount is typically administered in a titration regimen comprising at least one unit dose.

[0045] Treating: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of the disease and / or who exhibits only early signs of the disease, with the intent of reducing the risk of developing morbidity associated with the disease.

[0046] chemical definition Acyl: As used herein, the term “acyl” refers to a group consisting of R Z -(C=O)-(wherein, RZ refers to, for example, any alkyl, alkenyl, alkynyl, heteroalkyl, or heteroalkylene.

[0047] Aliphatic: As used herein, the term aliphatic refers to C1-C 50 Aliphatic refers to hydrocarbons, including both saturated and unsaturated hydrocarbons. Aliphatic groups can be linear, branched, or cyclic. For example, C1-C 20 Aliphatic: C1-C 20 Alkyl (e.g., linear or branched C1-C 20 saturated alkyl), C2-C 20 Alkenyl (e.g., straight-chain or branched C4-C 20 Dienyl, linear or branched C6-C 20 trienyl, etc.) and C2-C 20 Alkynyl (e.g., straight-chain or branched C-C 20 alkynyl). 20 Aliphatic: C3 to C 20 Cycloaliphatic (e.g., C3-C 20 Cycloalkyl, C4-C 20 Cycloalkenyl or C8-C 20 In certain embodiments, an aliphatic group can include one or more cycloaliphatic and / or one or more heteroatoms (such as oxygen, nitrogen, or sulfur) and can be optionally substituted with one or more substituents, such as alkyl, halo, alkoxy, hydroxy, amino, aryl, ether, ester, or amide. An aliphatic group can be unsubstituted or substituted with one or more substituents, as described herein. For example, an aliphatic group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected) halogen, —COR″, —COH, —COR″, —CN, —OH, —OR″, —OCOR′, —OCOR″, —NH, —NHR″, —N(R″)2, —SR″, or —SOR″, where each instance of R″ is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In embodiments, R" is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently an unsubstituted C1-C3 alkyl. In embodiments, the aliphatic is unsubstituted. In embodiments, the aliphatic does not contain any heteroatoms. Alkyl: As used herein, the term "alkyl" refers to acyclic straight chain and branched hydrocarbon groups, such as "(C1-C 30 ") alkyl" refers to an alkyl group having 1 to 30 carbon atoms. The alkyl group can be straight chain or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentyl hexyl, isohexyl, and the like. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms, straight chain or branched alkyl. Other alkyl groups will be readily apparent to the skilled artisan given the benefit of this disclosure. The alkyl group can be unsubstituted or substituted with one or more substituents, as described herein. For example, an alkyl group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, —COR″, —COH, —COR″, —CN, —OH, —OR″, —OCOR′, —OCOR″, —NH, —NHR″, —N(R″)2, —SR″, or —SOR″, where each instance of R″ is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In embodiments, R" is independently an unsubstituted C1-C3 alkyl. In embodiments, the alkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents described herein). In embodiments, the alkyl group is substituted with an -OH group and may also be referred to herein as a "hydroxyalkyl" group, where the prefix represents the -OH group and "alkyl" is as defined herein.

[0048] As used herein, "alkyl" also refers to a group of straight-chain or branched saturated hydrocarbon groups having 1 to 50 carbon atoms ("C1-C 50 In some embodiments, an alkyl group has 1 to 40 carbon atoms ("C1-C 40 In some embodiments, an alkyl group has 1 to 30 carbon atoms ("C1-C 30 In some embodiments, an alkyl group has 1 to 20 carbon atoms ("C1-C 20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C1-C 10In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-C9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-C7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include, without limitation, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C1-C 50 In certain embodiments, the alkyl group is a substituted C1-C 50 It is alkyl.

[0049] The addition of the suffix "-ene" to a base indicates that the group is a divalent moiety; for example, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0050] Alkylene: The term "alkylene," as used herein, represents a saturated divalent straight- or branched-chain hydrocarbon group and is exemplified by methylene, ethylene, isopropylene, and the like. Similarly, the term "alkenylene," as used herein, represents an unsaturated divalent straight- or branched-chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, and the term "alkynylene," as used herein, represents an unsaturated divalent straight- or branched-chain hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that may occur at any stable point along the chain. In certain embodiments, alkylene, alkenylene, or alkynylene groups can contain one or more cyclic aliphatic and / or one or more heteroatoms (such as oxygen, nitrogen, or sulfur) and can be optionally substituted with one or more substituents, such as alkyl, halo, alkoxy, hydroxy, amino, aryl, ether, ester, or amide. For example, alkylene, alkenylene, or alkynylene can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, —COR″, —COH, —COR″, —CN, —OH, —OR″, —OCOR″, —OCOR″, —NH2, —NHR″, —N(R″)2, —SR″, or —SOR″, where each instance of R″ is independently selected from C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In embodiments, R" is independently an unsubstituted C1-C3 alkyl. In certain embodiments, the alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, the alkylene, alkenylene, or alkynylene does not contain any heteroatoms. Alkenyl: As used herein, "alkenyl" refers to any straight or branched hydrocarbon chain with one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, e.g., "(C2-C 30 ")Alkenyl" refers to an alkenyl group having 2 to 30 carbons. For example, alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In embodiments, an alkenyl contains one, two, or three carbon-carbon double bonds. In embodiments, an alkenyl contains a single carbon-carbon double bond. In embodiments, multiple double bonds (e.g., two or three) are conjugated. Alkenyl groups can be unsubstituted or substituted with one or more substituents, as described herein. For example, an alkenyl group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, —COR″, —COH, —COR″, —CN, —OH, —OR″, —OCOR″, —OCOR″, —NH, —NHR″, —N(R″)2, —SR″, or —SOR″, where each instance of R″ is independently C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In embodiments, R" is independently an unsubstituted C1-C3 alkyl. In embodiments, the alkenyl is unsubstituted. In embodiments, the alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents described herein). In embodiments, the alkenyl group is substituted with an -OH group and may also be referred to herein as a "hydroxyalkenyl" group, where the prefix represents the -OH group and "alkenyl" is as defined herein.

[0051] As used herein, "alkenyl" also refers to a group of straight-chain or branched hydrocarbon groups having 2 to 50 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C2-C 50 In some embodiments, an alkenyl group has 2 to 40 carbon atoms (“C-C 40 In some embodiments, an alkenyl group has 2 to 30 carbon atoms (“C-C 30 In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C-C 20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C-C 10In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-C9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2-C7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-C4 alkenyl groups include, without limitation, ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the above-mentioned C2-C4 alkenyl groups and pentenyl ( C5 ), pentadienyl ( C5 ), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C2-C 50 In certain embodiments, the alkenyl group is a substituted C-C 50 It is alkenyl.

[0052] Alkynyl: As used herein, "alkynyl" refers to any hydrocarbon chain of straight or branched configuration with one or more carbon-carbon triple bonds present at any stable point along the chain, e.g., "C2-C 30"Alkynyl" refers to an alkynyl group having 2 to 30 carbons. Examples of alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like. In embodiments, an alkynyl group contains one carbon-carbon triple bond. An alkynyl group can be unsubstituted or substituted with one or more substituents, as described herein. For example, an alkynyl group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected) halogen, -COR", -COH, -COR", -CN, -OH, -OR", -OCOR", -OCOR", -NH, -NHR", -N(R"), -SR", or -SOR", where each instance of R" is independently C1 to C6. 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently an unsubstituted alkyl (e.g., an unsubstituted C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently unsubstituted C1-C3 alkyl. In embodiments, the alkynyl is unsubstituted. In embodiments, the alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents described herein).

[0053] As used herein, "alkynyl" also refers to a group of straight-chain or branched hydrocarbon groups having 2 to 50 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C2-C 50 Alkynyl groups with one or more triple bonds and one or more double bonds are also called "ene-ynes." In some embodiments, alkynyl groups have 2 to 40 carbon atoms ("C2-C 40In some embodiments, an alkynyl group has 2 to 30 carbon atoms (“C-C 30 In some embodiments, an alkynyl group has 2 to 20 carbon atoms (“C-C 20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C-C 10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2-C9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-C7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-C5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-C4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-C3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-C4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2-C4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C2-C6 alkynyl group. 50 In certain embodiments, the alkynyl group is a substituted C-C 50 It is alkynyl.

[0054] Aryl: The term "aryl," used alone or as part of a larger moiety such as "aralkyl," refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, said ring system having a single point of attachment to the rest of the molecule, at least one ring of the system being aromatic, and each ring of the system containing 4 to 7 ring members. In embodiments, an aryl group has 6 ring carbon atoms ("(C6)aryl," e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracen. "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryls include phenyl, naphthyl, and anthracene.

[0055] As used herein, "aryl" also refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 shared π electrons in the cyclic arrangement), where the aromatic ring system has 6 to 14 ring carbon atoms and 0 heteroatoms ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl," e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C6-C6 14 In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0056] Arylene: As used herein, the term "arylene" refers to an aryl group that is divalent (i.e., has two points of attachment to the molecule). Exemplary arylenes include phenylene (e.g., unsubstituted phenylene or substituted phenylene).

[0057] Carbocyclyl: As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C3-C6"). 10 "C-C carbocyclyl" refers to a group of non-aromatic cyclic hydrocarbon groups having 3 to 8 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C-C carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C-C 10carbocyclyl). Exemplary C3-C6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 carbocyclyl groups include, without limitation, the aforementioned C3-C6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3~C 10 Carbocyclyl groups include, without limitation, the aforementioned C3 to C8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) etc. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic carbocyclyl") or tricyclic system (including fused, bridged, or spiro ring systems such as "tricyclic carbocyclyl"), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the radical or point of attachment is on the carbocyclyl ring, and in such cases the number of carbon atoms continues to designate the number of carbon atoms in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is unsubstituted (C3-C6 10 ) carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-C10 It is a carbocyclyl.

[0058] In some embodiments, a "carbocyclyl" or "carbocyclic" is referred to as a "cycloalkyl," i.e., a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C3-C 10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C6 cycloalkyl"). 10 Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the aforementioned (C5-C6) cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0059] Halogen: As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0060] Heteroalkyl: The term "heteroalkyl" refers to a branched or unbranched alkyl, alkenyl, or alkynyl group having 1 to 14 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. Heteroalkyl groups can optionally contain monocyclic, bicyclic, or tricyclic rings, each ring desirably having 3 to 6 ring members. Examples of heteroalkyls include polyethers such as methoxymethyl and ethoxyethyl.

[0061] Heteroalkylene: The term "heteroalkylene," as used herein, represents a divalent form of the heteroalkyl groups described herein.

[0062] Heteroaryl: The term "heteroaryl," as used herein, refers to a fully unsaturated heteroatom-containing ring in which at least one ring atom is a heteroatom such as, but not limited to, nitrogen and oxygen.

[0063] As used herein, "heteroaryl" also refers to a radical of a 5-14-membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4 ring heteroatoms) ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, and in such cases the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., in either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0064] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has one or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, a 5- to 6-membered heteroaryl has one or two ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted with one or more substituents (a "substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0065] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0066] As used herein, "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (a "3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups are either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems (fused, bridged, or spiro ring systems such as "tricyclic heterocyclyl"), and may be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" refers to a ring system in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is on the carbocyclyl ring or the heterocyclyl ring, or .... The heterocyclyl ring may be fused with one or more aryl or heteroaryl groups, and the point of attachment may be on the heterocyclyl ring; in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of a heterocyclyl group is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0067] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (a "5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has one or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5- to 6-membered heterocyclyl has one or two ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.

[0068] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyldinyl, decahydro-1,8-naphthyldinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7- Examples include, but are not limited to, tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0069] Heterocycloalkyl: The term "heterocycloalkyl," as used herein, refers to a non-aromatic ring in which at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. A heterocycloalkyl group can be substituted or unsubstituted.

[0070] As understood from the above, alkyl, alkenyl, alkynyl, acyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted in certain embodiments. Optionally substituted refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" refers to a group in which at least one hydrogen present on a group is substituted with an acceptable substituent, e.g., a compound that is stable upon substitution, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. " means substituted with a substituent that results in the formation of a stable moiety. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any of the substituents described herein, that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0071] Exemplary carbon atom substituents include -CN, -NO2, -N3, -SO2, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3+X - , -N(OR cc )R bb , -SeH, -SeR aa、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)Raa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C1~C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 14 Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd or The two geminal hydrogens on the carbon atom are the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is replaced by R aa Each example is independently C1 to C 50Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 aryl and 5- to 14-membered heteroaryl, or two R aa groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb Each instance of is independently -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C1~C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 aryl and 5- to 14-membered heteroaryl, or two R bbThe groups, taken together with the heteroatom to which they are attached, form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd are independently substituted with groups, R cc Examples of each are hydrogen, C1 to C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 aryl and 5- to 14-membered heteroaryl, or two R cc The groups, taken together with the heteroatom to which they are attached, form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3+X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff)2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C1~C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd the substituents can be linked to form =O or =S; R ee Each example is independently C1 to C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50Alkynyl, C3-C 10 Carbocyclyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff Examples of each are hydrogen, C1 to C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-10 membered heterocyclyl, C6-C 10 aryl and 5- to 10-membered heteroaryl, or two R ff The groups, taken together with the heteroatom to which they are attached, form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, and R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-C 50 Alkyl, -ON(C1-C 50 alkyl)2, -N(C1-C 50 alkyl)2, -N(C1-C 50 Alkyl)3+X - , -NH(C1~C 50 alkyl)2+X - , -NH2(C1~C 50 alkyl) + X - , -NH3+X - , -N(OC1~C 50 Alkyl) (C1-C 50 alkyl), -N(OH)(C1-C 50 alkyl), -NH(OH), -SH, -SC1~C 50 Alkyl, -SS(C1-C 50 alkyl), -C(=O)(C1-C50 alkyl), -CO2H, -CO2(C1-C 50 alkyl), -OC(=O)(C1-C 50 alkyl), -OCO2(C1-C 50 alkyl), -C(=O)NH2, -C(=O)N(C1-C 50 alkyl)2, -OC(=O)NH(C1-C 50 alkyl), -NHC(=O)(C1-C 50 alkyl), -N(C1-C 50 Alkyl)C(=O)(C1-C 50 alkyl), -NHCO2(C1-C 50 alkyl), -NHC(=O)N(C1-C 50 alkyl)2, -NHC(=O)NH(C1-C 50 alkyl), -NHC(=O)NH2, -C(=NH)O(C1-C 50 alkyl), -OC(=NH)(C1-C 50 alkyl), -OC(=NH)OC1~C 50 Alkyl, -C(=NH)N(C1-C 50 alkyl)2, -C(=NH)NH(C1-C 50 alkyl), -C(=NH)NH2, -OC(=NH)N(C1-C 50 alkyl)2, -OC(NH)NH(C1-C 50 alkyl), -OC(NH)NH2, -NHC(NH)N(C1-C 50 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-C 50 alkyl), -SO2N(C1-C 50 alkyl)2, -SO2NH(C1-C 50 alkyl), -SO2NH2, -SO2(C1-C 50 alkyl), -SO2O(C1-C 50 alkyl), -OSO2(C1-C6 alkyl), -SO(C1-C6 alkyl), -Si(C1-C 50 alkyl)3, -OSi(C1-C6 alkyl)3, -C(=S)N(C1-C 50 alkyl)2, C(=S)NH(C1-C 50alkyl), C(=S)NH2, -C(=O)S(C1-C6 alkyl), -C(=S)S(C1-C6 alkyl), -SC(=S)S(C1-C6 alkyl), -P(=O)2(C1-C 50 alkyl), -P(=O)(C1-C 50 alkyl)2, -OP(=O)(C1-C 50 alkyl)2, -OP(=O)(OC1~C 50 Alkyl)2, C1-C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S, and X - is the counter ion.

[0072] As used herein, the term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0073] As used herein, a "counterion" is a negatively charged group that is attached to a positively charged quaternary amine to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 -, sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.), and carboxylate ions (e.g., acetic acid, ethanoic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, etc.).

[0074] Nitrogen atoms can be substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C1~C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclyl, 3-14 membered heterocyclyl, C6-C 14 aryl and 5-14 membered heteroaryl, or two R ccThe groups, taken together with the N atom to which they are attached, form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd is as defined above.

[0075] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also called an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0076] For example, an amide group (e.g., —C(═O)R aa ), include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0077] Carbamate groups (e.g., -C(=O)OR aa), nitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylcarbamate, ... Tetylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t -Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, Al Cyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonoethyl carbamate (Peoc), 2-triphenylphosphonoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2 ,2-Dimethoxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborin carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-Methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,Examples include, but are not limited to, 6-trimethylbenzylcarbamate.

[0078] Sulfonamide groups (e.g., -S(=O)R aa ) and the like, examples of nitrogen protecting groups include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), and 2,4,6-trimethylbenzenesulfonamide (Mts). , 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0079] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilyl. Azacyclopentane adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, Quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine N-Benzylamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,Examples of suitable amines include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0080] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0081] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4 ,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o- Nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- (oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4 -oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzene Sulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate (E)-2 Examples of suitable amines include, but are not limited to, methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0082] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a thiol protecting group). Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0083] Exemplary sulfur protecting groups include alkyl, benzyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, 2,4,6-trimethoxybenzyl, o-hydroxybenzyl, p-hydroxybenzyl, o-acetoxybenzyl, p-acetoxybenzyl, p-nitrobenzyl, 4-picolyl, 2-quinolinylmethyl, 2-picolyl N-oxide, 9-anthrylmethyl, 9-fluorenylmethyl, xanthenyl, ferrocenylmethyl, diphenylmethyl, bis(4-methoxyphenyl)methyl, 5-dibenzosuberyl, triphenylmethyl, diphenyl-4-pyridylmethyl, phenyl, 2,4-dinitrophenyl, t-butyl, 1-adamantyl, methoxymethyl (MOM), isobutoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzylthiomethyl, phenylthiomethyl, thiazolidino, acetamidomethyl, trimethylacetamidomethyl, benzamidomethyl, allyloxycarbonylaminomethyl, phenyl ... Nylacetamidomethyl, phthalimidomethyl, acetylmethyl, carboxymethyl, cyanomethyl (2-nitro-1-phenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl, 2-cyanoethyl, 2-(trimethylsilyl)ethyl, 2,2-bis(carbethoxy)ethyl (1-m-nitrophenyl-2-benzoyl)ethyl, 2-phenylsulfonylethyl, 2-(4-methylphenylsulfonyl)-2-methylprop-2-yl, acetyl, benzoyl, trimethylsilyl These include, but are not limited to, trifluoroacetyl, N-[[(p-biphenylyl)isopropoxy]carbonyl]-N-methyl]-γ-aminothiobutyrate, 2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, N-ethyl, N-methoxymethyl, sulfonate, sulfenylthiocarbonate, 3-nitro-2-pyridinesulfenyl sulfide, and oxathiolone.

[0084] Compounds of the Invention Liposome-based vehicles are considered attractive carriers for therapeutic drugs and are still the subject of ongoing development efforts. Although liposome-based vehicles containing specific lipid components have shown promising results in terms of encapsulation, stability and site localization, there is still a great need for improvements in liposome-based delivery systems. For example, a significant drawback of liposome delivery systems relates to the construction of liposomes with sufficient cell culture or in vivo stability to reach desired target cells and / or intracellular compartments, and the ability of such liposome delivery systems to efficiently release encapsulated materials into such target cells.

[0085] In particular, there remains a need for improved lipid compounds that demonstrate improved pharmacokinetic properties and have the ability to deliver macromolecules, such as nucleic acids, to a wide variety of cell types and tissues with increased efficiency. Importantly, there also remains a need for the identification of novel lipid compounds that are characterized as having an improved safety profile and capable of efficiently delivering encapsulated nucleic acids and polynucleotides to target cells, tissues, and organs.

[0086] Described herein is a novel class of cationic lipid compounds for improving the in vivo delivery of therapeutic agents such as nucleic acids. In particular, the cationic lipids described herein, optionally in combination with other lipids, can be used to formulate lipid-based nanoparticles (e.g., liposomes) for encapsulating therapeutic agents such as nucleic acids (e.g., DNA, siRNA, mRNA, microRNA) for therapeutic uses such as disease treatment and prevention (vaccine) purposes.

[0087] In embodiments, the compounds of the present invention described herein can provide one or more desirable features or characteristics. That is, in certain embodiments, the compounds of the present invention described herein can be characterized as having one or more properties that provide such compounds with advantages over other similarly classified lipids. For example, the compounds disclosed herein can allow for control and adjustment of the properties of the liposome composition (e.g., lipid nanoparticle) of which they are a component. In particular, the compounds disclosed herein can be characterized by enhanced transfection efficiency and their ability to induce specific biological outcomes. Such outcomes may include, for example, enhanced cellular uptake, endosomal / lysosomal disruption, and / or enhanced intracellular release of encapsulated material (e.g., polynucleotides). Furthermore, the compounds disclosed herein have advantageous pharmacokinetic properties, biodistribution, and efficacy.

[0088] This application demonstrates that the cationic lipids of the present invention are synthetically amenable from readily available starting materials.

[0089] Additionally, the cationic lipids of the present invention contain cleavable groups such as esters, amides, and disulfides. These cleavable groups (e.g., esters, amides, and disulfides) are believed to improve biodegradability and therefore contribute to the favorable safety profile of the lipids.

[0090] Compounds that are cationic lipids are provided herein. For example, the cationic lipids of the present invention have the formula (I): [ka] (Wherein A is -N(R 1 )- or -SS-; R 1 is an optionally substituted (C1-C6) alkyl; a and c are integers independently selected from 1, 2, 3, or 4; b and d are integers independently selected from 1, 2, 3, 4, 5, or 6; Z 1 is a covalent bond, [ka] or -SS-, and the left side of each depicted structure is selected from -(CH2) b - is bonded to Z 2 is a covalent bond, [ka] or -SS-, and the right side of each depicted structure is selected from -(CH2) d - is bonded to Each Y 1 are independently selected from hydrogen or —OH; Each R 8 are independently selected from hydrogen or optionally substituted (C1-C6) alkyl; R 2A , R 2B , R 2C and R 2D is optionally substituted (C5-C 25 ) alkyl, optionally substituted (C5-C 25 ) alkenyl or -W 1 -X 1 are each independently selected from Each W 1 is a covalent bond, optionally substituted (C1-C 10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and each X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, -*O-(C=O)- optionally substituted (C3-C 25 ) alkyl or -O-(C=O)- optionally substituted (C3-C25 ) alkenyl, and the atom marked with an * is independently selected from W 1 If is a covalent bond, W 1 or -CH(Y 1 )-bonded to) or a pharmaceutically acceptable salt thereof.

[0091] In embodiments, the cationic lipids of the present invention are those in which A is -N(R 1 In embodiments, the cationic lipids of the present invention include compounds of formula (IA): [ka] or a pharmaceutically acceptable salt thereof.

[0092] In embodiments, the cationic lipids of the present invention are those in which A is -N(R 1 )- and Y 1 In an embodiment, the cationic lipid of the present invention comprises a compound of formula (IA1): [ka] or a pharmaceutically acceptable salt thereof.

[0093] In embodiments, the cationic lipids of the present invention are those in which A is -N(R 1 )- and Y 1 is OH and Z 1 and Z 2 and each is an ester. In an embodiment, the cationic lipids of the present invention comprise a compound of formula (I) wherein A is -N(R 1 )- and Y 1 is OH and Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b - and Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d In an embodiment, the cationic lipid of the present invention is linked to the formula (IA1i): [ka] or a pharmaceutically acceptable salt thereof.

[0094] In embodiments, the cationic lipids of the present invention are those in which A is -N(R 1 )- and Y 1 is OH, a=1, c=1, and Z 1 and Z 2 and each is an ester. In an embodiment, the cationic lipids of the present invention include compounds of formula (I) where A is -N(R 1 )- and Y 1 is OH, a=1, c=1, and Z 1 but, [ka] and the left side of the structure shown is -(CH2) b - and Z 2 but, [ka] and the right side of the structure shown is -(CH2) d In an embodiment, the cationic lipid of the present invention comprises a compound of formula (IA1ia): [ka] or a pharmaceutically acceptable salt thereof.

[0095] In embodiments, the cationic lipids of the present invention have the structure A=-N(R 1 )- and Y 1In an embodiment, the cationic lipid of the present invention comprises a compound of formula (IA2): [ka] or a pharmaceutically acceptable salt thereof.

[0096] In embodiments, the cationic lipid of the present invention has the formula (IB): [ka] or a pharmaceutically acceptable salt thereof.

[0097] In embodiments, the cationic lipid of the present invention has the formula (IC): [ka] or a pharmaceutically acceptable salt thereof.

[0098] In embodiments, the cationic lipid of the present invention has the formula (ID): [ka] or a pharmaceutically acceptable salt thereof.

[0099] In embodiments, the cationic lipids of the present invention have the formula (IE): [ka] or a pharmaceutically acceptable salt thereof.

[0100] In embodiments, the cationic lipid of the present invention has the formula (IA1ii): [ka] or a pharmaceutically acceptable salt thereof.

[0101] In embodiments, the cationic lipid of the present invention has the formula (IA1iia): [ka] or a pharmaceutically acceptable salt thereof.

[0102] In embodiments, the cationic lipid of the present invention has the formula (IA1iii): [ka] or a pharmaceutically acceptable salt thereof.

[0103] In embodiments, the cationic lipid of the present invention has the formula (IA1iiia): [ka] or a pharmaceutically acceptable salt thereof.

[0104] In embodiments, A is —N(R 1 In an embodiment, R 1 is (C1-C6) alkyl. In embodiments, R 1 is methyl. In embodiments, R 1 is (C1-C6) alkylene-R A and R A -OH, -N(R 6 )(R 7 ), or [ka] and each R 6 and R 7 are independently selected from optionally substituted (C1-C6) alkyl. In embodiments, R A is —OH. In embodiments, R A is -N(R 6 )(R 7 In an embodiment, R A teeth, [ka] In an embodiment, R 6 and R 7 is methyl. In an embodiment, A is -SS-.

[0105] In embodiments, a is 1 or 2, and preferably the cationic lipid has a structure according to any one of formula (IA), formula (IA1), or formula (IA2). In embodiments, a is 1, and preferably the cationic lipid has a structure according to (i) formula (IB), or (ii) formula (IA1ii) or formula (IA1iii). In embodiments, a is 2, and preferably the cationic lipid has a structure according to any one of formula (IC), formula (ID), or formula (IE). In embodiments, a is 3. In embodiments, a is 4.

[0106] In embodiments, b is 2, 3, or 4, and preferably the cationic lipid has a structure according to any one of formula (IA), (IA1), or (IA2). In embodiments, b is 3 or 4, and preferably the cationic lipid has a structure according to (i) formula (IA1ia), or (ii) formula (IA1ii), (IA1iia), (IA1iii), or (IA1iiia). In embodiments, b is 3, and preferably the cationic lipid has a structure according to any one of formula (IB), (ID), or (IE). In embodiments, b is 4, and preferably the cationic lipid has a structure according to formula (IC). In embodiments, b is 1. In embodiments, b is 2. In embodiments, b is 5. In embodiments, b is 6.

[0107] In embodiments, c is 1 or 2, and preferably the cationic lipid has a structure according to any one of formula (IA), formula (IA1), or formula (IA2). In embodiments, c is 1, and preferably the cationic lipid has a structure according to (i) formula (IB), or (ii) formula (IA1ii) or formula (IA1iii). In embodiments, c is 2, and preferably the cationic lipid has a structure according to any one of formula (IC), formula (ID), or formula (IE). In embodiments, c is 3. In embodiments, c is 4.

[0108] In embodiments, d is 2, 3, or 4, and preferably the cationic lipid has a structure according to any one of formula (IA), (IA1), or (IA2). In embodiments, d is 3 or 4, and preferably the cationic lipid has a structure according to (i) formula (IA1ia), or (ii) formula (IA1ii), (IA1iia), (IA1iii), or (IA1iiia). In embodiments, d is 3, and preferably the cationic lipid has a structure according to any one of formula (IB), (ID), or (IE). In embodiments, d is 4, and preferably the cationic lipid has a structure according to formula (IC). In embodiments, d is 1. In embodiments, d is 2. In embodiments, d is 5. In embodiments, d is 6.

[0109] In an embodiment, Z 1 is a covalent bond. In embodiments, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b In one embodiment, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b In one embodiment, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b In one embodiment, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b In one embodiment, Z 1 is -SS-.

[0110] In an embodiment, Z 2 is a covalent bond. In embodiments, Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d In one embodiment, Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d In one embodiment, Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d In one embodiment, Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d In one embodiment, Z 2 is -SS-.

[0111] In an embodiment, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b - and Z 2 is -SS-, and preferably the cationic lipid has a structure according to any one of formula (IA) or formula (IA1).

[0112] In an embodiment, Z 1 and Z 2 are both -SS-, and preferably the cationic lipid has a structure according to either one of formula (IA) or formula (IA1).

[0113] In an embodiment, Z 1 and Z 2 are both covalent bonds, and preferably the cationic lipid has a structure according to any one of formula (IA), formula (IA1) or formula (IA2).

[0114] In an embodiment, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b - and Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d -, and preferably the cationic lipid has a structure according to any one of formula (IA), formula (IA1), formula (IA2), formula (IC) or formula (ID).

[0115] In an embodiment, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b - and Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d -, and preferably the cationic lipid has a structure according to any one of formula (IA2), formula (Ib) or formula (IE).

[0116] In an embodiment, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b - and Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d -, and preferably the cationic lipid has a structure according to any one of formula (IA) or formula (IA1).

[0117] In an embodiment, Z 1 teeth, [ka] and the left side of the structure shown is -(CH2) b - and Z 2 teeth, [ka] and the right side of the structure shown is -(CH2) d -, and preferably the cationic lipid has a structure according to any one of formula (IA) or formula (IA1).

[0118] In some embodiments, at least one Y 1 is —OH. In embodiments, at least one Y 1 is hydrogen. In some embodiments, Y 1is —OH. In some embodiments, Y 1 is hydrogen.

[0119] In embodiments, each R 8 is hydrogen. In embodiments, each R 8 is an optionally substituted (C1-C6) alkyl. In embodiments, each R 8 is independently selected from hydrogen or methyl. In an embodiment, each R 8 is methyl.

[0120] In embodiments, R 2A is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 2A is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 2A is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 2A is optionally substituted (C6 to C 12 ) alkyl.

[0121] In embodiments, R 2A is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 2A is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 2A is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 2A is optionally substituted (C 15 ~C 20 ) alkenyl.

[0122] In embodiments, R 2A -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 )-.

[0123] In embodiments, R 2B is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 2B is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 2B is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 2B is optionally substituted (C6 to C 12 ) alkyl.

[0124] In embodiments, R 2B is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 2B is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 2B is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 2B is optionally substituted (C 15 ~C 20 ) alkenyl.

[0125] In embodiments, R 2B -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 )-.

[0126] In embodiments, R 2C is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 2C is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 2C is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 2C is optionally substituted (C6 to C 12 ) alkyl.

[0127] In embodiments, R 2C is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 2C is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 2C is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 2C is optionally substituted (C 15 ~C 20 ) alkenyl.

[0128] In embodiments, R 2C -W 1 -X 1 In an embodiment, W1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In an embodiment, X 1is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 )-.

[0129] In embodiments, R 2D is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 2D is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 2D is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 2D is optionally substituted (C6 to C 12 ) alkyl.

[0130] In embodiments, R 2D is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 2D is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 2D is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 2D is optionally substituted (C 15 ~C 20 ) alkenyl.

[0131] In embodiments, R 2D -W 1 -X1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In an embodiment, X1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 1 )-.

[0132] In embodiments, each R 2A , R 2B , R 2C and R 2D teeth, [ka] and preferably, each R 2A , R 2B , R 2C and R 2D is independently selected from alternatives (ii), (iii), (iv), (v), (vi), (viii), (ix), (x), (xi), (xii), (xiii) or (xiv).

[0133] In embodiments, each R 2A , R 2B , R 2C and R 2D teeth, [ka] [ka] and preferably, each R 2A , R 2B , R 2C and R 2Dare independently selected from alternatives (ii), (iii), (iv), (v), (vi), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi) or (xvii).

[0134] In embodiments, R 2A , R 2B , R 2C and R 2D are the same. In an embodiment, R 2A and R 2B is the same as R 2C and R 2D are the same. In an embodiment, R 2A and R 2C is the same as R 2B and R 2D are the same. In an embodiment, R 2A and R 2C is the same as R 2B and R 2D is different.

[0135] The cationic lipids of the present invention have the formula (II): [ka] (In the formula, R 3 is selected from hydrogen or optionally substituted (C1-C6) alkyl; R 4 is selected from hydrogen, —OH, —NH2, optionally substituted (C1-C6) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C3) alkylene-optionally substituted aryl or optionally substituted (C1-C3) alkylene-optionally substituted heteroaryl; e and g are integers independently selected from 0, 1, 2, 3, or 4; f and h are integers independently selected from 1, 2, 3, 4, 5, or 6; Each Y 2 are independently selected from hydrogen or —OH; R 5A , R 5B , R 5C and R 5D is optionally substituted (C5-C 25 ) alkyl, optionally substituted (C5-C 25 ) alkenyl or -W 1 -X 1 are each independently selected from Each W 1 is a covalent bond, optionally substituted (C1-C 10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and each X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, -*O-(C=O)- optionally substituted (C3-C 25 ) alkyl or -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is independently selected from W 1 If is a covalent bond, W 1 or -CH(Y 2 )-bonded to) or a pharmaceutically acceptable salt thereof.

[0136] In embodiments, the cationic lipid of the present invention has the formula (IIA): [ka] or a pharmaceutically acceptable salt thereof.

[0137] In embodiments, the cationic lipids of the present invention are 2 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), where =OH. [ka] or a pharmaceutically acceptable salt thereof.

[0138] In embodiments, the cationic lipids of the present invention are 2 =OH, R 3 = hydrogen, e and g = 0. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) 2 =OH, R 4 = hydrogen, e and g = 0. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) 2 =OH, R 3 and R 4 = hydrogen and e and g = 0. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0139] In embodiments, the cationic lipids of the present invention are 2 = hydrogen. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0140] In embodiments, the cationic lipids of the present invention are R 3 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), where =H. [ka] (In the formula, R 4 is selected from (C1-C6) alkyl, phenyl or benzyl or a pharmaceutically acceptable salt thereof. In embodiments, R 4 is selected from methyl, isopropyl, phenyl, or benzyl. 4 is methyl. In embodiments, R 4 is isopropyl. In embodiments, R 4 is phenyl. In embodiments, R 4 is benzyl.

[0141] In embodiments, the cationic lipids of the present invention are R 3 In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II): [ka] (In the formula, R 4 is selected from (C1-C6) alkyl or a pharmaceutically acceptable salt thereof. In embodiments, R 4 is selected from methyl or ethyl. In embodiments, R 4 is methyl. In embodiments, R 4 is ethyl.

[0142] In embodiments, the cationic lipids of the present invention are R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where R =OH. 3 = methyl and R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0143] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (II), where e=1 and g=1. In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (II), where R3 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where R = methyl, e = 1 and g = 1. 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where R =OH, e=1, and g=1. 3 = methyl, R 4 ═OH, e=1, and g=1. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0144] In embodiments, the cationic lipids of the present invention are 2 =OH and R 3 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where Y = hydrogen. 2 =OH and R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where Y =OH. 2 =OH, R 3 = hydrogen and R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0145] In embodiments, the cationic lipids of the present invention are 2 =OH, R 3 = hydrogen, e and g = 0. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) 2 =OH, R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where Y =OH, e and g = 0. 2=OH, R 3 = hydrogen, R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), where =OH, e and g = 0. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (IID1): [ka] or a pharmaceutically acceptable salt thereof.

[0146] In embodiments, the cationic lipids of the present invention are 2 =OH and R 3 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where Y = hydrogen. 2 =OH and R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where Y =NH2. 2 =OH, R 3 = hydrogen and R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), where =NH2. [ka] or a pharmaceutically acceptable salt thereof.

[0147] In embodiments, the cationic lipids of the present invention are 2 =OH, R 3 = hydrogen, e and g = 0. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) 2 =OH, R 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II) where Y = NH, e and g = 0. 2 =OH, R 3 = hydrogen, R 4 =NH2, e and g = 0. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0148] In embodiments, the cationic lipid of the present invention has the formula (IIIC1ii): [ka] or a pharmaceutically acceptable salt thereof.

[0149] In embodiments, the cationic lipid of the present invention has the formula (IIC2): [ka] or a pharmaceutically acceptable salt thereof.

[0150] In embodiments, the cationic lipid of the present invention has the formula (IIC2i): [ka] or a pharmaceutically acceptable salt thereof.

[0151] In embodiments, R 3 is hydrogen. In embodiments, R 3 is an optionally substituted (C1-C6) alkyl. In embodiments, R 3 is methyl.

[0152] In embodiments, R 4 is selected from hydrogen, —OH, —NH, optionally substituted (C1-C6) alkyl, optionally substituted phenyl, or optionally substituted (C1-C3) alkylene-optionally substituted phenyl. In embodiments, R 4 is hydrogen. In embodiments, R 4 is —OH. In embodiments, R 4 is —NH. In embodiments, R 4is an optionally substituted (C1-C6) alkyl. In embodiments, R 4 is methyl. In embodiments, R 4 is ethyl. In embodiments, R 4 is isopropyl. In embodiments, R 4 is optionally substituted aryl. In embodiments, R 4 is optionally substituted phenyl. In embodiments, R 4 is phenyl. In embodiments, R 4 is optionally substituted (C1-C3) alkylene-optionally substituted aryl. In embodiments, R 4 is optionally substituted (C1-C3) alkylene-optionally substituted phenyl. In embodiments, R 4 is optionally substituted benzyl. In embodiments, R 4 is benzyl. In embodiments, R 4 is optionally substituted heteroaryl. In embodiments, R 4 is an optionally substituted (C1-C3) alkylene-optionally substituted heteroaryl.

[0153] In embodiments, e is 0, 1, or 2, and preferably the cationic lipid has a structure according to any one of Formula (IIA), Formula (IIA1), or Formula (IIB). In embodiments, e is 1, and preferably the cationic lipid has a structure according to any one of Formula (IIA2) or Formula (IIC). In embodiments, e is 0, and preferably the cationic lipid has a structure according to any one of (i) Formula (IIA1i), Formula (IID), or Formula (IIE), or (ii) Formula (IIC1), Formula (IIC2), or Formula (IIE). In embodiments, e=2. In embodiments, e=3. In embodiments, e=4.

[0154] In embodiments, f is 3, 4, 5, or 6, and preferably the cationic lipid has a structure according to formula (IIC1i). In embodiments, f is 3, 4, or 5, and preferably the cationic lipid has a structure according to formula (IIA1i). In embodiments, f=3 or 4, and preferably the cationic lipid has a structure according to formula (IID1). In embodiments, f is 3, and preferably the cationic lipid has a structure according to any one of (i) formula (IIA), formula (IIA1), formula (IIA2), formula (IIB), formula (IIC), or formula (IIE1), or (ii) formula (IIC1), formula (IIC1ii), formula (IIE), or formula (IIE1). In embodiments, f is 4, and preferably the cationic lipid has a structure according to formula (IIC2) or formula (IIC2i). In embodiments, f=1. In embodiments, f=2. In embodiments, f=4. In an embodiment, f=5. In an embodiment, f=6.

[0155] In embodiments, g is 0 or 1, and preferably the cationic lipid has a structure according to any one of Formula (IIA), Formula (IIA1), or Formula (IIB). In embodiments, g is 0, and preferably the cationic lipid has a structure according to any one of (i) Formula (IIA1i), Formula (IIA2), Formula (IID), or Formula (IIE), or (ii) Formula (IIC1), Formula (IIC2), or Formula (IIE). In embodiments, g is 1, and preferably the cationic lipid has a structure according to Formula (IIC). In embodiments, g is 2. In some embodiments, g is 3. In embodiments, g is 4.

[0156] In embodiments, h is 3, 4, 5, or 6, and preferably the cationic lipid has a structure according to formula (IIC1i). In embodiments, h is 3, 4, or 5, and preferably the cationic lipid has a structure according to formula (IIA1i). In embodiments, h is 3 or 4, and preferably the cationic lipid has a structure according to formula (IID1). In embodiments, h is 3, and preferably the cationic lipid has a structure according to any one of (i) formula (IIA), formula (IIA1), formula (IIA2), formula (IIB), formula (IIC), or formula (IIE1), or (ii) formula (IIC1), formula (IIC1ii), formula (IIE), or formula (IIE1). In embodiments, h is 4, and preferably the cationic lipid has a structure according to formula (IIC2) or formula (IIC2i). In embodiments, h is 1. In embodiments, h is 2. In embodiments, h is 4. In embodiments, h is 5. In embodiments, h is 6.

[0157] In some embodiments, at least one Y 2 is —OH. In embodiments, at least one Y 2 is hydrogen. In some embodiments, Y 2 is —OH. In some embodiments, Y 2 is hydrogen.

[0158] In embodiments, R 5A is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 5A is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 5A is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 5A is optionally substituted (C6 to C 12 ) alkyl.

[0159] In embodiments, R 5A is optionally substituted (C5-C 25) alkenyl. In embodiments, R 5A is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 5A is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 5A is optionally substituted (C 15 ~C 20 ) alkenyl.

[0160] In embodiments, R 5A -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 )-.

[0161] In embodiments, R 5B is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 5B is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 5B is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 5B is optionally substituted (C6 to C 12 ) alkyl.

[0162] In embodiments, R 5B is optionally substituted (C5-C 25) alkenyl. In embodiments, R 5B is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 5B is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 5B is optionally substituted (C 15 ~C 20 ) alkenyl.

[0163] In embodiments, R 5B -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 )-.

[0164] In embodiments, R 5C is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 5C is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 5C is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 5C is optionally substituted (C6 to C 12 ) alkyl.

[0165] In embodiments, R 5C is optionally substituted (C5-C 25) alkenyl. In embodiments, R 5C is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 5C is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 5C is optionally substituted (C 15 ~C 20 ) alkenyl.

[0166] In embodiments, R 5C -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 )-.

[0167] In embodiments, R 5D is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 5D is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 5D is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 5D is optionally substituted (C6 to C 12 ) alkyl.

[0168] In embodiments, R 5D is optionally substituted (C5-C 25) alkenyl. In embodiments, R 5D is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 5D is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 5D is optionally substituted (C 15 ~C 20 ) alkenyl.

[0169] In embodiments, R 5D -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1or -CH(Y 2 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 2 )-.

[0170] In embodiments, each R 5A , R 5B , R 5C and R 5D teeth, [ka] and preferably, each R 5A , R 5B , R 5C and R 5D is independently selected from alternatives (i), (ii), (iii), (vii), (viii), (xi) or (xiv).

[0171] In embodiments, each R 5A , R5B , R 5C and R 5D teeth, [ka] [ka] [ka] and preferably, each R 5A , R 5B , R 5C and R 5D is independently selected from alternatives (i), (ii), (iii), (vii), (viii), (xi) or (xiv).

[0172] In embodiments, R 5A , R 5B , R 5C and R 5D are the same. In an embodiment, R 5A and R 5B is the same as R 5C and R 5D are the same. In an embodiment, R 5A and R 5C is the same as R 5B and R 5D are the same.

[0173] The cationic lipids of the present invention have the formula (III): [ka] (In the formula, R 9 is selected from hydrogen or optionally substituted (C1-C6) alkyl; R 10is selected from hydrogen, —OH, —NH2, optionally substituted (C1-C6) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C3) alkylene-optionally substituted aryl or optionally substituted (C1-C3) alkylene-optionally substituted heteroaryl; i and k are integers independently selected from 0, 1, 2, 3, or 4; j and l are integers independently selected from 1, 2, 3, 4, 5, or 6; Each Y 3 are independently selected from hydrogen or —OH; Each R 12 are independently selected from hydrogen or optionally substituted (C1-C6) alkyl; R 11A , R 11B , R 11C and R 11D is optionally substituted (C5-C 25 ) alkyl, optionally substituted (C5-C 25 ) alkenyl or -W 1 -X 1 are each independently selected from Each W 1 is a covalent bond, optionally substituted (C1-C 10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and each X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, -*O-(C=O)- optionally substituted (C3-C 25 ) alkyl or -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is independently selected from W 1 If is a covalent bond, W 1or -CH(Y 3 )-bonded to) or a pharmaceutically acceptable salt thereof.

[0174] In embodiments, the cationic lipids of the present invention are 3 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (III), where =OH. [ka] or a pharmaceutically acceptable salt thereof.

[0175] In embodiments, the cationic lipids of the present invention are 3 =OH, R 9 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (III) where Y = methyl and i and k = 0. 3 =OH, R 10 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (III) where Y =OH and i and k=0. 3 =OH, R 9 = methyl, R 10 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (III), where =OH and i and k=0. [ka] or a pharmaceutically acceptable salt thereof.

[0176] In embodiments, the cationic lipid of the present invention has the formula (IIIB): [ka] or a pharmaceutically acceptable salt thereof.

[0177] In embodiments, the cationic lipid of the present invention has the formula (IIIB1): [ka] or a pharmaceutically acceptable salt thereof.

[0178] In embodiments, R 9 is hydrogen. In embodiments, R 9 is an optionally substituted (C1-C6) alkyl. In embodiments, R 9 is methyl.

[0179] In embodiments, R 10 is hydrogen. In embodiments, R 10 is —OH. In embodiments, R 10 is —NH. In embodiments, R 10 is an optionally substituted (C1-C6) alkyl. In embodiments, R 10 is methyl. In embodiments, R 10 is ethyl. In embodiments, R 10 is isopropyl. In embodiments, R 10 is optionally substituted aryl. In embodiments, R 10 is optionally substituted phenyl. In embodiments, R 10 is phenyl. In embodiments, R 10 is optionally substituted (C1-C3) alkylene-optionally substituted aryl. In embodiments, R 10 is optionally substituted (C1-C3) alkylene-optionally substituted phenyl. In embodiments, R 10 is optionally substituted benzyl. In embodiments, R 10 is benzyl. In embodiments, R 10 is optionally substituted heteroaryl. In embodiments, R 10 is an optionally substituted (C1-C3) alkylene-optionally substituted heteroaryl.

[0180] In embodiments, i is 0. In embodiments, i is 1. In embodiments, i is 2. In embodiments, i is 3. In embodiments, i is 4.

[0181] In embodiments, j is 3 or 4. In embodiments, j is 1. In embodiments, j is 2. In embodiments, j is 3, and preferably the cationic lipid has a structure according to any one of Formula (IIIB) or Formula (IIIB1). In embodiments, j is 4. In embodiments, j is 5. In embodiments, j is 6.

[0182] In embodiments, k is 0. In embodiments, k is 1. In embodiments, k is 2. In embodiments, k is 3. In embodiments, k is 4.

[0183] In embodiments, l is 3 or 4. In embodiments, l is 1. In embodiments, l is 2. In embodiments, l is 3, and preferably, the cationic lipid has a structure according to any one of Formula (IIIB) or Formula (IIIB1). In embodiments, l is 4. In embodiments, l is 5. In embodiments, l is 6.

[0184] In some embodiments, at least one Y 3 is —OH. In embodiments, at least one Y 3 is hydrogen. In some embodiments, Y 3 is —OH. In some embodiments, Y 3 is hydrogen.

[0185] In embodiments, each R 12 is hydrogen. In embodiments, each R 12 is an optionally substituted (C1-C6) alkyl. In embodiments, each R 12 is methyl.

[0186] In embodiments, R 11A is optionally substituted (C5-C25 ) alkyl. In embodiments, R 11A is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 11A is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 11A is optionally substituted (C6 to C 12 ) alkyl. In embodiments, R 11A is optionally substituted (C8 to C 10 ) alkyl.

[0187] In embodiments, R 11A is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 11A is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 11A is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 11A is optionally substituted (C 15 ~C 20 ) alkenyl.

[0188] In embodiments, R 11A -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 )-.

[0189] In embodiments, R 11B is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 11B is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 11B is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 11B is optionally substituted (C6 to C 12 ) alkyl. In embodiments, R 11B is optionally substituted (C8 to C 10 ) alkyl.

[0190] In embodiments, R 11B is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 11B is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 11B is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 11B is optionally substituted (C 15 ~C 20 ) alkenyl.

[0191] In embodiments, R 11B -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 )-.

[0192] In embodiments, R 11C is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 11C is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 11C is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 11C is optionally substituted (C6 to C 12 ) alkyl. In embodiments, R 11C is optionally substituted (C8 to C 10 ) alkyl.

[0193] In embodiments, R 11C is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 11C is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 11C is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 11C is optionally substituted (C 15 ~C 20 ) alkenyl.

[0194] In embodiments, R 11C -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1or -CH(Y 3 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 )-.

[0195] In embodiments, R 11D is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 11D is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 11D is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 11D is optionally substituted (C6 to C 12 ) alkyl. In embodiments, R 11D is optionally substituted (C8 to C 10 ) alkyl.

[0196] In embodiments, R 11D is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 11D is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 11D is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 11D is optionally substituted (C 15 ~C 20 ) alkenyl.

[0197] In embodiments, R 11D -W 1 -X 1 In an embodiment, W 1is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 3 )-.

[0198] In embodiments, each R 11A , R 11B , R 11C and R 11D teeth, [ka] and preferably, each R 11A , R 11B , R 11C and R 11D is independently selected from option (ii) or (iii).

[0199] In embodiments, each R 11A , R 11B , R 11C and R 11D teeth, [ka] [ka] and preferably, each R 11A , R 11B , R 11C and R 11D is independently selected from alternatives (ii), (iii), (viii), (xi), (xiv), (xv), (xvi) or (xvii).

[0200] In embodiments, R 11A , R11B , R 11C and R 11D are the same. In an embodiment, R 11A and R 11C is the same as R 11B and R 11D are the same. In an embodiment, R 11A and R 11C is the same as R 11B and R 11D is different.

[0201] The cationic lipids of the present invention have the formula (IV): [ka] (In the formula, m and n are integers independently selected from 1, 2, 3, 4, 5, or 6; Z 3 is an aromatic amino acid residue, and the α-carbon carboxyl group (-C(O)O-) of the aromatic amino acid residue is -(CH2) m -, and the α-carbon aminyl group (—NH—) of an aromatic amino acid residue is bonded to Z 4 is connected to Z 4 teeth, [ka] The right side of each shown structure is selected from -(CH2) n - is bonded to Each Y 4 are independently selected from hydrogen or —OH; R 13A , R 13B , R 13C and R 13D is optionally substituted (C5-C 25 ) alkyl, optionally substituted (C5-C 25 ) alkenyl or -W 1 -X 1 are each independently selected from Each W 1 is a covalent bond, optionally substituted (C1-C10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and each X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, -*O-(C=O)- optionally substituted (C3-C 25 ) alkyl or -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is independently selected from W 1 If is a covalent bond, W 1 or -CH(Y 4 )-bonded to) or a pharmaceutically acceptable salt thereof.

[0202] In embodiments, the cationic lipids of the present invention are 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (IVA): [ka] (In the formula, R 14 is an optionally substituted (C1-C6)-alkylene-R 15 and R 15 is selected from optionally substituted aryl or optionally substituted heteroaryl or a pharmaceutically acceptable salt thereof.

[0203] In embodiments, the cationic lipids of the present invention are 4 In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (IVA1): [ka] (In the formula, R 14 is an optionally substituted (C1-C6)-alkylene-R 15 and R 15 is selected from optionally substituted aryl or optionally substituted heteroaryl or a pharmaceutically acceptable salt thereof.

[0204] In embodiments, the cationic lipid of the present invention has the formula (IVA2): [ka] (In the formula, R 14 is an optionally substituted (C1-C6)-alkylene-R 15 and R 15 is selected from optionally substituted aryl or optionally substituted heteroaryl or a pharmaceutically acceptable salt thereof.

[0205] In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6.

[0206] In embodiments, n is 4 or 5. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6.

[0207] In an embodiment, Z 4 teeth, [ka] and the right side of the structure shown is -(CH2) n In one embodiment, Z 4 teeth, [ka] and the right side of the structure shown is -(CH2) n - is bonded to

[0208] In some embodiments, at least one Y 4 is —OH. In embodiments, at least one Y 4 is hydrogen. In some embodiments, Y 4 is —OH. In some embodiments, Y 4 is hydrogen.

[0209] In embodiments, R 14 is an optionally substituted (C1-C6)-alkylene-R 15 In an embodiment, R 15 is optionally substituted aryl. In embodiments, R 15 is an optionally substituted heteroaryl.

[0210] In embodiments, R 14 is —(CH)—optionally substituted aryl. In embodiments, R 14 is —(CH)—optionally substituted aryl. In embodiments, R 14 is —(CH)—optionally substituted heteroaryl. In embodiments, R 14 is —(CH)— optionally substituted heteroaryl. In embodiments, R 14 is —(CH)—optionally substituted phenyl. In embodiments, R 14 is —(CH)— optionally substituted phenyl. In embodiments, R 14 is —(CH)-optionally substituted imidazolyl. In embodiments, R 14 is —(CH)-optionally substituted imidazolyl. In embodiments, R 14is —(CH)-optionally substituted indolyl. In embodiments, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14 teeth, [ka] In an embodiment, R 14teeth, [ka] is.

[0211] In embodiments, R 13A is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 13A is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 13A is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 13A is optionally substituted (C6 to C 12 ) alkyl. In embodiments, R 13A is optionally substituted (C8 to C 10 ) alkyl.

[0212] In embodiments, R 13A is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 13A is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 13A is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 13A is optionally substituted (C 15 ~C 20 ) alkenyl.

[0213] In embodiments, R 13A -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 )-.

[0214] In embodiments, R 13B is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 13B is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 13B is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 13B is optionally substituted (C6 to C 12 ) alkyl. In embodiments, R 13B is optionally substituted (C8 to C 10 ) alkyl.

[0215] In embodiments, R 13B is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 13B is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 13B is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 13B is optionally substituted (C 15 ~C 20 ) alkenyl.

[0216] In embodiments, R 13B -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 )-.

[0217] In embodiments, R 13C is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 13C is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 13C is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 13C is optionally substituted (C6 to C 12 ) alkyl. In embodiments, R 13C is optionally substituted (C8 to C 10 ) alkyl.

[0218] In embodiments, R 13C is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 13C is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 13C is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 13C is optionally substituted (C 15 ~C 20 ) alkenyl.

[0219] In embodiments, R 13C -W1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or ~CH(Y 4 ) is connected to the X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y4 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 )-.

[0220] In embodiments, R 13D is optionally substituted (C5-C 25 ) alkyl. In embodiments, R 13D is optionally substituted (C5-C 20 ) alkyl. In embodiments, R 13D is optionally substituted (C5-C 15 ) alkyl. In embodiments, R 13D is optionally substituted (C6 to C 12 ) alkyl. In embodiments, R 13D is optionally substituted (C8 to C 10 ) alkyl.

[0221] In embodiments, R 13D is optionally substituted (C5-C 25 ) alkenyl. In embodiments, R 13D is optionally substituted (C5-C 20 ) alkenyl. In embodiments, R 13D is optionally substituted (C 10 ~C 20 ) alkenyl. In embodiments, R 13D is optionally substituted (C 15~C 20 ) alkenyl.

[0222] In embodiments, R 13 D -W 1 -X 1 In an embodiment, W 1 is a covalent bond. In embodiments, W 1 is optionally substituted (C1 to C 10 ) alkylene. In embodiments, W 1 is an optionally substituted (C1-C8) alkylene. In embodiments, W 1 is an optionally substituted (C1-C6) alkylene. In embodiments, W 1 is an optionally substituted (C1-C5) alkylene. In embodiments, W 1 is optionally substituted (C2 to C 10 ) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C8) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C6) alkenylene. In embodiments, W 1 is an optionally substituted (C2-C5) alkenylene. In embodiments, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or ~CH(Y 4 ) is connected to the X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C5-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -(*C=O)-O-optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 20 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C5-C 18 ) alkyl, and the atoms marked with an * are W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -O-(C=O)- optionally substituted (C3-C 25 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C3-C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In some embodiments, X 1 is -O-(C=O)- optionally substituted (C5-C20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In an embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 20 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 In one embodiment, X 1 is -*O-(C=O)- optionally substituted (C 10 ~C 18 ) alkenyl, and the atom marked with an * is W 1 If is a covalent bond, W 1 or -CH(Y 4 )-.

[0223] In embodiments, each R 13A , R 13B , R 13C and R 13D teeth, [ka] and preferably, each R 13A , R 13B , R 13C and R 13D is option (ii).

[0224] In embodiments, each R 13A , R 13B , R 13C and R 13D teeth, [ka] [ka] and preferably, each R 13A , R 13B , R 13C and R13D is option (ii), (iii), (viii), (xi), (xiv) or (xv).

[0225] In embodiments, R 13A , R 13B , R 13C and R 13D are the same.

[0226] In embodiments, W of any of the formulae defined herein may be 1 ~X 1 Each W in 1 is a covalent bond, optionally substituted (C1-C 10 ) alkylene or optionally substituted (C2-C 10 ) alkenylene, and W of any of the formulae defined herein 1 ~X 1 Each X in 1 is -(*C=O)-O-optionally substituted (C3-C 25 ) branched alkyl, -(*C=O)-O- optionally substituted (C3-C 25 ) branched alkenyl, -*O-(C=O)- optionally substituted (C 25 ) branched alkyl or -*O-(C=O)- optionally substituted (C3-C 25 ) branched alkenyl, and the atom marked with an * is independently selected from W 1 If is a covalent bond, W 1 or -CH(Y 1 )-.

[0227] In embodiments, the substituents are optionally unsubstituted.

[0228] In embodiments, the cationic lipids of the present invention have any one of the structures in Table A or a pharmaceutically acceptable salt thereof.

[0229] In embodiments, the cationic lipids of the present invention have any one of the structures in Table B or a pharmaceutically acceptable salt thereof.

[0230] In embodiments, the cationic lipids of the present invention include: (i) one or more non-cationic lipids; (ii) one or more cholesterol-based lipids; (iii) one or more PEG-modified lipids; Provided herein are compositions further comprising:

[0231] In embodiments, the composition is a lipid nanoparticle, optionally a liposome. In embodiments, the one or more cationic lipids comprise about 30 mol% to 60 mol% of the lipid nanoparticle. In embodiments, the one or more non-cationic lipids comprise 10 mol% to 50 mol% of the lipid nanoparticle. In embodiments, the one or more PEG-modified lipids comprise 1 mol% to 10 mol% of the lipid nanoparticle. In embodiments, the cholesterol-based lipids comprise 10 mol% to 50 mol% of the lipid nanoparticle.

[0232] In embodiments, the lipid nanoparticles encapsulate mRNA encoding a nucleic acid, optionally a peptide or protein. In embodiments, the peptide is an antigen. In embodiments, the lipid nanoparticles encapsulate mRNA encoding a peptide or protein. As used herein, the phrase "encapsulation rate" refers to the percentage of a therapeutic agent (e.g., mRNA) that is effectively encapsulated within a liposome-based vehicle (e.g., lipid nanoparticle) relative to the initial percentage of therapeutic agent present in the lipid phase. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 50% mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 55% mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 60% mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 65% mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 70% mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 75% mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 80% mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 85% of mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 90% of mRNA. In embodiments, the lipid nanoparticles have an encapsulation rate of at least 95% of mRNA. In embodiments, the encapsulation rate is calculated by performing a Ribogreen assay (Invitrogen) with or without the presence of 0.1% Triton-X 100.

[0233] In an embodiment, the composition of the invention is for use in a vaccine.

[0234] In an embodiment, the compositions of the invention are for use in therapy.

[0235] In embodiments, the compositions of the present disclosure are for use in a method of treating or preventing a disease amenable to treatment or prevention by a peptide or protein encoded by the mRNA, and which is optionally (a) a protein deficiency, optionally affecting the liver, lungs, brain, or muscles, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

[0236] In embodiments, methods are provided for treating or preventing a disease, said methods comprising administering a composition of the invention to a subject in need thereof, wherein the disease is amenable to treatment or prevention with a peptide or protein encoded by the mRNA, and optionally the disease is (a) a protein deficiency, optionally affecting the liver, lungs, brain or muscles, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

[0237] In embodiments, the composition is administered intranasally, intravenously, intrathecally, intramuscularly, or by pulmonary delivery, optionally via aerosol. In embodiments, the composition is administered intramuscularly.

[0238] Exemplary Compounds In embodiments, the cationic lipids of the present invention comprise a compound selected from those shown in Table A, or a pharmaceutically acceptable salt thereof.

[0239] Exemplary compounds include those set forth in Table A or a pharmaceutically acceptable salt thereof.

[0240] [Table 1]

[0241] [Table 2]

[0242] [Table 3]

[0243] Table 4

[0244] Table 5

[0245] Table 6

[0246] Table 7

[0247] Table 8

[0248] Table 9

[0249] Table 10

[0250] Table 11

[0251] Table 12

[0252] Table 13

[0253] Table 14

[0254] [Table 15]

[0255] [Table 16]

[0256] [Table 17]

[0257] [Table 18]

[0258] [Table 19]

[0259] Any of the compounds identified in Table A above may be provided in the form of a pharmaceutically acceptable salt, and such salts are intended to be encompassed by the present invention.

[0260] In embodiments, the cationic lipids of the present invention comprise a compound selected from those shown in Table B, or a pharmaceutically acceptable salt thereof.

[0261] Exemplary compounds include those set forth in Table B or a pharmaceutically acceptable salt thereof.

[0262] [Table 20]

[0263] [Table 21]

[0264] Table 22

[0265] Table 23

[0266] Table 24

[0267] Table 25

[0268] Table 26

[0269] Table 27

[0270] Table 28

[0271] Table 29

[0272] Table 30

[0273] Table 31

[0274] [Table 32]

[0275] Any of the compounds identified in Table B above may be provided in the form of a pharmaceutically acceptable salt, and such salts are intended to be encompassed by the present invention.

[0276] The compounds of the invention described herein can be prepared according to methods known in the art, including the exemplary syntheses of the Examples provided herein.

[0277] nucleic acid The compounds of the invention described herein can be used to prepare compositions useful for the delivery of nucleic acids.

[0278] Nucleic acid synthesis The nucleic acid according to the present invention can be synthesized according to any known method. For example, the mRNA according to the present invention can be synthesized by in vitro transcription (IVT). Briefly, IVT is typically carried out using a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may contain DTT and magnesium ions, and an appropriate RNA polymerase (e.g., T3, T7, mutant T7, or SP6 RNA polymerase), DNAse I, pyrophosphatase, and / or RNAse inhibitor. The exact conditions will vary depending on the specific application.

[0279] In some embodiments, for the preparation of mRNA according to the present invention, a DNA template is transcribed in vitro. A suitable DNA template typically has a promoter for in vitro transcription, such as a T3, T7, mutant T7, or SP6 promoter, followed by the desired nucleotide sequence for the desired mRNA and a termination signal.

[0280] The desired mRNA sequence according to the present invention can be determined and incorporated into a DNA template using standard methods. For example, starting from the desired amino acid sequence (e.g., an enzyme sequence), virtual reverse translation is performed based on the degenerate genetic code. An optimization algorithm can then be used to select suitable codons. Typically, the G / C content is optimized to achieve the highest possible G / C content, and on the other hand, the frequency of tRNAs according to codon usage can be taken into account as much as possible. The optimized RNA sequence can be established and displayed, for example, using a suitable display device, and compared with the original (wild-type) sequence. Secondary structure can also be analyzed to calculate the stabilizing and destabilizing properties or regions of the RNA, respectively.

[0281] modified mRNA In some embodiments, mRNA according to the present invention can be synthesized as unmodified or modified mRNA. Modified mRNA includes nucleotide modifications in RNA. Thus, modified mRNA according to the present invention can include nucleotide modifications, for example, backbone modifications, sugar modifications, or base modifications. In some embodiments, mRNA is synthesized from naturally occurring nucleotides and / or nucleotide analogs (modified nucleotides), including, but not limited to, purines (adenine (A), guanine (G)) or pyrimidines (thymine (T), cytosine (C), uracil (U)), and modified nucleotides, analogs or derivatives of purines and pyrimidines, such as 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isothiazol-1-yl (A-methyl-Adenine), ... Pentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methyl-cytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1-methyl-inosine, pseudouracil (5-uracil), dihydro-uracil, 2-thio-uracil, 4 -thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil, 5'-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 1-methyl-pseudouracil, queusine, β-D-mannosyl-queusine, wybutoxosine, and phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine, inosine, and the like.The preparation of such analogs is known to those skilled in the art from, for example, U.S. Pat. Nos. 4,373,071, 4,401,796, 4,415,732, 4,458,066, 4,500,707, 4,668,777, 4,973,679, 5,047,524, 5,132,418, 5,153,319, 5,262,530, and 5,700,642, the disclosures of which are incorporated by reference in their entirety.

[0282] Pharmaceutical formulations of cationic lipids and nucleic acids In certain embodiments, the compounds of the invention described herein and pharmaceutical and liposomal compositions comprising such lipids can be used in formulations to facilitate delivery of encapsulated materials (e.g., one or more polynucleotides, such as mRNA) to one or more target cells and subsequent transfection of one or more target cells. For example, in certain embodiments, the cationic lipids described herein (and liposomal compositions comprising such lipids, etc.) are characterized by one or more of the following release properties that provide such compounds with advantages over receptor-mediated endocytosis, clathrin- and caveolae-mediated endocytosis, phagocytosis and macropinocytosis, fusogenicity, endosomal or lysosomal disruption, and other similarly classified lipids.

[0283] According to the present invention, a nucleic acid described herein, e.g., an mRNA encoding a protein described herein (e.g., a full-length, fragment, or portion of a protein), can be delivered via a delivery vehicle comprising a compound of the invention described herein.

[0284] As used herein, the terms "delivery vehicle," "transfer vehicle," "nanoparticle," or grammatical equivalents are used interchangeably.

[0285] For example, the present invention provides compositions (e.g., pharmaceutical compositions) comprising a compound described herein and one or more polynucleotides. The compositions (e.g., pharmaceutical compositions) may further comprise one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and / or one or more PEG-modified lipids.

[0286] In certain embodiments, the compositions exhibit enhanced (e.g., increased) ability to transfect one or more target cells. Accordingly, methods of transfecting one or more target cells are also provided herein. Such methods generally involve contacting one or more target cells with a cationic lipid and / or pharmaceutical composition disclosed herein (e.g., a liposome formulation comprising a compound described herein encapsulating one or more polynucleotides), thereby transfecting the one or more target cells with the encapsulated material (e.g., one or more polynucleotides). As used herein, the term "transfect" or "transfection" refers to the intracellular introduction of one or more encapsulated materials (e.g., nucleic acids and / or polynucleotides) into a cell (e.g., a target cell). The introduced polynucleotides can be stably or transiently maintained in the target cell. The term "transfection efficiency" refers to the relative amount of such encapsulated material (e.g., polynucleotides) taken up by, introduced into, and / or expressed by a target cell subject to transfection. In practice, transfection efficiency can be estimated by the amount of reporter polynucleotide product produced by target cells after transfection. In certain embodiments, the compounds and pharmaceutical compositions described herein exhibit high transfection efficiency, thereby improving the likelihood that an appropriate dose of encapsulated material (e.g., one or more polynucleotides) will be delivered to the pathology site and subsequently expressed, while minimizing potential systemic adverse effects or toxicity associated with the compound or its encapsulated contents.

[0287] For example, after transfection of one or more target cells with a polynucleotide encapsulated in one or more lipid nanoparticles comprising the pharmaceutical or liposome compositions disclosed herein, production of the product (e.g., polypeptide or protein) encoded by such polynucleotide may be stimulated, enhancing the ability of such target cells to express the polynucleotide and, for example, produce the polypeptide or protein of interest. For example, transfection of target cells with one or more compounds or pharmaceutical compositions encapsulating mRNA will enhance (i.e., increase) the production of the protein or enzyme encoded by such mRNA.

[0288] Furthermore, the delivery vehicles described herein (e.g., liposomal delivery vehicles) can be formulated to preferentially distribute to other target tissues, cells, or organs, such as the heart, lungs, kidneys, or spleen. In embodiments, the lipid nanoparticles of the present invention can be formulated to achieve enhanced delivery to target cells and tissues. For example, a polynucleotide (e.g., mRNA) encapsulated in one or more of the compounds or pharmaceutical compositions and liposomal compositions described herein can be delivered to and / or transfected into a targeted cell or tissue. In some embodiments, the encapsulated polynucleotide (e.g., mRNA) can be expressed by the target cell and a functional polypeptide product can be produced (and optionally excreted), thereby conferring beneficial properties to the target cell or tissue, for example. Such an encapsulated polynucleotide (e.g., mRNA) can encode, for example, a hormone, enzyme, receptor, polypeptide, peptide, or other protein of interest.

[0289] Liposomal Delivery Vehicles In some embodiments, the composition is a suitable delivery vehicle. In some embodiments, the suitable delivery vehicle is a liposome delivery vehicle, such as a lipid nanoparticle.

[0290] The terms "liposome delivery vehicle" and "liposome composition" are used interchangeably.

[0291] Concentrating liposome compositions with one or more of the cationic lipids disclosed herein can be used as a means to improve the safety profile or to impart one or more desirable properties to such concentrated liposome compositions (e.g., improved delivery of encapsulated polynucleotides to one or more target cells and / or reduced in vivo toxicity of the liposome composition). Accordingly, pharmaceutical compositions, particularly liposome compositions, comprising one or more of the cationic lipids disclosed herein are also contemplated.

[0292] Thus, in certain embodiments, the compounds of the invention described herein may be used as components of liposome compositions to facilitate or enhance the delivery and release of encapsulated materials (e.g., one or more therapeutic agents) to one or more target cells (e.g., by permeabilizing or fusing with the lipid membranes of such target cells).

[0293] As used herein, liposome delivery vehicles, such as lipid nanoparticles, are generally characterized as microscopic vesicles with an internal aqueous space separated from the external medium by one or more bilayer membranes. The liposome bilayer is typically formed by amphiphilic molecules containing spatially separated hydrophilic and hydrophobic domains, such as synthetic or naturally occurring lipids (Lasic, Trends Biotechnol., 16:307-321, 1998). The liposome bilayer can also be formed by amphiphilic polymers and surfactants (e.g., polymerosomes, niosomes, etc.). In the context of the present invention, liposome delivery vehicles are generally useful for transporting desired mRNA to target cells or tissues.

[0294] In certain embodiments, such compositions (eg, liposomal compositions) are loaded or encapsulated with a material such as, for example, one or more biologically active polynucleotides (eg, mRNA).

[0295] In embodiments, a composition (e.g., a pharmaceutical composition) comprises an mRNA encoding a protein encapsulated within a liposome. In embodiments, the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids, wherein at least one cationic lipid is a compound of the invention as described herein. In embodiments, the composition comprises an mRNA encoding a peptide or protein (e.g., any peptide or protein described herein). In embodiments, the composition comprises an mRNA encoding a peptide (e.g., any peptide described herein). In embodiments, the composition comprises an mRNA encoding a protein (e.g., any protein described herein).

[0296] In embodiments, a composition (eg, a pharmaceutical composition) comprises a nucleic acid encapsulated within a liposome, wherein the liposome comprises a compound described herein.

[0297] In embodiments, the nucleic acid is an mRNA encoding a peptide or protein. In embodiments, the mRNA encodes a peptide or protein for delivery to or use in treatment of the lung or lung cells of a subject. In embodiments, the mRNA encodes a peptide or protein for delivery to or use in treatment of the liver or liver cells of a subject. Still other exemplary mRNAs are described herein.

[0298] In embodiments, the liposome delivery vehicle (eg, lipid nanoparticle) may have a net positive charge.

[0299] In embodiments, the liposome delivery vehicle (eg, lipid nanoparticle) may have a net negative charge.

[0300] In embodiments, the liposome delivery vehicle (eg, lipid nanoparticle) may have a net neutral charge.

[0301] In embodiments, lipid nanoparticles encapsulating nucleic acids (eg, mRNA encoding a peptide or protein) comprise one or more compounds of the invention described herein.

[0302] For example, the amount of a compound of the invention described herein in a composition can be described as a percentage ("wt %") of the total dry weight of all lipids in the composition (e.g., the total dry weight of all lipids present in a liposome composition).

[0303] In embodiments of the pharmaceutical compositions described herein, a compound of the invention described herein is present in an amount that is about 0.5% to about 30% by weight (e.g., about 0.5% to about 20% by weight) of the total dry weight of all lipids present in the composition (e.g., a liposome composition).

[0304] In embodiments, the compounds of the invention described herein are present in an amount that is about 1% to about 30%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, or about 5% to about 25% by weight of the total dry weight of all lipids present in a composition (e.g., a liposome composition). In embodiments, the compounds of the invention described herein are present in an amount that is about 0.5% to about 5%, about 1% to about 10%, about 5% to about 20%, or about 10% to about 20% by weight of the total dry weight of all lipids present in a composition, such as a liposome delivery vehicle.

[0305] In embodiments, the amount of a compound of the invention described herein is present in an amount that is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% by weight of the total dry weight of total lipid in the composition (e.g., liposome composition).

[0306] In embodiments, the amount of a compound of the invention described herein is present in an amount that is about 5%, about 10%, about 15%, about 20%, about 25% or less by weight of the total dry weight of total lipid in a composition (e.g., a liposome composition), and is present in an amount that is about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% by weight or less.

[0307] In embodiments, the composition (e.g., a liposomal delivery vehicle such as a lipid nanoparticle) comprises about 0.1% to about 20% by weight (e.g., about 0.1% to about 15% by weight) of a compound described herein. In embodiments, the delivery vehicle (e.g., a liposomal delivery vehicle such as a lipid nanoparticle) comprises about 0.5%, about 1%, about 3%, about 5%, or about 10% by weight of a compound described herein. In embodiments, the delivery vehicle (e.g., a liposomal delivery vehicle such as a lipid nanoparticle) comprises up to about 0.5%, about 1%, about 3%, about 5%, about 10%, about 15%, or about 20% by weight of a compound described herein. In embodiments, this percentage results in improved beneficial effects (e.g., improved delivery to target tissues such as the liver or lungs).

[0308] The amount of a compound of the invention described herein in a composition can also be described as a percentage ("mol %) of the total molar amount of total lipid in the composition (e.g., the total molar amount of all lipids present in a liposome delivery vehicle).

[0309] In embodiments of the pharmaceutical compositions described herein, the compounds of the invention described herein are present in an amount that is from about 0.5 mol % to about 50 mol % (e.g., from about 0.5 mol % to about 20 mol %) of the total molar amount of all lipids present in the composition, such as a liposome delivery vehicle.

[0310] In embodiments, the compounds of the invention described herein are present in an amount that is about 0.5 mol% to about 5 mol%, about 1 mol% to about 10 mol%, about 5 mol% to about 20 mol%, about 10 mol% to about 20 mol%, about 15 mol% to about 30 mol%, about 20 mol% to about 35 mol%, about 25 mol% to about 40 mol%, about 30 mol% to about 45 mol%, about 35 mol% to about 50 mol%, about 40 mol% to about 55 mol%, or about 45 mol% to about 60 mol% of the total molar amount of all lipids present in a composition, such as a liposome delivery vehicle. In embodiments, a compound of the invention as described herein is present in an amount of about 1 mol% to about 60 mol%, 1 mol% to about 50 mol%, 1 mol% to about 40 mol%, 1 mol% to about 30 mol%, about 1 mol% to about 20 mol%, about 1 mol% to about 15 mol%, about 1 mol% to about 10 mol%, about 5 mol% to about 55 mol%, about 5 mol% to about 45 mol%, about 5 mol% to about 35 mol%, or about 5 mol% to about 25 mol% of the total molar amount of all lipids present in a composition, such as a liposome delivery vehicle.

[0311] In certain embodiments, the compounds of the invention described herein can comprise from about 0.1 mol% to about 50 mol%, or from 0.5 mol% to about 50 mol%, or from about 1 mol% to about 50 mol%, or from about 5 mol% to about 50 mol%, or from about 10 mol% to about 50 mol%, or from about 15 mol% to about 50 mol%, or from about 20 mol% to about 50 mol%, or from about 25 mol% to about 50 mol%, or from about 30 mol% to about 50 mol% of the total amount of lipid in a composition (e.g., a liposome delivery vehicle).

[0312] In certain embodiments, the compounds of the present invention described herein may constitute more than 0.1 mol%, or more than about 0.5 mol%, or more than about 1 mol%, or more than about 5 mol%, or more than about 10 mol%, or more than about 20 mol%, or more than about 30 mol%, or more than about 40 mol% of the total amount of lipid in the lipid nanoparticle.

[0313] In certain embodiments, the described compounds may constitute less than about 60 mol%, or less than about 55 mol%, or less than about 50 mol%, or less than about 45 mol%, or less than about 40 mol%, or less than about 35 mol%, or less than about 30 mol%, or less than about 25 mol%, or less than about 10 mol%, or less than about 5 mol%, or less than about 1 mol% of the total amount of lipid in a composition (e.g., a liposome delivery vehicle).

[0314] In embodiments, the amount of a compound of the invention described herein is present in an amount that is at least about 5 mol%, about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, about 55 mol%, about 60 mol%, about 65 mol%, about 70 mol%, about 75 mol%, about 80 mol%, about 85 mol%, about 90 mol%, about 95 mol%, about 96 mol%, about 97 mol%, about 98 mol%, or about 99 mol% of the total molar amount of total lipid in the composition (e.g., liposome composition).

[0315] In embodiments, the amount of a compound of the invention described herein is present in an amount that is less than or equal to about 5 mol%, about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, about 55 mol%, about 60 mol%, about 65 mol%, about 70 mol%, about 75 mol%, about 80 mol%, about 85 mol%, about 90 mol%, about 95 mol%, about 96 mol%, about 97 mol%, about 98 mol%, or about 99 mol% of the total molar amount of total lipid in the composition (e.g., liposome composition).

[0316] In embodiments, this percentage results in improved beneficial effects (eg, improved delivery to target tissues such as the liver or lungs).

[0317] In a typical embodiment, a composition of the present invention (e.g., a liposome composition) comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids, wherein at least one cationic lipid is a compound of the present invention as described herein. For example, a composition suitable for carrying out the present invention comprises four lipid components, including a compound of the present invention as described herein as the cationic lipid component, a non-cationic lipid, a cholesterol-based lipid, and a PEG-modified lipid. The non-cationic lipid can be DOPE or DEPE. The cholesterol-based lipid can be cholesterol. The PEG-modified lipid can be DMG-PEG2K.

[0318] In further embodiments, pharmaceutical (e.g., liposomal) compositions comprise one or more of a PEG-modified lipid, a non-cationic lipid, and a cholesterol lipid. In other embodiments, such pharmaceutical (e.g., liposomal) compositions comprise one or more PEG-modified lipids, one or more non-cationic lipids, and one or more cholesterol lipids. In further embodiments, such pharmaceutical (e.g., liposomal) compositions comprise one or more PEG-modified lipids and one or more cholesterol lipids.

[0319] In embodiments, a composition (e.g., lipid nanoparticle) encapsulating a nucleic acid (e.g., an mRNA encoding a peptide or protein) comprises one or more compounds of the invention described herein and one or more lipids selected from the group consisting of cationic lipids, non-cationic lipids, and PEGylated lipids.

[0320] In embodiments, compositions (e.g., lipid nanoparticles) encapsulating nucleic acids (e.g., mRNA encoding a peptide or protein) comprise one or more compounds of the invention described herein, one or more lipids selected from the group consisting of cationic lipids, non-cationic lipids, and PEGylated lipids, and further comprise a cholesterol-based lipid. Typically, such compositions have four lipid components, including a compound of the invention as described herein as the cationic lipid component, a non-cationic lipid (e.g., DOPE), a cholesterol-based lipid (e.g., cholesterol), and a PEG-modified lipid (e.g., DMG-PEG2K).

[0321] In embodiments, lipid nanoparticles encapsulating nucleic acids (e.g., mRNA encoding a peptide or protein) comprise one or more compounds of the invention as described herein and one or more lipids selected from the group consisting of cationic lipids, non-cationic lipids, PEGylated lipids, and cholesterol-based lipids.

[0322] According to various embodiments, the cationic lipid, non-cationic lipid and / or PEG-modified lipid that constitute lipid nanoparticles and the relative molar ratio of these lipids to each other are based on the characteristics of selected lipids, the properties of the intended target cells, and the characteristics of the nucleic acid to be delivered.Further considerations include, for example, the saturation of alkyl chains and the size, charge, pH, pKa, membrane fusion activity and toxicity of selected lipids.Therefore, the molar ratio can be adjusted accordingly.

[0323] cationic lipids In addition to any of the compounds of the invention described herein, the compositions may include one or more additional cationic lipids.

[0324] In some embodiments, liposome can contain one or more additional cationic lipids.As used herein, the term "cationic lipid" refers to any of several lipid species that have a net positive charge at selected pH, such as physiological pH.Several cationic lipids have been described in the literature, and many of them are commercially available.

[0325] Additional cationic lipids suitable for use in the compositions include those cationic lipids described in the literature.

[0326] Helper lipids The composition (e.g., liposome composition) may also include one or more helper lipids. Such helper lipids include non-cationic lipids. As used herein, the phrase "non-cationic lipid" refers to any neutral, zwitterionic, or anionic lipid. As used herein, the phrase "anionic lipid" refers to any of several lipid species that have a net negative charge at a selected pH, such as physiological pH. Non-cationic lipids include distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), 1,2-dierucoyl-sn-glycero-3-phosphoethanolamine (DEPE), palmitoyloleoylphosphatidylcholine (POPC), and palmitoyloleoyl-phosphatidylethanolamine. Examples of suitable non-cationic or helper lipids include, but are not limited to, dioleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, 1-stearoyl-2-oleoyl-phosphatidiethanolamine (SOPE), or mixtures thereof. A suitable non-cationic or helper lipid for implementing the present invention is dioleoylphosphatidylethanolamine (DOPE). Alternatively, 1,2-dierucoyl-sn-glycero-3-phosphoethanolamine (DEPE) can be used as the non-cationic or helper lipid.

[0327] In some embodiments, the non-cationic lipid is a neutral lipid, ie, a lipid that has no net charge under the conditions in which the composition is formulated and / or administered.

[0328] In some embodiments, the noncationic lipids may be present in a molar ratio (mol%) of about 5% to about 90%, about 5% to about 70%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 10% to about 70%, about 10% to about 50%, or about 10% to about 40% of the total lipids present in the composition. In some embodiments, the total noncationic lipids may be present in a molar ratio (mol%) of about 5% to about 90%, about 5% to about 70%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 10% to about 70%, about 10% to about 50%, or about 10% to about 40% of the total lipids present in the composition. In some embodiments, the percentage of non-cationic lipids in the liposomes can be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage of total non-cationic lipids in the liposomes can be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage of total non-cationic lipids in the liposomes can be less than about 5 mol%, less than about 10 mol%, less than about 20 mol%, less than about 30 mol%, or less than about 40 mol%. In some embodiments, the percentage of total non-cationic lipids in the liposomes can be less than about 5 mol%, less than about 10 mol%, less than about 20 mol%, less than about 30 mol%, or less than about 40 mol%.

[0329] In some embodiments, the noncationic lipids may be present in a weight ratio (wt%) of about 5% to about 90%, about 5% to about 70%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 10% to about 70%, about 10% to about 50%, or about 10% to about 40% of the total lipids present in the composition. In some embodiments, the total noncationic lipids may be present in a weight ratio (wt%) of about 5% to about 90%, about 5% to about 70%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 10% to about 70%, about 10% to about 50%, or about 10% to about 40% of the total lipids present in the composition. In some embodiments, the percentage of non-cationic lipids in the liposomes can be greater than about 5% by weight, greater than about 10% by weight, greater than about 20% by weight, greater than about 30% by weight, or greater than about 40% by weight. In some embodiments, the percentage of total non-cationic lipids in the liposomes can be greater than about 5% by weight, greater than about 10% by weight, greater than about 20% by weight, greater than about 30% by weight, or greater than about 40% by weight. In some embodiments, the percentage of total non-cationic lipids in the liposomes can be less than about 5% by weight, less than about 10% by weight, less than about 20% by weight, less than about 30% by weight, or less than about 40% by weight. In some embodiments, the percentage of total non-cationic lipids in the liposomes can be less than about 5% by weight, less than about 10% by weight, less than about 20% by weight, less than about 30% by weight, or less than about 40% by weight.

[0330] Cholesterol-based lipids In some embodiments, the composition (e.g., liposome composition) comprises one or more cholesterol-based lipids. For example, a suitable cholesterol-based lipid for carrying out the present invention is cholesterol. Other suitable cholesterol-based lipids include, for example, DC-Chol (N,N-dimethyl-N-ethylcarboxamidocholesterol), 1,4-bis(3-N-oleylamino-propyl)piperazine (Gao, et al. Biochem. Biophys. Res. Comm. 179, 280 (1991); Wolf et al. BioTechniques 23, 139 (1997); U.S. Pat. No. 5,744,335), beta-sitosterol, delta 5 avenasterol, or imidazole cholesterol ester (ICE), having the following structure: [ka]

[0331] In some embodiments, the cholesterol-based lipid may be present in a molar ratio (mol%) of about 1% to about 30% or about 5% to about 20% of the total lipid present in the liposome. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle may be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle may be about 5 mol% or less, about 10 mol% or less, about 20 mol% or less, about 30 mol% or less, or about 40 mol% or less.

[0332] In some embodiments, the cholesterol-based lipid may be present in a weight ratio (wt%) of about 1% to about 30% or about 5% to about 20% of the total lipid present in the liposome. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle may be greater than about 5 wt%, greater than about 10 wt%, greater than about 20 wt%, greater than about 30 wt%, or greater than about 40 wt%. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle may be about 5 wt% or less, about 10 wt% or less, about 20 wt% or less, about 30 wt% or less, or about 40 wt% or less.

[0333] PEGylated lipids In some embodiments, the composition (e.g., liposome composition) comprises one or more additional PEGylated lipids. A suitable PEG-modified or PEGylated lipid for practicing the present invention is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2K).

[0334] The use of derivatized lipids, such as polyethylene glycol (PEG)-modified phospholipids and derivatized ceramides (PEG-CER), including N-octanoyl-sphingosine-1-[succinyl(methoxypolyethylene glycol)-2000] (C8 PEG-2000 ceramide), in combination with one or more compounds of the invention, and in some embodiments, in combination with other lipids that together comprise the liposome, is also contemplated by the present invention. In some embodiments, particularly useful exchangeable lipids have shorter acyl chains (e.g., C 14 or C 18 ) is a PEG-ceramide.

[0335] Additional contemplated PEG-modified lipids (also referred to herein as PEGylated lipids, which term is used synonymously with PEG-modified lipids) include, but are not limited to, C6-C 20The PEG-modified lipid or PEGylated lipid may include a polyethylene glycol chain up to 5 kDa long covalently bonded to the lipid, which may contain one or more alkyl chains of 5 kDa in length. In some embodiments, the PEG-modified lipid or PEGylated lipid is PEGylated cholesterol or PEG-2K. The addition of such components may prevent complex aggregation, increase the circulation life and provide a means for increasing the delivery of lipid-nucleic acid compositions to target cells (Klibanov et al. (1990) FEBS Letters, 268(1):235-237), or they may be selected to be rapidly removed from the formulation in vivo (see U.S. Patent No. 5,885,613).

[0336] The additional PEG-modified phospholipids and derivatized lipids of the present invention may be present in a molar ratio (mol %) of about 0% to about 10%, about 0.5% to about 10%, about 1% to about 10%, about 2% to about 10%, or about 3% to about 5% of the total lipid present in the composition (e.g., liposome composition).

[0337] Pharmaceutical Formulations and Therapeutic Uses The compounds of the invention described herein can be used to prepare compositions (e.g., to construct liposomal compositions) that facilitate or enhance the delivery and release of an encapsulated material (e.g., one or more therapeutic polynucleotides) into one or more target cells (e.g., by permeabilizing or fusing with the lipid membranes of such target cells).

[0338] For example, when a liposome composition (e.g., lipid nanoparticle) comprises or is enriched with one or more of the compounds disclosed herein, a phase transition in the lipid bilayer of one or more target cells can facilitate delivery of the encapsulated material (e.g., one or more therapeutic polynucleotides encapsulated in the lipid nanoparticle) to one or more target cells.

[0339] Similarly, in certain embodiments, the compounds of the invention described herein may be used to prepare liposomal vehicles characterized by reduced toxicity in vivo, which in certain embodiments is a function of the high transfection efficiency associated with the compositions disclosed herein, such that smaller amounts of such compositions can be administered to a subject to achieve a desired therapeutic response or outcome.

[0340] Thus, pharmaceutical formulations containing the described compounds and nucleic acids provided by the present invention can be used for various therapeutic and / or disease prevention purposes. To facilitate in vivo delivery of nucleic acids, the compounds and nucleic acids described herein can be formulated in combination with one or more additional pharmaceutical carriers, targeting ligands, or stabilizing reagents. In some embodiments, the compounds described herein can be formulated via a premixed lipid solution. In other embodiments, compositions containing the compounds described herein can be formulated using post-insertion techniques into nanoparticle lipid membranes. For drug formulation and administration techniques, reference may be made to "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest edition.

[0341] Suitable routes of administration include, for example, oral, rectal, vaginal, transmucosal, intratracheal, or pulmonary or intestinal administration, including inhalation; parenteral delivery, including intradermal, transdermal (topical), intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intracerebroventricular, intravenous, intraperitoneal, or intranasal. In particular embodiments, intramuscular administration is to a muscle selected from the group consisting of skeletal muscle, smooth muscle, and cardiac muscle. In some embodiments, administration results in delivery of the nucleic acid to muscle cells. In some embodiments, administration results in delivery of the nucleic acid to hepatocytes (i.e., liver cells).

[0342] A common route for administering the liposome compositions of the present invention can be intravenous delivery, particularly when treating metabolic disorders, especially those affecting the liver (e.g., ornithine transcarbamylase (OTC) deficiency). Alternatively, depending on the disease or disorder being treated, the liposome compositions can be administered via pulmonary delivery (e.g., for the treatment of cystic fibrosis). For vaccination, the liposome compositions of the present invention are typically administered intramuscularly. Alternatively, the liposome compositions of the present invention can be administered intranasally for vaccination. Diseases or disorders affecting the eye can be treated by administering the liposome compositions of the present invention intravitreally.

[0343] Alternatively or additionally, the pharmaceutical formulations of the present invention can be administered in a local rather than systemic manner, for example, via injection of the pharmaceutical formulation directly into the targeted tissue (e.g., in a sustained-release formulation). Local delivery can be achieved in a variety of ways depending on the targeted tissue. Exemplary tissues to which mRNA can be delivered and / or expressed include, but are not limited to, the liver, kidney, heart, spleen, serum, brain, skeletal muscle, lymph nodes, skin, and / or cerebrospinal fluid. In embodiments, the liver is the targeted tissue. For example, an aerosol containing a composition of the present invention can be inhaled (for nasal, tracheal, or bronchial delivery), the composition of the present invention can be injected, for example, at the site of injury, disease manifestation, or pain, the composition can be provided in a lozenge for oral, tracheal, or esophageal application, can be supplied in the form of a liquid, tablet, or capsule for gastric or intestinal administration, can be supplied in the form of a suppository for rectal or vaginal application, or can even be delivered to the eye using a cream, eye drops, or even an injection.

[0344] The compositions described herein can include mRNA that encodes peptides (eg, polypeptides such as proteins), including those described herein.

[0345] In embodiments, the mRNA encodes a polypeptide.

[0346] In embodiments, the mRNA encodes a peptide, hi embodiments, the peptide is an antigen.

[0347] In embodiments, the mRNA encodes a protein.

[0348] The present invention provides a method for delivering a composition having a full-length mRNA molecule encoding a peptide or protein of interest for use in treating a subject, e.g., a human subject or a cell in a human subject, or a cell to be treated and delivered to a human subject.

[0349] Delivery method The delivery route used in the method of the present invention allows for non-invasive self-administration of the compound of the present invention. In some embodiments, the method comprises intranasal, intratracheal, or pulmonary administration by aerosolization, nebulization, or injection of a composition comprising mRNA encoding a therapeutic peptide or protein in a suitable transfection or lipid carrier vehicle as described above. In some embodiments, the peptide or protein is encapsulated in a liposome. In some embodiments, the liposome comprises a lipid that is a compound of the present invention. As used herein below, administration of a compound of the present invention includes administration of a composition comprising a compound of the present invention.

[0350] While local lung cells and tissues are potential targets that can serve as biological depots or reservoirs for the production and secretion of proteins encoded by mRNA, the present applicants have discovered that administering compounds of the present invention to the lung via aerosolization, nebulization, or injection results in distribution of non-secreted proteins even outside of lung cells. Without wishing to be bound by any particular theory, it is contemplated that the nanoparticle compositions of the present invention cross the pulmonary airway-blood barrier, resulting in the transfer of intact nanoparticles to non-pulmonary cells and tissues, such as the heart, liver, and spleen, allowing the encoded peptide or protein to be produced in those non-pulmonary tissues. Thus, the utility of the compounds and methods of the present invention extends beyond the production of therapeutic proteins in lung cells and tissues and can be used for delivery to non-pulmonary target cells and / or tissues. They are useful for the management and treatment of numerous diseases. In certain embodiments, the compounds of the present invention used in the methods of the present invention result in the distribution of mRNA-encapsulated nanoparticles and the production of the encoded peptide or protein in the liver, spleen, heart, and / or other non-pulmonary cells. For example, administration of a compound of the invention by aerosolization, nebulization, or pulmonary instillation will result in the composition itself and its peptide or protein product (e.g., antigen or functional protein) being detectable in both local cells and tissues of the lung and, as a result of transfer of the mRNA and delivery vehicle to non-pulmonary cells, in peripheral target cells, tissues, and organs.

[0351] In certain embodiments, the compounds of the present invention can be used in the methods of the present invention to specifically target peripheral cells or tissues. It is contemplated that, after pulmonary delivery, the compounds of the present invention cross the pulmonary blood barrier and distribute to cells other than local lung cells. Thus, the compounds disclosed herein can be administered to a subject via a pulmonary administration route (e.g., by inhalation) using various approaches known to those skilled in the art, and distributed to both local target cells and tissues in the lung and peripheral non-lung cells and tissues (e.g., liver, spleen, kidney, heart, skeletal muscle cells, lymph nodes, brain, cerebrospinal fluid, and plasma). As a result, both local lung cells and peripheral non-lung cells can function as biological reservoirs or depots capable of producing and / or secreting translation products encoded by one or more polynucleotides. Thus, the present invention is not limited to the treatment of pulmonary diseases or conditions, but can also be used as a non-invasive means of facilitating the delivery of polynucleotides or the production of peptides or proteins encoded thereby to end organs, tissues, and cells (e.g., liver cells) that would otherwise be achieved only by systemic administration. Exemplary peripheral non-pulmonary cells include, but are not limited to, hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, bone cells, stem cells, mesenchymal cells, neural cells, cardiac cells, adipocytes, vascular smooth muscle cells, cardiac muscle cells, skeletal muscle cells, beta cells, pituitary cells, synovial lining cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, granulocytes, and tumor cells.

[0352] After administration of the composition to a subject, the peptide or protein product (e.g., functional protein or enzyme) encoded by the mRNA is detectable in peripheral target tissues for at least about 1 to 7 days or more after administration of the compound to the subject. The amount of peptide or protein product necessary to achieve a therapeutic effect will vary depending on the condition being treated, the encoded peptide or protein, and the condition of the patient. For example, the peptide or protein product may be present in a concentration of at least 0.025 to 1.5 μg / ml (e.g., at least 0.050 μg / ml, at least 0.075 μg / ml, at least 0.1 μg / ml, at least 0.2 μg / ml, at least 0.3 μg / ml, at least 0.4 μg / ml, at least 0.5 μg / ml, at least 0.6 μg / ml, at least 0.7 μg / ml, at least 0.8 μg / ml, at least 0.9 μg / ml, at least 1.0 μg / ml, or at least In some embodiments, the compound may be detectable in a distal target tissue for at least about 1, 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, 30, 35, 40, 45 or more days after administration of the compound to a subject, at a concentration (e.g., a therapeutic concentration) of at least 1.1 μg / ml, at least 1.2 μg / ml, at least 1.3 μg / ml, at least 1.4 μg / ml or at least 1.5 μg / ml.

[0353] It has been demonstrated that nucleic acids can be delivered to the lungs by intratracheal administration of a liquid suspension of the compound and inhalation of the aerosol mist generated by a liquid nebulizer or by use of a dry powder device such as that described in U.S. Pat. No. 5,780,014, incorporated herein by reference.

[0354] In certain embodiments, the compounds of the present invention can be formulated so that they can be aerosolized or delivered as a particulate liquid or solid before or during administration to a subject. Such compounds can be administered with the aid of one or more suitable devices for administering such solid or liquid particulate compositions (e.g., aerosolized aqueous solutions or suspensions) to generate particles that are easily respirable or inhalable by a subject. In some embodiments, such devices (e.g., metered-dose inhalers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers, propellant-based inhalers, or insufflators) facilitate the administration of a predetermined mass, volume, or dose of the composition (e.g., about 0.5 mg / kg of mRNA per dose) to a subject. For example, in certain embodiments, the compounds of the present invention are administered to a subject using a metered-dose inhaler containing a suspension or solution comprising the compound and a suitable propellant. In certain embodiments, the compounds of the present invention can be formulated as particulate powders intended for inhalation (e.g., respirable dry particles). In certain embodiments, compositions of the invention formulated as respirable particles are respirable by a subject or delivered using a suitable device (e.g., average D50 or D90 particle size of about 500 μm, 400 μm, 300 μm, 250 μm, 200 μm, 150 μm, 100 μm, 75 μm, 50 μm, 25 μm, 20 μm, 15 μm, 12.5 μm, 10 μm, 5 μm, 2.5 μm or less). In yet other embodiments, compounds of the invention are formulated to include one or more pulmonary surfactants (e.g., lamellar bodies).In some embodiments, the compounds of the invention are administered at least 0.05 mg / kg, at least 0.1 mg / kg, at least 0.5 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0 mg / kg, at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least The subject may be administered a single dose of at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg, or at least 100 mg / kg body weight. In some embodiments, a compound of the invention is administered to a subject such that a total amount of at least 0.1 mg, at least 0.5 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 6.0 mg, at least 7.0 mg, at least 8.0 mg, at least 9.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of mRNA is administered in one or more doses. [Example]

[0355] While certain compounds, compositions and methods of the present invention have been described with specificity according to certain embodiments, the following examples are merely illustrative of the compounds of the present invention and are not intended to limit the same.

[0356] List of abbreviations: ACN: acetonitrile Boc: tert-butyloxycarbonyl DIPEA: N,N-diisopropylethylamine DCM: dichloromethane DMAP: 4-dimethylaminopyridine EDC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOAc: ethyl acetate THF: tetrahydrofuran IPA: Isopropyl alcohol LC-MS: Liquid chromatography mass spectrometry MeOH: Methanol MS: Mass spectrometry NaH: sodium hydride NaHCO3: Sodium bicarbonate Na2SO4: Sodium sulfate NH4Cl: Ammonium chloride NMR: nuclear magnetic resonance spectroscopy TFA: Trifluoroacetic acid TLC: Thin Layer Chromatography TLC / ELSD: Thin-layer chromatography / evaporative light scattering detector Pd / C: Palladium on carbon NaOH: Sodium hydroxide RT: room temperature SM: Starting material SiO2: silicon dioxide TBS: tert-butyldimethylsilyl TBDMS: tert-butyldimethylsilyl TLC: Thin Layer Chromatography

[0357] Example 1: Synthesis of compounds XXIV, XI, XXI, XXVII, XXVI, XXXV, XXX, XXXIII, XXVIII, XXXII, XXXIV, XXV, XXXVIII, XXXVI, XXXI and XXIX For example, compounds of the present invention can be prepared according to Scheme 1 (as shown in Figure 1).

[0358] Synthesis of Compound XXIV [ka] As shown in Scheme 1, where x is [ka] Step 1: To a 20 mL scintillation vial was added dicarboxylic acid 1 (71.1 mg, 1.0 equiv.), alcohol intermediate 2 (500 mg, 2.2 equiv.), DMAP (41.3 mg, 1.0 equiv.), DIPEA (0.12 mL, 2.0 equiv.), and anhydrous CHCl (7 mL). To this stirred solution at room temperature was added EDC (162 mg, 2.5 equiv.) in one portion. The reaction was stirred at room temperature for 16 hours and monitored by TLC (10% EtOAc in hexanes). After substantial consumption of 2, as determined by TLC, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO. The separated aqueous layer was extracted with EtOAc (twice), and the combined organic layers were then washed with brine and dried over sodium sulfate. The drying reagent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified using medium pressure chromatography (Combiflash) using a gradient of 0-10% EtOAc in hexanes to isolate the desired product (3) from the remaining starting material (2). The combined fractions containing (3) were concentrated to dryness to give the TBS ether intermediate (3) (426 mg, 83%) as a viscous colorless oil. The identity of the product was confirmed by MS.

[0359] result: MS(ESI+) Calculated value C 84 H 176 N2O8S2Si 4, [M+H] + =1518.2, measurement value = 1518.9 + 760.0 [M / 2].

[0360] As shown in Scheme 1, where x is [ka] Step 2: To a plastic 20 mL scintillation vial was added TBS ether (3) (426 mg, 1.0 equiv.) and anhydrous THF (4 mL). The resulting solution was stirred and cooled to 0 °C using an ice bath. A 70% HF-pyridine solution (1.44 mL, 197 equiv. of HF) was added dropwise and stirred at the same temperature for 5 min. The mixture was then slowly warmed to room temperature and stirred for 16 h at room temperature. After completion of the reaction, monitored by MS, the reaction mixture was cooled to 0 °C and quenched by the batchwise addition of solid NaHCO 3 . After gas formation was minimized, the resulting mixture was diluted with EtOAc and neutralized with aqueous NaHCO 3 until pH = 7–8. The neutralized aqueous layer was extracted with EtOAc (twice), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying reagent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified using a 0-60% EtOAc gradient in hexanes to give compound XXIV (246 mg, 83%) as a colorless viscous oil.

[0361] result: MS(ESI+) Calculated value C 60 H 120 N2O8S 2, [M+H] + =1061.8, measured values ​​=1061.7 and 531.4[M / 2].

[0362] Synthesis of Compound XI [ka] As shown in Scheme 1, where x is [ka] The desired intermediate 3 was obtained according to the procedure of Compound XXIV using dicarboxylic acid 1 (1.0 equivalent) and general alcohol intermediate 2 (2.2 equivalents). After confirmation by MS, the TBS ether 3 was treated with 70% HF-pyridine solution to give Compound XI (97 mg) as a colorless viscous oil.

[0363] result: MS(ESI+) Calculated value C 59 H 119 N3O 8, [M+H] + = 998.9, measured values ​​= 998.8 and 500.0 [M / 2].

[0364] Synthesis of Compound XXI [ka] As shown in Scheme 1, where x is [ka] (where the ester bonded to x is inverted): The desired intermediate 3 was obtained according to the procedure for Compound XXIV using dicarboxylic acid 1 (1.0 equivalent) and general alcohol intermediate 2 (2.2 equivalents). After confirmation by MS, the TBS ether 3 was treated with 70% HF-pyridine solution to give Compound XXI (135 mg) as a colorless viscous oil.

[0365] result: MS(ESI+) Calculated value C 67 H 136 N4O 8, [M+H] + = 1126.0, measured values ​​= 1125.9 and 563.5 [M / 2].

[0366] Synthesis of Compound XXVII [ka] As shown in Scheme 1, where x is [ka] The desired intermediate (3) was obtained according to the procedure for Compound XXIV using dicarboxylic acid (1) (1.0 equivalent) and general alcohol intermediate (2) (2.2 equivalents). After confirmation by MS, the TBS ether (3) was treated with 70% HF-pyridine solution to give Compound XXVII (272 mg) as a colorless viscous oil.

[0367] result: MS(ESI+) Calculated value C 59 H 118 N2O 8, [M+H] + = 983.9, measured values ​​= 984.4 and 492.8 [M / 2].

[0368] Synthesis of Compound XXVI [ka] As shown in Scheme 1, where x is [ka] The desired intermediate (3) was obtained according to the procedure for Compound XXIV using dicarboxylic acid (1) (1.0 equivalent) and general alcohol intermediate (2) (2.2 equivalents). After confirmation by MS, the TBS ether (3) was treated with 70% HF-pyridine solution to give Compound XXVI (174 mg) as a colorless viscous oil.

[0369] result: MS(ESI+) Calculated value C 58 H 116 N2O 8, [M+H] + = 969.9, measured values ​​= 969.2 and 485.1 [M / 2].

[0370] Synthesis of Compound XXXV [ka] As shown in Scheme 1, where x is [ka] The desired intermediate 3 was obtained according to the procedure of Compound XXIV using dicarboxylic acid 1 (1.0 equivalent) and general alcohol intermediate 2 (2.2 equivalents). After confirmation by MS, the TBS ether 3 was treated with 70% HF-pyridine solution to give Compound XXXV (33 mg) as a colorless viscous oil.

[0371] result: MS(ESI+) Calculated value C 61 H 122 N2O 8, [M+H] + = 1011.9, measured values ​​= 1012.2 and 506.1 [M / 2].

[0372] Synthesis of Compound XXX [ka] As shown in Scheme 1, where x is [ka] The desired intermediate (3) was obtained according to the procedure of Compound XXIV using dicarboxylic acid (1) (1.0 equivalent) and general alcohol intermediate (2) (2.2 equivalents). After confirmation by MS, the TBS ether (3) was treated with 70% HF-pyridine solution to give Compound XXX (81 mg) as a colorless viscous oil.

[0373] result: MS(ESI+) Calculated value C 60 H 120 N2O 8, [M+H] + = 997.9, measured values ​​= 997.2 and 499.3 [M / 2].

[0374] Synthesis of Compound XXXIII [ka] As shown in Scheme 1, where x is [ka] The desired intermediate (3) was obtained according to the procedure of Compound XXIV using dicarboxylic acid (1) (1.0 equivalent) and general alcohol intermediate (2) (2.2 equivalents). After confirmation by MS, the TBS ether (3) was treated with 70% HF-pyridine solution to give Compound XXXIII (113 mg) as a colorless viscous oil.

[0375] result: MS(ESI+) Calculated value C 64 H 120 N2O 8, [M+H] + = 1045.9, measured values ​​= 1045.2 and 523.2 [M / 2].

[0376] Synthesis of Compound XXVIII [ka] As shown in Scheme 1, where x is [ka] The desired intermediate (3) was obtained according to the procedure for Compound XXIV using dicarboxylic acid (1) (1.0 equivalent) and general alcohol intermediate (2) (2.2 equivalents). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to give Compound XXVIII (120 mg) as a colorless viscous oil.

[0377] result: MS(ESI+) Calculated value C 60 H 120 N2O 8, [M+H] + = 997.9, measured values ​​= 998.2 and 499.1 [M / 2].

[0378] Synthesis of Compound XXXII [ka] As shown in Scheme 1, where x is [ka] The desired intermediate 3 was obtained according to the procedure for Compound XXIV using dicarboxylic acid 1 (1.0 equivalent) and general alcohol intermediate 2 (2.2 equivalents). After confirmation by MS, the TBS ether 3 was treated with 70% HF-pyridine solution to give Compound XXXII (150 mg) as a colorless viscous oil.

[0379] result: MS(ESI+) Calculated value C 60 H 120 N2O 8, [M+H] + = 997.9, measured values ​​= 998.2 and 499.1 [M / 2].

[0380] Synthesis of Compound XXXIV [ka] As shown in Scheme 1, where x is [ka] The desired intermediate 3 was obtained according to the procedure for Compound XXIV using dicarboxylic acid 1 (1.0 equivalent) and general alcohol intermediate 2 (2.2 equivalents). After confirmation by MS, the TBS ether 3 was treated with 70% HF-pyridine solution to give Compound XXXIV (101 mg) as a colorless viscous oil.

[0381] result: MS(ESI+) Calculated value C 65 H 122 N2O 8, [M+H] + = 1059.9, measured values ​​= 1059.2 and 530.3 [M / 2].

[0382] Synthesis of Compound XXV [ka] As shown in Scheme 1, where x is [ka] The desired intermediate (3) was obtained according to the procedure for Compound XXIV using dicarboxylic acid (1) (1.0 equivalent) and general alcohol intermediate (2) (2.2 equivalents). After confirmation by MS, the TBS ether (3) was treated with 70% HF-pyridine solution to give Compound XXV (31 mg) as a colorless viscous oil.

[0383] result: MS(ESI+) Calculated value C 57 H 114 N2O 8, [M+H] + = 955.9, measurements = 955.2 and 478.1 [M / 2].

[0384] Synthesis of Compound XXXVIII [ka] As shown in Scheme 1, where x is [ka] The desired intermediate (3) was obtained according to the procedure for Compound XXIV using dicarboxylic acid (1) (1.0 equivalent) and general alcohol intermediate (2) (2.2 equivalents). After confirmation by MS, the TBS ether (3) was treated with 70% HF-pyridine solution to give Compound XXXVIII (55 mg) as a colorless viscous oil.

[0385] result: MS(ESI+) Calculated value C 60 H 120 N2O 9, [M+H] + = 1013.9, measured values ​​= 1013.1 and 507.2 [M / 2].

[0386] Synthesis of Compound XXXVI [ka] As shown in Scheme 1, where x is [ka] The desired intermediate 3 was obtained according to the procedure for Compound XXIV using dicarboxylic acid 1 (1.0 equivalent) and general alcohol intermediate 2 (2.2 equivalents). After confirmation by MS, the TBS ether 3 was treated with 70% HF-pyridine solution to give Compound XXXVI (56 mg) as a colorless viscous oil.

[0387] result: MS(ESI+) Calculated value C 62 H 124 N2O 8, [M+H] + = 1025.9, measured values ​​= 1025.3 and 513.3 [M / 2].

[0388] Synthesis of Compound XXXI [ka] As shown in Scheme 1, where x is [ka] The desired intermediate (3) was obtained according to the procedure of Compound XXIV using dicarboxylic acid (1) (1.0 equivalent) and general alcohol intermediate (2) (2.2 equivalents). After confirmation by MS, the TBS ether (3) was treated with 70% HF-pyridine solution to give Compound XXXI (113 mg) as a colorless viscous oil.

[0389] result: MS(ESI+) Calculated value C 62 H 124 N2O 8, [M+H] + = 1025.9, measured values ​​= 1026.8 and 514.0 [M / 2].

[0390] Synthesis of Compound XXIX [ka] As shown in Scheme 1, where x is [ka] and R is [ka] NMR (δ 1.0, ... The crude material was purified using Combiflash with 50% EtOAc in hexane to isolate the desired product, Compound XXIX. The combined fractions containing Compound XXIX were concentrated to dryness to obtain the lipid product, Compound XXIX (90 mg, 53%), as a viscous colorless oil.

[0391] result: MS(ESI+) Calculated value C 84 H 176 N2O8S2Si 4, [M+H] + = 1025.8, measured values ​​= 1025.2 and 513.1 [M / 2].

[0392] Example 2: Synthesis of Compounds V and XVI For example, compounds of the present invention can be prepared according to Scheme 2 (as shown in Figure 2).

[0393] Synthesis of Compound V [ka] As shown in Scheme 2, where x is [ka] Step 1: To a 20 mL scintillation vial was added aminodiol 7 (37.5 mg, 0.45 equiv.), acid intermediate 8 (500 mg, 1.0 equiv.), DMAP (85.5 mg, 1.0 equiv.), DIPEA (0.73 mL, 6.0 equiv.), and anhydrous CHCl (7 mL). To this stirred solution at room temperature was added EDC (268 mg, 2.0 equiv.) in one portion. The reaction was stirred at room temperature for 16 hours and monitored by TLC (10% EtOAc in hexanes). After substantial consumption of 8, as determined by TLC, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO. The separated aqueous layer was extracted with EtOAc (twice), and the combined organic layers were then washed with brine and dried over sodium sulfate. The drying reagent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified using Combiflash with 0-10% EtOAc in hexanes to isolate the desired product (9) from the remaining starting material (8). The combined product-containing fractions were concentrated to dryness to give the TBS ether intermediate (9) (318 mg, 67%) as a viscous colorless oil. The identity of the product was confirmed by MS.

[0394] result: MS(ESI+) Calculated value C 87 H 183 N3O8Si 4, [M+H] + =1511.3, Measurement =1512.2.

[0395] As shown in Scheme 2, where x is [ka] Step 2: To a plastic 20 mL scintillation vial was added TBS ether (9) (318 mg, 1.0 equiv.) and anhydrous THF (3 mL). The resulting solution was stirred and cooled to 0 °C using an ice bath. A 70% HF-pyridine solution (1.08 mL, 197 equiv. of HF) was added dropwise and stirred at the same temperature for 5 min. The mixture was then slowly warmed to room temperature and stirred for 16 h at room temperature. After completion of the reaction, monitored by MS, the reaction mixture was cooled to 0 °C and quenched by the batchwise addition of solid NaHCO3. After gas formation was minimized, the resulting mixture was diluted with EtOAc and neutralized with aqueous NaHCO3 until pH = 7–8. The neutralized aqueous layer was extracted with EtOAc (twice), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying reagent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified using a 0-20% MeOH gradient in CH2Cl2 to give compound V (181 mg, 82%) as a colorless viscous oil.

[0396] result: MS(ESI+) Calculated value C 63 H 127 N3O 8, [M+H] + =1055.0, measured value =1054.8.

[0397] Synthesis of Compound XVI [ka] As shown in Scheme 2, where x is [ka] and R is [ka] To a 20 mL scintillation vial was added aminodiol 7 (21.0 mg, 1.0 equiv.), acid intermediate 11 (270 mg, 2.0 equiv.), DMAP (21.6 mg, 1.0 equiv.), DIPEA (0.13 mL, 4.2 equiv.), and anhydrous CHCl (3.5 mL). To this stirred solution was added EDC (84.7 mg, 2.5 equiv.) in one portion at room temperature. The reaction was stirred at room temperature for 16 hours and monitored by MS. After significant consumption of 11, as determined by MS, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO. The separated aqueous layer was extracted with EtOAc (twice), and the combined organic layers were then washed with brine and dried over sodium sulfate. The drying reagent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified using Combiflash with 10% MeOH in CH2Cl2 to isolate the desired product, Compound XVI. The combined product-containing fractions were concentrated to dryness to give the lipid product, Compound XVI (65 mg, 27%), as a viscous colorless oil.

[0398] result: MS(ESI+) Calculated value C 83 H 151 N3O 12, [M+H] + =1383.1, Measurement =1383.2.

[0399] Example 3: Synthesis of Compound XLI For example, compounds of the present invention can be prepared according to Scheme 3 (as shown in Figure 3).

[0400] Synthesis of intermediate [2] [ka] As shown in Scheme 3, potassium 2-methylpropan-2-olate (33.9 g, 303 mmol) was added to a stirred solution of 8-bromooctanoic acid [1] (15.0 g, 67.2 mmol) in tetrahydrofuran (0.5 L, 6.14 mol). The reaction mixture was stirred at 90 °C for 16 h. TLC showed that SM was consumed and a new spot formed. The reaction mixture was diluted with cold water (500 mL) and acidified to pH 2-3 using 2 N aqueous HCl, then extracted with EtOAc (2 × 500 mL). The organic layer was dried over anhydrous NaSO, filtered, and evaporated to give oct-7-enoic acid [2] (10.0 g, crude) as a pale yellow oil. The crude product was used directly in the next step.

[0401] result: 1H-NMR(400MHz,CDCl3)-10.5-11.00(brs,1H),5.84-5.73(m,1H),5.00-4.90(m,2H),2.31- 2.28(t,J=7.6Hz,2H),2.06-2.01(q,J=7.6Hz,2H),1.65-1.58(m,2H),1.46-1.36(m,4H)ppm.

[0402] Synthesis of intermediate [4] [ka] As shown in Scheme 3, to a stirred solution of oct-7-enoic acid [2] (10 g, 70.3 mmol) in dimethylformamide (200 mL) was added dipotassium carbonate (29.2 g, 211 mmol), followed by (bromomethyl)benzene [3] (10 mL, 84.4 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The reaction progress was monitored by TLC / ELSD. The reaction mixture was diluted with cold water (200 mL) and extracted with diethyl ether (2 x 500 mL). The organic layer was washed with saturated NaHCO3 (500 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by silica gel flash column chromatography (0–10% ethyl acetate in heptane) to afford benzyl oct-7-enoate [4] (6.5 g, 39.7% yield) as a pale yellow oil.

[0403] result: 1H-NMR(400MHz,CDCl3)-7.39-7.30(m,5H),5.84-5.74(m,1H),5.11(s,2H),5.01-4.92(m,2H),2 .38-2.34(t,J=7.6Hz,2H),2.06-2.01(q,J=7.6Hz,2H),1.69-1.61(m,2H),1.44-1.27(m,4H)ppm.

[0404] Synthesis of intermediate [5] [ka] As shown in Scheme 3, to a stirred solution of benzyl oct-7-enoate [4] (6.5 g, 28 mmol) in dichloromethane (50 mL) was added 3-chlorobenzene-1-carboperoxoic acid (14.5 g, 83.9 mmol) to the reaction mass at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. After 16 h, the progress of the reaction was monitored by TLC. The reaction mass was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (100 mL) and brine (100.0 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography (0–10% ethyl acetate in heptane gradient) to afford benzyl 6-(oxiran-2-yl)hexanoate [5] (5.5 g, 79% yield) as a yellow oil.

[0405] result: 1H-NMR(400MHz,CDCl3)-7.37-7.32(m,5H),5.11(s,2H),2.90-2.87(m,1H),2.75-2.73(m,1H),2.46- 2.44(m,1H),2.39-2.35(t,J=7.6Hz,2H),1.70-1.63(m,2H),1.56-1.43(m,4H),1.39-1.26(m,2H)ppm.

[0406] Synthesis of intermediate [6] [ka] As shown in Scheme 3, to a stirred solution of benzyl 6-(oxiran-2-yl)hexanoate [5] (7.73 g, 31.1 mmol) in isopropanol (0.1 L) was added 3-aminopropan-1-ol [5a] (1.11 g, 14.8 mmol) at RT under an inert atmosphere. The resulting reaction mixture was stirred at 95 °C for 20 h. The progress of the reaction was monitored by TLC. The reaction mass was evaporated under reduced pressure to give the crude product, which was purified by silica gel flash column chromatography using a 3-5% MeOH in DCM gradient as the eluent to give benzyl 8-{[8-(benzyloxy)-2-hydroxy-8-oxooctyl](3-hydroxypropyl)amino}-7-hydroxyoctanoate [6] (3.2 g, 37.7% yield) as a colorless oil.

[0407] result: ELSD analysis: purity 99.02%, calculated value for C33H49NO7 = 571.35, found value = 572.30 (m / z, M+H+).

[0408] Synthesis of intermediate [7]: [ka] As shown in Scheme 3, to a stirred solution of benzyl 8-{[8-(benzyloxy)-2-hydroxy-8-oxooctyl](3-hydroxypropyl)amino}-7-hydroxyoctanoate [6] (3.2 g, 5.6 mmol) in dichloromethane (0.1 L) was added tert-butyl(chloro)dimethylsilane (6.75 g, 44.8 mmol) and 1H-imidazole (5.33 g, 78.4 mmol) under an inert atmosphere at room temperature. The resulting reaction mass was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mass was filtered through a sintered funnel. The filtrate was evaporated under reduced pressure to give the crude product, which was purified by silica gel flash column chromatography (0–20% ethyl acetate in heptane) to give benzyl 8-{5-[6-(benzyloxy)-6-oxohexyl]-2,2,3,3,12,12,13,13-octamethyl-4,11dioxa-7-aza-3,12disilatetradecan-7-yl}-7-[(tert-butyldimethylsilyl)oxy]octanoate [7] (3.5 g, 68.4% yield) as a colorless liquid.

[0409] result: ELSD analysis: purity 97.95%, calculated value for C51H91NO7Si3 = 913.61, found value = 914.50 (m / z, M+H+).

[0410] Synthesis of intermediate [8] [ka] As shown in Scheme 3, to a stirred solution of benzyl 8-{5-[6-(benzyloxy)-6-oxohexyl]-2,2,3,3,12,12,13,13-octamethyl-4,11-dioxa-7-aza-3,12-disilatetradecan-7-yl}-7-[(tert-butyldimethylsilyl)oxy]octanoate [7] (4.3 g, 4.7 mmol) in methanol (15 mL) and tetrahydrofuran (15 mL) was added palladium on carbon (10% w / w, 50% water) (1.5 g, 14.1 mmol) in portions under a nitrogen atmosphere. The resulting reaction mass was degassed and purged with hydrogen at room temperature, then stirred under hydrogen balloon pressure for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the celite bed was washed twice with methanol. The methanol was evaporated to dryness to give 7-[5-(5-carboxypentyl)-2,2,3,3,12,12,13,13-octamethyl-4,11-dioxa-7-aza-3,12-disilatetradecan-7-yl]-8-octanoic acid [8] (3.4 g, 98% yield) as a colorless liquid.

[0411] result: ELSD analysis: purity 99.33%, calculated value C37H79NO7Si3 = 733.52, found = 734.50 (m / z, M+H+).

[0412] Synthesis of intermediate

[10] [ka] As shown in Scheme 3, to a stirred solution of 7-[5-(5-carboxypentyl)-2,2,3,3,12,12,13,13-octamethyl-4,11-dioxa-7-aza-3,12-disilatetradecan-7-yl]-8-octanoic acid [8] (3.5 g, 4.77 mmol) in dichloromethane (70 mL) was added {3-[cyano(ethyl)amino]propyl}dimethylazaninium chloride (2.74 g, 14.3 mmol) and DMAP (587 mg, 4.77 mmol) under an inert atmosphere at room temperature, followed 15 minutes later by the addition of (2Z)-non-2-en-1-ol [9] (1.69 g, 11.9 mmol) under an inert atmosphere at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mass was quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography (0-10% ethyl acetate in heptane) to give (2Z)-non-2-en-1-yl 7-(2,2,3,3,12,12,13,13-octamethyl-5-{6-[(2Z)-non-2-en-1-yloxy]-6-oxohexyl}-4,11-dioxa-7-aza-3,12-disilatetradecan-7-yl)-8-octanoate

[10] (3.7 g, 79% yield) as a colorless liquid.

[0413] result: ELSD analysis: purity 96.75%, calculated value C 55 H 111 NO7Si3 = 981.77, Measured = 982.60 (m / z, M+H+).

[0414] Synthesis of intermediate

[11] [ka] As shown in Scheme 3, to a stirred solution of (2Z)-non-2-en-1-yl 7-(2,2,3,3,12,12,13,13-octamethyl-5-{6-[(2Z)-non-2-en-1-yloxy]-6-oxohexyl}-4,11-dioxa-7-aza-3,12-disilatetradecan-7-yl)-8-octanoate

[10] (3.6 g, 3.66 mmol) in tetrahydrofuran (30 mL) was added pyridine hydrogen fluoride complex (1.45 g, 14.7 mmol) at 0 °C and then stirred for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution to a saturated pH of 8 and extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography (0–5% MeOH in DCM) to give (2Z)-non-2-en-1-yl 7-hydroxy-8-({2-hydroxy-8-[(2Z)-non-2-en-1-yloxy]-8-oxooctyl}(3-hydroxypropyl)amino)octanoate

[11] (1.8 g, 76% yield) as a pale yellow liquid.

[0415] result: ELSD analysis: purity 98.33%, calculated value C 37 H 69 NO7 = 639.51, Measured Value = 640.45 (m / z, M+H+).

[0416] Synthesis of compound XLI [ka] As shown in Scheme 3, a stirred solution of (2Z)-non-2-en-1-yl 7-hydroxy-8-({2-hydroxy-8-[(2Z)-non-2-en-1-yloxy]-8-oxooctyl}(3-hydroxypropyl)amino)octanoate

[11] (829 mg, 1.3 mmol) and 3-hydroxy-3-methylpentanedioic acid

[12] (0.1 g, 617 μmol) in dichloromethane (15 mL) was cooled to 0 °C, and {3-[cyano(ethyl)amino]propyl}dimethylazanium chloride (355 mg, 1.85 mmol) and 4-(dimethylamino)pyridin-1-ium (228 mg, 1.85 mmol) were added sequentially at room temperature. The resulting reaction mixture was stirred at room temperature for 48 hours. The progress of the reaction was monitored by ELSD / TLC (SM was consumed). The reaction mass was diluted with DCM (30 mL) and washed with water (50 mL). The organic layer was dried over NaSO, filtered, concentrated under reduced pressure, and the crude product was purified by preparative HPLC (ACN / 0.1% TFA in water) to give the desired 1,5-bis({3-[bis({2-hydroxy-8-[(2Z)-non-2-en-1-yloxy]-8-oxooctyl})amino]propyl}) 3-hydroxy-3-methylpentanedioate TFA salt Compound XLI (0.1 g, 11.5% yield) as a colorless liquid.

[0417] result: 1H-NMR(400MHz,CDCl3)-5.67-5.60(m,4H),5.34-5.48(m,4H),4.62-4.60(d,J=6.8Hz,8H) ,4.26-4.22(m,4H),4.12-4.00(m,4H),3.49-3.38(m,4H),3.22-3.05(m,8H),2.77-2.70(m, 2H),2.61-2.54(m,4H),2.33-2.29(t,J=7.6Hz,8H),2.20-2.10(m,4H),2.10-2.06(m,8H), 1.65-1.58(m,8H),1.58-1.42(m,12H),1.41-1.27(m,45H)0.89-0.86(t,J=7.2Hz,12H)ppm.

[0418] ELSD analysis: purity 99.95%, calculated value C80 H 144 N2O 17 = 1405.05, measured value = 1405.85 (m / z, M+H+).

[0419] Example 4: Synthesis of Compound LXXII For example, compounds of the present invention can be prepared according to Scheme 4 (as shown in Figure 4).

[0420] Synthesis of intermediate [2] [ka] As shown in Scheme 4, to a stirred solution of 8-bromooctanoic acid [1] (15.0 g, 67.2 mmol) in tetrahydrofuran (0.5 L, 6.14 mol) was added potassium 2-methylpropan-2-olate (33.9 g, 303 mmol). The reaction mixture was stirred at 90 °C for 16 h. TLC showed that SM was consumed and a new spot formed. The reaction mixture was diluted with cold water (500 mL) and acidified to pH 2-3 using 2 N aqueous HCl, then extracted with EtOAc (2 × 500 mL). The organic layer was dried over anhydrous NaSO, filtered, and evaporated to give oct-7-enoic acid [2] (10.0 g, crude) as a pale yellow oil. The crude product was used directly in the next step.

[0421] result: 1H-NMR(400MHz,CDCl3)-10.5-11.00(brs,1H),5.84-5.73(m,1H),5.00-4.90(m,2H),2.31- 2.28(t,J=7.6Hz,2H),2.06-2.01(q,J=7.6Hz,2H),1.65-1.58(m,2H),1.46-1.36(m,4H)ppm.

[0422] Synthesis of intermediate [4] [ka] As shown in Scheme 4, to a stirred solution of oct-7-enoic acid [2] (6.8 g, 47.8 mmol) in dichloromethane (100 mL, 469 mmol), DMAP (5.89 g, 47.8 mmol) and ({[3-(dimethylamino)propyl]imino}methylidene)(ethyl)amine hydrochloride (18.3 g, 95.6 mmol) were added at room temperature. Then, heptadecan-9-ol [3] (13.5 g, 52.6 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was diluted with DCM and washed with brine solution. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product, which was used for column chromatography (0-5% ethyl acetate) to give the desired product heptadecan-9-yl oct-7-enoate [4] (10.5 g, 57.68% yield) as a colorless liquid.

[0423] result: 1H NMR (400MHz, CDCl3):δ 5.83-5.74(m,1H),5.02-4.98(m,1H),4.97-4.92(m,1H),4.88-4.85(m,1H),2.30-2.26(t,J=7.6Hz,2H),2.07-2 .02(q,J=6.8Hz,2H),1.65-1.60(m,2H),1.56-1.49(m,4H),1.42-1.25(m,28H),0.89-0.86(t,J=6.8Hz,6H)ppm.

[0424] Synthesis of intermediate [5] [ka] As shown in Scheme 4, to a stirred solution of heptadecan-9-yl oct-7-enoate [4] (10.5 g, 52.5 mmol) in dichloromethane (200 mL) was added 3-chlorobenzene-1-carboperoxoic acid (10.5 g, 60.7 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction mass was monitored by ELSD / TLC (SM was consumed). The resulting reaction mixture was washed with cold aqueous sodium bicarbonate solution (500 mL). The resulting organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude product was purified by flash column chromatography (SiO2: 0–5% ethyl acetate in hexanes) to afford the desired heptadecan-9-yl 6-(oxiran-2-yl)hexanoate [5] (9.2 g, 84.08% yield) as a colorless liquid.

[0425] result: 1H-NMR(400MHz,CDCl3)-4.86(q,J=6.0Hz,1H),2.92-2.87(br,1H),2.75-2.73(m,1H),2.46-2.44(m,1H),2.29(t, J=7.6Hz,2H),1.66-1.62(m,2H),1.55-1.44(m,7H),1.41-1.36(m,2H),1.25(br,25H),0.89-0.85(t,J=6.8Hz,6H).

[0426] ELSD analysis: purity 99.93%, calculated value C 25 H 48 O2 = 396.36, Measured Value = 397.20 (m / z, M+H+) & 419.35 (m / z, M+Na+).

[0427] Synthesis of intermediate [8] [ka] As shown in Scheme 4, a solution of hex-5-enoic acid [6] (10 g, 87.6 mmol), {3-[cyano(ethyl)amino]propyl}dimethylazaninium chloride (25.2 g, 131 mmol), and DMAP (5.4 g, 43.8 mmol) in dichloromethane (150 mL) at room temperature was prepared. Undecane-1-ol [7] (13.6 g, 78.8 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with DCM and washed with brine. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2: 0–5% ethyl acetate in hexane) to afford the desired undecyl hex-5-enoate [8] (19.8 g, 84.19% yield) as a colorless oil.

[0428] result: 1H-NMR(400MHz,CDCl3)-δ 5.83-5.73(m,1H),5.05-4.96(m,2H),4.07-4.03(t,J=6.8Hz,2H),2.38-2.30(m,2H),2.11-2.06(q,J= 7.2Hz,2H),1.77-1.68(m,2H),1.64-1.57(m,2H),1.30-1.21(m,16H),0.87-0.83(t,J=6.8Hz,3H)ppm.

[0429] Synthesis of intermediate [9] [ka] As shown in Scheme 4, to a stirred solution of undecyl hex-5-enoate [8] (19.8 g, 73.8 mmol) in dichloromethane (200 mL) was added 3-chlorobenzene-1-carboperoxoic acid (25.5 g, 148 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction mass was monitored by TLC (SM was consumed). The resulting reaction mixture was washed with cold aqueous sodium bicarbonate solution (200 mL). The resulting organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude product was purified by flash column chromatography (SiO2: 5–15% ethyl acetate in hexanes) to afford the desired undecyl 4-(oxiran-2-yl)butanoate [9] (17.8 g, 84.84% yield) as a pale yellow liquid.

[0430] result: 1H-NMR(400MHz,CDCl3)-δ 4.09-4.06(t,J=6.8Hz,2H),2.96-2.91(m,1H),2.78-2.76(t,J=4.8Hz,1H),2.50-2.48(m,1H),2.40-2 .37(m,2H),1.86-1.77(m,2H),1.66-1.53(m,4H),1.31-1.27(m,16H),0.90-0.87(t,J=6.8Hz,3H)ppm.

[0431] ELSD analysis: purity 95.53%, calculated value C 17 H 32 O3 = 284.24, Measured = 285.20 (m / z, M+H+).

[0432] Synthesis of intermediate

[11] [ka] As shown in Scheme 4, a stirred solution of 3-aminopropan-1-ol

[10] (4.7 g, 62.6 mmol) and undecyl 4-(oxiran-2-yl)butanoate [9] (17.8 g, 62.6 mmol) in isopropanol (100 mL) was heated at 90 °C for 16 h. The reaction progress was monitored by the consumption of SM. The reaction mixture was concentrated, and the crude product was purified by flash column chromatography (SiO: 0–20% methanol in dichloromethane) to afford the desired undecyl 5-hydroxy-6-[(3-hydroxypropyl)amino]hexanoate

[11] (6.5 g, 28.89% yield) as a pale yellow liquid.

[0433] result: ELSD analysis: purity 99.56%, calculated value C 20 H 41 NO4 = 359.30, Measured value = 360.65 (m / z, M+H+).

[0434] Intermediate

[12] [ka] As shown in Scheme 4, a stirred solution of undecyl 5-hydroxy-6-[(3-hydroxypropyl)amino]hexanoate

[11] (6.2 g, 17.2 mmol) and heptadecan-9-yl 6-(oxiran-2-yl)hexanoate [5] (7.52 g, 19 mmol) in isopropanol (100 mL) was heated at 90 °C for 16 h. The reaction progress was monitored by the consumption of SM. The reaction mixture was concentrated, and the crude product was purified by flash column chromatography (SiO2: 0–20% methanol in dichloromethane) to afford the desired heptadecan-9-yl 7-hydroxy-8-{[2-hydroxy-6-oxo-6-(undecyloxy)hexyl](3-hydroxypropyl)amino}octanoate

[12] (6.3 g, 48.31% yield) as a pale yellow liquid.

[0435] result: ELSD analysis: purity 99.73%, calculated value C 45 H89 NO7 = 755.66, Measured value = 756.55 (m / z, M+H+).

[0436] Synthesis of compound LXXII [ka] As shown in Scheme 4, a stirred solution of 3-hydroxy-3-methylpentanedioic acid

[13] (0.2 g, 1.23 mmol) and heptadecan-9-yl 7-hydroxy-8-{[2-hydroxy-6-oxo-6-(undecyloxy)hexyl](3-hydroxypropyl)amino}octanoate

[12] (1.77 g, 2.34 mmol) in dichloromethane (8 mL) was cooled to 0 °C and EDC.HCl (709 mg, 3.7 mmol) was added, followed by DMAP (456 mg, 3.7 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction progress was monitored by electroluminescence / television chromatographic analysis (SM was consumed). Water (25 mL) was added to the reaction mixture and extracted with DCM (3 × 50 mL). The resulting organic layer was dried over NaSO and concentrated under reduced pressure, and the crude product was purified by flash column chromatography (SiO: 0–5% methanol in dichloromethane) to give 1,5-bis(3-{[8-(heptadecan-9-yloxy)-2-hydroxy-8-oxooctyl][2-hydroxy-6-oxo-6-(undecyloxy)hexyl]amino}propyl) 3-hydroxy-3-methylpentanedioate Compound LXXII (0.4 g, 19.79%, yield) as a colorless liquid.

[0437] result: 1H NMR (400MHz, CDCl3):δ 4.89-4.82(m,2H),4.26-4.22(m,1H),4.18-4.14(m,3H),4.07-4.03(t,J=6.4Hz,4H),3.6 (brs,4H),3.28-3.26(br,2H),2.75-2.60(m,7H),2.58-2.52(m,2H),2.49-2.39(m,4H),2 .37-2.31(m,4H),2.30-2.26(t,J=7.2Hz,4H),1.80-1.79(m,6H),1.67-1.57(m,14H),1.5 0-1.49(m,8H),1.45-1.39(m,6H),1.36-1.25(brs,94H),0.89-0.86(t,J=7.2Hz,18H)ppm.

[0438] ELSD analysis: purity 96.73%, calculated value C 96 H 184 N2O 17 = 1637.36, measured value = 1638.10 (m / z, M+H+).

[0439] Example 5: Synthesis of Compound XXXVII For example, compounds of the present invention can be prepared according to Scheme 5 (as shown in Figure 5).

[0440] Synthesis of intermediate [3] [ka] As shown in Scheme 5, a mixture of 2-octyloxirane [2] (21.8 g, 140 mmol) and 3-aminopropan-1-ol [1] (5 g, 66.6 mmol) in isopropanol (100 mL, 654 mmol) was heated to 95 °C for 20 h under a nitrogen atmosphere. The reaction progress was monitored by electroluminescence / telescopic liquid chromatography (ELSD / TLC; SM was consumed). The reaction mixture was concentrated, and the crude product was purified by flash column chromatography (SiO: 0–20% methanol in dichloromethane) to afford the desired 1-[(2-hydroxydecyl)(3-hydroxypropyl)amino]decan-2-ol [3] (22 g, 85% yield) as an off-white solid.

[0441] result: ELSD analysis: purity 99.85%, calculated value C 23 H 49 NO3 = 387.37, Measured value = 388.35 (m / z, M+H+).

[0442] Synthesis of Compound XXXVII [ka] As shown in Scheme 5, to a stirred solution of 3-hydroxy-3-methylpentanedioic acid [4] (0.1 g, 617 μmol) in dichloromethane (20 mL, 312 mmol), 4-(dimethylamino)pyridin-1-ium (456 mg, 3.7 mmol), {3-[cyano(ethyl)amino]propyl}dimethylazanium chloride (355 mg, 1.85 mmol), and 1-[(2-hydroxydecyl)(3-hydroxypropyl)amino]decan-2-ol [3] (526 mg, 1.36 mmol) were added under an inert atmosphere at room temperature. The resulting reaction mixture was stirred at room temperature for 48 hours. After 48 hours, the reaction progress was monitored by TLC, and the starting material was completely consumed. The reaction mass was evaporated under reduced pressure and then washed five times with heptane. The combined heptane fractions were evaporated under reduced pressure to obtain the crude reaction mass. The crude compound was purified by preparative HPLC (ACN / 0.1% TFA in water) as a gradient eluent to give 1,5-bis({3-[bis(2-hydroxydecyl)amino]propyl}) 3-hydroxy-3-methylpentanedioate. Trifluoroacetate compound XXXVII (0.14 g, 25% yield) was obtained as a colorless liquid.

[0443] result: 1H NMR (400MHz, CDCl3):δ 8.85-8.65(brs,1H),8.55-8.35(brs,1H),5.38-5.29(m,4H),4.96(s,1H),4.23-4.17(m,4H),4.07(s,4H),3.48-3.35(m,4H),3.19-3.05 (m,10H),2.80-2.70(m,2H),2.61-2.55(m,2H),2.14(s,4H),1.44-1.30(m,12H),1.29-1.25(brs,45H),0.89-0.86(t,J=6.8Hz,12H)ppm.

[0444] ELSD analysis: purity 99.92%, calculated value C 52 H 104 N2O9 = 900.77, Measured = 901.60 (m / z, M+H+).

[0445] Example 6: Synthesis of Compound XL For example, compounds of the present invention can be prepared according to Scheme 6 (as shown in Figure 6).

[0446] Synthesis of intermediate [3] [ka] As shown in Scheme 6, a mixture of 2-octyloxirane [2] (18.4 g, 118 mmol) and 4-aminobutan-1-ol [1] (5 g, 56.1 mmol) in isopropanol (100 mL) was stirred and heated to 95 °C for 20 h under a nitrogen atmosphere. The reaction progress was monitored by electroluminescence / telescopic liquid chromatography (ELSD / TLC) (SM was consumed). The reaction mixture was concentrated, and the crude product was purified by flash column chromatography (SiO2: 0–10% methanol in dichloromethane) to afford the desired 1-[(4-hydroxybutyl)(2-hydroxydecyl)amino]decan-2-ol [3] (20.0 g, 91% yield) as a white solid compound.

[0447] result: ELSD analysis: purity 99.85%, calculated value C 24 H 51NO3 = 401.39, Measured value = 402.45 (m / z, M+H+).

[0448] Synthesis of intermediate [4] [ka] As shown in Scheme 6, dichloromethane (50 mL, 781 mmol) was added to a stirred solution of 1-[(4-hydroxybutyl)(2-hydroxydecyl)amino]decan-2-ol [3] (5.0 g, 12.4 mmol) in (chlorodiphenylmethyl)benzene (4.16 g, 14.9 mmol) and pyridine (985 mg, 12.4 mmol) under cooling and inert atmosphere. The reaction mass was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC / ELSD. The reaction mass was diluted with DCM (50 mL), washed with fresh water (20 mL), and extraction was performed with DCM (3 x 50 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1-[(2-hydroxydecyl)[4-(triphenylmethoxy)butyl]amino]decan-2-ol [4] (8 g, 12.4 mmol) as a colorless liquid, which was used directly in the next step.

[0449] result: ELSD analysis: purity 97.95%, calculated value C 43 H 65 NO3 = 643.50, Measured value = 644.45 (m / z, M+H+).

[0450] Synthesis of intermediate [5] [ka] As shown in Scheme 6, to a stirred solution of 1-[(2-hydroxydecyl)[4-(triphenylmethoxy)butyl]amino]decan-2-ol [4] (8.0 g, 12.4 mmol) in dichloromethane (0.1 L, 1.56 mol) was added 1H-imidazole (7.61 g, 112 mmol) and tert-butyl(chloro)dimethylsilane (11.2 g, 74.5 mmol) sequentially under an inert atmosphere. The resulting reaction mass was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. SM was completely consumed. The reaction was quenched with ice-cold water (100 mL) and extracted with DCM (2 x 50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude reaction mass. The crude product was purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as an eluent gradient to give 2,2,3,3,11,11,12,12-octamethyl-5,9-dioctyl-7-[4-(triphenylmethoxy)butyl]-4,10-dioxa-7-aza-3,11-disilatridecane [5] (10.7 g, 98.5% yield after two steps) as a colorless liquid.

[0451] result: ELSD analysis: purity 99.91%, calculated value C 55 H 93 NO3Si2 = 871.67, Measured = 872.55 (m / z, M+H+).

[0452] Synthesis of intermediate [6] [ka] As shown in Scheme 6, to a stirred solution of 2,2,3,3,11,11,12,12-octamethyl-5,9-dioctyl-7-[4-(triphenylmethoxy)butyl]-4,10-dioxa-7-aza-3,11-disilatridecane [5] (5 g, 5.73 mmol) in dichloromethane (20 mL, 312 mmol) was added triethylsilyl (1.32 g, 11.5 mmol) at 0 °C, followed by the dropwise addition of trifluoroacetic acid (3.27 g, 28.7 mmol) under an inert atmosphere. The reaction was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. The reaction mass was quenched with saturated aqueous NaHCO3 solution until pH 8. The compound was extracted with DCM (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. The crude compound was purified by silica gel flash column chromatography by using 10–30% ethyl acetate in hexane as gradient eluent to give 4-(2,2,3,3,11,11,12,12-octamethyl-5,9-dioctyl-4,10dioxa-7-aza-3,11disilatridecan-7-yl)butan-1-ol [6] (3.0 g, 83% yield) as a pale yellow liquid.

[0453] result: ELSD analysis: purity 99.48%, calculated value C 36 H 79 NO3Si2 = 629.56, Measured = 630.55 (m / z, M+H+).

[0454] Synthesis of intermediate [8] [ka] As shown in Scheme 6, a stirred solution of 4-(2,2,3,3,11,11,12,12-octamethyl-5,9-dioctyl-4,10-dioxa-7-aza-3,11-disilatridecan-7-yl)butan-1-ol [6] (2.45 g, 3.89 mmol) and 3-hydroxy-3-methylpentanedioic acid [7] (0.5 g, 3.4 mmol) in dichloromethane (50 mL, 781 mmol) was cooled to 0 °C, and {3-[cyano(ethyl)amino]propyl}dimethylazaninium chloride (1.06 g, 5.55 mmol) was added, followed by 4-(dimethylamino)pyridin-1-ium (684 mg, 5.55 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction progress was monitored by electroluminescence / telescopic liquid crystal display (ELSD / TLC). Water (50 mL) was added to the reaction mixture and extracted with DCM (3 × 50 mL). The organic layer was collected, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica column chromatography (0–100% ethyl acetate in hexanes) as gradient eluent to afford 1,5-bis[4-(2,2,3,3,11,11,12,12-octamethyl-5,9-dioctyl-4,10-dioxa-7-aza-3,11-disilatridecan-7-yl)butyl] 3-hydroxy-3-methylpentanedioate [8] (700 mg, 14.9% yield) as a pale yellow liquid.

[0455] result: ELSD analysis: purity 99.20%, calculated value C 78 H 164 N2O9Si4 = 1385.15, Measured = 1386.85 (m / z, M+H+).

[0456] Synthesis of Compound XL [ka] As shown in Scheme 6, to a stirred solution of 1,5-bis[4-(2,2,3,3,11,11,12,12-octamethyl-5,9-dioctyl-4,10-dioxa-7-aza-3,11-disilatridecan-7-yl)butyl] 3-hydroxy-3-methylpentanedioate [8] (0.7 g, 505 μmol) in tetrahydrofuran (5 mL, 61.4 mmol) was slowly added pyridine hydrofluoride (0.3 g, 3.03 mmol) under an inert atmosphere at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and ELSD data. After completion of the reaction, the reaction mass was quenched with saturated sodium bicarbonate to pH 8. Extraction was performed with ethyl acetate (3 x 50 ml). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography to obtain 1,5-bis({4-[bis(2-hydroxydecyl)amino]butyl}) 3-hydroxy-3-methylpentanedioate Compound XL (126 mg, yield 26.8%) as a colorless liquid.

[0457] result: 1H NMR (400MHz, CDCl3): δ 4.13-4.08(m 4H),3.65-3.60(m,4H),2.71-2.53(m,8H),2.49-2.38(m,8H),1.70-1.58(m,4H),1.56-1.49(m,4H ),1.48-1.43(m,4H),1.42-1.33(brs,10H),1.34-1.2(brs,45H),0.89-0.86(t,J=6.8Hz,12H)ppm.

[0458] ELSD analysis: purity 99.35%, calculated value C 54 H 108 N2O9 = 928.81, Measured = 929.60 (m / z, M+H+).

[0459] Example 7: Synthesis of Compound XXXIX For example, compounds of the present invention can be prepared according to Scheme 7 (as shown in Figure 7).

[0460] Synthesis of intermediate [3] [ka] As shown in Scheme 7, a solution of 4-aminobutan-1-ol [1] (3 g, 33.7 mmol) and 2-decyloxirane [2] (12.4 g, 67.3 mmol) in propan-2-ol (60 mL) was stirred at 90 °C for 20 h. The reaction progress was monitored by TLC / ELSD. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel flash chromatography (0–7% methanol in dichloromethane) as a gradient eluent to give 1-[(4-hydroxybutyl)(2-hydroxydodecyl)amino]dodecan-2-ol [3] (11.2 g, 24.5 mmol) as a pale yellow liquid.

[0461] result: ELSD analysis: purity 99.94%, calculated value C 28 H 59 NO3 = 457.45, Measured value = 458.45 (m / z, M+H+).

[0462] Synthesis of Compound XXXIX [ka] As shown in Scheme 7, to a stirred solution of 3-hydroxy-3-methylpentanedioic acid [4] (0.4 g, 2.47 mmol) in dichloromethane (10 mL) was added {3-[cyano(ethyl)amino]propyl}dimethylazanium chloride (1.47 g, 7.65 mmol) and DMAP (942 mg, 7.65 mmol), followed by 1-[(4-hydroxybutyl)(2-hydroxydodecyl)amino]dodecan-2-ol [3] (2.37 g, 5.18 mmol) under an inert atmosphere at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The progress of the reaction was monitored by TLC / ELSD. The reaction mass was evaporated under reduced pressure to give the crude product, which was purified by preparative HPLC (acetonitrile / 0.1% TFA in water) as gradient eluent to give 1,5-bis({4-[bis(2-hydroxydodecyl)amino]butyl}) 3-hydroxy-3-methylpentanedioate TFA salt Compound XXXIX (310 mg, 11.9% yield) as a colorless semi-solid.

[0463] result: 1H NMR (400MHz, CDCl3):δ 4.14(brs,4H),4.05(brs,4H),3.68(brs,1H),3.47-3.28(m,16H),2.71-2.67(m,2H),2.67-2.56(m,2H) ),1.88(brs,4H),1.73(brs,4H),1.50-1.38(m,14H),1.26(brs,61H),0.89-0.86(t,J=6.8Hz,12H)ppm.

[0464] ELSD analysis: purity 99.84%, calculated value C 62 H 124 N2O9 = 1040.93, Measured = 1041.75 (m / z, M+H+).

[0465] Example 8: Synthesis of Compound XLV For example, compounds of the present invention can be prepared according to Scheme 8 (as shown in Figure 8).

[0466] Synthesis of intermediate [3] [ka] As shown in Scheme 8, to a stirred solution of 5-aminopentan-1-ol [1] (1.0 g, 9.69 mmol) in isopropanol (20 mL), 2-octyloxirane [2] (3.33 g, 21.3 mmol) was added and stirred at 90 °C for 16 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was evaporated under reduced pressure to give the crude product, which was purified by silica gel flash column chromatography (0–5% MeOH in DCM) to give 1-[(2-hydroxydecyl)(5-hydroxypentyl)amino]decan-2-ol [3] (2.65 g, 65.77% yield) as a greenish liquid.

[0467] result: ELSD analysis: purity 99.66%, calculated value C 25 H 53 NO3 = 415.40, Measured value = 416.35 (m / z, M+H+).

[0468] Synthesis of intermediate [4] [ka] As shown in Scheme 8, to a stirred solution of 1-[(2-hydroxydecyl)(5-hydroxypentyl)amino]decan-2-ol [3] (2.4 g, 5.77 mmol) in DCM (25 mL) was added (chlorodiphenylmethyl)benzene (1.77 g, 6.35 mmol) and pyridine (685 mg, 8.66 mmol) under cooling and inert atmosphere. The reaction mass was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC / ELSD. The reaction mass was diluted with DCM (50 mL) and washed with fresh water (50 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 1-[(2-hydroxydecyl)[5-(triphenylmethoxy)pentyl]amino]decan-2-ol [4] (3.8 g, crude) as a colorless liquid, which was used dire...

Claims

1. Formula (I): 【Chemistry 1】 (Wherein A is —N(R １ )- or -S-S-; R １ is optionally substituted (C １ ~C ６ ) alkyl, a and c are integers independently selected from 1, 2, 3, or 4; b and d are integers independently selected from 1, 2, 3, 4, 5, or 6; Z １ は, shared combination, 【Chemistry 2】 or -S-S-, and the left side of each depicted structure is selected from -(CH ２ ) ｂ - is bonded to Z ２ は, shared combination, 【Transformation 3】 or -S-S-, and the right side of each depicted structure is selected from -(CH ２ ) ｄ - is bonded to Each Y １ are independently selected from hydrogen or —OH; Each R ８ is hydrogen or an optionally substituted (C １ ~C ６ ) alkyl; R ２Ａ , R ２Ｂ , R ２Ｃ and R ２Ｄ is optionally substituted (C ５ ~C ２５ ) alkyl, optionally substituted (C ５ ~C ２５ ) alkenyl or -W １ -X １ are each independently selected from Each W １ is a covalent bond, optionally substituted (C １ ~C １０ ) alkylene or optionally substituted (C ２ ~C １０ ) alkenylene, and Each X １ is -(*C=O)-O-optionally substituted (C ３ ~C ２５ ) alkyl, -(*C=O)-O- optionally substituted (C ３ ~C ２５ ) alkenyl, -*O-(C=O)- optionally substituted (C ３ ~C ２５ ) alkyl or -*O-(C=O)- optionally substituted (C ３ ~C ２５ ) alkenyl, and the atoms marked with * are independently selected from W １ is a covalent bond, W １ or -CH(Y １ ) - bonded to or a pharmaceutically acceptable salt thereof.

2. Formula (II): 【Chemistry 4】 (In the formula, R ３ is hydrogen or an optionally substituted (C １ ~C ６ ) alkyl; R ４ is hydrogen, —OH, —NH ２ , optionally substituted (C １ ~C ６ ) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C １ ~C ３ ) alkylene-optionally substituted aryl or optionally substituted (C １ ~C ３ ) alkylene-optionally substituted heteroaryl; e and g are integers independently selected from 0, 1, 2, 3, or 4; f and h are integers independently selected from 1, 2, 3, 4, 5, or 6; Each Y ２ are independently selected from hydrogen or —OH; R ５Ａ , R ５Ｂ , R ５Ｃ and R ５Ｄ is optionally substituted (C ５ ~C ２５ ) alkyl, optionally substituted (C ５ ~C ２５ ) alkenyl or -W １ -X １ are each independently selected from Each W １ is a covalent bond, optionally substituted (C １ ~C １０ ) alkylene or optionally substituted (C ２ ~C １０ ) alkenylene, and Each X １ is -(*C=O)-O-optionally substituted (C ３ ~C ２５ ) alkyl, -(*C=O)-O- optionally substituted (C ３ ~C ２５ ) alkenyl, -*O-(C=O)- optionally substituted (C ３ ~C ２５ ) alkyl or -*O-(C=O)- optionally substituted (C ３ ~C ２５ ) alkenyl, and the atoms marked with * are independently selected from W １ is a covalent bond, W １ or -CH(Y ２ ) - bonded to or a pharmaceutically acceptable salt thereof.

3. Formula (III): 【Transformation 5】 (In the formula, R ９ is hydrogen or an optionally substituted (C １ ~C ６ ) alkyl; R １０ is hydrogen, —OH, —NH ２ , optionally substituted (C １ ~C ６ ) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C １ ~C ３ ) alkylene-optionally substituted aryl or optionally substituted (C １ ~C ３ ) alkylene-optionally substituted heteroaryl; i and k are integers independently selected from 0, 1, 2, 3, or 4; j and l are integers independently selected from 1, 2, 3, 4, 5, or 6; Each Y ３ are independently selected from hydrogen or —OH; Each R １２ is hydrogen or an optionally substituted (C １ ~C ６ ) alkyl; R １１Ａ , R １１Ｂ , R １１Ｃ and R １１Ｄ is optionally substituted (C ５ ~C ２５ ) alkyl, optionally substituted (C ５ ~C ２５ ) alkenyl or -W １ -X １ are each independently selected from Each W １ is a covalent bond, optionally substituted (C １ ~C １０ ) alkylene or optionally substituted (C ２ ~C １０ ) alkenylene, and Each X １ is -(*C=O)-O-optionally substituted (C ３ ~C ２５ ) alkyl, -(*C=O)-O- optionally substituted (C ３ ~C ２５ ) alkenyl, -*O-(C=O)- optionally substituted (C ３ ~C ２５ ) alkyl or -*O-(C=O)- optionally substituted (C ３ ~C ２５ ) alkenyl, and the atoms marked with * are independently selected from W １ is a covalent bond, W １ or -CH(Y ３ ) - bonded to or a pharmaceutically acceptable salt thereof.

4. Formula (IV): 【Transformation 6】 (In the formula, m and n are integers independently selected from 1, 2, 3, 4, 5, or 6; Z ３ is an aromatic amino acid residue, and the α-carbon carboxyl group (—C(O)O—) of the aromatic amino acid residue is —(CH ２ ) ｍ and the α-carbon aminyl group (—NH—) of the aromatic amino acid residue is bonded to Z ４ is connected to Z ４ teeth, 【Transformation 7】 and the right side of each depicted structure is selected from -(CH ２ ) ｎ - is bonded to Each Y ４ are independently selected from hydrogen or —OH; R １３Ａ , R １３Ｂ , R １３Ｃ and R １３Ｄ is optionally substituted (C ５ ~C ２５ ) alkyl, optionally substituted (C ５ ~C ２５ ) alkenyl or -W １ -X １ are each independently selected from Each W １ is a covalent bond, optionally substituted (C １ ~C １０ ) alkylene or optionally substituted (C ２ ~C １０ ) alkenylene, and Each X １ is -(*C=O)-O-optionally substituted (C ３ ~C ２５ ) alkyl, -(*C=O)-O- optionally substituted (C ３ ~C ２５ ) alkenyl, -*O-(C=O)- optionally substituted (C ３ ~C ２５ ) alkyl or -*O-(C=O)- optionally substituted (C ３ ~C ２５ ) alkenyl, and the atoms marked with * are independently selected from W １ is a covalent bond, W １ or -CH(Y ４ ) - bonded to or a pharmaceutically acceptable salt thereof.

5. A compound selected from (i) those listed in Table A or a pharmaceutically acceptable salt thereof, or (ii) those listed in Table B or a pharmaceutically acceptable salt thereof.

6. A composition comprising the cationic lipid according to any one of claims 1 to 5, (i) one or more non-cationic lipids; (ii) one or more cholesterol-based lipids; and (iii) one or more PEG-modified lipids; and The composition further comprising:

7. 7. The composition of claim 6, which is a lipid nanoparticle, optionally a liposome.

8. The composition of claim 7 , wherein the lipid nanoparticles encapsulate a nucleic acid, optionally an mRNA encoding a peptide or protein.

9. The composition of claim 7 or 8, wherein the lipid nanoparticles encapsulate mRNA encoding a peptide or protein.

10. 10. The composition of claim 8 or 9 for use in a vaccine.

11. A composition according to any one of claims 8 to 10 for use in therapy.

12. 10. The composition of claim 9 for use in a method for treating or preventing a disease amenable to treatment or prevention by the peptide or protein encoded by the mRNA, and which is optionally (a) a protein deficiency optionally affecting the liver, lungs, brain or muscles, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

13. The composition for use according to any one of claims 10 to 12, which is administered intranasally, intravenously, intrathecally or intramuscularly, or by pulmonary delivery, optionally via aerosol.

14. 10. A method of treating or preventing a disease, comprising administering to a subject in need thereof the composition of claim 9, wherein the disease is suitable for treatment or prevention by the peptide or protein encoded by the mRNA, and optionally the disease is (a) a protein deficiency, optionally affecting the liver, lungs, brain or muscles, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

15. 15. The method of claim 14, wherein the composition is administered intranasally, intravenously, intrathecally, or intramuscularly, or by pulmonary delivery, optionally via aerosol.

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