Diester and amide cationic lipids

Abstract

The present invention provides, in part, a diester and amide cationic lipid compound of formula (I): # imgabs0 # or a pharmaceutically acceptable salt thereof; a diester and amide cationic lipid compound of formula (II): # imgabs 1 # or a pharmaceutically acceptable salt thereof; a diester and amide cationic lipid compound of formula (III): # imgabs2 # (III), or a pharmaceutically acceptable salt thereof; and a diester and amide cationic lipid compound of formula (IV): # imgabs3 # or a pharmaceutically acceptable salt thereof. The compounds provided herein can be used to deliver and express mRNA and encoded proteins, for example, as components of liposomal delivery vehicles, and thus can be used to treat various diseases, disorders, and conditions, such as those associated with the lack of one or more proteins.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from European application No. 22307007.9, filed on December 22, 2022, which is incorporated by reference in its entirety. Background Art

[0002] The delivery of nucleic acids has been widely explored as a potential therapeutic option for certain disease states. In particular, messenger RNA (mRNA) therapy has become an increasingly important option for preventing and treating various diseases (e.g., in the use of vaccines).

[0003] The effective sending of the nucleic acid of liposome sealing remains an active research field.The cationic lipid component of the liposome of encapsulating nucleic acid plays an important role in promoting the effective encapsulation of nucleic acid during the liposome load.In addition, cationic lipid can play an important role in the Cytoplasm of target cell that nucleic acid carrier is effectively discharged into from liposome.Have been found to be suitable for the various cationic lipids used in vivo.Yet, still need to identify and can synthesize efficiently and cheaply and do not form the lipid of potential poisonous by product.

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

[0005] The present inventors have surprisingly found that when delivering mRNA encoding a peptide or protein, the cationic lipids made from commercially available acyclic linkers (such as malonic acid and aminomalonic acid) have high levels of expression of the peptide or protein while having reduced size and complexity. Compared with earlier lipidoid cationic lipids, the size and complexity of this reduction allow for more rapid development of new lipid analogs, and the claimed cationic lipids are also advantageous when it comes to downstream scale-up and manufacturing. Summary of the Invention

[0006] The present invention especially provides a class of novel cationic lipid compounds, for the in vivo delivery of therapeutic agents such as nucleic acids. It is envisioned that these compounds can highly effectively deliver therapeutic agents and vaccines in vivo, while maintaining favorable safety characteristics. The lipid nanoparticles comprising cationic lipids of the present invention (such as compounds LXXIII and LXXIV) also show enhanced thermal stability, which is of value to the development of corresponding therapeutic agents and vaccines.

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

[0008] In one aspect, provided herein are cationic lipids having a structure according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein A is selected from -N(R 1 )- or -SS-; R 1 is optionally substituted (C1-C6)alkyl; a and c are each independently an integer selected from 1, 2, 3 or 4; b and d are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Z 1 Selected from covalent bonds, or -SS-, where the left side of each depicted structure is connected to -(CH2) b - combine; Z 2 Selected from covalent bonds, or -SS-, where the right side of each depicted structure is connected to -(CH2) d - combine; Each Y 1 independently selected from hydrogen or -OH; Each R 8 independently selected from hydrogen or optionally substituted (C1-C6)alkyl; R 2A 、R 2B 、R 2C and R 2D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connect.

[0009] In one aspect, provided herein is a cationic lipid having a structure according to Formula (II): or a pharmaceutically acceptable salt thereof, where 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 each independently an integer selected from 0, 1, 2, 3, or 4; f and h are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Each Y 2 independently selected from hydrogen or -OH; R 5A 、R 5B 、R 5C and R 5D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connect.

[0010] In one aspect, provided herein is a cationic lipid having a structure according to Formula (III): or a pharmaceutically acceptable salt thereof, where 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 each independently an integer selected from 0, 1, 2, 3, or 4; j and l are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Each Y 3 independently selected from hydrogen or -OH; Each R 12 independently selected from hydrogen or optionally substituted (C1-C6)alkyl; R 11A 、R 11B 、R 11C and R 11D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connect.

[0011] In one aspect, provided herein is a cationic lipid having a structure according to Formula (IV): or a pharmaceutically acceptable salt thereof, in m and n are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Z 3 It is an aromatic amino acid residue in which the α-carbon carboxyl group (-C(=O)-O-) of the aromatic amino acid residue is in contact with -(CH2) m - combined with the α-carbonyl group (-NH-) of the aromatic amino acid residue and Z 4 Combine; Z 4 Selected from The right side of each depicted structure is connected with -(CH2) n - combine; Each Y 4 independently selected from hydrogen or -OH; R 13A 、R 13B 、R 13C and R 13D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connect.

[0012] In one aspect, provided herein are cationic lipids having formula (I) that are pharmaceutically acceptable salts.

[0013] In one aspect, provided herein are cationic lipids having formula (II) that are pharmaceutically acceptable salts.

[0014] In one aspect, provided herein are cationic lipids having formula (III) that are pharmaceutically acceptable salts.

[0015] In one aspect, provided herein are cationic lipids having formula (IV) that are pharmaceutically acceptable salts.

[0016] In one aspect, provided herein are compositions comprising a cationic lipid of the 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 compositions are lipid nanoparticles, optionally liposomes.

[0017] In one aspect, compositions comprising the cationic lipids of the invention can be used in therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Scheme 1, the reaction scheme of Example 1, is depicted.

[0019] Figure 2 Scheme 2, the reaction scheme for Example 2, is depicted.

[0020] Figure 3 Scheme 3, the reaction scheme for Example 3, is depicted.

[0021] Figure 4 Scheme 4, the reaction scheme of Example 4, is depicted.

[0022] Figure 5 Scheme 5, the reaction scheme for Example 5, is depicted.

[0023] Figure 6 Scheme 6, the reaction scheme of Example 6, is depicted.

[0024] Figure 7 Scheme 7, the reaction scheme of Example 7, is depicted.

[0025] Figure 8 Scheme 8, the reaction scheme for Example 8, is depicted.

[0026] Figure 9 Scheme 9, the reaction scheme for Example 9, is depicted.

[0027] Figure 10 Scheme 10, the reaction scheme for Example 10, is depicted.

[0028] Figure 11 Scheme 11, the reaction scheme for Example 11, is depicted.

[0029] Figure 12 Scheme 12, the reaction scheme for Example 12, is depicted.

[0030] Figure 13 Scheme 13, the reaction scheme for Example 13, is depicted.

[0031] Figure 14 Scheme 14, the reaction scheme for Example 14, is depicted.

[0032] Figure 15 Scheme 15, the reaction scheme for Example 15, is depicted.

[0033] Figure 16 Scheme 16, the reaction scheme for Example 16, is depicted.

[0034] Figure 17 Scheme 17, the reaction scheme for Example 17, is depicted.

[0035] Figure 18 Scheme 18, the reaction scheme for Example 18, is depicted.

[0036] Figure 19 Scheme 19, the reaction scheme for Example 19, is depicted.

[0037] Figure 20 Scheme 20, the reaction scheme for Example 20, is depicted.

[0038] Figure 21 The reaction scheme of Scheme 21, Example 21, is depicted.

[0039] Figure 22 Scheme 22, the reaction scheme for Example 22, is depicted.

[0040] Figure 23 Scheme 23, the reaction scheme for Example 23, is depicted.

[0041] Figure 24 Scheme 24, the reaction scheme for Example 24, is depicted.

[0042] Figure 25 Scheme 25, the reaction scheme for Example 25, is depicted.

[0043] Figure 26 Scheme 26, the reaction scheme for Example 26, is depicted.

[0044] Figure 27 The reaction scheme of Scheme 27, Example 27, is depicted.

[0045] Figure 28 Scheme 28, the reaction scheme for Example 28, is depicted.

[0046] Figure 29The reaction scheme of Scheme 29, Example 29, is depicted.

[0047] Figure 30 Scheme 30, the reaction scheme for Example 30, is depicted.

[0048] Figure 31 The reaction scheme of Scheme 31, Example 31, is depicted.

[0049] Figure 32 Scheme 32, the reaction scheme for Example 32, is depicted.

[0050] Figure 33 The reaction scheme of Scheme 33, Example 33, is depicted.

[0051] Figure 34 Scheme 34, the reaction scheme for Example 34, is depicted.

[0052] Figure 35 Scheme 35, the reaction scheme for Example 35, is depicted.

[0053] Figure 36 Scheme 36, the reaction scheme for Example 36, is depicted.

[0054] Figure 37 The reaction scheme of Scheme 37, Example 37, is depicted.

[0055] Figure 38 Scheme 38, the reaction scheme for Example 38, is depicted.

[0056] Figure 39 The reaction scheme of Scheme 39, Example 39, is depicted.

[0057] Figure 40 Scheme 40, the reaction scheme for Example 40, is depicted.

[0058] Figure 41 The reaction scheme of Scheme 41, Example 41, is depicted.

[0059] Figure 42 The reaction scheme of Scheme 42, Example 42, is depicted.

[0060] Figure 43 The reaction scheme of Scheme 43, Example 43, is depicted.

[0061] Figure 44 The reaction scheme of Scheme 44, Example 44, is depicted.

[0062] Figure 45 Scheme 45, the reaction scheme for Example 45, is depicted.

[0063] Figure 46 Scheme 46, the reaction scheme for Example 46, is depicted.

[0064] Figure 47 The reaction scheme of Scheme 47, Example 47, is depicted.

[0065] Figure 48 The reaction scheme of Scheme 48, Example 48, is depicted.

[0066] Figure 49 The reaction scheme of Scheme 49, Example 49, is depicted.

[0067] Figure 50 Scheme 50, the reaction scheme for Example 50, is depicted.

[0068] Figure 51 Depicts the in vivo hEPO protein production produced by intramuscular delivery of hEPO mRNA using lipid nanoparticles comprising compounds XII, XIV, XV, XXV, XXXII, and XXXVIII as described herein. As shown in the figure, using these compounds as part of the lipid nanoparticles can result in high levels of in vivo hEPO protein production after administration. DETAILED DESCRIPTION definition

[0069] In order to make the present invention more easily understood, certain terms are first defined below. Additional definitions of the following terms and other terms are set forth throughout the specification. Publications and other references cited herein that describe the background of the present invention and provide additional details about its implementation are hereby incorporated by reference.

[0070] 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 of H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid; in some embodiments, the amino acid is a d-amino acid; in some embodiments, the amino acid is a l-amino acid. "Standard amino acid" refers to any of the twenty standard l-amino acids commonly found in naturally occurring peptides. "Non-standard amino acid" refers to any amino acid other than a standard amino acid, whether synthetically prepared or obtained from a natural source. As used herein, "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 carboxyl-terminal and / or amino-terminal amino acids in peptides) can be modified by methylation, amidation, acetylation, protecting groups, and / or substitution with other chemical groups that can alter the circulatory half-life of the peptide without adversely affecting its activity. Amino acids can participate in disulfide bonds. An amino acid may contain one or more post-translational modifications, such as association with one or more chemical entities (e.g., a methyl group, an acetate group, an acetyl group, a phosphate group, a formyl moiety, an isoprenoid group, a sulfate group, a polyethylene glycol moiety, a lipid moiety, a carbohydrate moiety, a biotin moiety, etc.). The term "amino acid" is used interchangeably with "amino acid residue" and may refer to a free amino acid and / or an amino acid residue of a peptide. Whether it refers to a free amino acid or a residue of a peptide will be apparent from the context in which the term is used.

[0071] 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 that includes 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 L-His (H) is sometimes classified as a basic residue due to the pKa of its heteroaromatic nitrogen atom, histidine is classified as an aromatic residue herein because its side chain includes a heteroaromatic ring. Examples of aromatic amino acids include the following:

[0072] Animal: As used herein, the term "animal" refers to any member of the kingdom Animalia. 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 can be a transgenic animal, a genetically engineered animal, and / or a clone.

[0073] Approximately or approximately: As used herein, the term "approximately" or "about" when 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 of a stated reference value in either direction (greater or less), unless otherwise specified or otherwise apparent from the context (except where such a number would exceed 100% of the possible value).

[0074] Biologically active: As used herein, the term "biologically active" refers to the characteristic of any agent that is active in a biological system, particularly in an organism. For example, an agent that has a biological effect on an organism when administered to that organism is considered biologically active.

[0075] Delivery: As used herein, the term "delivery" encompasses both local and systemic delivery. For example, delivery of mRNA encompasses both delivery of the mRNA to a target tissue and expression and retention of the encoded protein within the target tissue (also referred to as "local distribution" or "local delivery"), and delivery of the mRNA to a target tissue and expression and secretion of the encoded protein into the patient's circulatory system (e.g., serum) and systemic distribution and uptake by other tissues (also referred to as "systemic distribution" or "systemic delivery").

[0076] Expression: As used herein, "expression" of a nucleic acid sequence refers to the translation of mRNA into polypeptides, the assembly of multiple polypeptides into complete proteins (e.g., enzymes), and / or post-translational modifications of polypeptides or fully assembled proteins (e.g., enzymes). In this application, the terms "expression" and "production," and their grammatical equivalents, are used interchangeably.

[0077] Functional: As used herein, a "functional" biomolecule is a biomolecule in a form in which it exhibits the properties and / or activities that characterize it.

[0078] Half-life: As used herein, the term "half-life" is the time required for the concentration or activity of a nucleic acid or protein to decrease to half of its value measured at the beginning of a time period.

[0079] 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 a particular theory, helper lipids can increase stability, rigidity, and / or fluidity within the lipid bilayer / nanoparticle.

[0080] Improvement, increase, or decrease: As used herein, the terms "improvement," "increase," or "decrease," or grammatical equivalents, indicate a value relative to a baseline measurement, e.g., a measurement in the same individual prior to initiation of a treatment described herein, or a measurement in a control subject (or multiple control subjects) in the absence of a treatment described herein. A "control subject" is a subject having the same form of disease as the subject being treated who is approximately the same age as the subject being treated.

[0081] In vitro: As used herein, the term "in vitro" refers to events that occur in an artificial environment (eg, in a test tube or reaction vessel, in cell culture, etc.) rather than within a multicellular organism.

[0082] In vivo: As used herein, the term "in vivo" refers to events that occur within multicellular organisms (e.g., humans and non-human animals). In the context of cell-based systems, the term can be used to refer to events that occur within living cells (as opposed to, for example, in vitro systems).

[0083] Isolated: As used herein, the term "isolated" refers to a substance and / or entity that is (1) separated from at least some of the components with which it was associated when originally produced (whether in nature and / or in an experimental setting) and / or (2) produced, prepared, and / or manufactured by the hand of man. An isolated substance and / or entity can be 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% separated from other components with which it was originally associated. In some embodiments, the isolated pharmaceutical 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 more than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. As used herein, calculations of the percent purity of isolated substances and / or entities should not include excipients (e.g., buffers, solvents, water, etc.).

[0084] 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 and one or more polymers. In some embodiments, liposomes suitable for use in 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.

[0085] 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 modified and unmodified RNA. The term "modified mRNA" relates to an mRNA that comprises at least one chemically modified nucleotide. An mRNA may contain one or more coding regions and non-coding regions. An mRNA can be purified from a natural source, produced using a recombinant expression system and optionally purified, chemically synthesized, and the like. Where appropriate, for example, in the case of a chemically synthesized molecule, the mRNA may comprise nucleoside analogs, such as analogs with chemically modified bases or sugars, backbone modifications, and the like. Unless otherwise indicated, mRNA sequences are presented in a 5' to 3' direction. In some embodiments, the mRNA is or comprises a natural nucleoside (e.g., adenosine, guanosine, cytidine, uridine); a nucleoside analog (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolopyrimidine, 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-methylcytidine); guanosine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanosine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); inserted 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).

[0086] 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 via a phosphodiester bond. In some embodiments, "nucleic acid" refers to a single nucleic acid residue (e.g., a nucleotide and / or nucleoside). In some embodiments, "nucleic acid" refers to a polynucleotide chain comprising a single nucleic acid residue. In some embodiments, "nucleic acid" encompasses RNA and single-stranded and / or double-stranded DNA and / or cDNA. In some embodiments, "nucleic acid" encompasses ribonucleic acid (RNA), including but not limited to any 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), multimer coding nucleic acid (MCNA), polymer coding nucleic acid (PCNA), guide RNA (gRNA) and CRISPR RNA (crRNA). In some embodiments, "nucleic acid" encompasses deoxyribonucleic acid (DNA), including but not limited to any 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 can be in the form of antisense DNA, plasmid DNA, a portion of a plasmid DNA, pre-condensed DNA, a product of a polymerase chain reaction (PCR), a vector (e.g., P1, PAC, BAC, YAC, artificial chromosome), an expression cassette, a chimeric sequence, chromosomal DNA, or a derivative of these groups.In embodiments, the RNA may be in the form of messenger RNA (mRNA), ribosomal RNA (rRNA), signal recognition particle RNA (7SL RNA or SRP RNA), transfer RNA (tRNA), transfer 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), splicing leader RNA (SL RNA), antisense RNA (aRNA or asRNA), cis-natural antisense transcript (cis-NAT), CRISPR RNA (crRNA), long noncoding RNA (lncRNA), microRNA (miRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), transcribed siRNA (tasiRNA), repeat-associated siRNA (rasiRNA), 73K RNA, retrotransposon, viral genome, viroid, satellite RNA, or derivatives thereof. In some embodiments, the nucleic acid is an mRNA encoding a protein (e.g., an enzyme).

[0087] Patient: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition 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 both prenatal and postnatal forms.

[0088] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable" refers to substances that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0089] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail 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 an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of an amino group formed by 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, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, and arylsulfonates. Additional pharmaceutically acceptable salts include salts formed by quaternizing amines using appropriate electrophiles (e.g., alkyl halides) to form quaternized alkylated amino salts.

[0090] Systemic distribution or delivery: As used herein, the term "systemic distribution" or "systemic delivery," or grammatical equivalents thereof, refers to a delivery or distribution mechanism or method that affects the entire body or entire organism. Typically, systemic distribution or delivery is accomplished via the body's circulatory system (e.g., bloodstream). Compare to the definition of "local distribution or delivery."

[0091] 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). Humans include both prenatal and postnatal forms. In various embodiments, the subject is a human. The subject can be a patient, which refers to a person who goes to a healthcare provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject can have or be susceptible to a disease or disorder, but may or may not exhibit symptoms of the disease or disorder.

[0092] Substantially: As used herein, the term "substantially" refers to the qualitative condition of exhibiting the full or nearly full extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, are completed and / or proceed to completion or achieve or avoid an absolute result. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0093] Target tissue: As used herein, the term "target tissue" refers to any tissue affected by the disease to be treated. In some embodiments, target tissues include those tissues that exhibit pathology, symptoms, or characteristics associated with the disease.

[0094] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount that, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, prevent, and / or delay the onset of one or more symptoms of the disease, disorder, and / or condition. One of ordinary skill in the art will understand that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0095] Treatment: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, relieve, alleviate, suppress, prevent, delay onset, reduce severity, and / or reduce the incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who do not exhibit signs of disease and / or who exhibit only early signs of disease for the purpose of reducing the risk of developing pathology associated with the disease. Chemical definition

[0096] Acyl: As used herein, the term "acyl" refers to an R Z -(C=O)-, where R Z is, for example, any alkyl, alkenyl, alkynyl, heteroalkyl, or heteroalkylene group.

[0097] Aliphatic: As used herein, the term aliphatic refers to C1-C 50Hydrocarbons include both saturated and unsaturated hydrocarbons. Aliphatic hydrocarbons can be straight chain, branched chain, or cyclic. For example, C1-C 20 Aliphatic can include C1-C 20 Alkyl (e.g., straight or branched C1-C 20 saturated alkyl), C2-C 20 Alkenyl (e.g., straight or branched C4-C 20 Dienyl, straight chain or branched C6-C 20 triene, etc.) and C2-C 20 Alkynyl (e.g., straight or branched C2-C 20 C1-C 20 Aliphatic can include C3-C 20 Cyclic aliphatic (e.g., C3-C 20 Cycloalkyl, C4-C 20 Cycloalkenyl, or C8-C 20 In certain embodiments, the aliphatic group may contain one or more cyclic aliphatic groups and / or one or more heteroatoms (such as oxygen, nitrogen, or sulfur), and may be optionally substituted with one or more substituents (such as alkyl, halo, alkoxy, hydroxy, amino, aryl, ether, ester, or amide). The aliphatic group is unsubstituted or substituted with one or more substituents as described herein. For example, the aliphatic group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR", -CO2H, -CO2R", -CN, -OH, -OR", -OCOR', -OCOR", -NH2, -NHR", -N(R")2, -SR", or -SO2R", wherein each instance of R" is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 alkyl, or C1-C3 alkyl). In embodiments, R" is independently unsubstituted C1-C3 alkyl. In embodiments, the aliphatic is unsubstituted. In embodiments, the aliphatic does not include any heteroatoms. Alkyl: As used herein, the term "alkyl" means acyclic straight and branched hydrocarbon groups, such as "C1-C 30"Alkyl" refers to an alkyl group having 1-30 carbon atoms. The alkyl group can be straight 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" means a straight or branched chain alkyl group having 1 to 6 carbon atoms. Other alkyl groups will be apparent to those skilled in the art given the benefit of this disclosure. The alkyl group can be unsubstituted or substituted with one or more substituents as described herein. For example, the alkyl group can be substituted with one or more of halogen, -COR", -CO2H, -CO2R", -CN, -OH, -OR", -OCOR', -OCOR", -NH2, -NHR", -N(R")2, -SR", or -SO2R" (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein each instance of R" is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R" is independently unsubstituted C1-C3 alkyl. In some embodiments, the alkyl group is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkyl group is substituted with an -OH group and may also be referred to herein as a "hydroxyalkyl" group, where the prefix indicates an -OH group and "alkyl" is as described herein.

[0098] As used herein, "alkyl" also refers to a group having from 1 to 50 carbon atoms, a straight or branched chain saturated hydrocarbon group ("C1-C 50 In some embodiments, the alkyl group has 1 to 40 carbon atoms ("C1-C 40 In some embodiments, the alkyl group has 1 to 30 carbon atoms ("C1-C 30 In some embodiments, the alkyl group has 1 to 20 carbon atoms ("C1-C 20 In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C1-C 10In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1-C9 alkyl”). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1-C7 alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, the 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, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Additional 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 ("substituted alkyl") with one or more substituents. In certain embodiments, an alkyl group is an unsubstituted C1-C6 alkyl group. 50 In certain embodiments, the alkyl group is a substituted C1-C 50 alkyl.

[0099] Adding the suffix "-ene" to a group 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.

[0100] Alkylene: As used herein, the term "alkylene" represents a saturated divalent straight or branched hydrocarbon group, such as methylene, ethylene, isopropylene, and the like. Similarly, as used herein, the term "alkenylene" represents an unsaturated divalent straight or branched hydrocarbon group having one or more unsaturated carbon-carbon double bonds, which may occur at any stable point along the chain; and the term "alkynylene" herein represents an unsaturated divalent straight or branched hydrocarbon group having one or more unsaturated carbon-carbon triple bonds, which may occur at any stable point along the chain. In certain embodiments, an alkylene, alkenylene, or alkynylene group may contain one or more cyclic aliphatic groups and / or one or more heteroatoms (such as oxygen, nitrogen, or sulfur), and may be optionally substituted with one or more substituents (such as alkyl, halo, alkoxy, hydroxy, amino, aryl, ether, ester, or amide). For example, an alkylene, alkenylene, or alkynylene group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR", -CO2H, -CO2R", -CN, -OH, -OR", -OCOR", -OCOR", -NH2, -NHR", -N(R")2, -SR", or -SO2R", wherein each instance of R" is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R" is independently unsubstituted C1-C3 alkyl. In some embodiments, the alkylene, alkenylene, or alkynylene group is unsubstituted. In some embodiments, the alkylene, alkenylene, or alkynylene group does not include any heteroatoms. Alkenyl: As used herein, "alkenyl" means any straight or branched hydrocarbon chain having one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, such as "C2-C 30"Alkenyl" refers to an alkenyl group having 2-30 carbon atoms. For example, alkenyl includes prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, etc. In embodiments, the alkenyl group contains 1, 2, or 3 carbon-carbon double bonds. In embodiments, the alkenyl group contains a single carbon-carbon double bond. In embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. The alkenyl group can be unsubstituted or substituted. The alkylene group may be substituted with one or more substituents as described herein. For example, the alkylene group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR", -CO2H, -CO2R", -CN, -OH, -OR", -OCOR", -OCOR", -NH2, -NHR", -N(R")2, -SR", or -SO2R", wherein each instance of R" is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R" is independently unsubstituted C1-C3 alkyl. In some embodiments, alkenyl is unsubstituted. In some embodiments, alkenyl is substituted with (e.g., 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In some embodiments, alkenyl is substituted with an -OH group and may also be referred to herein as a "hydroxyalkenyl" group, where the prefix indicates an -OH group and "alkenyl" is as described herein.

[0101] As used herein, "alkenyl" also refers to a group ("C2-C 50 In some embodiments, an alkenyl group has 2 to 40 carbon atoms ("C2-C 40 In some embodiments, an alkenyl group has 2 to 30 carbon atoms ("C2-C 30 In some embodiments, an alkenyl group has 2 to 20 carbon atoms ("C2-C 20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-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 may be Examples of C2-C4 alkenyl groups include, but are not limited to, vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl groups include the above-mentioned C2-C4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents. In certain embodiments, an alkenyl group is an unsubstituted C2-C4 alkenyl group. 50 In certain embodiments, alkenyl is a substituted C2-C 50 Alkenyl.

[0102] Alkynyl: As used herein, "alkynyl" means a hydrocarbon chain in a straight or branched configuration having one or more carbon-carbon triple bonds occurring at any stable point along the chain, for example, "C2-C 30 "Alkynyl" refers to an alkynyl group having 2-30 carbon atoms. 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, the alkynyl group contains one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more substituent groups as described herein. For example, the alkynyl group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR", -CO2H, -CO2R", -CN, -OH, -OR", -OCOR", -OCO2R", -NH2, -NHR", -N(R")2, -SR", or -SO2R", wherein each instance of R" is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15Alkyl, C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In embodiments, R" is independently unsubstituted C1-C3 alkyl. In embodiments, alkynyl is unsubstituted. In embodiments, alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0103] As used herein, "alkynyl" also refers to a group ("C2-C 50 Alkynyl groups with one or more triple bonds and one or more double bonds are also known as "enynes." In some embodiments, the alkynyl group has 2 to 40 carbon atoms ("C2-C 40 In some embodiments, an alkynyl group has 2 to 30 carbon atoms ("C2-C 30 In some embodiments, an alkynyl group has 2 to 20 carbon atoms ("C2-C 20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2-C 10In some embodiments, an alkynyl group has 2 to 9 carbon atoms (a "C2-C9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (a "C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (a "C2-C7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (a "C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (a "C2-C5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (a "C2-C4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (a "C2-C3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms (a "C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). Examples of C2-C4 alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-C6 alkenyl include the above-mentioned C2-C4 alkynyl as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents. In certain embodiments, an alkynyl group is an unsubstituted C2-C4 alkynyl group. 50 In certain embodiments, the alkynyl group is a substituted C2-C 50 Alkynyl.

[0104] Aryl: The term "aryl" used alone or as part of a larger moiety (as in "aralkyl") refers to a monocyclic, bicyclic, or tricyclic carbon ring system having a total of six to fourteen ring members, wherein the ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic, and wherein each ring in the system contains 4 to 7 ring members. In embodiments, aryl has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, aryl has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Exemplary aryl groups include phenyl, naphthyl, and anthracene.

[0105] As used herein, "aryl" also refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in the cyclic array) ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms (a "C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (a "C 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl group") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6-C 14 In certain embodiments, aryl is a substituted C6-C 14 Aryl.

[0106] Arylene: As used herein, the term "arylene" refers to a divalent (ie, having two points of attachment to the molecule) aromatic group. Exemplary arylene groups include phenylene (eg, unsubstituted phenylene or substituted phenylene).

[0107] Carbocyclyl: As used herein, "carbocyclyl" or "carbocyclic" refers to a non-aromatic ring system having from 3 to 10 ring carbon atoms ("C3-C 10 In some embodiments, the carbocyclyl group has 3 to 8 carbon atoms (“C3-C8 carbocyclyl”). In some embodiments, the carbocyclyl group has 3 to 7 carbon atoms (“C3-C7 carbocyclyl”). In some embodiments, the carbocyclyl group has 3 to 6 carbon atoms (“C3-C6 carbocyclyl”). In some embodiments, the carbocyclyl group has 4 to 6 carbon atoms (“C4-C6 carbocyclyl”). In some embodiments, the carbocyclyl group has 5 to 6 carbon atoms (“C5-C6 carbocyclyl”). In some embodiments, the carbocyclyl group has 5 to 10 carbon atoms (“C5-C 10Carbocyclyl”). Exemplary C3-C6 carbocyclyls 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 carbocyclyls include, but are not limited to, the above-mentioned C3-C6 carbocyclyls as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), and the like. Exemplary C3-C 10 Carbocyclic groups include, but are not limited to, the aforementioned C3-C8 carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As shown in the foregoing examples, in certain embodiments, the carbocyclyl is a monocyclic ring ("monocyclic carbocyclyl") or a polycyclic ring (e.g., containing a fused, bridged, or spirocyclic ring system, such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")) and may be saturated or may contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the carbocyclic ring system. Unless otherwise stated, each instance of a carbocyclyl is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In certain embodiments, a carbocyclyl is an unsubstituted C3-C 10 In certain embodiments, the carbocyclyl group is a substituted C3-C 10 Carbocyclic group.

[0108] In some embodiments, "carbocyclyl" or "carbocyclic" is referred to as "cycloalkyl," i.e., a monocyclic saturated carbocyclyl having from 3 to 10 ring carbon atoms ("C3-C 10 In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms (“C3-C6, cycloalkyl”). In some embodiments, cycloalkyl groups have 4 to 6 ring carbon atoms (“C4-C6 cycloalkyl”). In some embodiments, cycloalkyl groups have 5 to 6 ring carbon atoms (“C5-C6 cycloalkyl”). In some embodiments, cycloalkyl groups have 5 to 10 ring carbon atoms (“C5-C 10Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the above-mentioned C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the above-mentioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of cycloalkyl is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted (“substituted cycloalkyl”) with one or more substituents. In certain embodiments, cycloalkyl groups are unsubstituted C3-C6 cycloalkyl groups. 10 In certain embodiments, the cycloalkyl group is a substituted C3-C 10 Cycloalkyl.

[0109] Halogen: As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0110] Assorted alkyl: the term "assorted alkyl" means a side chain or unbranched alkyl, alkenyl or alkynyl group having from 1 to 14 carbon atoms except that 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S and P. Assorted alkyl includes tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiester, phosphoramidates, sulfonamides and disulfides. Assorted alkyl can optionally include monocycles, dicycles or tricycles, wherein each ring desirably has three to six members. The example of assorted alkyl includes polyethers, such as methoxymethyl and ethoxyethyl.

[0111] Heteroalkylene: As used herein, the term "heteroalkylene" refers to a divalent form of a heteroalkyl group as described herein.

[0112] Heteroaryl: As used herein, the term "heteroaryl" is 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.

[0113] As used herein, "heteroaryl" also refers to a group 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 in common in the ring array) 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, wherein each heteroatom is 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 can be a carbon or nitrogen atom when valence permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent 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, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members continues to specify the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For polycyclic heteroaryls in which one ring contains no heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0114] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has one or more (e.g., one, two, or three) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heteroaryl group has one or two ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. Unless otherwise stated, each example of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0115] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, aza Oxalic acid thia Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0116] As used herein, "heterocyclyl" or "heterocyclic" refers to 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, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("3-14 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom when valence permits. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged, or spirocyclic ring system, such as a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl")), and may be saturated or may contain one or more carbon-carbon double bonds or carbon-carbon triple bonds. A heterocyclyl polycyclic ring system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyls (wherein the point of attachment is on the carbocyclyl or heterocyclyl ring), or a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups (wherein the point of attachment is on the heterocyclyl ring), and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, each example of a heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In certain embodiments, a heterocyclyl is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, a heterocyclyl is a substituted 3-14 membered heterocyclyl.

[0117] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has one or more (e.g., one, two, or three) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heterocyclyl has one or two ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.

[0118] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thioalkyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclyls include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepine yl, 1,4,5,7-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.

[0119] Heterocycloalkyl: As used herein, the term "heterocycloalkyl" is 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. Heterocycloalkyl groups may be substituted or unsubstituted.

[0120] As will be appreciated from the foregoing, in certain embodiments, the alkyl, alkenyl, alkynyl, acyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted. Optionally substituted refers to groups that may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Typically, the term "substituted" means that at least one hydrogen present on a group is replaced by a permissible substituent, e.g., a substituent that produces a stable compound upon substitution, e.g., does not spontaneously undergo a reaction such as by a conventional reaction. The term "substituted" refers to a group that is a compound that undergoes a transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise stated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. It is contemplated that the term "substituted" includes substitutions by all permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations to obtain stable compounds. For purposes of the present invention, heteroatoms such as nitrogen may have a hydrogen substituent and / or any suitable substituent as described herein that satisfies the valence of the heteroatoms and results in the formation of a stable moiety.

[0121] Exemplary carbon atom substituents include, but are not limited to, halogen, -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)R aa 、-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 Carbocyclic group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substitution; Or the two geminal hydrogens on the carbon atom are replaced by 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 Replacement;

[0122] R aa Each instance of is independently selected from C1-C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclic group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R ddgroup substitution;

[0123] R bb Each instance of is independently selected from hydrogen, -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 Carbocyclic group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, or two R bb The groups, together with the heteroatoms to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0124] R cc Each instance of is independently selected from hydrogen, C1-C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclic group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, or two R ccThe groups, together with the heteroatoms to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0125] R dd Each instance of is independently selected from 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(Ree )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 Carbocyclic group, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4, or 5 R gg Group substitution, or two geminal R dd Substituents may be linked to form =O or =S;

[0126] R ee Each instance of is independently selected from C1-C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclic, C6-C 10 Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4, or 5 R gg group substitution;

[0127] R ff Each instance of is independently selected from hydrogen, C1-C 50 Alkyl, C2-C 50 Alkenyl, C2-C 50 Alkynyl, C3-C 10 Carbocyclic group, 3-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, or two R ff The groups, together with the heteroatoms to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R gg group substitution; and

[0128] R ggEach instance of is independently 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-C 50 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 50alkyl), -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 50 alkyl), 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 Carbocyclic, C6-C 10 Aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X - It is a counter ion.

[0129] As used herein, the term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0130] As used herein, a "counter ion" is a negatively charged group that binds to a positively charged quaternary amine to maintain electrical neutrality. Exemplary counter ions include halide ions (e.g., F - 、Cl - Br - , I - )、NO3 - 、ClO4 - OH - 、H2PO4 -、HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0131] Where valence permits, the nitrogen atoms may be substituted or unsubstituted and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -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 Carbocyclic group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, or two R cc The groups, together with the nitrogen atom to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substituted, and wherein R aa 、R bb 、R ccand R dd As defined above.

[0132] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as 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, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, which is incorporated herein by reference.

[0133] For example, a nitrogen protecting group (such as an amide group (e.g., -C(=O)R aa )) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'dithiobenzyloxyamido)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0134] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzamidocarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethylcarbamate (Teoc), 2-phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1-(4-biphenyl)ethylcarbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethylcarbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethylcarbamate (Pyoc), 2-(N,N-dicyclohexylamido)ethylcarbamate, tert-butylcarbamate (BOC), 1-adamantylcarbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, 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-methylsulfonyl ethylcarbamate, 2-(p-toluenesulfonyl)ethylcarbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphinoethylcarbamate (Peoc), 2-triphenylphosphinoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-Dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, tert-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furylmethylcarbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinoyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-l-cyclopropylmethyl carbamate, 1-methyl-1(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0135] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2R aa ) include, but are not limited to, 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), 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 phenacylmethylsulfonamide.

[0136] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-toluenesulfonylaminoacyl derivatives, N'-phenylaminosulfonyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazide adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexanes, -2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, 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-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylimine, N-(5,5-dimethyl-3-oxo-1-cyclohexyl)imine

[0014] Examples of the present invention include, but are not limited to, 1,2-dinitrobenzophenone ...

[0137] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxy protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, which is incorporated herein by reference.

[0138] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 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-methylenebenzofuran-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-(phenyloxyseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 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'-dinitrodiphenylmethyl, 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(levulinyloxyphenyl)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-benzodithiofuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate , triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid acetal), pivalate, adamantate, 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 (P sec), 2-(triphenylphosphino)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-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 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, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphoramide, alkyl N-phenylcarbamate, borate, dimethylphosphinothioate, alkyl 2,4-dinitrophenylsulfinate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and toluenesulfonate (Ts).

[0139] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known as a thiol protecting group). Sulfur protecting groups are well known in the art and include those nitrogen protecting groups described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0140] Exemplary sulfur protecting groups include, but are not limited to, 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-quinolylmethyl, 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, tert-butyl, 1-adamantyl, methoxymethyl (MOM), isobutoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzylthiomethyl, phenylthiomethyl, thiazolidino, acetamidomethyl, trimethylacetamidomethyl, benzamidomethyl, allyloxycarbonylaminomethyl 1-nitrophenyl-2-benzoyl) ethyl, 2-phenylsulfonylethyl, 2-(4-methylphenylsulfonyl)-2-methylpropane-2-yl) thiazolinyl, 2-(2,4-dinitrophenyl)ethyl, 2-cyanoethyl, 2-(trimethylsilyl)ethyl, 2,2-bis(carboethoxy)ethyl, (1-m-nitrophenyl-2-benzoyl) ... -yl, acetyl, benzoyl, trifluoroacetyl, N-[[(p-biphenyl)isopropoxy]carbonyl]-N-methyl]-γ-aminothiobutyrate, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, N-ethyl, N-methoxymethyl, sulfonate, thiothiocarbonate, 3-nitro-2-pyridylthiothiosulfide, oxathiolone. Compounds of the present invention

[0141] Liposome-based vehicles are considered to be attractive carriers for therapeutic agents, and are still subject to sustained development efforts. Although the liposome-based vehicles comprising some lipid components have shown promising results in terms of encapsulation, stability and site location, there is still a great need to improve the delivery system based on liposomes. For example, the significant shortcoming of liposome delivery systems relates to the structure of liposomes with enough cell cultures or in vivo stability to arrive at desired target cells and / or intracellular compartments, and the ability of such liposome delivery systems to effectively release the material encapsulated therein to such target cells.

[0142] In particular, there remains a need for improved lipid compounds that exhibit improved pharmacokinetic properties and that are capable of delivering macromolecules such as nucleic acids to a variety of cell types and tissues with enhanced efficiency. Importantly, there remains a particular need for novel lipid compounds characterized by improved safety and the ability to effectively deliver encapsulated nucleic acids and polynucleotides to target cells, tissues, and organs.

[0143] A novel cationic lipid compound is described herein for the improved in vivo delivery of therapeutic agents (such as nucleic acids). In particular, cationic lipids as described herein can optionally be used together with other lipids to prepare lipid-based nanoparticles (such as liposomes), which are for therapeutic purposes such as disease treatment and prevention (vaccine) purposes, for encapsulating therapeutic agents such as nucleic acids (such as, DNA, siRNA, mRNA, MicroRNA).

[0144] In an embodiment, the compounds of the present invention as described herein can provide one or more desired features or characteristics. That is, in certain embodiments, the compounds of the present invention as described herein can be characterized as having one or more characteristics, so that such compounds have advantages relative to other similarly classified lipids. For example, the compounds disclosed herein can be used to control and adjust the characteristics of the liposome compositions (e.g., lipid nanoparticles) of which they are components. In particular, the characteristics of the compounds disclosed herein can be enhanced transfection efficiency and the ability to stimulate specific biological results thereof. Such results can include, for example, enhanced cellular uptake, endosome / lysosome destruction ability and / or promote encapsulation materials (e.g., polynucleotides) to be released within the cell. In addition, the compounds disclosed herein have favorable pharmacokinetic properties, biodistribution and efficiency.

[0145] This application demonstrates that the cationic lipids of the present invention are synthetically processed from readily available starting materials.

[0146] In addition, cationic lipids of the present invention have cleavable groups, such as ester groups, amide groups and disulfides. These cleavable groups (such as esters, amides and disulfides) are envisioned to improve biodegradability and thereby contribute to the favourable safety profile of lipids.

[0147] Provided herein are compounds that are cationic lipids. For example, cationic lipids of the present invention include compounds having a structure according to formula (I): or a pharmaceutically acceptable salt thereof, wherein A is selected from -N(R 1 )- or -SS-; R 1 is optionally substituted (C1-C6)alkyl; a and c are each independently an integer selected from 1, 2, 3 or 4; b and d are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Z 1 Selected from covalent bonds, or -SS-, where the left side of each depicted structure is connected to -(CH2) b - combine; Z 2 Selected from covalent bonds, or -SS-, where the right side of each depicted structure is connected to -(CH2) d - combine; Each Y 1 independently selected from hydrogen or -OH; Each R 8 independently selected from hydrogen or optionally substituted (C1-C6)alkyl; R 2A 、R 2B 、R 2C and R 2D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connect.

[0148] In embodiments, the cationic lipids of the present invention include compounds having formula (I), wherein A is -N(R 1 In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IA): or a pharmaceutically acceptable salt thereof.

[0149] In embodiments, the cationic lipids of the present invention include compounds having formula (I), wherein A is -N(R 1 )-and Y 1 In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IA1): or a pharmaceutically acceptable salt thereof.

[0150] In embodiments, the cationic lipids of the present invention include compounds having formula (I), wherein A is -N(R 1 )-,Y 1 is OH, and Z 1 and Z 2 In an embodiment, the cationic lipids of the present invention include compounds having formula (I), wherein A is -N(R 1 )-,Y 1 It's OH, Z 1 yes The left side of the structure depicted is with -(CH2) b - Combined, and Z 2 yes The right side of the structure depicted is with -(CH2) d In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IA1i): or a pharmaceutically acceptable salt thereof.

[0151] In embodiments, the cationic lipids of the present invention include compounds having formula (I), wherein A is -N(R 1 )-,Y 1 is OH, a=1, c=1, and Z 1 and Z2 In an embodiment, the cationic lipids of the present invention include compounds having formula (I), wherein A is -N(R 1 )-,Y 1 is OH, a=1, c=1, Z 1 yes The left side of the structure depicted is with -(CH2) b - Combined, and Z 2 yes The right side of the structure depicted is with -(CH2) d -binding. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IA1ia): or a pharmaceutically acceptable salt thereof.

[0152] In embodiments, the cationic lipids of the present invention include compounds having formula (I), wherein A = -N(R 1 )-and Y 1 =H. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IA2): or a pharmaceutically acceptable salt thereof.

[0153] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (IB): or a pharmaceutically acceptable salt thereof.

[0154] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (IC): or a pharmaceutically acceptable salt thereof.

[0155] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (ID): or a pharmaceutically acceptable salt thereof.

[0156] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IE): or a pharmaceutically acceptable salt thereof.

[0157] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (IA1ii): or a pharmaceutically acceptable salt thereof.

[0158] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IA1iia): or a pharmaceutically acceptable salt thereof.

[0159] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (IA1iii): or a pharmaceutically acceptable salt thereof.

[0160] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (IA1iiia): or a pharmaceutically acceptable salt thereof.

[0161] In an embodiment, A is -N(R 1 )-. In an embodiment, R 1 is (C1-C6) alkyl. In the embodiment, R 1 In an embodiment, R 1 is (C1-C6)alkylene-R A , where R A Selected from -OH, -N(R 6 )(R 7 ),or where R 6 and R 7 Each is independently selected from optionally substituted (C1-C6) alkyl. A In the embodiment, R A Yes-N(R 6 )(R 7 ). In an embodiment, R A yes In an embodiment, R 6 and R 7 In an embodiment, A is -SS-.

[0162] In embodiments, a is 1 or 2, preferably wherein the cationic lipid has a structure according to any one of Formula (IA), Formula (IA1), or Formula (IA2). In embodiments, a is 1, preferably wherein the cationic lipid has a structure according to (i) Formula (IB) or (ii) Formula (IA1ii) or Formula (IA1iii). In embodiments, a is 2, preferably wherein 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.

[0163] In embodiments, b is 2, 3 or 4, preferably wherein the cationic lipid has a structure according to any one of Formula (IA), (IA1), or (IA2). In embodiments, b is 3 or 4, preferably wherein the cationic lipid has a structure according to (i) Formula (IA1ia) or (ii) Formula (IA1ii), (IA1iia), (IA1iii), or (IA1iiia). In embodiments, b is 3, preferably wherein the cationic lipid has a structure according to any one of Formula (IB), (ID), or (IE). In embodiments, b is 4, preferably wherein 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.

[0164] In embodiments, c is 1 or 2, preferably wherein the cationic lipid has a structure according to any one of Formula (IA), (IA1), or (IA2). In embodiments, c is 1, preferably wherein the cationic lipid has a structure according to (i) Formula (IB) or (ii) Formula (IA1ii) or (IA1iii). In embodiments, c is 2, preferably wherein the cationic lipid has a structure according to any one of Formula (IC), (ID), or (IE). In embodiments, c is 3. In embodiments, c is 4.

[0165] In embodiments, d is 2, 3 or 4, preferably wherein the cationic lipid has a structure according to any one of Formula (IA), (IA1), or (IA2). In embodiments, d is 3 or 4, preferably wherein the cationic lipid has a structure according to (i) Formula (IA1ia) or (ii) Formula (IA1ii), (IA1iia), (IA1iii), or (IA1iiia). In embodiments, d is 3, preferably wherein the cationic lipid has a structure according to any one of Formula (IB), (ID), or (IE). In embodiments, d is 4, preferably wherein 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.

[0166] In an embodiment, Z 1 is a covalent bond. In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b -combined. In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b -combined. In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b -combined. In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b -combined. In an embodiment, Z 1 It's -SS-.

[0167] In an embodiment, Z 2 is a covalent bond. In an embodiment, Z 2 yes The right side of the structure depicted is with -(CH2) d -combined. In an embodiment, Z 2 yes The right side of the structure depicted is with -(CH2) d -combined. In an embodiment, Z 2 yes The right side of the structure depicted is with -(CH2) d -combined. In an embodiment, Z 2 yes The right side of the structure depicted is with -(CH2) d -combined. In an embodiment, Z 2 It's -SS-.

[0168] In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b - Combined, and Z 2 is -SS-, preferably wherein the cationic lipid has a structure according to any one of Formula (IA) or Formula (IA1).

[0169] In an embodiment, Z 1 and Z 2 Both are -SS-, preferably wherein the cationic lipid has a structure according to either Formula (IA) or Formula (IA1).

[0170] In an embodiment, Z 1 and Z 2Both are covalent bonds, preferably wherein the cationic lipid has a structure according to any one of Formula (IA), Formula (IA1) or Formula (IA2).

[0171] In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b - Combined, and Z 2 yes The right side of the structure depicted is with -(CH2) d - conjugation, preferably wherein the cationic lipid has a structure according to any one of Formula (IA), Formula (IA1), Formula (IA2), Formula (IC) or Formula (ID).

[0172] In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b - Combined, and Z 2 yes The right side of the structure depicted is with -(CH2) d - conjugation, preferably wherein the cationic lipid has a structure according to any one of Formula (IA2), Formula (IB) or Formula (IE).

[0173] In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b - Combined, and Z 2 yes The right side of the structure depicted is with -(CH2) d - conjugation, preferably wherein the cationic lipid has a structure according to any one of formula (IA) or formula (IA1).

[0174] In an embodiment, Z 1 yes The left side of the structure depicted is with -(CH2) b - Combined, and Z 2 yes The right side of the structure depicted is with -(CH2) d - conjugation, preferably wherein the cationic lipid has a structure according to any one of formula (IA) or formula (IA1).

[0175] In an embodiment, at least one Y 1 In an embodiment, at least one Y 1 is hydrogen. In an embodiment, Y 1 In the embodiment, Y 1 It's hydrogen.

[0176] In an embodiment, each R 8 is hydrogen. In an embodiment, each R 8 is optionally substituted (C1-C6)alkyl. In an embodiment, each R 8 In an embodiment, each R 8 It's methyl.

[0177] In an embodiment, R 2A is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 2A is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 2A is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 2A is optionally substituted (C6-C 12 )alkyl.

[0178] In an embodiment, R 2A is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 2A is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 2A is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 2A is optionally substituted (C 15 -C 20 ) alkenyl.

[0179] In an embodiment, R 2A Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1)-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connect.

[0180] In an embodiment, R 2B is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 2B is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 2B is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 2B is optionally substituted (C6-C 12 )alkyl.

[0181] In an embodiment, R 2B is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 2B is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 2B is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 2B is optionally substituted (C 15 -C 20 ) alkenyl.

[0182] In an embodiment, R 2B Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connect.

[0183] In an embodiment, R 2C is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 2C is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 2C is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 2C is optionally substituted (C6-C 12 )alkyl.

[0184] In an embodiment, R 2C is optionally substituted (C5-C25 ) alkenyl. In an embodiment, R 2C is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 2C is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 2C is optionally substituted (C 15 -C 20 ) alkenyl.

[0185] In an embodiment, R 2C Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1)-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20)alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y1 )-connect.

[0186] In an embodiment, R 2D is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 2D is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 2D is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 2D is optionally substituted (C6-C 12 )alkyl.

[0187] In an embodiment, R 2D is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 2D is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 2D is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 2D is optionally substituted (C 15 -C 20 ) alkenyl.

[0188] In an embodiment, R 2D Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connect.

[0189] In an embodiment, R 2A 、R 2B 、R 2C and R 2D Each independently selected from: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) Preferably, R 2A 、R 2B 、R 2C and R 2D Each is independently selected from option (ii), (iii), (iv), (v), (vi), (viii), (ix), (x), (xi), (xii), (xiii) or (xiv).

[0190] In an embodiment, R 2A 、R 2B 、R 2C and R 2D Each independently selected from: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) (xiv) (xv) (xvi) or (xvii) Preferably, R 2A 、R 2B 、R 2C and R 2D Each is independently selected from option (ii), (iii), (iv), (v), (vi), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi) or (xvii).

[0191] In an embodiment, R 2A 、R 2B 、R 2C and R 2D In the embodiment, R 2A and R 2B are the same and R 2C and R 2D In the embodiment, R 2A and R 2C are the same and R 2B and R 2D In the embodiment, R2A and R 2C are the same and R 2B and R 2D are different.

[0192] Cationic lipids of the present invention also include compounds having a structure according to formula (II): or a pharmaceutically acceptable salt thereof, where 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 each independently an integer selected from 0, 1, 2, 3, or 4; f and h are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Each Y 2 independently selected from hydrogen or -OH; R 5A 、R 5B 、R 5C and R 5D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connect.

[0193] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (IIA): or a pharmaceutically acceptable salt thereof.

[0194] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH. In embodiments, the cationic lipids of the present invention include compounds having a structure according to Formula (IIA1): or a pharmaceutically acceptable salt thereof.

[0195] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 3 = hydrogen, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 4 = hydrogen, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 3 and R 4 = hydrogen, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IIA1i): or a pharmaceutically acceptable salt thereof.

[0196] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 = hydrogen. In embodiments, the cationic lipids of the present invention include compounds having a structure according to Formula (IIA2): or a pharmaceutically acceptable salt thereof.

[0197] In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein R 3 =H. In embodiments, the cationic lipids of the present invention include compounds having a structure according to Formula (IIB): or a pharmaceutically acceptable salt thereof, wherein R 4is selected from (C1-C6) alkyl, phenyl or benzyl. 4 is selected from methyl, isopropyl, phenyl or benzyl. 4 In an embodiment, R 4 is isopropyl. In an embodiment, R 4 In an embodiment, R 4 It's benzyl.

[0198] In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein R 3 = methyl. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IIC): or a pharmaceutically acceptable salt thereof, wherein R 4 In an embodiment, R 4 In an embodiment, R 4 In an embodiment, R 4 It's ethyl.

[0199] In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein R 4 =OH. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein R 3 = methyl and R 4 =OH. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IIC1): or a pharmaceutically acceptable salt thereof.

[0200] In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein e=1 and g=1. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein R 3 = methyl, e = 1 and g = 1. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein R 4 =OH, e=1 and g=1. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein R 3 = methyl, R 4 =OH, e=1 and g=1. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IIC1i): or a pharmaceutically acceptable salt thereof.

[0201] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH and R 3 = hydrogen. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH and R 4 =OH. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 3 = hydrogen and R 4 =OH. In embodiments, the cationic lipids of the present invention include compounds having a structure according to Formula (IID): or a pharmaceutically acceptable salt thereof.

[0202] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 3 = hydrogen, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 4 =OH, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 3 =Hydrogen, R 4 =OH, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IID1): or a pharmaceutically acceptable salt thereof.

[0203] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH and R 3 = hydrogen. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH and R 4 =NH2. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 3 = hydrogen and R 4=NH2. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IIE): or a pharmaceutically acceptable salt thereof.

[0204] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 3 = hydrogen, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 4 =NH2, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (II), wherein Y 2 =OH, R 3 =Hydrogen, R 4 =NH2, and e and g = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IIE1): or a pharmaceutically acceptable salt thereof.

[0205] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IIC1ii): or a pharmaceutically acceptable salt thereof.

[0206] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IIC2): or a pharmaceutically acceptable salt thereof.

[0207] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IIC2i): or a pharmaceutically acceptable salt thereof.

[0208] In an embodiment, R 3 is hydrogen. In an embodiment, R 3 is optionally substituted (C1-C6)alkyl. 3 It's methyl.

[0209] In an embodiment, R 4is selected from hydrogen, -OH, -NH2, optionally substituted (C1-C6) alkyl, optionally substituted phenyl, or optionally substituted (C1-C3) alkylene-optionally substituted phenyl. 4 is hydrogen. In an embodiment, R 4 In the embodiment, R 4 is -NH2. In an embodiment, R 4 is an optionally substituted (C1-C6)alkyl. 4 In an embodiment, R 4 In an embodiment, R 4 is isopropyl. In an embodiment, R 4 is an optionally substituted aryl group. In an embodiment, R 4 is an optionally substituted phenyl group. In an embodiment, R 4 In an embodiment, R 4 is optionally substituted (C1-C3)alkylene-optionally substituted aryl. 4 is optionally substituted (C1-C3)alkylene-optionally substituted phenyl. 4 is an optionally substituted benzyl group. In an embodiment, R 4 In an embodiment, R 4 is an optionally substituted heteroaryl. In an embodiment, R 4 is optionally substituted (C1-C3)alkylene-optionally substituted heteroaryl.

[0210] In embodiments, e is 0, 1 or 2, preferably wherein the cationic lipid has a structure according to any one of Formula (IIA), (IIA1) or (IIB). In embodiments, e is 1, preferably wherein the cationic lipid has a structure according to any one of Formula (IIA2) or (IIC). In embodiments, e is 0, preferably wherein the cationic lipid has a structure according to any one of (i) Formula (IIA1i), (IID), or (IIE), or (ii) Formula (IIC1), (IIC2) or (IIE). In embodiments, e=2. In embodiments, e=3. In embodiments, e=4. In embodiments, f is 3, 4, 5 or 6, preferably wherein the cationic lipid has a structure according to Formula (IIC1i). In embodiments, f is 3, 4 or 5, preferably wherein the cationic lipid has a structure according to Formula (IIA1i). In embodiments, f=3 or 4, preferably wherein the cationic lipid has a structure according to Formula (IID1). In embodiments, f is 3, preferably wherein 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, preferably wherein 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 embodiments, f=5. In embodiments, f=6.

[0211] In embodiments, g is 0 or 1, preferably wherein the cationic lipid has a structure according to any one of Formula (IIA) (IIA1) or (IIB) (IIB). In embodiments, g is 0, preferably wherein 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, preferably wherein the cationic lipid has a structure according to Formula (IIC). In embodiments, g is 2. In embodiments, g is 3. In embodiments, g is 4.

[0212] In embodiments, h is 3, 4, 5 or 6, preferably wherein the cationic lipid has a structure according to Formula (IIC1i). In embodiments, h is 3, 4 or 5, preferably wherein the cationic lipid has a structure according to Formula (IIA1i). In embodiments, h is 3 or 4, preferably wherein the cationic lipid has a structure according to Formula (IID1). In embodiments, h is 3, preferably wherein 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, wherein h is 4, preferably wherein 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.

[0213] In an embodiment, at least one Y 2 In an embodiment, at least one Y2 is hydrogen. In an embodiment, Y 2 In the embodiment, Y 2 It's hydrogen.

[0214] In an embodiment, R 5A is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 5A is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 5A is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 5A is optionally substituted (C6-C 12 )alkyl.

[0215] In an embodiment, R 5A is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 5A is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 5A is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 5A is optionally substituted (C 15 -C 20 ) alkenyl.

[0216] In an embodiment, R 5A Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connect.

[0217] In an embodiment, R 5B is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 5B is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 5B is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 5B is optionally substituted (C6-C 12 )alkyl.

[0218] In an embodiment, R 5B is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 5B is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 5B is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 5B is optionally substituted (C 15 -C 20 ) alkenyl.

[0219] In an embodiment, R 5B Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connect.

[0220] In an embodiment, R 5C is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 5C is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 5C is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 5C is optionally substituted (C6-C 12 )alkyl.

[0221] In an embodiment, R 5C is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 5C is optionally substituted (C5-C 20) alkenyl. In an embodiment, R 5C is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 5C is optionally substituted (C 15 -C 20 ) alkenyl.

[0222] In an embodiment, R 5C Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18)alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connect.

[0223] In an embodiment, R 5Dis optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 5D is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 5D is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 5D is optionally substituted (C6-C 12 )alkyl.

[0224] In an embodiment, R 5D is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 5D is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 5D is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 5D is optionally substituted (C 15 -C 20 ) alkenyl.

[0225] In an embodiment, R 5D Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connect.

[0226] In an embodiment, R 5A 、R 5B 、R 5C and R 5D Each independently selected from: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) or (xiv) Preferably, R 5A 、R 5B 、R 5C and R 5D Each is independently selected from option (i), (ii), (iii), (vii), (viii), (xi) or (xiv).

[0227] In an embodiment, R 5A 、R 5B 、R 5C and R 5D Each independently selected from: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) or (xiv) (xv) (xvi) or (xvii) Preferably, R 5A 、R 5B 、R 5C and R 5D Each is independently selected from option (i), (ii), (iii), (vii), (viii), (xi) or (xiv).

[0228] In an embodiment, R 5A 、R 5B 、R 5C and R 5D In the embodiment, R 5A and R 5B are the same and R 5C and R 5D In the embodiment, R 5A and R 5C are the same and R 5B and R 5D are the same.

[0229] Cationic lipids of the present invention also include compounds having a structure according to formula (III): or a pharmaceutically acceptable salt thereof, where R 9is 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 each independently an integer selected from 0, 1, 2, 3, or 4; j and l are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Each Y 3 independently selected from hydrogen or -OH; Each R 12 independently selected from hydrogen or optionally substituted (C1-C6)alkyl; R 11A 、R 11B 、R 11C and R 11D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connect.

[0230] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (III), wherein Y 3 =OH. In embodiments, the cationic lipids of the present invention include compounds having a structure according to formula (IIIA): or a pharmaceutically acceptable salt thereof.

[0231] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (III), wherein Y 3 =OH, R 9 = methyl, and i and k = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (III), wherein Y 3 =OH, R 10 =OH, and i and k = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (III), wherein Y 3 =OH, R 9 = methyl, R 10 =OH, and i and k = 0. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IIIA1): or a pharmaceutically acceptable salt thereof.

[0232] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (IIIB): or a pharmaceutically acceptable salt thereof.

[0233] In embodiments, cationic lipids of the present invention include compounds having a structure according to Formula (IIIB1): or a pharmaceutically acceptable salt thereof.

[0234] In an embodiment, R 9 is hydrogen. In an embodiment, R 9 is optionally substituted (C1-C6)alkyl. 9 It's methyl.

[0235] In an embodiment, R 10 is hydrogen. In an embodiment, R 10 In the embodiment, R 10 is -NH2. In an embodiment, R 10 is optionally substituted (C1-C6)alkyl. 10 In an embodiment, R 10 In an embodiment, R 10 is isopropyl. In an embodiment, R 10 is an optionally substituted aryl group. In an embodiment, R 10 is an optionally substituted phenyl group. In an embodiment, R10 In an embodiment, R 10 is optionally substituted (C1-C3)alkylene-optionally substituted aryl. 10 is optionally substituted (C1-C3)alkylene-optionally substituted phenyl. 10 is an optionally substituted benzyl group. In an embodiment, R 10 In an embodiment, R 10 is an optionally substituted heteroaryl. In an embodiment, R 10 is optionally substituted (C1-C3)alkylene-optionally substituted heteroaryl.

[0236] In an embodiment, i is 0. In an embodiment, i is 1. In an embodiment, i is 2. In an embodiment, i is 3. In an embodiment, i is 4.

[0237] In embodiments, j is 3 or 4. In embodiments, j is 1. In embodiments, j is 2. In embodiments, j is 3, preferably wherein 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.

[0238] In an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2. In an embodiment, k is 3. In an embodiment, k is 4.

[0239] In embodiments, l is 3 or 4. In embodiments, l is 1. In embodiments, l is 2. In embodiments, l is 3, preferably wherein 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.

[0240] In an embodiment, at least one Y 3 In an embodiment, at least one Y 3 is hydrogen. In an embodiment, Y 3 In the embodiment, Y 3 It's hydrogen.

[0241] In an embodiment, each R 12 is hydrogen. In an embodiment, each R 12 is optionally substituted (C1-C6)alkyl. In an embodiment, each R 12 It's methyl.

[0242] In an embodiment, R 11A is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R11A is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 11A is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 11A is optionally substituted (C6-C 12 ) alkyl. In an embodiment, R 11A is optionally substituted (C8-C 10 )alkyl.

[0243] In an embodiment, R 11A is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 11A is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 11A is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 11A is optionally substituted (C 15 -C 20 ) alkenyl.

[0244] In an embodiment, R 11A Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connect.

[0245] In an embodiment, R 11B is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 11B is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 11B is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 11B is optionally substituted (C6-C 12 ) alkyl. In an embodiment, R 11B is optionally substituted (C8-C 10 )alkyl.

[0246] In an embodiment, R 11B is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 11B is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 11B is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 11B is optionally substituted (C 15 -C 20 ) alkenyl.

[0247] In an embodiment, R 11B Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3)-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connect.

[0248] In an embodiment, R 11C is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 11C is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 11C is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 11C is optionally substituted (C6-C 12 ) alkyl. In an embodiment, R 11C is optionally substituted (C8-C 10 )alkyl.

[0249] In an embodiment, R 11C is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 11C is optionally substituted (C5-C20 ) alkenyl. In an embodiment, R 11C is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 11C is optionally substituted (C 15 -C 20 ) alkenyl.

[0250] In an embodiment, R 11C Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connect.

[0251] In an embodiment, R11D is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 11D is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 11D is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 11D is optionally substituted (C6-C 12 ) alkyl. In an embodiment, R 11D is optionally substituted (C8-C 10 )alkyl.

[0252] In an embodiment, R 11D is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 11D is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 11D is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 11D is optionally substituted (C 15 -C 20 ) alkenyl.

[0253] In an embodiment, R 11D Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connect.

[0254] In an embodiment, R 11A 、R 11B 、R 11C and R 11D Each independently selected from: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) or (xiv) Preferably, R 11A 、R 11B 、R 11C and R 11D Each independently selected from option (ii) or (iii).

[0255] In an embodiment, R 11A 、R 11B 、R 11C and R 11DEach independently selected from: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) (xiv) (xv) (xvi) or (xvii) Preferably, R 11A 、R 11B 、R 11C and R 11D Each is independently selected from option (ii), (iii), (viii), (xi), (xiv), (xv), (xvi) or (xvii).

[0256] In an embodiment, R 11A 、R 11B 、R 11C and R 11D In the embodiment, R 11A and R 11C are the same and R 11B and R 11D In the embodiment, R 11A and R 11C are the same and R 11B and R 11D are different.

[0257] Cationic lipids of the present invention also include compounds having a structure according to formula (IV): or a pharmaceutically acceptable salt thereof, in m and n are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Z 3 is an aromatic amino acid residue in which the α-carbon carboxyl group (-C(O)O-) of the aromatic amino acid residue is in a state of contact with the -(CH2) m - combined, and the α-carbonyl group (-NH-) of the aromatic amino acid residue is combined with Z 4 Combine; Z 4 Selected from The right side of each depicted structure is connected with -(CH2) n - combine; Each Y 4 independently selected from hydrogen or -OH; R 13A 、R 13B 、R 13C and R 13D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connect.

[0258] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to formula (IV), wherein Y 4 =OH. In embodiments, the cationic lipids of the present invention include compounds having a structure according to Formula (IVA): where R 14is an optionally substituted (C1-C6)-alkylene-R 15 ;as well as R 15 Selected from optionally substituted aryl or optionally substituted heteroaryl or a pharmaceutically acceptable salt thereof.

[0259] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IVA), wherein Y 4 =OH. In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IVA1): where R 14 is an optionally substituted (C1-C6)-alkylene-R 15 ;as well as R 15 Selected from optionally substituted aryl or optionally substituted heteroaryl or a pharmaceutically acceptable salt thereof.

[0260] In an embodiment, the cationic lipids of the present invention include compounds having a structure according to Formula (IVA2): or a pharmaceutically acceptable salt thereof where R 14 is an optionally substituted (C1-C6)-alkylene-R 15 ;as well as R 15 is selected from optionally substituted aryl or optionally substituted heteroaryl.

[0261] In an embodiment, m is 1. In an embodiment, m is 2. In an embodiment, m is 3. In an embodiment, m is 4. In an embodiment, m is 5. In an embodiment, m is 6.

[0262] In an embodiment, n is 4 or 5. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4. In an embodiment, n is 5. In an embodiment, n is 6.

[0263] In an embodiment, Z 4 yes The right side of the structure depicted is with -(CH2) n -combined. In an embodiment, Z 4 yes The right side of the structure depicted is with -(CH2) n -Combination.

[0264] In an embodiment, at least one Y 4 In an embodiment, at least one Y 4 is hydrogen. In an embodiment, Y 4 In the embodiment, Y 4 It's hydrogen.

[0265] In an embodiment, R 14 is an optionally substituted (C1-C6)-alkylene-R 15 In an embodiment, R 15 is an optionally substituted aryl group. In an embodiment, R 15 is optionally substituted heteroaryl.

[0266] In an embodiment, R 14 is -(CH2)- optionally substituted aryl. In an embodiment, R 14 is -(CH2)2- optionally substituted aryl. In an embodiment, R 14 is -(CH2)- optionally substituted heteroaryl. In an embodiment, R 14 is -(CH2)2- optionally substituted heteroaryl. In an embodiment, R 14 is -(CH2)- optionally substituted phenyl. In an embodiment, R 14 is -(CH2)2- optionally substituted phenyl. In an embodiment, R 14 is -(CH2)- optionally substituted imidazole. In an embodiment, R 14 is -(CH2)2- optionally substituted imidazole. In an embodiment, R 14 is -(CH2)- optionally substituted indolyl. In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes In an embodiment, R 14 yes

[0267] In an embodiment, R 13A is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 13A is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 13A is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 13A is optionally substituted (C6-C 12 ) alkyl. In an embodiment, R 13A is optionally substituted (C8-C 10 )alkyl.

[0268] In an embodiment, R 13A is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 13A is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 13A is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 13A is optionally substituted (C 15 -C 20 ) alkenyl.

[0269] In an embodiment, R 13A Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25)alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4)-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connect.

[0270] In an embodiment, R 13B is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 13B is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 13B is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 13B is optionally substituted (C6-C 12 ) alkyl. In an embodiment, R 13B is optionally substituted (C8-C 10 )alkyl.

[0271] In an embodiment, R 13B is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 13B is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 13B is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 13B is optionally substituted (C 15 -C 20 ) alkenyl.

[0272] In an embodiment, R 13B Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connect.

[0273] In an embodiment, R 13C is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 13C is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 13C is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 13C is optionally substituted (C6-C 12 ) alkyl. In an embodiment, R 13C is optionally substituted (C8-C 10 )alkyl.

[0274] In an embodiment, R13C is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 13C is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 13C is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 13C is optionally substituted (C 15 -C 20 ) alkenyl.

[0275] In an embodiment, R 13C Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connect.

[0276] In an embodiment, R 13D is optionally substituted (C5-C 25 ) alkyl. In an embodiment, R 13D is optionally substituted (C5-C 20 ) alkyl. In an embodiment, R 13D is optionally substituted (C5-C 15 ) alkyl. In an embodiment, R 13D is optionally substituted (C6-C 12 ) alkyl. In an embodiment, R 13D is optionally substituted (C8-C 10 )alkyl.

[0277] In an embodiment, R 13D is optionally substituted (C5-C 25 ) alkenyl. In an embodiment, R 13D is optionally substituted (C5-C 20 ) alkenyl. In an embodiment, R 13D is optionally substituted (C 10 -C 20 ) alkenyl. In an embodiment, R 13D is optionally substituted (C 15 -C 20 ) alkenyl.

[0278] In an embodiment, R 13D Yes-W 1 -X 1 In an embodiment, W 1 is a covalent bond. In an embodiment, W 1 is optionally substituted (C1-C 10 ) alkylene. In an embodiment, W 1 is an optionally substituted (C1-C8)alkylene. 1 is an optionally substituted (C1-C6)alkylene. 1 is an optionally substituted (C1-C5)alkylene. 1 is optionally substituted (C2-C 10 ) alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C8)alkenylene. In an embodiment, W 1 is an optionally substituted (C2-C6)alkenylene. In an embodiment, W 1is an optionally substituted (C2-C5)alkenylene. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 20) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -(*C=O)-O- optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 18 )alkyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 25 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C3-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4)-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C5-C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 20 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connected. In an embodiment, X 1 is -*O-(C=O)-optionally substituted (C 10 -C 18 ) alkenyl, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connect.

[0279] In an embodiment, R 13A 、R 13B 、R 13C and R 13D Each independently selected from: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) or (xiv) Preferably, R 13A 、R 13B 、R 13C and R13D Each is option (ii).

[0280] In an embodiment, R 13A 、R 13B 、R 13C and R 13D Each independently selected from: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) (xiv) (xv) (xvi) or (xvii) Preferably, R 13A 、R 13B 、R 13C and R 13D Each is option (ii), (iii), (viii), (xi), (xiv) or (xv).

[0281] In an embodiment, R 13A 、R 13B 、R 13C and R 13D are the same.

[0282] In embodiments, W of any of the formulae defined herein is 1 -X 1 Each W in 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and W of any of the formulas defined herein 1 -X 1 Each X in 1 Independently selected from -(*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 (C3-C 25 ) branched alkyl, or -*O-(C=O)- optionally substituted (C3-C 25 ) a branched alkenyl group, wherein the atom marked with * is adjacent to W 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connect.

[0283] In embodiments, substituents are not optionally substituted.

[0284] In embodiments, the cationic lipid of the present invention has any one of the structures in Table A, or a pharmaceutically acceptable salt thereof.

[0285] In embodiments, the cationic lipid of the present invention has any one of the structures in Table B, or a pharmaceutically acceptable salt thereof.

[0286] In an embodiment, provided herein is a composition comprising a cationic lipid of the present invention, and further comprising: (i) one or more non-cationic lipids, (ii) one or more cholesterol-based lipids, and (iii) one or more PEG-modified lipids.

[0287] In an embodiment, the composition is a lipid nanoparticle, optionally a liposome. In an embodiment, the one or more cationic lipids constitute about 30mol%-60mol% of the lipid nanoparticle. In an embodiment, the one or more non-cationic lipids constitute 10mol%-50mol% of the lipid nanoparticle. In an embodiment, the one or more PEG-modified lipids constitute 1mol%-10mol% of the lipid nanoparticle. In an embodiment, cholesterol-based lipids constitute 10mol%-50mol% of the lipid nanoparticle.

[0288] In embodiments, the lipid nanoparticles encapsulate nucleic acids, optionally mRNA encoding 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 "percentage encapsulation" refers to the portion of the therapeutic agent (e.g., mRNA) effectively encapsulated within a liposome-based vehicle (e.g., lipid nanoparticle) relative to the initial portion of the therapeutic agent present in the lipid phase. In embodiments, the lipid nanoparticles have an encapsulation percentage for the mRNA of at least 50%. In embodiments, the lipid nanoparticles have an encapsulation percentage for the mRNA of at least 55%. In embodiments, the lipid nanoparticles have an encapsulation percentage for the mRNA of at least 60%. In embodiments, the lipid nanoparticles have an encapsulation percentage for the mRNA of at least 65%. In embodiments, the lipid nanoparticles have an encapsulation percentage for the mRNA of at least 70%. In embodiments, the lipid nanoparticles have an encapsulation percentage for the mRNA of at least 75%. In embodiments, the lipid nanoparticles have an encapsulation percentage for the mRNA of at least 80%. In embodiments, the lipid nanoparticles have an encapsulation percentage for the mRNA of at least 85%. In embodiments, the lipid nanoparticles have an mRNA encapsulation percentage of at least 90%. In embodiments, the lipid nanoparticles have an mRNA encapsulation percentage of at least 95%. In embodiments, the encapsulation percentage is calculated by performing a Ribogreen assay (Invitrogen) in the presence and absence of 0.1% Triton-X 100.

[0289] In an embodiment, the composition of the invention is for use in a vaccine.

[0290] In embodiments, the compositions of the invention are for use in therapy.

[0291] In embodiments, the compositions of the invention are for use in a method of treating or preventing a disease amenable to treatment or prevention by a peptide or protein encoded by an mRNA, optionally wherein the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lung, brain or muscle, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

[0292] In an embodiment, a method for treating or preventing a disease is provided, wherein the method comprises administering a composition of the invention to a subject in need thereof, and wherein the disease is amenable to treatment or prevention by a peptide or protein encoded by the mRNA, optionally wherein the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lung, brain or muscle, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

[0293] In embodiments, the composition is administered intranasally, intravenously, intrathecally, or intramuscularly, or by pulmonary delivery, optionally by aerosolization. In embodiments, the composition is administered intramuscularly. Exemplary compounds

[0294] In embodiments, the cationic lipids of the present invention include a compound selected from those depicted in Table A, or a pharmaceutically acceptable salt thereof.

[0295] Exemplary compounds include those described in Table A, or pharmaceutically acceptable salts thereof. Table A

[0296] Any of the compounds identified above in Table A may be provided in the form of a pharmaceutically acceptable salt, and such salts are intended to be encompassed by the present invention.

[0297] In embodiments, the cationic lipids of the present invention include a compound selected from those depicted in Table B, or a pharmaceutically acceptable salt thereof.

[0298] Exemplary compounds include those described in Table B, or pharmaceutically acceptable salts thereof. Table B

[0299] Any of the compounds identified above in Table B may be provided in the form of a pharmaceutically acceptable salt, and such salts are intended to be encompassed by the present invention.

[0300] The compounds of the invention as described herein can be prepared according to methods known in the art, including the exemplary syntheses of the examples provided herein. Nucleic Acids

[0301] The compounds of the invention as described herein can be used to prepare compositions for the delivery of nucleic acids. Nucleic acid synthesis

[0302] Nucleic acids according to the present invention can be synthesized according to any known method. For example, mRNA according to the present invention can be synthesized via in vitro transcription (IVT). Briefly, IVT is typically performed using a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that can include DTT and magnesium ions, and an appropriate RNA polymerase (e.g., T3, T7, a mutant T7, or SP6 RNA polymerase), DNase I, pyrophosphatase, and / or an RNase inhibitor. The exact conditions will vary depending on the specific application.

[0303] In certain embodiments, to prepare mRNA according to the present invention, the DNA template is transcribed in vitro. Suitable DNA templates typically have a promoter for in vitro transcription (e.g., T3, T7, mutated T7 or SP6 promoters), followed by the desired nucleotide sequence and termination signal for the desired mRNA.

[0304] Can use standard method to determine and be incorporated in the DNA template according to one or more required mRNA sequences of the present invention.For example, starting from required amino acid sequence (for example, enzyme sequence), carry out virtual reverse translation based on degenerate genetic code.Then can use optimization algorithm to select suitable codon.Typically, can optimize G / C content to realize G / C content as high as possible on the one hand, consider the frequency of tRNA according to the use of codon as much as possible on the other hand.Can set up and show the RNA sequence of optimization, for example, by suitable display device and compare with original (wild type) sequence.Can also analyze secondary structure and calculate stable and unstable characteristics, or calculate the zone of RNA respectively. Modified mRNA

[0305] In certain embodiments, mRNA according to the present invention can be synthesized as unmodified or modified mRNA. Modified mRNA includes nucleotide modifications in RNA. Therefore, modified mRNA according to the present invention can include nucleotide modifications, which are, for example, backbone modifications, sugar modifications, or base modifications. In some embodiments, mRNA can be 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 analogs or derivatives of modified nucleotide purines and pyrimidines, such as, for example, 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-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-cytosine, uracil, 4-thiouracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluorouracil, 5-bromouracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thiouracil, 5-methyl-uracil, N-uracil-5-oxyacetate methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thiouracil Pyrimidine, 5'-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 1-methyl-pseudouracil, queuosine, β-D-mannosyl-queuosine, wybutoxosine, and phosphoramidites, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine, and inosine. The preparation of such analogs is known to those skilled in the art, for example, from U.S. Pat. No. 4,373,071, U.S. Pat. No. 4,401,796, U.S. Pat. No. 4,415,732, U.S. Pat. No. 4,458,066, U.S. Pat. No. 4,500,707, U.S. Pat. No. 4,668,777, U.S. Pat. No. 4,973,679, U.S. Pat. No. 5,047,524, U.S. Pat. No. 5,132,418, U.S. Pat. No. 5,153,319, U.S. Pat. Nos. 5,262,530 and 5,700,642, the disclosures of which are incorporated by reference in their entireties. Pharmaceutical formulations of cationic lipids and nucleic acids

[0306] In certain embodiments, the compounds of the invention as described herein and drugs and liposome compositions comprising such lipids can be used in formulations to facilitate delivery of encapsulated material (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 compositions, such as liposome compositions comprising such lipids) are characterized by causing one or more of receptor-mediated endocytosis, clathrin-mediated and caveolae-mediated endocytosis, phagocytosis and macropinocytosis, fusogenicity, endosomal or lysosomal destruction, and / or releasable properties, which provide advantages of such compounds over other similarly classified lipids.

[0307] According to the present invention, nucleic acids, such as mRNA encoding a protein as described herein (eg, full length, fragments, or portions of the protein), can be delivered via a delivery vehicle comprising a compound of the invention as described herein.

[0308] As used herein, the terms "delivery vehicle," "transfer vehicle," "nanoparticle," or grammatical equivalents thereof are used interchangeably.

[0309] For example, the invention provides a composition (e.g., a pharmaceutical composition) comprising a compound as described herein and one or more polynucleotides. The composition (e.g., a pharmaceutical composition) 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.

[0310] In certain embodiments, compositions show enhanced (for example, increased) ability to transfect one or more target cells. Therefore, there is also provided herein a method for transfecting one or more target cells. Such methods generally include contacting the one or more target cells with cationic lipids and / or pharmaceutical compositions disclosed herein (for example, liposome formulations of compounds described herein comprising encapsulating one or more polynucleotides) so that the one or more target cells are transfected by the material (for example, one or more polynucleotides) encapsulated therein. As used herein, the term "transfection (transfect)" or "transfection (transfection)" refers to the intracellular introduction of one or more encapsulated materials (for example, nucleic acids and / or polynucleotides) into cells (for example, into target cells). The polynucleotides introduced can be stably or transiently maintained in target cells. The term "transfection efficiency" refers to the relative amount of such encapsulated materials (for example, polynucleotides) absorbed, introduced and / or expressed by the target cells being transfected. In fact, transfection efficiency can be estimated by the amount of the reporter polynucleotide products produced by target cells after transfection. In certain embodiments, the compounds and pharmaceutical compositions described herein exhibit high transfection efficiency, thereby increasing the likelihood that an appropriate dose of encapsulated material (e.g., one or more polynucleotides) can be delivered to the site of pathology and subsequently expressed while minimizing potential systemic adverse reactions or toxicities associated with the compound or its encapsulated contents.

[0311] After transfection of one or more target cells by, for example, a polynucleotide encapsulated in one or more lipid nanoparticles comprising a pharmaceutical or liposome composition disclosed herein, the production of a product (e.g., a polypeptide or protein) encoded by such a polynucleotide can be stimulated and the ability of such target cells to express the polynucleotide and produce, for example, a polypeptide or protein of interest can be enhanced. For example, transfection of a target cell by one or more compounds or pharmaceutical compositions encapsulating mRNA will enhance (i.e., increase) the production of a protein or enzyme encoded by such an mRNA.

[0312] In addition, delivery vehicles described herein (for example, liposome delivery vehicles) can be prepared to preferentially be distributed to other target tissues, cells or organs, such as heart, lung, kidney, spleen. In an embodiment, lipid nanoparticles of the present invention can be prepared to realize the delivery to the enhancement of target cells and tissues. For example, the polynucleotides (for example, mRNA) encapsulated in one or more of compound described herein or medicine and liposome compositions can be delivered to target cells or tissues and / or transfected target cells or tissues. In certain embodiments, the polynucleotides (for example, mRNA) of encapsulation can be expressed by target cells and produce (and in some cases drain) functional polypeptide products, thereby giving the useful characteristic of for example target cells or tissues. The polynucleotides (for example, mRNA) of this type of encapsulation can encode for example hormones, enzymes, receptors, polypeptides, peptides or other proteins of interest. Liposomal delivery vehicles

[0313] In some embodiments, the composition is a suitable delivery vehicle. In some embodiments, the composition is a liposomal delivery vehicle, such as a lipid nanoparticle.

[0314] The terms "liposomal delivery vehicle" and "liposomal composition" are used interchangeably.

[0315] Enriching liposome compositions with one or more of the cationic lipids disclosed herein can be used as a means to improve safety or otherwise impart one or more desired characteristics of such enriched liposome compositions (e.g., improved delivery of encapsulated polynucleotides to one or more target cells and / or reduced in vivo toxicity of the liposome compositions). Therefore, pharmaceutical compositions and particularly liposome compositions comprising one or more of the cationic lipids disclosed herein are also contemplated.

[0316] Thus, in certain embodiments, the compounds of the invention as described herein can 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 permeating or fusing with the lipid membranes of such target cells).

[0317] As used herein, liposome delivery vehicles (for example, lipid nanoparticles) are generally characterized as microscopic vesicles with internal aqueous space, and this internal aqueous space is isolated from external medium by the film with one or more double layers. The bilayer membrane of liposome is typically formed by amphipathic molecules, such as synthetic or natural lipids, and these lipids include spatially separated hydrophilic and hydrophobic domains (Lasic, Trends Biotechnol. [biotechnology trends], 16: 307-321, 1998). The bilayer membrane of liposome can also be formed by amphipathic polymers and surfactants (for example, polymers, nonionic surfactant vesicles etc.). In the context of the present invention, liposome delivery vehicles are typically used for transporting desired mRNA to target cells or tissues.

[0318] In certain embodiments, such compositions (eg, liposomal compositions) are loaded with or otherwise encapsulate a material, such as one or more biologically active polynucleotides (eg, mRNA).

[0319] In an embodiment, a composition (e.g., a pharmaceutical composition) includes an mRNA encoding a protein encapsulated within a liposome. In an embodiment, the liposome includes one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids, and wherein at least one cationic lipid is a compound of the invention as described herein. In an embodiment, the composition includes an mRNA encoding a peptide or protein (e.g., any peptide or protein described herein). In an embodiment, the composition includes an mRNA encoding a peptide (e.g., any peptide described herein). In an embodiment, the composition includes an mRNA encoding a protein (e.g., any protein described herein).

[0320] In embodiments, a composition (eg, a pharmaceutical composition) comprises a nucleic acid encapsulated within a liposome, wherein the liposome comprises a compound described herein.

[0321] In embodiments, the nucleic acid is an mRNA encoding a peptide or protein. In embodiments, the mRNA encodes a peptide or protein for use in delivery to or treatment of a subject's lungs or lung cells. In embodiments, the mRNA encodes a peptide or protein for use in delivery to or treatment of a subject's liver or liver cells. Other exemplary mRNAs are also described herein.

[0322] In embodiments, the liposomal delivery vehicle (eg, lipid nanoparticle) can have a net positive charge.

[0323] In embodiments, the liposomal delivery vehicle (eg, lipid nanoparticle) can have a net negative charge.

[0324] In embodiments, the liposomal delivery vehicle (eg, lipid nanoparticle) can have a net neutral charge.

[0325] In embodiments, lipid nanoparticles encapsulating nucleic acids (eg, mRNA encoding a peptide or protein) comprise one or more compounds of the invention as described herein.

[0326] For example, the amount of a compound of the invention in a composition as described herein can be described as a percentage ("wt %") of the combined dry weight of all lipids of the composition (e.g., the combined dry weight of all lipids present in a liposome composition).

[0327] In embodiments of the pharmaceutical compositions described herein, the compound of the invention as described herein is present in an amount of about 0.5 wt % to about 30 wt % (e.g., about 0.5 wt % to about 20 wt %) as the combined dry weight of all lipids present in the composition (e.g., a liposomal composition).

[0328] In an embodiment, a compound of the invention as described herein is present in an amount of about 1 wt % to about 30 wt %, about 1 wt % to about 20 wt %, about 1 wt % to about 15 wt %, about 1 wt % to about 10 wt %, or about 5 wt % to about 25 wt % of the combined dry weight of all lipids present in a composition (e.g., a liposomal composition). In an embodiment, a compound of the invention as described herein is present in an amount of about 0.5 wt % to about 5 wt %, about 1 wt % to about 10 wt %, about 5 wt % to about 20 wt %, or about 10 wt % to about 20 wt % of the combined dry weight of all lipids present in a composition (e.g., a liposomal delivery vehicle).

[0329] In embodiments, the amount of a compound of the invention as described herein is present in an amount of at least about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt% of the combined dry weight of total lipids in a composition (e.g., a liposome composition).

[0330] In embodiments, the amount of a compound of the invention as described herein is present in an amount that does not exceed about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt% of the combined dry weight of the total lipids in the composition (e.g., a liposome composition).

[0331] In an embodiment, compositions (for example, liposome delivery vehicle, such as lipid nanoparticle) include about 0.1wt% to about 20wt% (for example, about 0.1wt% to about 15wt%) compound described herein. In an embodiment, delivery vehicle (for example, liposome delivery vehicle, such as lipid nanoparticle) include about 0.5wt%, about 1wt%, about 3wt%, about 5wt% or about 10wt% compound described herein. In an embodiment, delivery vehicle (for example, liposome delivery vehicle, such as lipid nanoparticle) include up to about 0.5wt%, about 1wt%, about 3wt%, about 5wt%, about 10wt%, about 15wt% or about 20wt% compound described herein. In an embodiment, this percentage results in improved beneficial effect (for example, to target tissue such as the improved delivery of liver or lung).

[0332] The amount of a compound of the invention in a composition as described herein can also be described as a percentage ("mol %") of the combined moles of total lipids in the composition (eg, the combined moles of all lipids present in a liposomal delivery vehicle).

[0333] In embodiments of the pharmaceutical compositions described herein, the compound of the invention as described herein is present in an amount of about 0.5 mol % to about 50 mol % (e.g., about 0.5 mol % to about 20 mol %) as the combined molar amount of all lipids present in the composition (e.g., a liposomal delivery vehicle).

[0334] In embodiments, the compound of the invention as described herein is present in an amount of 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 combined molar amount of all lipids present in the composition (e.g., liposomal delivery vehicle). In embodiments, the 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 combined molar amount of all lipids present in the composition (e.g., liposomal delivery vehicle).

[0335] In certain embodiments, the compounds of the invention as described herein may 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 lipids in a composition (e.g., a liposomal delivery vehicle).

[0336] In certain embodiments, the compound of the invention as described herein may comprise greater than about 0.1 mol%, or greater than about 0.5 mol%, or greater than about 1 mol%, 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% of the total amount of lipid in the lipid nanoparticle.

[0337] In certain embodiments, the compound as described may comprise 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%, 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 lipids in a composition (e.g., a liposomal delivery vehicle).

[0338] In embodiments, the amount of a compound of the invention as described herein is present in an amount of 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 combined molar amount of total lipids in a composition (e.g., a liposome composition).

[0339] In embodiments, the amount of a compound of the invention as described herein is present in an amount that does not exceed 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 combined molar amount of total lipids in a composition (e.g., a liposome composition).

[0340] In embodiments, this percentage results in an improved beneficial effect (eg, improved delivery to a target tissue such as the liver or lung).

[0341] In typical embodiments, compositions of the present invention (e.g., liposome compositions) include 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, compositions suitable for practicing the present invention have four lipid components, which include a compound of the present invention as described herein as a 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.

[0342] In another embodiment, the pharmaceutical (e.g., liposome) composition comprises one or more of a PEG-modified lipid, a non-cationic lipid, and a cholesterol lipid. In other embodiments, such a pharmaceutical (e.g., liposome) composition comprises: one or more PEG-modified lipids; one or more non-cationic lipids; and one or more cholesterol lipids. In yet another embodiment, such a pharmaceutical (e.g., liposome) composition comprises: one or more PEG-modified lipids and one or more cholesterol lipids.

[0343] In an embodiment, a composition (e.g., a lipid nanoparticle) encapsulating a nucleic acid (e.g., an mRNA encoding a peptide or protein) comprises one or more compounds of the invention as described herein and one or more lipids selected from the group consisting of a cationic lipid, a non-cationic lipid, and a PEGylated lipid.

[0344] In an embodiment, the composition (e.g., lipid nanoparticle) of the encapsulated nucleic acid (e.g., mRNA encoding a peptide or protein) includes one or more compounds of the present invention as described herein; one or more lipids selected from the group consisting of cationic lipids, non-cationic lipids, and PEGylated lipids; and further comprising a cholesterol-based lipid. Typically, such a composition has four lipid components, which include a compound of the present invention as described herein as a 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).

[0345] In an embodiment, 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.

[0346] According to various embodiments, the selection of the cationic lipid, non-cationic lipid and / or PEG-modified lipid constituting lipid nanoparticles and the relative molar ratio of such lipids to each other are based on the feature of selected one or more lipids, the property of expected target cells, the feature of mRNA to be delivered. Other considerations include, for example, the size, charge, pH, pKa, fusogenicity and toxicity of the saturation of the alkyl chain and selected one or more lipids. Therefore, the mol ratio can be adjusted accordingly. Cationic lipids

[0347] In addition to any compound of the invention as described herein, the composition may comprise one or more additional cationic lipids.

[0348] In certain embodiments, liposomes can include one or more other cationic lipids. As used herein, phrase "cationic lipid" refers to any one of a variety of lipid substances having a net positive charge at a selected pH (such as physiological pH). Several cationic lipids have been described in the literature, many of which are commercially available.

[0349] Suitable additional cationic lipids for use in the compositions include those described in the literature. Helper lipids

[0350] Composition (for example, liposome composition) can also include one or more helper lipids. Such helper lipids include non-cationic lipids. As used herein, phrase "non-cationic lipids" refers to any neutral lipid, zwitterionic lipid or anionic lipid. As used herein, phrase "anionic lipids" refers to any of the various lipid substances that carry a net negative charge at a selected pH (such as physiological pH). Non-cationic lipids include but are not limited to distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), 1,2-dierucoyl-sn-glycero-3-phosphoethanolamine (DEPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (DPPC), palmitoyloleoyl-phosphatidylethanolamine (DPPG), palmitoyloleoyl ... The present invention also can be used as the lipid of the present invention.The lipid of the present invention can be used as the lipid of the present invention.

[0351] In some embodiments, the non-cationic lipid is a neutral lipid, ie, a lipid that carries no net charge under the conditions under which the composition is formulated and / or administered.

[0352] In some embodiments, the non-cationic lipids can be present in an amount 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 non-cationic lipids can be present in an amount 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 liposome can be greater than about 5mol%, greater than about 10mol%, greater than about 20mol%, greater than about 30mol%, or greater than about 40mol%. In some embodiments, the percentage of total non-cationic lipids in the liposome can be greater than about 5mol%, greater than about 10mol%, greater than about 20mol%, greater than about 30mol%, or greater than about 40mol%. In some embodiments, the percentage of non-cationic lipids in the liposome is no more than about 5mol%, no more than about 10mol%, no more than about 20mol%, no more than about 30mol%, or no more than about 40mol%. In some embodiments, the percentage of total non-cationic lipids in the liposome can be no more than about 5mol%, no more than about 10mol%, no more than about 20mol%, no more than about 30mol%, or no more than about 40mol%.

[0353] In some embodiments, the non-cationic lipid can be present in an amount of from about 5% to about 90%, from about 5% to about 70%, from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, from about 10% to about 70%, from about 10% to about 50%, or from about 10% to about 40% of the total lipid present in the composition. In some embodiments, the total non-cationic lipid can be present in an amount of from about 5% to about 90%, from about 5% to about 70%, from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, from about 10% to about 70%, from about 10% to about 50%, or from about 10% to about 40% of the total lipid present in the composition. In some embodiments, the percentage of non-cationic lipid in the liposome can be greater than about 5wt%, greater than about 10wt%, greater than about 20wt%, greater than about 30wt%, or greater than about 40wt%. In some embodiments, the percentage of total non-cationic lipids in the liposome can be greater than about 5wt%, greater than about 10wt%, greater than about 20wt%, greater than about 30wt% or greater than about 40wt%. In some embodiments, the percentage of non-cationic lipids in the liposome is no more than about 5wt%, no more than about 10wt%, no more than about 20wt%, no more than about 30wt% or no more than about 40wt%. In some embodiments, the percentage of total non-cationic lipids in the liposome can be no more than about 5wt%, no more than about 10wt%, no more than about 20wt%, no more than about 30wt% or no more than about 40wt%. Cholesterol-based lipids

[0354] In some embodiments, compositions (e.g., liposome compositions) include one or more cholesterol-based lipids. For example, a suitable cholesterol-based lipid for practicing the present invention is cholesterol. Other suitable cholesterol-based lipids include, for example, DC-Chol (N, N-dimethyl-N-ethylformamidocholesterol), 1,4-bis(3-N-oleylamino-propyl)piperazine (Gao, et al. Biochem.Biophys.Res.Comm. [Biochemistry and Biophysics Research Communications] 179,280 (1991); Wolf et al. BioTechniques [Biotechnology] 23,139 (1997); U.S. Patent No. 5,744,335), β-sitosterol, δ5 avenasterol, or imidazole cholesterol ester (ICE) with the following structure, (“ICE”).

[0355] In some embodiments, the cholesterol-based lipid can be present in the following molar ratio (mol%): 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 can be greater than about 5mol%, greater than about 10mol%, greater than about 20mol%, greater than about 30mol%, or greater than about 40mol%. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle can be no more than about 5mol%, no more than about 10mol%, no more than about 20mol%, no more than about 30mol%, or no more than about 40mol%.

[0356] In some embodiments, the cholesterol-based lipid may be present in an amount (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 no more than about 5 wt %, no more than about 10 wt %, no more than about 20 wt %, no more than about 30 wt %, or no more than about 40 wt %. PEGylated lipids

[0357] In some embodiments, the composition (e.g., liposome composition) comprises one or more additional PEGylated lipids. A suitable PEG-modified lipid or PEGylated lipid suitable for use in practicing the present invention is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2K).

[0358] For example, the present invention also contemplates the use of polyethylene glycol (PEG)-modified phospholipids and derivatized lipids (e.g., derivatized ceramides (PEG-CER), including N-octanoyl-sphingosine-1-[succinyl(methoxypolyethylene glycol)-2000] (C8 PEG-2000 ceramide)) in combination with one or more of the compounds of the invention as described herein, and in some embodiments, in combination with other lipids that together comprise the liposomes. In some embodiments, particularly useful exchangeable lipids are those with shorter acyl chains (e.g., C 14 or C 18 ) of PEG-ceramide.

[0359] Additional PEG-modified lipids contemplated (also referred to herein as PEGylated lipids, which term is interchangeable with PEG-modified lipids) include, but are not limited to, lipids covalently attached to C6-C 20In some embodiments, the PEGylated lipid or PEGylated lipid is a PEGylated cholesterol or PEG-2K. The addition of such components can prevent complex aggregation and can also provide a means for increasing circulation life and increasing the delivery of lipid-nucleic acid compositions to target cells (Klibanov et al. (1990) FEBS Letters [FEBS Letters, 268 (1): 235-237), or they can be selected to quickly swap out formulations in vivo (see U.S. Patent No. 5,885,613).

[0360] The additional PEG-modified phospholipids and derivatized lipids of the present invention can be present in a molar ratio (mol %) of from 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 lipids present in the composition (e.g., a liposome composition). Pharmaceutical preparations and therapeutic uses

[0361] The compounds of the invention as described herein can be used to prepare compositions (e.g., for constructing liposome compositions) that facilitate or enhance the delivery and release of encapsulated materials (e.g., one or more therapeutic polynucleotides) to one or more target cells (e.g., by permeating or fusing with the lipid membranes of such target cells).

[0362] For example, when a liposomal composition (e.g., lipid nanoparticle) contains or is otherwise enriched with one or more of the compounds disclosed herein, a phase transition in the lipid bilayer of the 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 the one or more target cells.

[0363] Similarly, in certain embodiments, the compounds of the invention as described herein can be used to prepare liposomal vehicles characterized by their reduced in vivo toxicity. In certain embodiments, the reduced toxicity is a function of the high transfection efficiency associated with the compositions disclosed herein, such that reduced amounts of such compositions can be administered to a subject to achieve a desired therapeutic response or outcome.

[0364] Thus, pharmaceutical formulations comprising the compounds described in the present invention and the provided nucleic acids can be used for various therapeutic and / or prophylactic purposes. To facilitate the delivery of nucleic acids in vivo, the compounds and nucleic acids described herein can be formulated in combination with one or more additional pharmaceutical carriers, targeting ligands, or stabilizing agents. In some embodiments, the compounds described herein can be formulated via a pre-mixed lipid solution. In other embodiments, a post-insertion technique can be used to formulate a composition comprising the compounds described herein into the lipid membrane of nanoparticles. Techniques for the formulation and administration of drugs can be found in the latest version of "Remington’s Pharmaceutical Sciences", Mack Publishing Co., Easton, Pa.

[0365] Suitable routes of administration include, for example, oral, rectal, vaginal, transmucosal, pulmonary including intratracheal or inhalation, or enteral administration; parenteral delivery, including intradermal, transdermal (topical), intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intraperitoneal, or intranasal. In certain 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 a muscle cell. In some embodiments, administration results in delivery of the nucleic acid to a hepatocyte (i.e., liver cell).

[0366] A common route of administration of the liposomal 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 to be treated, the liposomal compositions can be administered via pulmonary delivery (e.g., for treating cystic fibrosis). For vaccination, the liposomal compositions of the present invention are typically administered intramuscularly. Alternatively, the liposomal compositions of the present invention can be used for vaccination by intranasal administration. The liposomal compositions of the present invention can be administered intravitreally to treat diseases or disorders affecting the eye.

[0367] Alternatively or additionally, the pharmaceutical formulations of the present invention can be administered in a local rather than systemic manner, for example, by direct injection of the pharmaceutical formulation into the targeted tissue (e.g., in a sustained release formulation). Depending on the tissue to be targeted, local delivery can be achieved in various ways. Exemplary tissues to which mRNA can be delivered and / or expressed include, but are not limited to, liver, kidney, heart, spleen, serum, brain, skeletal muscle, lymph nodes, skin, and / or cerebrospinal fluid. In an embodiment, the tissue to be targeted is in the liver. For example, an aerosol containing the composition of the present invention can be inhaled (for nasal, tracheal, or bronchial delivery); for example, the composition of the present invention can be injected into an injury, disease manifestation, or pain site; the composition can be provided in the form of a lozenge for oral, tracheal, or esophageal application; can be provided in the form of a liquid, tablet, or capsule for administration to the stomach or intestine; can be provided in the form of a suppository for rectal or vaginal application; or can even be delivered to the eye using a cream, drops, or even an injection.

[0368] The compositions described herein can include mRNA encoding a peptide, including a peptide (eg, a polypeptide, such as a protein) described herein.

[0369] In embodiments, the mRNA encodes a polypeptide.

[0370] In embodiments, the mRNA encodes a peptide. In embodiments, the peptide is an antigen.

[0371] In embodiments, the mRNA encodes a protein.

[0372] The present invention provides methods for delivering compositions having full-length mRNA molecules encoding a peptide or protein of interest for use in treating a subject, such as a human subject, or cells of a human subject, or cells treated and delivered to a human subject. Delivery Method

[0373] The delivery route used in the inventive method allows for non-invasive self-administration of the compound of the present invention. In certain embodiments, these methods relate to intranasal, intratracheal or pulmonary administration of compositions by aerosolization, atomization or instillation, the compositions comprising mRNA encoding therapeutic peptides or proteins (in suitable transfection or lipid carrier vehicles as described above). In certain embodiments, the peptide or protein is encapsulated by liposomes. In certain embodiments, the liposomes comprise lipids, which are compounds of the present invention. As used hereinafter, the administration of the compounds of the present invention includes the administration of compositions comprising the compounds of the present invention.

[0374] Although local cells and tissues of the lungs represent potential targets that can be used as biological reservoirs or storage depots to produce and secrete proteins encoded by mRNA, the applicant has found that administering the compounds of the present invention to the lungs via aerosolization, atomization, or instillation can result in even non-secreted proteins being distributed outside the lung cells. Without wishing to be bound by any particular theory, it is contemplated that the nanoparticle compositions of the present invention pass through the lung airway-blood barrier, resulting in the transfer of intact nanoparticles to non-lung cells and tissues, such as the heart, liver, and spleen, producing encoded peptides or proteins in these non-lung tissues. Therefore, the uses of the compounds of the present invention and the methods of the present invention are not limited to producing therapeutic proteins in lung cells and lung tissues, but can also be used for delivery to non-lung target cells and / or tissues. They are useful for managing and treating a variety of diseases. In certain embodiments, the compounds of the present invention used in the methods of the present invention result in the distribution of nanoparticles encapsulating mRNA and the production of encoded peptides or proteins in the liver, spleen, heart, and / or other non-lung cells. For example, administration of a compound of the invention to the lung by aerosolization, nebulization, or instillation will result in detection of the composition itself and its peptide or protein product (e.g., antigen or functional protein) in local cells and tissues of the lung, as well as in peripheral target cells, tissues, and organs (due to translocation of the mRNA and delivery vehicle to non-lung cells).

[0375] 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. After pulmonary delivery, it is contemplated that the compounds of the present invention pass through the pulmonary airway-blood barrier and are distributed to cells other than local lung cells. Therefore, the compounds disclosed herein can be administered to subjects by pulmonary administration routes (using various methods known to those skilled in the art (e.g., by inhalation)) and distributed to local target cells and tissues of the lung, and peripheral non-lung cells and tissues (e.g., liver, spleen, kidney, heart, skeletal muscle, lymph nodes, brain, cerebrospinal fluid and plasma cells). Therefore, local cells of the lung and peripheral non-lung cells can be used as biological storage reservoirs or depots, and translation products encoded by one or more polynucleotides can be produced and / or secreted. Therefore, the present invention is not limited to treating lung diseases or illnesses, but can be used as a non-invasive means to promote the delivery of polynucleotides or the production of peptides or proteins encoded therein in peripheral organs, tissues and cells (e.g., hepatocytes), which can only be achieved by systemic administration. Exemplary peripheral non-lung 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, cardiomyocytes, 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.

[0376] After administration of the composition to a subject, the peptide or protein product (e.g., a functional protein or enzyme) encoded by the mRNA can be detected in peripheral target tissues for at least about one to seven days or longer after administration of the compound to the subject. The amount of peptide or protein product required 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 can be detected in peripheral target tissues at a concentration (e.g., a therapeutic concentration) of at least 0.025-1.5 μg / ml (e.g., at least 0.050 μg / ml, at least 0.060 μg / ml, at least 0.080 μg / ml, at least 0.090 μg / ml, at least 10.00 μg / ml, at least 11.00 μg / ml, at least 12.00 μg / ml, at least 13.00 μg / ml, at least 14.00 μg / ml, at least 15.00 μg / ml, at least 16.00 μg / ml, at least 17.00 μg / ml, at least 18.00 μg / ml, at least 19.00 μg / ml, at least 20.00 μg / ml, at least 21.00 μg / ml, at least 22.00 μg / ml, at least 23.00 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, 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).

[0377] 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 an aerosol mist generated by a liquid nebulizer or using a dry powder device such as that described in US Patent 5,780,014, incorporated herein by reference.

[0378] In certain embodiments, the compounds of the present invention can be formulated so that they can be aerosolized or otherwise delivered as granular liquid or solid before being applied to the subject or when being applied to the subject. Such compounds can be used with the help of one or more suitable devices for applying such solid or liquid particulate compositions (such as, aerosolized aqueous solutions or suspensions) to produce the particles that the subject is easy to breathe in or inhale. In certain embodiments, such devices (such as, metered dose inhaler, jet nebulizer, ultrasonic nebulizer, dry powder inhaler, inhaler based on propellant or insufflator) help to apply the compositions (such as, about 0.5mg / kg mRNA per dose) of predetermined mass, volume or dosage to the subject. For example, in certain embodiments, the compounds of the present invention are applied to the subject using a metered dose inhaler equipped with a suspension or solution comprising compound and suitable propellant. In certain embodiments, the compounds of the present invention can be formulated as particulate powders (such as, respirable dry particles) intended for inhalation. In certain embodiments, the compositions of the invention formulated as respirable particles are of an appropriate size so that they can be inhaled by a subject or delivered using a suitable device (e.g., an average D50 or D90 particle size of less than 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, the compounds of the invention are formulated to include one or more lung surfactants (e.g., lamellar bodies). In some embodiments, a compound of the invention is administered to a subject such that 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, is administered in a single dose. / kg, at least 20 mg / kg, 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 at one or more doses. Examples

[0379] While certain compounds, compositions, and methods of the present invention have been specifically described according to certain embodiments, the following examples are merely illustrative of the compounds of the present invention and are not intended to be limiting thereof. List of abbreviations: ACN: acetonitrile Boc: tert-Butoxycarbonyl 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 / Carbon NaOH: sodium hydroxide RT: room temperature SM: Starting material SiO2: Silicon dioxide TBS: tert-butyldimethylsilyl TBDMS: tert-butyldimethylsilyl TLC: Thin layer chromatography Example 1: Synthesis of Compounds XXIV, XI, XXI, XXVII, XXVI, XXXV, XXX, XXXIII, XXVIII, XXXII, XXXIV, XXV, XXXVIII, XXXVI, XXXI and XXIX

[0380] For example, the compounds of the present invention can be prepared according to Scheme 1 (e.g. Figure 1 prepared as described in . Synthesis of compound XXIV

[0381] As depicted in Scheme 1, (where x is ): Step 1 - To a 20 mL scintillation vial were added the dicarboxylic acid (1) (71.1 mg, 1.0 equiv), the alcohol intermediate (2) (500 mg, 2.2 equiv), DMAP (41.3 mg, 1.0 equiv), DIPEA (0.12 mL, 2.0 equiv) and anhydrous CH2Cl2 (7 mL). To this stirred solution was added EDC (162 mg, 2.5 equiv) in one portion at room temperature. The reaction was stirred at room temperature for 16 h and monitored by TLC (10% EtOAc in hexanes). After substantial consumption of (2) as determined by TLC, the reaction mixture was partitioned between layers of EtOAc and saturated NaHCO3 aqueous solution. The separated aqueous layer was extracted with EtOAc (2×), and the combined organic layers were then washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to provide the crude product. The crude material was purified using medium pressure chromatography (Combiflash) using a gradient of 0-10% EtOAc in hexanes to separate the desired product (3) from the remaining starting material (2). The combined fractions containing (3) were concentrated to dryness to provide the TBS ether intermediate (3) (426 mg, 83%) as a viscous colorless oil. The identity of the product was confirmed by MS. result:

[0382] MS (ESI+) calculated value C 84 H 176 N2O8S2Si 4, [M+H] + =1518.2, observed value =1518.9+760.0[M / 2].

[0383] As depicted in Scheme 1, (where x is ): Step 2- TBS ether (3) (426 mg, 1.0 equivalents) and anhydrous THF (4 mL) were added to a 20 mL scintillation vial of plastic. The resulting solution was stirred and cooled to 0 ° C using an ice bath, then 70% HF-pyridine solution (1.44 mL, 197 equivalents of HF) was added dropwise and stirred at the same temperature for 5 minutes, then allowed to slowly warm to room temperature and stirred at room temperature for 16 h. After the reaction was completed as monitored by MS, the reaction mixture was cooled to 0 ° C and quenched by adding solid NaHCO3 in batches. After gas formation had been minimized, the resulting mixture was diluted with EtOAc and neutralized with a NaHCO3 aqueous solution until pH = 7-8. The neutralized aqueous layer was extracted with EtOAc (2 ×), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed via filtration and the filtrate was concentrated under reduced pressure to provide a crude product. The crude material was purified using a 0-60% EtOAc in hexanes gradient to afford Compound XXIV (246 mg, 83%) as a colorless viscous oil. result:

[0384] MS (ESI+) calculated value C 60 H 120 N2O8S 2, [M+H] + =1061.8, observed values ​​=1061.7 and 531.4[M / 2]. Synthesis of compound XI

[0385] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XI (97 mg) as a colorless viscous oil. result:

[0386] MS (ESI+) calculated value C 59 H 119 N3O 8, [M+H] + =998.9, observed values ​​=998.8 and 500.0[M / 2]. Synthesis of compound XXI

[0387] As depicted in Scheme 1, (where x is and the ester bonded to x is reversed): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv.) and common alcohol intermediate (2) (2.2 equiv.) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXI (135 mg) as a colorless viscous oil. result:

[0388] MS (ESI+) calculated value C 67 H 136 N4O 8, [M+H] + =1126.0, observed values ​​=1125.9 and 563.5[M / 2]. Synthesis of compound XXVII

[0389] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv.) and common alcohol intermediate (2) (2.2 equiv.) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXVII (272 mg) as a colorless viscous oil. result:

[0390] MS (ESI+) calculated value C 59 H 118 N2O 8, [M+H] + =983.9, observed values ​​=984.4 and 492.8[M / 2]. Synthesis of compound XXVI

[0391] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXVI (174 mg) as a colorless viscous oil. result:

[0392] MS (ESI+) calculated value C 58 H 116 N2O 8, [M+H] + =969.9, observed values ​​=969.2 and 485.1[M / 2]. Synthesis of compound XXXV

[0393] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXXV (33 mg) as a colorless viscous oil. result:

[0394] MS (ESI+) calculated value C 61 H 122 N2O 8, [M+H] + =1011.9, observed values ​​=1012.2 and 506.1[M / 2]. Synthesis of compound XXX

[0395] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXX (81 mg) as a colorless viscous oil. result:

[0396] MS (ESI+) calculated value C 60 H 120 N2O 8, [M+H] + =997.9, observed values ​​=997.2 and 499.3[M / 2]. Synthesis of compound XXXIII

[0397] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXXIII (113 mg) as a colorless viscous oil. result:

[0398] MS (ESI+) calculated value C 64 H 120 N2O 8, [M+H]+ =1045.9, observed values ​​=1045.2 and 523.2[M / 2]. Synthesis of compound XXVIII

[0399] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv.) and common alcohol intermediate (2) (2.2 equiv.) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXVIII (120 mg) as a colorless viscous oil. result:

[0400] MS (ESI+) calculated value C 60 H 120 N2O 8, [M+H] + =997.9, observed values ​​=998.2 and 499.1[M / 2]. Synthesis of compound XXXII

[0401] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXXII (150 mg) as a colorless viscous oil. result:

[0402] MS (ESI+) calculated value C 60 H 120 N2O 8, [M+H] + =997.9, observed values ​​=998.2 and 499.1[M / 2]. Synthesis of compound XXXIV

[0403] As depicted in Scheme 1, (where x is ): The procedure for compound XXIV was followed using dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXXIV (101 mg) as a colorless viscous oil. result:

[0404] MS (ESI+) calculated value C 65 H 122 N2O 8, [M+H] + =1059.9, observed values ​​=1059.2 and 530.3[M / 2]. Synthesis of compound XXV

[0405] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXV (31 mg) as a colorless viscous oil. result:

[0406] MS (ESI+) calculated value C 57 H 114 N2O 8, [M+H] + =955.9, observed values ​​=955.2 and 478.1[M / 2]. Synthesis of compound XXXVIII

[0407] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv.) and common alcohol intermediate (2) (2.2 equiv.) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXXVIII (55 mg) as a colorless viscous oil. result:

[0408] MS (ESI+) calculated value C 60 H 120 N2O 9, [M+H] + =1013.9, observed values ​​=1013.1 and 507.2[M / 2]. Synthesis of compound XXXVI

[0409] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv) and common alcohol intermediate (2) (2.2 equiv) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXXVI (56 mg) as a colorless viscous oil. result:

[0410] MS (ESI+) calculated value C 62 H 124 N2O 8, [M+H] + =1025.9, observed values ​​=1025.3 and 513.3[M / 2]. Synthesis of compound XXXI

[0411] As depicted in Scheme 1, (where x is ): Following the procedure for compound XXIV, dicarboxylic acid (1) (1.0 equiv.) and common alcohol intermediate (2) (2.2 equiv.) were used to obtain the desired intermediate (3). After confirmation by MS, TBS ether (3) was treated with 70% HF-pyridine solution to provide compound XXXI (113 mg) as a colorless viscous oil. result:

[0412] MS (ESI+) calculated value C 62 H 124 N2O 8, [M+H] + =1025.9, observed values ​​=1026.8 and 514.0[M / 2]. Synthesis of compound XXIX

[0413] As depicted in Scheme 1, (where x is And R is ): To a 20 mL scintillation vial were added dicarboxylic acid (1) (20 mg, 1.0 equiv), synthetic alcohol intermediate (5) (222 mg, 2.78 equiv), DMAP (27.4 mg, 1.3 equiv), DIPEA (0.08 mL, 2.65 equiv) and anhydrous CH2Cl2 (5 mL). To this stirred solution was added EDC (107 mg, 3.3 equiv) in one portion at room temperature. The reaction was stirred at room temperature for 16 h and monitored by TLC (10% EtOAc in hexane). After substantial consumption of (5) as determined by TLC, the reaction mixture was partitioned between layers of EtOAc and saturated NaHCO3 aqueous solution. The separated aqueous layer was extracted with EtOAc (2×), and the combined organic layers were then washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to provide the crude product. The crude material was purified using Combiflash using 50% EtOAc in hexanes to isolate the desired product Compound XXIX. The combined fractions containing Compound XXIX were concentrated to dryness to afford the lipid product Compound XXIX (90 mg, 53%) as a viscous colorless oil. result:

[0414] MS (ESI+) calculated value C 84 H 176 N2O8S2Si 4, [M+H] + =1025.8, observed values ​​=1025.2 and 513.1[M / 2]. Example 2: Synthesis of Compounds V and XVI

[0415] For example, the compounds of the present invention can be prepared according to Scheme 2 (e.g. Figure 2 prepared as described in . Synthesis of compound V

[0416] As depicted in Scheme 2, (where x is ): Step 1 - To a 20 mL scintillation vial were added aminodiol (7) (37.5 mg, 0.45 eq), acid intermediate (8) (500 mg, 1.0 eq), DMAP (85.5 mg, 1.0 eq), DIPEA (0.73 mL, 6.0 eq) and anhydrous CHCl (7 mL). To this stirred solution was added EDC (268 mg, 2.0 eq) in one portion at room temperature. The reaction was stirred at room temperature for 16 h and monitored by TLC (10% EtOAc in hexanes). After substantial consumption of (8) as determined by TLC, the reaction mixture was partitioned between layers of EtOAc and saturated aqueous NaHCO. The separated aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to provide the crude product. The crude material was purified using a combiflash using 0-10% EtOAc in hexanes to separate the desired product (9) from the remaining starting material (8). The combined fractions containing the product were concentrated to dryness to provide the TBS ether intermediate (9) (318 mg, 67%) as a viscous colorless oil. The identity of the product was confirmed by MS. result:

[0417] MS (ESI+) calculated value C 87 H 183 N3O8Si 4, [M+H] + =1511.3, observed value =1512.2.

[0418] As depicted in Scheme 2, (where x is ): Step 2- TBS ether (9) (318 mg, 1.0 equivalents) and anhydrous THF (3 mL) were added to a 20 mL scintillation vial of plastic. The resulting solution was stirred and cooled to 0 ° C using an ice bath, then 70% HF-pyridine solution (1.08 mL, 197 equivalents of HF) was added dropwise and stirred at the same temperature for 5 minutes, then allowed to slowly warm to room temperature and stirred at room temperature for 16 h. After the reaction was completed as monitored by MS, the reaction mixture was cooled to 0 ° C and quenched by adding solid NaHCO3 in batches. After gas formation had been minimized, the resulting mixture was diluted with EtOAc and neutralized with a NaHCO3 aqueous solution until pH = 7-8. The neutralized aqueous layer was extracted with EtOAc (2 ×), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed via filtration and the filtrate was concentrated under reduced pressure to provide a crude product. The crude material was purified using a 0-20% MeOH in CH 2 Cl 2 gradient to afford Compound V (181 mg, 82%) as a colorless viscous oil. result:

[0419] MS (ESI+) calculated value C 63 H 127 N3O 8, [M+H] + =1055.0, observed value =1054.8. Synthesis of compound XVI

[0420] As depicted in Scheme 2, (where x is And R is ): To a 20 mL scintillation vial were added aminodiol (7) (21.0 mg, 1.0 eq), acid intermediate (11) (270 mg, 2.0 eq), DMAP (21.6 mg, 1.0 eq), DIPEA (0.13 mL, 4.2 eq) and anhydrous CH2Cl2 (3.5 mL). To this stirred solution was added EDC (84.7 mg, 2.5 eq) in one portion at room temperature. The reaction was stirred at room temperature for 16 h and monitored by MS. After substantial consumption of (11) as determined by MS, the reaction mixture was partitioned between layers of EtOAc and saturated NaHCO3 aqueous solution. The separated aqueous layer was extracted with EtOAc (2×), and the combined organic layers were then washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to provide the crude product. The crude material was purified using Combiflash using 10% MeOH in CH2Cl2 to isolate the desired product, Compound XVI. The combined fractions containing the product were concentrated to dryness to afford the lipid product Compound XVI (65 mg, 27%) as a viscous colorless oil. result:

[0421] MS (ESI+) calculated value C 83 H 151 N3O 12, [M+H] + =1383.1, observed value =1383.2. Example 3: Synthesis of Compound XLI

[0422] For example, the compounds of the present invention can be prepared according to Scheme 3 (e.g. Figure 3 prepared as described in . Synthesis of intermediate [2]

[0423] As depicted in Scheme 3: 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 was formed. The reaction mixture was diluted with cold water (500 mL) and acidified with 2N HCl aqueous solution until 2-3 pH, then extracted with EtOAc (2 × 500 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give oct-7-enoic acid [2] (10.0 g, crude product) as a light yellow oil. The crude product was used in the next step as it is. result:

[0424] 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. Synthesis of intermediate [4]

[0425] As depicted in Scheme 3: To a stirred solution of oct-7-enoic acid [2] (10 g, 70.3 mmol) in dimethylformamide (200 mL) was added potassium carbonate (29.2 g, 211 mmol) at room temperature, followed by (bromomethyl)benzene [3] (10 mL, 84.4 mmol). The reaction was allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by TLC / ELSD. The reaction mixture was diluted with cold water (200 mL) and extracted with ether (2 × 500 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (500 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product obtained was purified by silica gel flash column chromatography (0-10% ethyl acetate in heptane) to give oct-7-enoic acid benzyl ester [4] (6.5 g, 39.7% yield) as a light yellow oil. result:

[0426] 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. Synthesis of intermediate [5]

[0427] As depicted in Scheme 3: At 0 ° C, under a nitrogen atmosphere, 3-chlorobenzene-1-peroxyformic acid (14.5 g, 83.9 mmol) was added to a stirred solution of oct-7-enoic acid benzyl ester [4] (6.5 g, 28 mmol) in dichloromethane (50 mL) to the reaction mass. The reaction mixture was allowed to stir at room temperature for 16 h. After 16 h, the reaction progress was monitored by TLC. The reaction mass was diluted with DCM (50 mL), washed with a saturated aqueous solution of NaHCO (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 flash column chromatography on silica gel (0-10% ethyl acetate gradient in heptane) to obtain 6- (oxiran-2-yl) benzyl hexanoate [5] (5.5 g, 79% yield) as a yellow oil. result:

[0428] 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. Synthesis of intermediate [6]

[0429] As depicted in Scheme 3: At room temperature, under an inert atmosphere, to a stirred solution of 6-(oxiran-2-yl)hexanoic acid benzyl ester [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). 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 a crude product, which was purified by silica gel flash column chromatography using a 3%-5% MeOH gradient in DCM as an eluent to give 8-{[8-(benzyloxy)-2-hydroxy-8-oxooctyl](3-hydroxypropyl)amino}-7-hydroxyoctanoic acid benzyl ester [6] (3.2 g, 37.7% yield) as a colorless oil. result:

[0430] ELSD analysis: purity 99.02%, calculated value for C33H49NO7 = 571.35, observed value = 572.30 (m / z, M+H+). Synthesis of intermediate [7]:

[0431] As depicted 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) at room temperature under an inert atmosphere. The resulting reaction mass was allowed to stir at room temperature for 16 h. 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-4,11-dioxa-7-aza-3,12-disilatatetradec-7-yl}-7-[(tert-butyldimethylsilyl)oxy]octanoate [7] (3.5 g, 68.4% yield) as a colorless liquid. result:

[0432] ELSD analysis: purity 97.95%, calculated value C51H91NO7Si3 = 913.61, observed value = 914.50 (m / z, M+H+). Synthesis of intermediate [8]

[0433] As depicted 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-disilatatetradec-7-yl}-7-[(tert-butyldimethylsilyl)oxy]octanoate [7] (4.3 g, 4.7 mmol) in methanol (15 mL), tetrahydrofuran (15 mL) was added palladium on carbon (10% w / w with 50% moisture) (1.5 g, 14.1 mmol) portionwise under nitrogen atmosphere. The resulting reaction mass was degassed and purged with hydrogen at room temperature and then allowed to stir under hydrogen balloon pressure for 16 h. After completion of the reaction, the reaction mixture was filtered through celite and the celite bed was washed twice with methanol. Methanol was evaporated to dryness to give 7-[(tert-butyldimethylsilyl)oxy]-8-[5-(5-carboxypentyl)-2,2,3,3,12,12,13,13-octamethyl-4,11-dioxa-7-aza-3,12-disilatatetradec-7-yl]octanoic acid [8] (3.4 g, 98% yield) as a colorless liquid. result:

[0434] ELSD analysis: purity 99.33%, calculated value C37H79NO7Si3 = 733.52, observed value = 734.50 (m / z, M+H+). Synthesis of intermediate

[10]

[0435] As depicted in Scheme 3: To a stirred solution of 7-[(tert-butyldimethylsilyl)oxy]-8-[5-(5-carboxypentyl)-2,2,3,3,12,12,13,13-octamethyl-4,11-dioxa-7-aza-3,12-disilatatetradec-7-yl]octanoic acid [8] (3.5 g, 4.77 mmol) in dichloromethane (70 mL) was added {3-[cyano(ethyl)amino]propyl}dimethylammonium chloride (2.74 g, 14.3 mmol) and DMAP (587 mg, 4.77 mmol) at room temperature under an inert atmosphere, followed by the addition of (2Z)-non-2-en-1-ol [9] (1.69 g, 11.9 mmol) after 15 minutes at room temperature under an inert atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mass was quenched with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (0-10% ethyl acetate in heptane) to give (2Z)-non-2-en-1-yl 7-[(tert-butyldimethylsilyl)oxy]-8-(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-disilatetracea-7-yl)octanoate

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

[0436] ELSD analysis: purity 96.75%, calculated value C 55 H 111 NO7Si3=981.77, observed value=982.60 (m / z, M+H+). Synthesis of intermediate

[11]

[0437] As depicted in Scheme 3: To a stirred solution of (2Z)-non-2-en-1-yl 7-[(tert-butyldimethylsilyl)oxy]-8-(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-disilatatetradec-7-yl)octanoate

[10] (3.6 g, 3.66 mmol) in tetrahydrofuran (30 mL) at 0° C. was added pyridine hydrogen fluoride complex (1.45 g, 14.7 mmol) and allowed to stir for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate solution until pH 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 product 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 light yellow liquid. result:

[0438] ELSD analysis: purity 98.33%, calculated value C 37 H 69 NO7=639.51, observed value=640.45 (m / z, M+H+). Synthesis of compound XLI

[0439] As depicted 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-methylglutaric acid

[12] (0.1 g, 617 μmol) in dichloromethane (15 mL) was cooled to 0°C and {3-[cyano(ethyl)amino]propyl}dimethylammonium 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 h. 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 Na2SO4, filtered and 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-methylglutarate.TFA salt Compound XLI (0.1 g, 11.5% yield) as a colorless liquid. result:

[0440] 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.

[0441] ELSD analysis: purity 99.95%, calculated value C 80 H 144 N2O 17 =1405.05, observed value =1405.85 (m / z, M+H+). Example 4: Synthesis of Compound LXXII

[0442] For example, the compounds of the present invention can be prepared according to Scheme 4 (e.g. Figure 4 prepared as described in . Synthesis of intermediate [2]

[0443] As depicted 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 was formed. The reaction mixture was diluted with cold water (500 mL) and acidified with 2N HCl aqueous solution until 2-3 pH, then extracted with EtOAc (2 × 500 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give oct-7-enoic acid [2] (10.0 g, crude product) as a light yellow oil. The crude product was used in the next step as it is. result:

[0444] 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. Synthesis of intermediate [4]

[0445] As depicted 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) were added DMAP (5.89 g, 47.8 mmol) and ({[3-(dimethylamino)propyl]imino}methylene)(ethyl)amine hydrochloride (18.3 g, 95.6 mmol) at room temperature. After this, 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 h. 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, concentrated under reduced pressure to give a crude product, and the crude product 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. result:

[0446] 1H NMR (400MHz, CDCl3): δ5.83-5.74(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. Synthesis of intermediate [5]

[0447] As depicted in Scheme 4: At 0 ° C, 3-chlorobenzene-1-peroxycarboxylic acid (10.5 g, 60.7 mmol) was added to a stirred solution of heptadecan-9-yl oct-7-enoate [4] (10.5 g, 52.5 mmol) in dichloromethane (200 mL). The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction mass (SM was consumed) was monitored by ELSD / TLC. 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 hexane) to obtain the desired heptadecan-9-yl 6-(oxiran-2-yl) hexanoate [5] (9.2 g, 84.08% yield) as a colorless liquid. result:

[0448] 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).

[0449] ELSD analysis: purity 99.93%, calculated value C 25 H 48 O2 = 396.36, observed = 397.20 (m / z, M+H+) & 419.35 (m / z, M+Na+). Synthesis of intermediate [8]

[0450] As depicted in Scheme 4: at room temperature, to a solution of hex-5-enoic acid [6] (10 g, 87.6 mmol), {3-[cyano(ethyl)amino]propyl}dimethylammonium chloride (25.2 g, 131 mmol) and DMAP (5.4 g, 43.8 mmol) in dichloromethane (150 mL). After this, undecane-1-ol [7] (13.6 g, 78.8 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 16 h. 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, concentrated under reduced pressure, and the crude product was purified by flash column chromatography (SiO2: 0-5% ethyl acetate in hexane) to obtain the desired hex-5-enoic acid undecyl ester [8] (19.8 g, 84.19%, yield) as a colorless oil. result:

[0451] 1H-NMR (400MHz, CDCl3)-δ5.83-5.73(m,1H),5.05-4.96(m,2H),4.07-4.03(t,J=6.8Hz,2H),2.38-2.30(m,2H),2.1 1-2.06(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. Synthesis of intermediate [9]

[0452] As depicted in Scheme 4: To a stirred solution of hex-5-enoic acid undecyl ester [8] (19.8 g, 73.8 mmol) in dichloromethane (200 mL) at 0°C was added 3-chlorobenzene-1-peroxycarboxylic acid (25.5 g, 148 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction mass (SM was consumed) was monitored by TLC. 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 hexane) to give the desired 4-(oxiran-2-yl)butanoic acid undecyl ester [9] (17.8 g, 84.84% yield) as a light yellow liquid. result:

[0453] 1H-NMR (400MHz, CDCl3)-δ4.09-4.06(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.

[0454] ELSD analysis: purity 95.53%, calculated value C 17 H 32 O3 = 284.24, observed = 285.20 (m / z, M+H+). Synthesis of intermediate

[11]

[0455] As depicted in Scheme 4: A stirred solution of 3-aminopropan-1-ol

[10] (4.7 g, 62.6 mmol) and 4-(oxiran-2-yl)butanoic acid undecyl ester [9] (17.8 g, 62.6 mmol) in isopropanol (100 mL) was heated at 90° C. for 16 h. The progress of the reaction was monitored (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 obtain the desired 5-hydroxy-6-[(3-hydroxypropyl)amino]hexanoic acid undecyl ester

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

[0456] ELSD analysis: purity 99.56%, calculated value C 20 H 41 NO4 = 359.30, observed = 360.65 (m / z, M+H+). Synthesis of intermediate

[12]

[0457] As depicted in Scheme 4: a stirred solution of 5-hydroxy-6-[(3-hydroxypropyl)amino]hexanoic acid undecyl ester

[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 progress of the reaction was monitored (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 obtain the desired heptadecan-9-yl 7-hydroxy-8-{[2-hydroxy-6-oxo-6-(undecanyloxy)hexyl](3-hydroxypropyl)amino}octanoate

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

[0458] ELSD analysis: purity 99.73%, calculated value C 45 H 89 NO7=755.66, observed value=756.55 (m / z, M+H+). Synthesis of compound LXXII

[0459] As depicted in Scheme 4: A stirred solution of 3-hydroxy-3-methylglutaric acid

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

[12] (1.77 g, 2.34 mmol) in dichloromethane (8 mL) was cooled to 0° C., 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 progress of the reaction was monitored by ELSD / TLC (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 Na2SO4 and concentrated under reduced pressure, and the crude product was purified by flash column chromatography (SiO2: 0-5% methanol in dichloromethane) to obtain 1,5-bis(3-{[8-(heptadecan-9-yloxy)-2-hydroxy-8-oxooctyl][2-hydroxy-6-oxo-6-(undecyloxy)hexyl]amino}propyl)3-hydroxy-3-methylglutarate Compound LXXII (0.4 g, 19.79%, yield) as a colorless liquid. result:

[0460] 1H NMR (400MHz, CDCl3): δ4.89-4.82(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),2.49-2.3 9(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) ,1.50-1.49(m,8H),1.45-1.39(m,6H),1.36-1.25(brs,94H),0.89-0.86(t,J=7.2Hz,18H)ppm.

[0461] ELSD analysis: purity 96.73%, calculated value C 96 H 184 N2O 17 =1637.36, observed value =1638.10 (m / z, M+H+). Example 5: Synthesis of Compound XXXVII

[0462] For example, the compounds of the present invention can be prepared according to Scheme 5 (e.g. Figure 5 prepared as described in . Synthesis of intermediate [3]

[0463] As depicted 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 progress of the reaction was monitored by 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 obtain the desired 1-[(2-hydroxydecyl)(3-hydroxypropyl)amino]dec-2-ol [3] (22 g, yield: 85%) as an off-white solid. result:

[0464] ELSD analysis: purity 99.85%, calculated value C 23 H 49 NO3 = 387.37, observed = 388.35 (m / z, M+H+). Synthesis of compound XXXVII

[0465] As depicted in Scheme 5: To a stirred solution of 3-hydroxy-3-methylglutaric acid [4] (0.1 g, 617 μmol) in dichloromethane (20 mL, 312 mmol) was added 4-(dimethylamino)pyridin-1-ium (456 mg, 3.7 mmol), {3-[cyano(ethyl)amino]propyl}dimethylammonium chloride (355 mg, 1.85 mmol) and 1-[(2-hydroxydecyl)(3-hydroxypropyl)amino]dec-2-ol [3] (526 mg, 1.36 mmol) at room temperature under an inert atmosphere. The resulting reaction was allowed to stir at room temperature for 48 h. After 48 h, 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 5 times with heptane. The combined heptane fractions were evaporated under reduced pressure to give the crude reaction mass. The crude product was purified by preparative HPLC (ACN / 0.1% TFA in water) as gradient eluent to give 1,5-bis({3-[bis(2-hydroxydecyl)amino]propyl})3-hydroxy-3-methylglutarate trifluoroacetate Compound XXXVII (0.14 g, 25% yield) as a colorless liquid. result:

[0466] 1H NMR (400MHz, CDCl3): δ8.85-8.65(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.

[0467] ELSD analysis: purity 99.92%, calculated value C 52 H 104 N2O9 = 900.77, observed = 901.60 (m / z, M+H+). Example 6: Synthesis of Compound XL

[0468] For example, the compounds of the present invention can be prepared according to Scheme 6 (e.g. Figure 6 prepared as described in . Synthesis of intermediate [3]

[0469] As depicted 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 under a nitrogen atmosphere and heated to 95 ° C for 20 h. The progress of the reaction was monitored by ELSD / TLC (SM was consumed). The reaction mixture was concentrated and the crude product was purified by flash column chromatography (SiO : 0-10% methanol in dichloromethane) to obtain the desired 1-[(4-hydroxybutyl)(2-hydroxydecyl)amino]dec-2-ol [3] (20.0 g, 91% yield) as a white solid compound. result:

[0470] ELSD analysis: purity 99.85%, calculated value C 24 H 51 NO3 = 401.39, observed = 402.45 (m / z, M+H+). Synthesis of intermediate [4]

[0471] As depicted in Scheme 6: Under an inert atmosphere, to a stirred solution of 1-[(4-hydroxybutyl)(2-hydroxydecyl)amino...

Claims

1. A cationic lipid having a structure according to formula (I): or a pharmaceutically acceptable salt thereof, wherein A is selected from -N(R 1 )- or -SS-; R 1 is optionally substituted (C1-C6)alkyl; a and c are each independently an integer selected from 1, 2, 3 or 4; b and d are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Z 1 Selected from covalent bonds, or -SS-, where the left side of each depicted structure is connected to -(CH2) b - combine; Z 2 Selected from covalent bonds, or -SS-, where the right side of each depicted structure is connected to -(CH2) d - combine; Each Y 1 independently selected from hydrogen or -OH; Each R 8 independently selected from hydrogen or optionally substituted (C1-C6)alkyl; R 2A 、R 2B 、R 2C and R 2D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 1 )-connect.

2. A cationic lipid having a structure according to formula (II): or a pharmaceutically acceptable salt thereof, where 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 each independently an integer selected from 0, 1, 2, 3, or 4; f and h are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Each Y 2 independently selected from hydrogen or -OH; R 5A 、R 5B 、R 5C and R 5D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 2 )-connect.

3. A cationic lipid having a structure according to formula (III): or a pharmaceutically acceptable salt thereof, where 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 each independently an integer selected from 0, 1, 2, 3, or 4; j and l are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Each Y 3 independently selected from hydrogen or -OH; Each R 12 independently selected from hydrogen or optionally substituted (C1-C6)alkyl; R 11A 、R 11B 、R 11C and R 11D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 3 )-connect.

4. A cationic lipid having a structure according to formula (IV): or a pharmaceutically acceptable salt thereof, in m and n are each independently an integer selected from 1, 2, 3, 4, 5 or 6; Z 3 is an aromatic amino acid residue in which the α-carbon carboxyl group (-C(O)O-) of the aromatic amino acid residue is in a state of contact with the -(CH2) m - combined, and the α-carbonyl group (-NH-) of the aromatic amino acid residue is combined with Z 4 Combine; Z 4 Selected from The right side of each depicted structure is connected with -(CH2) n - combine; Each Y 4 independently selected from hydrogen or -OH; R 13A 、R 13B 、R 13C and R 13D are each independently selected from optionally substituted (C5-C 25 )alkyl, optionally substituted (C5-C 25 )alkenyl, or -W 1 -X 1 ; Each W 1 are independently selected from a covalent bond, an optionally substituted (C1-C 10 )alkylene or optionally substituted (C2-C 10 ) alkenylene; and Each X 1 Independently selected from -(*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, wherein the atom marked with * is 1 Connect or when W 1 When it is a covalent bond with -CH(Y 4 )-connect.

5. A compound selected from the group consisting of: (i) Table A or a pharmaceutically acceptable salt thereof; or (ii) Table B or a pharmaceutically acceptable salt thereof.

6. A composition comprising a cationic lipid as claimed in any one of the preceding claims and further comprising (i) one or more non-cationic lipids, (ii) one or more cholesterol-based lipids, and (iii) one or more PEG-modified lipids.

7. The composition according to claim 6, wherein The composition is a lipid nanoparticle, optionally a liposome.

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

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

10. A composition as claimed in claim 8 or 9 for use in a vaccine.

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

12. A composition as claimed in claim 9 for use in a method of treating or preventing a disease suitable for treatment or prevention by a peptide or protein encoded by the mRNA, optionally wherein the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lungs, brain or muscle, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

13. A composition for use as claimed in any one of claims 10 to 12, wherein The composition is administered intranasally, intravenously, intrathecally or intramuscularly, or by pulmonary delivery, optionally by aerosolization.

14. A method for treating or preventing a disease, wherein: The method comprises administering to a subject in need thereof a composition of claim 9, and wherein the disease is amenable to treatment or prevention by a peptide or protein encoded by the mRNA, optionally wherein the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lung, brain or muscle, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

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

Images