Dianhydrohexitol-based ionizable lipids for nucleic acid delivery

Abstract

The present invention provides, in part, a cationic dianhydrohexitol-based lipid having formula (I) and its sub-formula: (I), or a pharmaceutically acceptable salt thereof. The present invention also provides, in part, a cationic dianhydrohexitol-based lipid having formula (II) and its sub-formula: (II), 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-references to related applications

[0001] This application claims priority to European application number EP 23306049.0, filed on 28 June 2023, the entire disclosure of which is hereby incorporated by reference. Background Technology

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

[0003] Efficient delivery of liposome-encapsulated nucleic acids remains an active area of ​​research. Liposome-encapsulated nucleic acids can be administered intramuscularly (IM).

[0004] The cationic lipid components of liposomes play a crucial role in facilitating the efficient encapsulation of nucleic acids during liposome loading. Furthermore, cationic lipids can play a vital role in the efficient release of nucleic acid payloads from liposomes into the cytoplasm of target cells. Various cationic lipids suitable for in vivo use have been identified. However, there is still a need to identify cationic lipids effective for intramuscular delivery of mRNA (e.g., in vaccines, such as those against influenza or respiratory syncytial virus (RSV)). It is also necessary to identify cationic lipids that can be synthesized efficiently and inexpensively without forming potentially toxic byproducts. Summary of the Invention

[0005] This invention provides, in particular, a novel class of cationic lipid compounds for the in vivo delivery of therapeutic agents such as nucleic acids. The inventors of this invention have unexpectedly discovered that lipid nanoparticles comprising cationic lipids having a core based on disodihexitol (e.g., a core based on isosorbide, isomannitol, and isodulitol) are highly effective for intramuscular delivery of mRNA encapsulated in said lipid nanoparticles. In fact, lipid nanoparticles comprising the cationic lipids of this invention have exhibited high levels of expression of said peptides or proteins when delivered intramuscularly to encapsulate mRNA encoding said peptides or proteins. For example, when administered intramuscularly to mice, lipid nanoparticles comprising the cationic lipids of this invention and encapsulating human erythropoietin (hEPO) mRNA achieved improved hEPO mRNA expression; MC3 is currently the gold standard for in vivo delivery of, for example, siRNA (see WO 2010 / 144740).

[0006] The cationic lipids of this invention are also simpler to synthesize than other cationic lipids such as MC3. In fact, the synthesis of MC3 involves a six-step process and requires handling Grignard reagents. In contrast, this invention provides cationic lipids that can be prepared from readily available and inexpensive starting agents such as isosorbide (1,4:3,6-didehydr-D-glucol), isomannitol (1,4:3,6-didehydr-D-mannitol), and iso-idoteol (1,4:3,6-didehydr-L-idoteol).

[0007] The cationic lipids of the present invention also contain cleavable groups (e.g., esters, thioesters, disulfides, carbonates, carbamates, and thiocarbamates), which are envisioned to improve biodegradability and thus contribute to their advantageous safety.

[0008] These compounds are envisioned to enable efficient intramuscular delivery of therapeutics and vaccines (e.g., against influenza or respiratory syncytial virus (RSV)). Lipid nanoparticles containing these cationic lipid compounds are also envisioned to enable highly efficient in vivo delivery while maintaining favorable safety profiles. Furthermore, lipid nanoparticles containing these cationic lipid compounds are envisioned to exhibit improved in vivo degradation.

[0009] In one respect, this paper provides cationic lipids having a structure according to formula (I): (I) Or its pharmaceutically acceptable salt, wherein: A 1 Selected from -C(=O)O-, -C(=O)S-, -C(=O)NH-, -OC(=O)O-, -OC(=O)NH-, -NHC(=O)O-, -SC(=O)NH-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S-, and -SS-, wherein each of the listed structures is left-handedly bonded to -(CH2). a -; Z 1 The following are selected from -OC(=O)-, -SC(=O)-, -NHC(=O)-, -OC(=O)O-, -NHC(=O)O-, -OC(=O)NH-, -NHC(=O)S-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S-, and -SS-, wherein the right-hand side of each of the listed structures is bonded to -(CH2). a -; Each R is selected independently from: (i) , where each R 1Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; (ii) , where each R 2 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; (iii) , where each R 3 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; and (iv) , where each R 4 Independently selected from optional substituted cycloalkyl or optional substituted heterocyclic alkyl; At least three of the R's are independently selected from (i). (ii) Or (iii) ; Each 'a' is independently selected from 2, 3, 4, and 5; Each b is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; and Each c is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0010] In one respect, this article provides cationic lipids having formula (I), which are pharmaceutically acceptable salts.

[0011] In one respect, this paper provides cationic lipids having a structure according to formula (II): (II) Or its pharmaceutically acceptable salt, wherein: Each R is selected independently from: (i) , where each R 1Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; and (ii) , where each R 3 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Each 'a' is independently selected from 2, 3, 4, and 5; Each b is independently selected from 2, 3, 4, 5, 6, and 7; and Each 'c' is independently selected from 2, 3, 4, 5, 6, and 7.

[0012] In one respect, this article provides cationic lipids having formula (II), which are pharmaceutically acceptable salts.

[0013] In one aspect, this document provides compositions comprising the cationic lipids of the present invention or pharmaceutically acceptable salts thereof, 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.

[0014] In one aspect, the composition is lipid nanoparticles, optionally liposomes.

[0015] In one aspect, compositions comprising the cationic lipids of the present invention can be used in therapeutics, for example, to treat, prevent, or improve influenza or respiratory syncytial virus (RSV). Detailed Implementation definition

[0016] To facilitate understanding of the invention, certain terms are defined below. Further definitions of the following and other terms are set forth throughout the specification. Publications and other references cited herein to describe the background of the invention and to provide further details about its implementation are hereby incorporated by reference.

[0017] Amino acids: 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 universal structure H₂N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a d-amino acid; in some embodiments, an 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 it is 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 substitutes. Amino acids (including 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 cyclic half-life of the peptide without adversely affecting its activity. Amino acids can participate in disulfide bonds. Amino acids may contain one or more translational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprene-like groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.). The terms "amino acid" and "amino acid residue" are used interchangeably and can refer to free amino acids and / or amino acid residues of peptides. It is obvious from the context in which the term is used whether it refers to free amino acids or peptide residues.

[0018] Animal: As used herein, the term "animal" means any member of the animal kingdom. In some embodiments, "animal" means a human being at any developmental stage. In some embodiments, "animal" means a non-human animal at any developmental stage. In some embodiments, a non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, and / or pigs). In some embodiments, an animal includes, but is not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, an animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0019] Approximately or about: As used herein, the term “approximately” or “about” when applied to one or more target values ​​refers to a value similar to the stated reference value. In some embodiments, the term “approximately” or “about” refers to a range of values ​​falling 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 the stated reference value in either direction, unless otherwise stated or otherwise apparent from the context (except where such a number would exceed 100% of the possible value).

[0020] Biologically active: As used herein, the term "biologically active" refers to the characteristic of any agent that is active in a biological system and, in particular, in an organism. For example, an agent that has a biological effect on an organism when administered to that organism is considered biologically active.

[0021] Delivery: As used herein, the term “delivery” encompasses both local delivery and systemic delivery. For example, mRNA delivery encompasses the delivery of mRNA to a target tissue and the expression and retention of the encoded protein within that target tissue (also known as “local distribution” or “local delivery”), as well as the delivery of mRNA to a target tissue and the expression and secretion of the encoded protein into the patient’s circulatory system (e.g., serum) and the systemic distribution and uptake by other tissues (also known as “systemic distribution” or “systemic delivery”).

[0022] Expression: As used herein, “expression” of a nucleic acid sequence refers to the translation of mRNA into a polypeptide, the assembly of multiple polypeptides into a complete protein (e.g., an enzyme), and / or the post-translational modification of a polypeptide or a fully assembled protein (e.g., an enzyme). In this application, the terms “expression” and “production” and their grammatical equivalents are used interchangeably.

[0023] Functionality: As used herein, a “functional” biomolecule is a biomolecule that exhibits the properties and / or activities that characterize it.

[0024] 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.

[0025] Supporting lipids: As used herein, the term "supporting lipid" refers to any neutral or zwitterionic lipid material, including cholesterol. Without being bound by any particular theory, supporting lipids can increase the stability, rigidity, and / or fluidity within lipid bilayers / nanoparticles.

[0026] Improvement, increase, or decrease: As used herein, the terms “improvement,” “increase,” or “decrease,” or their grammatical equivalents, refer to a value relative to a baseline measurement, which is, for example, a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in a control subject (or multiple control subjects) in the absence of the treatment described herein. A “control subject” is a subject with the same form of disease as the subject being treated and who is approximately the same age as the subject being treated.

[0027] In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment (e.g., in test tubes or reaction vessels, in cell cultures, etc.) rather than within a multicellular organism.

[0028] In vivo: As used herein, the term "in vivo" refers to events that occur within multicellular organisms, such as humans and non-human animals. In 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.

[0029] Liposomes: As used herein, the term "liposome" refers to any layered, multilayered, or solid nanoparticle vesicle. Typically, liposomes as used herein can be formed by mixing one or more lipids or by mixing one or more lipids with one or more polymers. In some embodiments, liposomes suitable for use in the present invention contain one or more cationic lipids and optionally further include: (i) one or more non-cationic lipids, (ii) one or more cholesterol-based lipids, and / or (iii) One or more PEG-modified lipids.

[0030] Messenger RNA (mRNA): As used herein, the term “messenger RNA (mRNA)” or “mRNA” refers to a polynucleotide encoding at least one polypeptide. As used herein, mRNA encompasses both modified and unmodified RNA. The term “modified mRNA” refers to mRNA containing at least one chemically modified nucleotide. mRNA may contain one or more coding and noncoding regions. mRNA may be purified from natural sources, produced using recombinant expression systems, and optionally purified, chemically synthesized, etc. Where appropriate, for example, in the case of chemically synthesized molecules, mRNA may contain nucleoside analogs, such as analogs of chemically modified bases or sugars, backbone modifications, etc. Unless otherwise indicated, mRNA sequences are presented in a 5' to 3' orientation. In some embodiments, the mRNA is or comprises a natural nucleoside (e.g., adenosine, guanosine, cytidine, uridine); or a nucleoside analogue (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). Glycosides, 2-aminoadenosine, 7-deadenosine, 7-deadenosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, 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., thiophosphates and 5'-N-phosphoramide bonds).

[0031] Nucleic acid: As used herein, the term “nucleic acid” in its broadest sense refers to any compound and / or substance incorporated into or potentially incorporated into a polynucleotide chain. In some embodiments, a nucleic acid is a compound and / or substance incorporated into a polynucleotide chain via or potentially incorporated 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 containing a single nucleic acid residue. In some embodiments, “nucleic acid” encompasses RNA as well as 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), multimeric coding nucleic acid (MCNA), polymeric 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, DNA may be in the form of antisense DNA, plasmid DNA, a portion of plasmid DNA, pre-condensed DNA, a polymerase chain reaction (PCR) product, a vector (e.g., P1, PAC, BAC, YAC, artificial chromosome), an expression cassette, a chimeric sequence, chromosomal DNA, or derivatives of these groups.In embodiments, 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 Cahalanosome-specific RNA (scaRNA), guide RNA (gRNA), ribonuclease P (RNase P), Y RNA, telomerase RNA component (TERC), splicing leader RNA (SLRNA), antisense RNA (aRNA or asRNA), cis-natural antisense transcript (cis-NAT), CRISPR RNA (crRNA), long non-coding RNA (lncRNA), microRNA (miRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), transcribed siRNA (tasiRNA), repeat-associated siRNA (rasiRNA), 73K RNA, retrotransposons, viral genomes, viroids, satellite RNA, or derivatives of these groups. In some embodiments, nucleic acid is mRNA encoding a protein (such as an enzyme).

[0032] Patient: As used herein, the terms "patient" or "subject" refer to any biological organism to which the provided composition may be administered, for example, for experimental, diagnostic, preventative, 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.

[0033] Pharmaceutically acceptable: As used herein, the term “pharmaceutically acceptable” means, to the extent of reasonable medical judgment, a substance suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0034] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. described 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 formed by an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (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 using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, sulfonate, and arylsulfonate). Other pharmaceutically acceptable salts include those formed by quaternizing amines with suitable electrophilic agents (e.g., alkyl halides) to form quaternized alkylamino salts.

[0035] Whole-body distribution or delivery: As used herein, the terms “whole-body distribution” or “whole-body delivery,” or their grammatical equivalents, refer to a mechanism or method of delivery or distribution that affects the whole body or the whole organism. Typically, whole-body distribution or delivery is accomplished via the body’s circulatory system (e.g., blood flow). Compare this to the definition of “local distribution or delivery.”

[0036] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes both prenatal and postnatal forms. In many embodiments, the subject is a human being. A subject can be a patient, referring to a person who goes to a healthcare provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably with "individual" or "patient" herein. A subject may have or be susceptible to a disease or disorder, but may or may not exhibit symptoms of the disease or disorder.

[0037] Essentially: As used herein, the term “essentially” refers to a qualitative condition that exhibits all or nearly all of the intended characteristics or properties, or to a degree or extent. Those skilled in the art of biology will understand that biological and chemical phenomena rarely (if at all) complete and / or proceed to completion or achieve or avoid an absolute result. Therefore, the term “essentially” is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0038] Target tissue: As used herein, the term “target tissue” refers to any tissue affected by the disease to be treated. In some embodiments, target tissue includes those tissues that exhibit pathology, symptoms, or features associated with the disease.

[0039] Therapeutic effective amount: As used herein, the term "therapeutic effective amount" means an amount sufficient to treat, diagnose, prevent, and / or delay the onset of one or more symptoms of a disease, disorder, and / or condition when administered to a subject who has or is susceptible to such disease, disorder, and / or condition. Those skilled in the art will understand that a therapeutic effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0040] Treatment: As used herein, the term "treatment" means any method used to partially or completely alleviate, relieve, reduce, suppress, prevent, delay the onset, reduce the severity, and / or decrease 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 only exhibit early signs of disease for the purpose of reducing the risk of developing a disease-related pathology. Chemical definition

[0041] Acyl group: As used herein, the term "acyl group" refers to R Z -(C=O)-, where R Z It is, for example, any alkyl, alkenyl, ynyl, heteroalkyl, or heteroalkylene.

[0042] Aliphatic: As used in this article, the term "aliphatic" refers to (C1-C2) 50Hydrocarbons, including both saturated and unsaturated hydrocarbons. Aliphatic hydrocarbons can be straight-chain, branched, or cyclic. For example, (C1-C2) 20 Aliphatic compounds can include (C1-C1) 20 )alkyl (e.g., straight-chain or branched (C1-C1) 20 ) saturated alkyl), (C2-C 20 Alkenyl (e.g., straight-chain or branched (C4-C5)) 20 diene-based, straight-chain or branched (C6-C) 20 (trienyl, etc.), and (C2-C 20 ) alkynyl group (e.g., straight-chain or branched (C2-C) 20 )alkynyl group). (C1-C 20 Aliphatic compounds can include (C3-C) 20 ) Cyclic aliphatic (e.g., (C3-C) 20 )cycloalkyl, (C4-C 20 )cycloalkenyl, or (C8-C 20 (Cycloalkyne). In some embodiments, the aliphatic group may comprise one or more cyclic aliphatic groups and / or one or more heteroatoms (such as oxygen, nitrogen, or sulfur), and may optionally be substituted with one or more substituents (such as alkyl, halogen, alkoxy, hydroxyl, 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 of halogen, -COR'', -CO2H, -CO2R'', -CN, -OH, -OR'', -OCOR'', -OCO2R'', -NH2, -NHR'', -N(R'')2, -SR'', or -SO2R'' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein each example of R'' is independently (C1-C1). 20 Aliphatic (e.g., (C1-C) 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl. In the examples, R'' is independently an unsubstituted alkyl group (e.g., an unsubstituted (C1-C3)alkyl group). 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl). In the examples, R'' is independently an unsubstituted (C1-C3)alkyl. In the examples, aliphatic is unsubstituted. In the examples, aliphatic does not include any heteroatoms. Alkyl: As used herein, the term "alkyl" means acyclic straight-chain and branched hydrocarbon groups, such as "(C1-C3)alkyl". 30"Alkyl" refers to an alkyl group having 1 to 30 carbon atoms. Alkyl groups can be straight-chain or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, etc. The term "lower alkyl" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Other alkyl groups will be apparent to those skilled in the art in light of the benefits of this disclosure. Alkyl groups can be unsubstituted or branched by one or more carbon atoms. Multiple substituents as described herein may be used for substitution. For example, the alkyl group may be substituted with one or more of the following: halogen, -COR'', -CO2H, -CO2R'', -CN, -OH, -OR'', -OCOR'', -OCO2R'', -NH2, -NHR'', -N(R'')2, -SR'', or -SO2R'' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein each example of R'' is independently (C1-C2). 20 Aliphatic (e.g., (C1-C) 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl. In the examples, R'' is independently an unsubstituted alkyl group (e.g., an unsubstituted (C1-C3)alkyl group). 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl). In the examples, R'' is independently an unsubstituted (C1-C3)alkyl. In the examples, the alkyl group is substituted (e.g., 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In the examples, the alkyl group is substituted with a -OH group and may also be referred to herein as "hydroxyalkyl", wherein the prefix indicates a -OH group and "alkyl" is as described herein.

[0043] As used herein, "alkyl" also refers to a group having a straight-chain or branched saturated hydrocarbon group having 1 to 50 carbon atoms ("(C1-C50")). 50 Alkyl groups ("(C1-C4")) are used in some embodiments. In some embodiments, the alkyl group has 1 to 40 carbon atoms ("(C1-C4")). 40 Alkyl groups ("(C1-C2")) are present in some embodiments. In some embodiments, the alkyl group has 1 to 30 carbon atoms ("(C1-C2")). 30 Alkyl groups ("(C1-C2")) are present in some embodiments. In some embodiments, the alkyl group has 1 to 20 carbon atoms ("(C1-C2")). 20 Alkyl groups ("(C1-C1")) are present in some embodiments. In some embodiments, the alkyl group has 1 to 10 carbon atoms ("(C1-C1")). 10(C1-C9)alkyl. In some embodiments, the alkyl group has 1 to 9 carbon atoms ("(C1-C8)alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("(C1-C7)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, the 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). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In some embodiments, the alkyl group is unsubstituted (C1-C6). 50 Alkyl groups. In some embodiments, the alkyl group is substituted (C1-C2). 50 )alkyl.

[0044] The suffix "-ene" is attached to a group to indicate that the group is a divalent moiety. For example, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0045] Alkylene: As used herein, the term "alkylene" refers to a saturated divalent straight-chain or branched hydrocarbon group, and exemplified by methylene, ethylene, isopropylene, etc. Similarly, as used herein, the term "alkenylene" refers to an unsaturated divalent straight-chain or branched hydrocarbon group having one or more unsaturated carbon-carbon double bonds that can appear at any stable point along the chain, and the term "alkynylene" refers to an unsaturated divalent straight-chain or branched hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that can appear at any stable point along the chain. In some embodiments, alkylene, alkenylene, or alkynylene may comprise one or more cyclic aliphatic and / or one or more heteroatoms (such as oxygen, nitrogen, or sulfur), and may optionally be substituted with one or more substituents (such as alkyl, halogen, alkoxy, hydroxyl, amino, aryl, ether, ester, or amide). For example, the alkylene, alkenylene, or ynylene group may be substituted with one or more of the following: halogen, -COR'', -CO2H, -CO2R'', -CN, -OH, -OR'', -OCOR'', -OCO2R'', -NH2, -NHR'', -N(R'')2, -SR'', or -SO2R'' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein each example of R'' is independently (C1-C2). 20 Aliphatic (e.g., (C1-C) 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl. In the examples, R'' is independently an unsubstituted alkyl group (e.g., an unsubstituted (C1-C3)alkyl group). 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl). In the embodiments, R'' is independently an unsubstituted (C1-C3)alkyl. In some embodiments, the alkylene, alkenyl, or ynylene is unsubstituted. In some embodiments, the alkylene, alkenyl, or ynylene 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 can appear at any stable point along the chain, such as (C2-C3)alkyl. 30"Alkenyl" refers to an alkenyl group having 2-30 carbon atoms. For example, alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, etc. In embodiments, the alkenyl group comprises 1, 2, or 3 carbon-carbon double bonds. In embodiments, the alkenyl group comprises a single carbon-carbon double bond. In embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. The alkenyl group may be unsubstituted or substituted by one or more carbon atoms. The alkenyl group may be substituted with one or more of the following substituents as described herein: -COR'', -CO2H, -CO2R'', -CN, -OH, -OR'', -OCOR'', -OCO2R'', -NH2, -NHR'', -N(R'')2, -SR'', or -SO2R'' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein each example of R'' is independently (C1-C2). 20 Aliphatic (e.g., (C1-C) 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl. In the examples, R'' is independently an unsubstituted alkyl group (e.g., an unsubstituted (C1-C3)alkyl group). 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl). In the examples, R'' is independently an unsubstituted (C1-C3)alkyl. In the examples, the alkenyl group is unsubstituted. In the examples, the alkenyl group is substituted (e.g., 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In the examples, the alkenyl group is substituted with a -OH group and may also be referred to herein as "hydroxyalkenyl", where the prefix indicates a -OH group and "alkenyl" is as described herein.

[0046] As used herein, "alkenyl" also refers to a straight-chain or branched hydrocarbon group having 2 to 50 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). 50 ()alkenyl". In some embodiments, the alkenyl group has 2 to 40 carbon atoms ("(C2-C") 40 ()alkenyl". In some embodiments, the alkenyl group has 2 to 30 carbon atoms ("(C2-C") 30 ()alkenyl". In some embodiments, the alkenyl group has 2 to 20 carbon atoms ("(C2-C") 20 ()alkenyl". In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("(C2-C") 10(C2-C9)alkenyl. In some embodiments, the alkenyl has 2 to 9 carbon atoms ("(C2-C8)alkenyl"). In some embodiments, the alkenyl has 2 to 8 carbon atoms ("(C2-C7)alkenyl"). In some embodiments, the alkenyl has 2 to 7 carbon atoms ("(C2-C7)alkenyl"). In some embodiments, the alkenyl has 2 to 6 carbon atoms ("(C2-C6)alkenyl"). In some embodiments, the alkenyl has 2 to 5 carbon atoms ("(C2-C5)alkenyl"). In some embodiments, the alkenyl has 2 to 4 carbon atoms ("(C2-C4)alkenyl"). In some embodiments, the alkenyl has 2 to 3 carbon atoms ("(C2-C3)alkenyl"). In some embodiments, the alkenyl has 2 carbon atoms ("(C2)alkenyl"). The one or more carbon-carbon bicarbonates The bond can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 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-described (C2-C4)alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Further examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is unsubstituted (C2-C4). 50 Alkenyl group. In some embodiments, the alkenyl group is substituted (C2-C). 50 )alkenyl.

[0047] Alkynyl: As used herein, "alkynyl" means a hydrocarbon chain having a straight-chain or branched configuration with one or more carbon-carbon triple bonds appearing at any stable point along the chain, for example, "(C2-C 30 "Alynyl" refers to an alkynyl group having 2-30 carbons. Examples of alkynyl groups include prop-2-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-2-alkynyl, 3-methylpent-4-alkynyl, hex-2-alkynyl, hex-5-alkynyl, etc. In the examples, the alkynyl group contains a carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more substituents as described herein. For example, the alkynyl group can be substituted with one or more of halogen, -COR'', -CO2H, -CO2R'', -CN, -OH, -OR'', -OCOR'', -OCO2R'', -NH2, -NHR'', -N(R'')2, -SR'', or -SO2R'' (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents), wherein each example of R'' is independently (C1-C2). 20Aliphatic (e.g., (C1-C) 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl. In the examples, R'' is independently an unsubstituted alkyl group (e.g., an unsubstituted (C1-C3)alkyl group). 20 )alkyl, (C1-C 15 )alkyl, (C1-C 10 (C1-C3)alkyl). In the examples, R'' is independently an unsubstituted (C1-C3)alkyl. In the examples, the alkynyl group is unsubstituted. In the examples, the alkynyl group is substituted (e.g., 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0048] As used herein, “alkynyl” also refers to a straight-chain or branched hydrocarbon group having 2 to 50 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds). 50 The alkynyl group ("(C2-C")) is also referred to as "enynyne". In some embodiments, the alkynyl group has 2 to 40 carbon atoms ("(C2-C")). 40 () ynyl group). In some embodiments, the ynyl group has 2 to 30 carbon atoms ("(C2-C") 30 () ynyl group). In some embodiments, the ynyl group has 2 to 20 carbon atoms ("(C2-C"). 20 () ynyl group). In some embodiments, the ynyl group has 2 to 10 carbon atoms ("(C2-C") 10(C2-C9) ynyl group. In some embodiments, the ynyl group has 2 to 9 carbon atoms ("(C2-C8) ynyl group"). In some embodiments, the ynyl group has 2 to 8 carbon atoms ("(C2-C8) ynyl group"). In some embodiments, the ynyl group has 2 to 7 carbon atoms ("(C2-C7) ynyl group"). In some embodiments, the ynyl group has 2 to 6 carbon atoms ("(C2-C6) ynyl group"). In some embodiments, the ynyl group has 2 to 5 carbon atoms ("(C2-C5) ynyl group"). In some embodiments, the ynyl group has 2 to 4 carbon atoms ("(C2-C4) ynyl group"). In some embodiments, the ynyl group has 2 to 3 carbon atoms ("(C2-C3) ynyl group"). In some embodiments, the ynyl group has 2 carbon atoms ("(C2) ynyl group"). The (C2-C4) alkynyl group is an alkynyl group. The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of (C2-C4) alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. Examples of (C2-C6) alkenyl groups include the above-mentioned (C2-C4) alkynyl groups as well as pentynyl (C5), hexynyl (C6), etc. Further examples of alkynyl groups include heptyynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of an alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is unsubstituted (C2-C4). 50 ) alkynyl group. In some embodiments, the alkynyl group is substituted (C2-C... 50 ) yyn group.

[0049] Aryl: The term "aryl," as used alone or as part of the broader term "araneyl," refers to a monocyclic, bicyclic, or tricyclic carbocyclic system having a total of six to fourteen ring members, wherein the ring system has a single point attached to the remainder of the molecule, at least one ring in the system is aromatic, and each ring in the system contains four to seven ring members. In embodiments, the aryl group has six ring carbon atoms ("(C6)aryl", for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("(C6)aryl", for example, phenyl). 10 aryl, for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 cyclic carbon atoms (“(C 14 "Aryl" (e.g., anthracene). "Aryl" also includes cyclic systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the attachment group or attachment site is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Exemplary aryl groups include phenyl, naphthyl, and anthracene.

[0050] As used herein, "aryl" also refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in a ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("(C6-C 14 (C6)aryl. In some embodiments, the aryl group has 6 ring carbon atoms ("(C6)aryl"; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("(C6)aryl"). 10 aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 cyclic carbon atoms (“(C 14 "Aryl"; for example, anthracene. "Aryl" also includes cyclic systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the attachment group or attachment site is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Unless otherwise stated, each example of an aryl is either independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl group is unsubstituted (C6-C6). 14 )Aryl. In some embodiments, the aryl group is substituted (C6-C) 14 Aryl.

[0051] arylene: As used herein, the term "arylene" refers to a divalent (i.e., having two attachment sites with the molecule) aryl group. Exemplary arylene groups include phenylene (e.g., unsubstituted or substituted phenylene).

[0052] Carbocyclic group: As used herein, "carbocyclic group" or "carbocyclic" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("(C3-C10")). 10 A group consisting of a carbocyclic group ("(C3-C8) carbocyclic") and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms ("(C3-C7) carbocyclic"). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms ("(C3-C7) carbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms ("(C3-C6) carbocyclic"). In some embodiments, the carbocyclic group has 4 to 6 cyclic carbon atoms ("(C4-C6) carbocyclic"). In some embodiments, the carbocyclic group has 5 to 6 cyclic carbon atoms ("(C5-C6) carbocyclic"). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms ("(C5-C6) carbocyclic"). 10(C3-C6) carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary (C3-C8) carbocyclic groups include, but are not limited to, the above (C3-C6) carbocyclic groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary (C3-C6) carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutenyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), bicyclo[2.2.2]octyl (C8), etc. 10 Carbocyclic groups include, but are not limited to, the aforementioned (C3-C8) carbocyclic groups, as well as cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl (C 10 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or polycyclic (e.g., containing fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic carbocyclic”) or tricyclic systems (“tricyclic carbocyclic”)) and may be saturated or may contain one or more carbon-carbon double or triple bonds. “Carbocyclic” also includes cyclic systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the attachment point is on the carbocyclic 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 example of a carbocyclic group is independently unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is unsubstituted C3-C. 10 Carbocyclic group. In some embodiments, the carbocyclic group is substituted (C3-C4). 10 ) carbon cyclic group.

[0053] In some embodiments, "carbocyclic" or "carbocyclic" refers to "cycloalkyl", that is, a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("(C3-C10")). 10 (C3-C8)cycloalkyl. In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms ("(C3-C6)cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms ("(C3-C6)cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms ("(C4-C6)cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms ("(C5-C6)cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms ("(C5-C6)cycloalkyl").10 (C5-C6)cycloalkyl groups are cyclopentyl (C5) and cyclohexyl (C5). Examples of (C3-C6)cycloalkyl groups include the above-described (C5-C6) cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of (C3-C8) cycloalkyl groups include the above-described (C3-C6) cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each example of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is unsubstituted (C3-C6). 10 )cycloalkyl. In some embodiments, the cycloalkyl group is substituted (C3-C4). 10 )cycloalkyl.

[0054] Heteroalkyl: The term "heteroalkyl" refers to a branched or unbranched alkyl, alkenyl, or alkynyl group having 1 to 14 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyl groups include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphate diesters, phosphoramides, sulfonamides, and disulfides. Heteroalkyl groups may optionally include monocyclic, bicyclic, or tricyclic rings, wherein each ring desirably has three to six members. Examples of heteroalkyl groups include polyethers such as methoxymethyl and ethoxyethyl.

[0055] Heteroalkyl: As used herein, the term “heteroalkyl” refers to the divalent form of a heteroalkyl group as described herein.

[0056] Heteroaryl: As used herein, the term “heteroaryl” is a fully unsaturated ring containing heteroatoms, wherein at least one ring atom is a heteroatom, such as, but not limited to, nitrogen and oxygen.

[0057] As used herein, “heteroaryl” also refers to a group of a 5-14 member monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic array), having a cyclic carbon atom and one or more cyclic heteroatoms (e.g., 1, 2, 3, or 4 cyclic heteroatoms), wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-14 member heteroaryl”). In heteroaryls containing one or more nitrogen atoms, the attachment point can be a carbon atom or a nitrogen atom, where the valence allows. Heteroaryl polycyclic systems may include one or more heteroatoms in one or two rings. “Heteroaryl” includes cyclic systems in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the attachment point is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl cyclic system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the attachment point is on the aryl or heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. A polycyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) may have its attachment point on either ring (i.e., the ring carrying the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl)).

[0058] In some embodiments, a heteroaryl group is a 5-10 cyclic aromatic ring system having one or more (e.g., 1, 2, 3, or 4) cyclic heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-10 cyclic heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 cyclic aromatic ring system having one or more (e.g., 1, 2, 3, or 4) cyclic heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-8 cyclic heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 cyclic aromatic ring system having one or more (e.g., 1, 2, 3, or 4) cyclic heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-6 cyclic heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has one or more (e.g., 1, 2, or 3) cyclic heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6-membered heteroaryl group has one or two cyclic heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6-membered heteroaryl group has one cyclic 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 with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14-membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14-membered heteroaryl group.

[0059] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, aziryl, oxazinyl, and thioazinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridine, dibenzofuranyl, carbazoleyl, acridineyl, phenothiazinyl, phenothiazinyl, and phenothiazinyl.

[0060] As used herein, "heterocyclic group" or "heterocyclic" refers to a 3- to 14-membered non-aromatic ring system having a ring carbon atom 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- to 14-membered heterocyclic groups"). In heterocyclic groups containing one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group") or tricyclic systems ("tricyclic heterocyclic group")), and can be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclic polycyclic systems may include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes ring systems in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups (where the attachment point is on the carbocyclic or heterocyclic ring), or ring systems in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups (where the attachment point is on the heterocyclic ring), and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Unless otherwise stated, each example of a heterocyclic group is independently unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3-14 membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-14 membered heterocyclic group.

[0061] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and one or more (e.g., 1, 2, 3, or 4) cyclic heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and one or more (e.g., 1, 2, 3, or 4) cyclic heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and one or more (e.g., 1, 2, 3, or 4) cyclic heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has one or more (e.g., 1, 2, or 3) cyclic heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heterocyclic group has one or two cyclic heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.

[0062] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, ethylene oxide, and thioalkyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxadiazolinyl, and thiobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopentyl, oxadiazolinyl, and dithiopentanyl. 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 thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary bicyclic heterocyclic groups include, but are not limited to, indole, isoindole, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindole, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphridyl, decahydro-1,8-naphridyl, octahydropyrrolo[3,2-b]pyrrole, indolelinyl, phthalimide, naphthalimide, chromenyl, 1H-benzo[e][1,4]diazazolyl, 1,4,5,7-tetrahydropyranolo[3,4-b]pyrrole, 5,6- Dihydro-4H-furano[3,2-b]pyrrolithyl, 6,7-dihydro-5H-furano[3,2-b]pyrrolithyl, 5,7-dihydro-4H-thieno[2,3-c]pyrrolithyl, 2,3-dihydro-1H-pyrroli[2,3-b]pyridyl, 2,3-dihydrofurano[2,3-b]pyridyl, 4,5,6,7-tetrahydro-1H-pyrroli-[2,3-b]pyridyl, 4,5,6,7-tetrahydrofurano[3,2-c]pyridyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-tetrahydro-1,6-naphthidyl, etc.

[0063] Heterocyclic alkyl: As used herein, the term "heterocyclic alkyl" 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. Heterocyclic alkyl can be substituted or unsubstituted.

[0064] As can be understood from the above, in some embodiments, alkyl, alkenyl, alkynyl, acyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups as defined herein are optionally substituted. Optional substituted means that the group can 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" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted" means that at least one hydrogen atom present on the group is replaced by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, for example, does not spontaneously undergo substitution such as by recombination. Compounds transformed by exclusion, cyclization, elimination, or other reactions. Unless otherwise stated, a “substituted” group has a substituent at one or more substituted positions of the group, and when more than one position is substituted in any given structure, the substituent is the same or different at each position. The term “substituted” is contemplated to include substitution by all permissible substituents of an organic compound, resulting in the formation of any substituent described herein that results in a stable compound. The invention contemplates any and all such combinations to obtain stable compounds. For the purposes of the invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein, which satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0065] Exemplary carbon atom substituents include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2, -SO3H, -OH, and -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)Raa 、-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)(NRbb )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 ) ynyl group, (C3-C 14 ) carbocyclic group, 3-14 membered heterocyclic group, (C6-C 14 ) aryl, and 5-14 heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R dd Group substitution; Or two hydrogen atom on a carbon atom with =O, =S, =NN(R) groups 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 replace;

[0066] R aa Each example is independently selected from (C1-C 50 )alkyl, (C2-C 50 )alkenyl, (C2-C 50 ) ynyl group, (C3-C 10 ) carbocyclic group, 3-14 membered heterocyclic group, (C6-C 14 ) aryl, and 5-14 heteroaryl, or two R aa Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0067] R bb Each example is independently selected from hydrogen, -OH, -ORaa - 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 ) ynyl group, (C3-C 10 ) carbocyclic group, 3-14 membered heterocyclic group, (C6-C 14 ) aryl, and 5-14 heteroaryl, or two R bb The groups, together with the heteroatoms to which they are attached, form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0068] R cc Each example is independently selected from hydrogen, (C1-C) 50 )alkyl, (C2-C 50 )alkenyl, (C2-C 50 ) ynyl group, (C3-C 10 ) carbocyclic group, 3-14 membered heterocyclic group, (C6-C 14 ) aryl, and 5-14 heteroaryl, or two R cc The groups, together with the heteroatoms to which they are attached, form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0069] R dd Each example is independently selected from halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2、-N(R ff )3+X - -N(OR) ee )R ff -SH, -SR ee - SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、- OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee - OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee-P(=O)2R ee - P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2、(C1-C 50 )alkyl, (C2-C 50 )alkenyl, (C2-C 50 ) ynyl group, (C3-C 10 ) carbocyclic group, 3-10 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal R groups dd Substituents can be linked to form =O or =S;

[0070] R ee Each example is independently selected from (C1-C 50 )alkyl, (C2-C 50 )alkenyl, (C2-C 50 ) ynyl group, (C3-C 10 ) carbocyclic group, (C6-C 10 aryl, 3-10 membered heterocyclic, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0071] R ff Each example is independently selected from hydrogen, (C1-C) 50 )alkyl, (C2-C 50 )alkenyl, (C2-C 50 ) ynyl group, (C3-C 10 ) carbocyclic group, 3-10 membered heterocyclic group, (C6-C 10 ) aryl and 5-10 heteroaryl, or two R ff The groups, together with the heteroatoms to which they are attached, form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; and

[0072] R gg Each example independently is a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -O(Cl-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(O(C1-C) 50 )alkyl)((C1-C 50 )alkyl), -N(OH)((C1-C 50 )alkyl), -NH(OH), -SH, -S(C1-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)O(C1-C 50 )alkyl, -C(=NH)N((C1-C 50 )alkyl)2、-C(=NH)NH((C1-C 50 )alkyl), -C(=NH)NH2, -OC(=NH)N((C1-C 50 )alkyl)2、-OC(NH)NH((C1-C 50 )alkyl), -OC(NH)NH2, -NHC(NH)N((C1-C 50)alkyl)2、-NHC(=NH)NH2、-NHSO2((C1-C 50 )alkyl), -SO2N((C1-C 50 )alkyl)2、-SO2NH((C1-C 50 )alkyl), -SO2NH2, -SO2((C1-C 50 )alkyl), -SO2O((C1-C 50 -alkyl), -OSO2((C1-C6)alkyl), -SO((C1-C6)alkyl), -Si ... 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)(O(C1-C 50 )alkyl)2、(C1-C 50 )alkyl, (C2-C 50 )alkenyl, (C2-C 50 ) ynyl group, (C3-C 10) Carbocyclic group, (C6-C 10 ) aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two geminal R gg Substituents can be linked to form =O or =S; where X - It is a counter ion.

[0073] As used herein, the term “halogenated” or “halogen” refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br), or iodine (iodine, -I).

[0074] As used herein, a "counterion" is a negatively charged group that associates with a positively charged quaternary ammonium to maintain electronic neutrality. Exemplary counterions 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-5-sulfonate, ethane-1-sulfonic-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0075] Where valence permits, the nitrogen atom can be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, and -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 ) ynyl group, (C3-C 10 ) carbocyclic group, 3-14 membered heterocyclic group, (C6-C 14 ) aryl, and 5-14 heteroaryl, or two R cc The groups, together with the nitrogen atoms to which they are attached, form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R atoms. dd Group substitution, and wherein R aa R bb R ccand R dd As defined above.

[0076] In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also known as amino protecting groups). 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 edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0077] For example, nitrogen-protecting groups such as amide groups (e.g., -C(=O)R) aa This includes, but is not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridine amide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0078] Nitrogen protecting groups, such as urethane groups (e.g., -C(=O)OR), aaThis includes, but is not limited to, methyl carbamates, ethyl carbamates, 9-fluorenyl methyl carbamate (Fmoc), 9-(2-sulfonyl)fluorenyl methyl carbamate, 9-(2,7-dibromo)fluoroenyl methyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl ethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), and 1-(1-adamantyl)-1-methylethyl carbamate. (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 2-(p-Toluenesulfonyl)ethylcarbamate, [2-(1,3-dithionyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphoethylcarbamate (Peoc), 2-triphenylphosphoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonelmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-Dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl The following are listed as carbamates: 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-l-cyclopropylmethylcarbamate, 1-methyl-1(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-l-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-tert-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,6-trimethylbenzylcarbamate.

[0079] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2R) aa This includes, but is 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-pentamethylsomn-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethylsulfonamide.

[0080] Other nitrogen-protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, and N-methylamine. N-Allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptanamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl] ]amine (MMTr), N-9-phenylfluoreneamine (PhF), N-2,7-dichloro-9-fluorenemethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-picoylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N' N,N'-Dimethylaminomethylene)amine, N,N'-isopropylidene diamine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylimine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N -Nitroamines, N-nitrosamines, N-oxides of amines, diphenylphosphamides (Dpp), dimethylthiophosphamides (Mpt), diphenylthiophosphamides (Ppt), dialkylphosphamides, dibenzylphosphamides, diphenylphosphamides, benzenesulfinamides, o-nitrobenzenesulfinamides (Nps), 2,4-dinitrobenzenesulfinamides, pentachlorobenzenesulfinamides, 2-nitro-4-methoxybenzenesulfinamides, triphenylmethylsulfinamides, and 3-nitropyridinesulfinamides (Npys).

[0081] In some embodiments, the substituents present on the oxygen atom are oxygen protecting groups (also known as hydroxy protecting groups). 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 Edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0082] 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), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (T) HP), 3-bromotetrahydropyranyl, tetrahydrothiaranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiaranyl, 4-methoxytetrahydrothiaranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-bridged methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-l-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1 -Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyselenoyl)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-methylpyridinyl, 4-methylpyridinyl, 3-methyl-2-methylpyridinyl N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzocycloheptyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenyl Methyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoylmethyloxyphenyl)diphenylmethyl, 4,4',4”-tris(4,5-dichlorobenzoiminophenyl)methyl, 4,4',4”-tris(acetylpropionyloxyphenyl)methyl, 4,4',4”-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4”-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)xantholyl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiofuran-2-yl, benzisothiazolyl S,S-dioxane bridge, 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, triphenylmethoxy Acetates, phenoxyacetic acid esters, p-chlorophenoxyacetic acid esters, 3-phenylpropionate esters, 4-oxovalerate esters (acetylpropionate esters), 4,4-(ethylene dithio)valerate esters (acetylpropionyl dithioacetal), p-valerate esters, adamantinate esters, crotonate esters, 4-methoxycrotonate esters, benzoate esters, p-phenyl benzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonates, 9-fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonates, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonium)ethyl carbonate Esters (Peoc), alkyl isobutyl carbonates, alkyl vinyl carbonates, alkyl allyl carbonates, alkyl p-nitrophenyl carbonates, alkyl benzyl carbonates, alkyl p-methoxybenzyl carbonates, alkyl 3,4-dimethoxybenzyl carbonates, alkyl o-nitrobenzyl carbonates, alkyl p-nitrobenzyl carbonates, alkyl S-benzyl thiocarbonates, 4-ethoxy-1-naphthyl carbonates, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro- 4-Methylphenoxyacetic acid ester, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid ester, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid ester, dichlorophenylacetic acid ester, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthylcarbamate, nitrate esters, alkyl N,N,N',N'-tetramethyldiaminophosphate, alkyl N-phenylcarbamate, borate esters, dimethylphosphothio, alkyl 2,4-dinitrophenylsulfinate, sulfate esters, methanesulfonate (mesylate), benzylsulfonate, and toluenesulfonate (Ts).

[0083] In some embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also known as thiol protecting groups). Sulfur 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 edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0084] 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-pyridinemethyl, 2-quinolinylmethyl, 2-pyridinemethyl N-oxide, 9-anthraylmethyl, 9-fluorenylmethyl, xanthyl, ferroceneylmethyl, diphenylmethyl, bis(4-methoxyphenyl)methyl, 5-dibenzocycloheptanyl, triphenylmethyl, diphenyl-4-pyridylmethyl, phenyl, 2,4-dinitrophenyl, tert-butyl, 1-adamantyl, methoxymethyl (MOM), isobutoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzylthiomethyl, phenylthiomethyl, thiazolidino, acetamoxymethyl, trimethylacetamoxymethyl, benzamidemethyl, allyloxycarbonylaminomethyl methyl, phenylacetamidomethyl, phthalimidemethyl, acetylmethyl, carboxymethyl, cyanomethyl, (2-nitro-1-phenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl, 2-cyanoethyl, 2-(trimethylsilyl)ethyl, 2,2-bis(carbonylethoxy)ethyl, (1-m-nitrophenyl-2-benzoyl)ethyl, 2-phenylsulfonylethyl, 2-(4-methylphenylsulfonyl)-2-methylprop-2 - 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, thiosulfinate, 3-nitro-2-pyridinethiosulfinate, oxathiolone. The compounds of the present invention

[0085] Liposome-based mediators are considered attractive carriers for therapeutics and continue to be developed. While liposome-based mediators containing certain lipid components have shown good results in terms of encapsulation, stability, and site localization, liposome-based delivery systems still require significant improvement. For example, significant drawbacks of liposome delivery systems involve the construction of liposomes that are stable enough in cell culture or in vivo to reach the desired target cells and / or intracellular compartments, and the ability of such liposome delivery systems to efficiently release their encapsulating material into such target cells.

[0086] In particular, cationic lipids remain needed for efficient intramuscular delivery of mRNA (e.g., for the treatment of influenza or respiratory syncytial virus (RSV)). Improved lipid compounds are also needed that exhibit improved pharmacokinetic properties and are capable of delivering macromolecules such as nucleic acids to a variety of cell types and tissues with enhanced efficiency. Importantly, novel lipid compounds also remain in particular need, characterized by improved safety and the ability to efficiently deliver encapsulated nucleic acids and polynucleotides to target cells, tissues, and organs.

[0087] This article describes a novel class of cationic lipid compounds for improving the in vivo delivery of therapeutic agents such as nucleic acids (e.g., against influenza or respiratory syncytial virus (RSV)). Specifically, the cationic lipids described herein can optionally be used in conjunction with other lipids to formulate lipid-based nanoparticles (e.g., liposomes) for therapeutic purposes such as disease treatment and prevention (vaccines, e.g., against influenza or RSV), to encapsulate therapeutic agents such as nucleic acids (e.g., DNA, siRNA, mRNA, microRNA).

[0088] In the embodiments, the compounds of the present invention as described herein may provide one or more desired features or properties. That is, in some embodiments, the compounds of the present invention as described herein may be characterized by having one or more properties that provide an advantage over other similar classifications of lipids. For example, the compounds disclosed herein may allow control and customization of the properties of liposome compositions (e.g., lipid nanoparticles) in which they are components. In particular, the compounds disclosed herein may be characterized by enhanced transfection efficiency and their ability to elicit specific biological outcomes. Such outcomes may include, for example, enhanced cellular uptake, endosome / lysosome disruption, and / or promotion of the release of intracellular encapsulating materials (e.g., polynucleotides). The compounds disclosed herein may also be characterized by achieving high levels of expression of said peptides or proteins when delivered via intravenous, intrathecal, intramuscular, intranasal, sublingual, or pulmonary delivery (optionally via nebulization) of mRNA encoding said peptides or proteins. Furthermore, the compounds disclosed herein have favorable pharmacokinetic properties, biodistribution, and efficiency.

[0089] This application demonstrates that the cationic lipids of the present invention can not only be synthesized from readily available starting materials, but also possess unexpectedly high encapsulation efficiency.

[0090] In addition, the cationic lipids of the present invention have cleavable groups, such as ester groups. These cleavable groups (e.g., esters, thioesters, disulfides, carbonates, carbamates, and thiocarbamates) are believed to improve biodegradability, thereby contributing to the good safety of the lipids.

[0091] It is envisioned that the cationic lipids of the present invention can be highly efficient for intramuscular delivery of therapeutic agents and vaccines (e.g., against influenza or respiratory syncytial virus (RSV)). It is also envisioned that lipid nanoparticles comprising the cationic lipids of the present invention can be efficiently delivered in vivo while maintaining good safety. Furthermore, it is envisioned that lipid nanoparticles comprising the cationic lipids of the present invention can exhibit improved in vivo degradation.

[0092] This document provides compounds as cationic lipids. In the embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (I): (I) Or its pharmaceutically acceptable salt, wherein: A 1 Selected from -C(=O)O-, -C(=O)S-, -C(=O)NH-, -OC(=O)O-, -OC(=O)NH-, -NHC(=O)O-, -SC(=O)NH-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S-, and -SS-, wherein each of the listed structures is left-handedly bonded to -(CH2). a -; Z 1 The following are selected from -OC(=O)-, -SC(=O)-, -NHC(=O)-, -OC(=O)O-, -NHC(=O)O-, -OC(=O)NH-, -NHC(=O)S-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S-, and -SS-, wherein the right-hand side of each of the listed structures is bonded to -(CH2). a -; Each R is selected independently from: (i) , where each R 1 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; (ii) , where each R2 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; (iii) , where each R 3 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; and (iv) , where each R 4 Independently selected from optional substituted cycloalkyl or optional substituted heterocyclic alkyl; At least three of the R's are independently selected from (i). (ii) Or (iii) ; Each 'a' is independently selected from 2, 3, 4, and 5; Each b is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; and Each c is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0093] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (I'): (I') Or its pharmaceutically acceptable salt.

[0094] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IA): (IA) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2DIndependently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect.

[0095] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IE): (IE) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect.

[0096] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IB1a): (IB1a) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; Optionally, each 'a' is independently selected from 3 or 4.

[0097] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IB1b): (IB1b) Or a pharmaceutically acceptable salt thereof, wherein each R 1A R 1B R 1C and R 1D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, i) each a is 2, and / or ii) each b is independently selected from 5 or 7.

[0098] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IB1c): (IB1c) Or a pharmaceutically acceptable salt thereof, wherein each R 3A R 3B R 3C and R 3D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, i) each a is 3, and / or ii) each c is 6.

[0099] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IB1d): (IB1d) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; Optionally, each a is 3.

[0100] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (I''): (I'') Or its pharmaceutically acceptable salt.

[0101] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IB2a): (IB2a) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; Optionally, each 'a' is independently selected from 3 or 4.

[0102] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IC1a): (IC1a) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; Optionally, each 'a' is independently selected from 3 or 4.

[0103] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IC1b): (IC1b) Or a pharmaceutically acceptable salt thereof, wherein each R 1A R 1B R 1C and R 1D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, where each a is 2, and / or each b is independently selected from 5 or 7.

[0104] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IC2a): (IC2a) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; Optionally, each a is 3.

[0105] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (ID): (ID) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect.

[0106] In the embodiment, A 1It is -C(=O)NH-, where the listed structures are left-handedly bonded to -(CH2). a - and Z 1 It is -NHC(=O)-, where the right-hand side of the listed structures is bonded to -(CH2). a -; optionally, where each a is 3.

[0107] In the embodiment, A 1 It is -OC(=O)NH-, where the listed structures are left-handedly bonded to -(CH2). a - and Z 1 It is -NHC(=O)O-, where the right-hand side of the listed structures is bonded to -(CH2). a -; optionally, where each a is 3.

[0108] In the embodiment, A 1 It is -SC(=O)NH-, where the listed structures are left-handedly bonded to -(CH2). a - and Z 1 It is -NHC(=O)S-, in which the right-hand side of the listed structures is bonded to -(CH2). a -; optionally, where each a is 3.

[0109] In the embodiment, A 1 It is -C(=O)S-, where the listed structures are left-handedly bonded to -(CH2). a - and Z 1 It is -SC(=O)-, where the right-hand side of the listed structures is bonded to -(CH2). a -; optionally, where each a is 3.

[0110] In the embodiment, A 1 It is -SS-, and Z 1 It is -SS-; optionally, each a is 3.

[0111] In the embodiment, A 1 It is -S-, and Z 1 It is -S-; optionally, each a is 4.

[0112] In the embodiment, A 1 It is -SS-, and Z 1 It is -SC(=O)-, where the right-hand side of the listed structures is bonded to -(CH2). a -; optionally, where each a is 3.

[0113] In the embodiment, A 1 It is -NHC(=O)O-, in which the listed structures are bonded to -(CH2) on the left-hand side.a - and Z 1 It is -OC(=O)NH-, where the right-hand side of the listed structures is bonded to -(CH2). a -; optionally, where each a is 3.

[0114] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (II): (II) Or its pharmaceutically acceptable salt, wherein: Each R is selected independently from: (i) , where each R 1 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; and (ii) , where each R 3 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Each 'a' is independently selected from 2, 3, 4, and 5; Each b is independently selected from 2, 3, 4, 5, 6, and 7; and Each 'c' is independently selected from 2, 3, 4, 5, 6, and 7.

[0115] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (II'): (II') Or its pharmaceutically acceptable salt.

[0116] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IIA): (IIA) Or a pharmaceutically acceptable salt thereof, wherein each R 3A R 3B R 3C and R 3D It is independently selected from optional substituted alkyl, optional substituted alkenyl, and optional substituted alkynyl groups.

[0117] In embodiments, the cationic lipids of the present invention comprise compounds having a structure according to formula (IIB): (IIB) Or a pharmaceutically acceptable salt thereof, wherein each R 1AR 1B R 1C and R 1D It is independently selected from optional substituted alkyl, optional substituted alkenyl, and optional substituted alkynyl groups.

[0118] In embodiments, the cationic lipids of the present invention comprise compounds having formula (I) having a structure according to formula (ID1): Or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from: (i) , where each R 1 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; (ii) , where each R 2 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; (iii) , where each R 3 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, (i) each a is 3 or 4, and / or (ii) each b is 5, 6, or 7.

[0119] In embodiments, the cationic lipids of the present invention comprise compounds having formula (I) having a structure according to formula (ID2): Or a pharmaceutically acceptable salt thereof, wherein each R 1A R 1B R 1C and R 1D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, (i) each a is 4, and / or (ii) each b is independently selected from 5 or 7.

[0120] In embodiments, the cationic lipids of the present invention comprise compounds having formula (I) having a structure according to formula (IE1): Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; Optionally, each a is 3 or 4.

[0121] In embodiments, the cationic lipids of the present invention comprise compounds having formula (I) having a structure according to formula (IE2): Or its pharmaceutically acceptable salt, wherein d is 0 or 1, and Each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect; Optionally, each a is 3 or 4.

[0122] In the embodiment, A 1 and Z 1 They are the same. In the embodiment, A 1 and Z 1 They are different.

[0123] In the embodiment, A 1 It is -C(=O)O-, where the listed structures are left-handedly bonded to -(CH2). a - In the embodiment, A 1 It's -OC(=O)O-.

[0124] In the embodiment, A 1 It is -C(=O)S-, where the listed structures are left-handedly bonded to -(CH2). a - In the embodiment, A 1 It is -C(=O)NH-, where the listed structures are left-handedly bonded to -(CH2). a - In the embodiment, A 1 It is -OC(=O)NH-, where the listed structures are left-handedly bonded to -(CH2). a - In the embodiment, A 1 It is -NHC(=O)O-, in which the listed structures are bonded to -(CH2) on the left-hand side. a - In the embodiment, A 1 It is -SC(=O)NH-, where the listed structures are left-handedly bonded to -(CH2). a - In the embodiment, A 1 It is -OCH2CH2O-. In the embodiment, A 1 It is -OCH2O-. In the embodiment, A 1 It is -OCH(CH3)O-. In the embodiment, A 1 Yes -S-. In the embodiment, A 1 It is -SS-.

[0125] In the embodiment, Z 1 It is -OC(=O)-, where the right-hand side of the listed structures is bonded to -(CH2). a - In the embodiment, Z 1 It's -OC(=O)O-.

[0126] In the embodiment, Z1 It is -SC(=O)-, where the right-hand side of the listed structures is bonded to -(CH2). a - In the embodiment, Z 1 It is -NHC(=O)-, where the right-hand side of the listed structures is bonded to -(CH2). a - In the embodiment, Z 1 It is -NHC(=O)O-, where the right-hand side of the listed structures is bonded to -(CH2). a - In the embodiment, Z 1 It is -OC(=O)NH-, where the right-hand side of the listed structures is bonded to -(CH2). a - In the embodiment, Z 1 It is -NHC(=O)S-, in which the right-hand side of the listed structures is bonded to -(CH2). a - In the embodiment, Z 1 It is -OCH2CH2O-. In the embodiment, Z 1 It is -OCH2O-. In the embodiment, Z 1 It is -OCH(CH3)O-. In the embodiment, Z 1 Yes -S-. In the embodiment, Z 1 It is -SS-.

[0127] In one embodiment, each 'a' is independently selected from 3 and 4. In one embodiment, each 'a' is 2. In one embodiment, each 'a' is 3. In one embodiment, each 'a' is 4. In one embodiment, each 'a' is 5. In one embodiment, each 'a' is different. In one embodiment, the value of 'a' on the left-hand side of the depicted formula is 3 and the value of 'a' on the right-hand side of the depicted formula is 4. In one embodiment, the value of 'a' on the left-hand side of the depicted formula is 4 and the value of 'a' on the right-hand side of the depicted formula is 3.

[0128] In one embodiment, the value of 'a' on the left-hand side of the depicted form is 2. In another embodiment, the value of 'a' on the left-hand side of the depicted form is 3. In yet another embodiment, the value of 'a' on the left-hand side of the depicted form is 4. In yet another embodiment, the value of 'a' on the left-hand side of the depicted form is 5.

[0129] In one embodiment, the value of 'a' on the right-hand side of the depicted formula is 2. In another embodiment, the value of 'a' on the right-hand side of the depicted formula is 3. In yet another embodiment, the value of 'a' on the right-hand side of the depicted formula is 4. In yet another embodiment, the value of 'a' on the right-hand side of the depicted formula is 5.

[0130] In one embodiment, each b is independently selected from 5, 6, and 7. In another embodiment, each b is independently selected from 5 and 7. In one embodiment, each b is 2. In another embodiment, each b is 3. In another embodiment, each b is 4. In another embodiment, each b is 5. In another embodiment, each b is 6. In another embodiment, each b is 7. In another embodiment, each b is 8. In another embodiment, each b is 9. In another embodiment, each b is 10.

[0131] In one embodiment, each c is 2. In one embodiment, each c is 3. In one embodiment, each c is 4. In one embodiment, each c is 5. In one embodiment, each c is 6. In one embodiment, each c is 7. In one embodiment, each c is 8. In one embodiment, each c is 9. In one embodiment, each c is 10.

[0132] In the embodiments, each R 4 It is an optional substituted cycloalkyl group. In the examples, each R 4 It is an optional substituted heterocyclic alkyl group. In the examples, each R 4 yes .

[0133] In the embodiments, each R is independently selected from: (i) , where each R 1 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; (ii) , where each R 2 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 Connection; and (iii) , where each R 3 It is independently selected from optional substituted alkyl, optional substituted alkenyl, and optional substituted alkynyl groups.

[0134] In the embodiments, each R is independently selected. , where each R 1 It is independently selected from optional substituted alkyl, optional substituted alkenyl, and optional substituted alkynyl groups.

[0135] In the embodiments, each R 1 They are the same. In the embodiment, at least one R 1 They are different.

[0136] In the embodiment, R 1A R 1B R 1C and R 1D They are the same. In the embodiment, R 1A and R 1B They are the same. In the embodiment, R 1C and R 1D They are the same. In the embodiment, R 1A and R 1C They are the same. In the embodiment, R 1B and R 1D They are the same.

[0137] In the embodiment, R 1A and R 1B They are the same and R 1C and R 1D They are the same, but R is different. 1A and R 1B With R 1C and R 1D Different. In the embodiments, R 1A and R 1C They are the same and R 1B and R 1D They are the same, but R is different. 1A and R 1C With R 1B and R 1D different.

[0138] In the embodiments, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Independently selected from optional substituted (C5-C) 25 )alkyl, optionally substituted (C5-C 25 alkenyl and optionally substituted (C5-C) 25 ) yyn group.

[0139] In the embodiments, each R 1 Or each R 1A R1B R 1C and R 1D (When present) independently selected from optionally substituted alkyl groups. In the examples, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Independently selected from optional substituted (C5-C) 25 )alkyl. In the examples, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Independently selected from optional substitutions (C) 10 -C 20 )alkyl.

[0140] In the embodiments, each R 1A (When present) is an optionally substituted alkyl group. In the examples, each R 1A (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 1A (When present) is an optional substitution (C) 10 -C 20 )alkyl.

[0141] In the embodiments, each R 1B (When present) is an optionally substituted alkyl group. In the examples, each R 1B (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 1B (When present) is an optional substitution (C) 10 -C 20 )alkyl.

[0142] In the embodiments, each R 1C (When present) is an optionally substituted alkyl group. In the examples, each R 1C (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 1C (When present) is an optional substitution (C) 10 -C 20 )alkyl.

[0143] In the embodiments, each R 1D (When present) is an optionally substituted alkyl group. In the examples, each R 1D (When present) is an optional substitute (C5-C) 25)alkyl. In the examples, each R 1D (When present) is an optional substitution (C) 10 -C 20 )alkyl.

[0144] In the embodiments, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) independently selected from optionally substituted alkenyl groups. In the examples, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Independently selected from optional substituted (C5-C) 25 )alkenyl. In the examples, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Independently selected from optional substitutions (C) 10 -C 20 )alkenyl.

[0145] In the embodiments, each R 1A (When present) is an optional substituted alkenyl group. In the examples, each R 1A (When present) is an optional substitute (C5-C) 25 )alkenyl. In the examples, each R 1A (When present) is an optional substitution (C) 10 -C 20 )alkenyl.

[0146] In the embodiments, each R 1B (When present) is an optional substituted alkenyl group. In the examples, each R 1B (When present) is an optional substitute (C5-C) 25 )alkenyl. In the examples, each R 1B (When present) is an optional substitution (C) 10 -C 20 )alkenyl.

[0147] In the embodiments, each R 1C (When present) is an optional substituted alkenyl group. In the examples, each R 1C (When present) is an optional substitute (C5-C) 25 )alkenyl. In the examples, each R 1C (When present) is an optional substitution (C) 10 -C20 )alkenyl.

[0148] In the embodiments, each R 1D (When present) is an optional substituted alkenyl group. In the examples, each R 1D (When present) is an optional substitute (C5-C) 25 )alkenyl. In the examples, each R 1D (When present) is an optional substitution (C) 10 -C 20 )alkenyl.

[0149] In the embodiments, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) independently selected from optionally substituted alkynyl groups. In the examples, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Independently selected from optional substituted (C5-C) 25 ) ynyl group. In the examples, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Independently selected from optional substitutions (C) 10 -C 20 ) yyn group.

[0150] In the embodiments, each R 1A (When present) is an optional substituted alkynyl group. In the examples, each R 1A (When present) is an optional substitute (C5-C) 25 ) ynyl group. In the examples, each R 1A (When present) is an optional substitution (C) 10 -C 20 ) yyn group.

[0151] In the embodiments, each R 1B (When present) is an optional substituted alkynyl group. In the examples, each R 1B (When present) is an optional substitute (C5-C) 25 ) ynyl group. In the examples, each R 1B (When present) is an optional substitution (C) 10 -C 20 ) yyn group.

[0152] In the embodiments, each R1C (When present) is an optional substituted alkynyl group. In the examples, each R 1C (When present) is an optional substitute (C5-C) 25 ) ynyl group. In the examples, each R 1C (When present) is an optional substitution (C) 10 -C 20 ) yyn group.

[0153] In the embodiments, each R 1D (When present) is an optional substituted alkynyl group. In the examples, each R 1D (When present) is an optional substitute (C5-C) 25 ) ynyl group. In the examples, each R 1D (When present) is an optional substitution (C) 10 -C 20 ) yyn group.

[0154] In the embodiments, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Selected independently from: (i) , (ii) ,or (iii) Optionally, each R 1 Or each R 1A R 1B R 1C and R 1D (When present) Selected independently from options (i) and (ii).

[0155] In the embodiments, each R 1 Or each R 1A R 1B R 1C and R 1D (When it exists) is In the embodiment, each R 1 Or each R 1A R 1B R 1C and R 1D (When it exists) is In the embodiment, each R 1 Or each R 1A R 1B R 1C and R 1D (When it exists) is .

[0156] In the embodiments, each R 1A (When it exists) is In the embodiment, each R 1A (When it exists) is In the embodiment, each R 1A (When it exists) is .

[0157] In the embodiments, each R 1B (When it exists) is In the embodiment, each R 1B (When it exists) is In the embodiment, each R 1B (When it exists) is .

[0158] In the embodiments, each R 1C (When it exists) is In the embodiment, each R 1C (When it exists) is In the embodiment, each R 1C (When it exists) is .

[0159] In the embodiments, each R 1D (When it exists) is In the embodiment, each R 1D (When it exists) is In the embodiment, each R 1D (When it exists) is .

[0160] In the embodiments, each R is independently selected. , where each R 2 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1connect.

[0161] In the embodiments, each R 2 They are the same. In the embodiment, at least one R 2 They are different.

[0162] In the embodiment, R 2A R 2B R 2C and R 2D They are the same. In the embodiment, R 2A and R 2B They are the same. In the embodiment, R 2C and R 2D They are the same. In the embodiment, R 2A and R 2C They are the same. In the embodiment, R 2B and R 2D They are the same.

[0163] In the embodiment, R 2A and R 2B They are the same and R 2C and R 2D They are the same, but R is different. 2A and R 2B With R 2C and R 2D Different. In the embodiments, R 2A and R 2C They are the same and R 2B and R 2D They are the same, but R is different. 2A and R 2C With R 2B and R 2D different.

[0164] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from optional substituted (C5-C) 25 )alkyl, optionally substituted (C5-C 25 Alkenyl, optionally substituted (C5-C) 25 ) ynyl group, and -W 1 -X 1 , Each W 1 Independently selected from optional substituted (C1-C) 10 )alkylene and optionally substituted (C2-C 10 ) imidene group, and Each X1 Independently selected from - O-(C=O)-optionally substituted (C5-C) 25 )alkyl,-( C=O)-O-optionally substituted (C5-C) 25 )alkyl,- O-(C=O)-optionally substituted (C5-C) 25 )alkenyl, and -( C=O)-O-optionally substituted (C5-C) 25 )alkenyl, wherein The labeled atoms and W 1 connect.

[0165] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from optional substituted (C5-C) 25 alkyl, such as optionally substituted (C5-C) 20 )alkyl, and -W 1 -X 1 , Each W 1 Independently selected from optional substituted (C1-C) 10 Alkylenes, such as optionally substituted (C2-C6) alkylenes, and optionally substituted (C2-C6) alkylenes. 10 (C2-C6)-olefins, for example, optionally substituted (C2-C6)-olefins, and Each X 1 Independently selected from - O-(C=O)-optionally substituted (C5-C) 25 )alkyl, for example - O-(C=O)-optionally substituted (C8-C) 20 )alkyl,-( C=O)-O-optionally substituted (C5-C) 25 )alkyl, for example -( C=O)-O-optionally substituted (C8-C) 20 )alkyl,- O-(C=O)-optionally substituted (C5-C) 25 )alkenyl, for example - O-(C=O)-optionally substituted (C8-C) 20 )alkenyl, and -( C=O)-O-optionally substituted (C5-C) 25 )alkenyl, for example -( C=O)-O-optionally substituted (C8-C) 20 )alkenyl, wherein The labeled atoms and W 1 connect.

[0166] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from optionally substituted alkyl groups and -W 1 -X 1 Optionally, among them Each W 1 Independently selected from optionally substituted alkylene groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O- optional alkyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect.

[0167] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) independently selected from optionally substituted alkyl groups. In the examples, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from optional substituted (C5-C) 25 )alkyl. In the examples, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from optional substituted (C5-C) 20 )alkyl.

[0168] In the embodiments, each R 2A (When present) is an optionally substituted alkyl group. In the examples, each R 2A (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 2A (When present) is an optional substitute (C5-C) 20 )alkyl.

[0169] In the embodiments, each R 2B (When present) is an optionally substituted alkyl group. In the examples, each R 2B (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 2B (When present) is an optional substitute (C5-C) 20 )alkyl.

[0170] In the embodiments, each R 2C (When present) is an optionally substituted alkyl group. In the examples, each R 2C (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 2C (When present) is an optional substitute (C5-C) 20 )alkyl.

[0171] In the embodiments, each R 2D (When present) is an optionally substituted alkyl group. In the examples, each R 2D (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 2D (When present) is an optional substitute (C5-C) 20 )alkyl.

[0172] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) independently selected from optionally substituted alkenyl groups. In the examples, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from optional substituted (C5-C) 25 )alkenyl.

[0173] In the embodiments, each R 2A (When present) is an optional substituted alkenyl group. In the examples, each R 2A (When present) is an optional substitute (C5-C) 25 )alkenyl.

[0174] In the embodiments, each R 2B (When present) is an optional substituted alkenyl group. In the examples, each R 2B (When present) is an optional substitute (C5-C)25 )alkenyl.

[0175] In the embodiments, each R 2C (When present) is an optional substituted alkenyl group. In the examples, each R 2C (When present) is an optional substitute (C5-C) 25 )alkenyl.

[0176] In the embodiments, each R 2D (When present) is an optional substituted alkenyl group. In the examples, each R 2D (When present) is an optional substitute (C5-C) 25 )alkenyl.

[0177] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) independently selected from optionally substituted alkynyl groups. In the examples, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from optional substituted (C5-C) 25 ) yyn group.

[0178] In the embodiments, each R 2A (When present) is an optional substituted alkynyl group. In the examples, each R 2A (When present) is an optional substitute (C5-C) 25 ) yyn group.

[0179] In the embodiments, each R 2B (When present) is an optional substituted alkynyl group. In the examples, each R 2B (When present) is an optional substitute (C5-C) 25 ) yyn group.

[0180] In the embodiments, each R 2C (When present) is an optional substituted alkynyl group. In the examples, each R 2C (When present) is an optional substitute (C5-C) 25 ) yyn group.

[0181] In the embodiments, each R 2D (When present) is an optional substituted alkynyl group. In the examples, each R 2D (When present) is an optional substitute (C5-C) 25 ) yyn group.

[0182] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from -W 1 -X 1 .

[0183] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from -W 1 -X 1 ,in Each W 1 Independently selected from optionally substituted alkylene groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O- optional alkyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 connect.

[0184] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from -W 1 -X 1 , Each W 1 Independently selected from optional substituted (C1-C) 10 )alkylene and optionally substituted (C2-C 10 ) imidene group, and Each X 1 Independently selected from - O-(C=O)-optionally substituted (C5-C) 25 )alkyl,-( C=O)-O-optionally substituted (C5-C) 25 )alkyl,- O-(C=O)-optionally substituted (C5-C) 25 )alkenyl, and -( C=O)-O-optionally substituted (C5-C) 25 )alkenyl, wherein The labeled atoms and W1 connect.

[0185] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Independently selected from -W 1 -X 1 , Each W 1 Independently selected from optional substituted (C1-C) 10 Alkylenes, such as optionally substituted (C2-C6) alkylenes, and optionally substituted (C2-C6) alkylenes. 10 (C2-C6)-olefins, for example, optionally substituted (C2-C6)-olefins, and Each X 1 Independently selected from - O-(C=O)-optionally substituted (C5-C) 25 )alkyl, for example - O-(C=O)-optionally substituted (C8-C) 20 )alkyl,-( C=O)-O-optionally substituted (C5-C) 25 )alkyl, for example -( C=O)-O-optionally substituted (C8-C) 20 )alkyl,- O-(C=O)-optionally substituted (C5-C) 25 )alkenyl, for example - O-(C=O)-optionally substituted (C8-C) 20 )alkenyl, and -( C=O)-O-optionally substituted (C5-C) 25 )alkenyl, for example -( C=O)-O-optionally substituted (C8-C) 20 )alkenyl, wherein The labeled atoms and W 1 connect.

[0186] In the embodiments, each R 2A (When it exists) is -W 1 -X 1 .

[0187] In the embodiments, each R 2B (When it exists) is -W 1 -X 1 .

[0188] In the embodiments, each R 2C (When it exists) is -W1 -X 1 .

[0189] In the embodiments, each R 2D (When it exists) is -W 1 -X 1 .

[0190] In the embodiment, each W 1 Independently selected from optionally substituted alkylene groups. In the examples, each W 1 Independently selected from optional substituted (C1-C) 10 )alkylene. In the examples, each W 1 Independently selected from optional substituted (C2-C6) alkylene groups.

[0191] In the embodiment, each W 1 Independently selected from optionally substituted alkenyl groups. In the examples, each W 1 Independently selected from optional substituted (C2-C) 10 ) sub-alkenyl. In the examples, each W 1 Independently selected from optional substituted (C2-C6) alkenyl groups.

[0192] In the embodiment, each X 1 Independently selected from - O-(C=O)-Optionally substituted alkyl group, wherein... The labeled atoms and W 1 Connection. In this embodiment, each X 1 Independently selected from - O-(C=O)-optionally substituted (C5-C) 25 )alkyl, wherein The labeled atoms and W 1 Connection. In this embodiment, each X 1 Independently selected from - O-(C=O)-optionally substituted (C8-C) 20 )alkyl, wherein The labeled atoms and W 1 connect.

[0193] In the embodiment, each X 1 Independently selected from -( C=O)-O-Optionally substituted alkyl group, wherein... The labeled atoms and W 1 Connection. In this embodiment, each X 1 Independently selected from -( C=O)-O-optionally substituted (C5-C) 25 )alkyl, wherein The labeled atoms and W 1 Connection. In this embodiment, each X 1 Independently selected from -( C=O)-O-optionally substituted (C8-C) 20 )alkyl, wherein The labeled atoms and W 1 connect.

[0194] In the embodiment, each X 1 Independently selected from - O-(C=O)-optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 Connection. In this embodiment, each X 1 Independently selected from - O-(C=O)-optionally substituted (C5-C) 25 )alkenyl, wherein The labeled atoms and W 1 Connection. In this embodiment, each X 1 Independently selected from - O-(C=O)-optionally substituted (C8-C) 20 )alkenyl, wherein The labeled atoms and W 1 connect.

[0195] In the embodiment, each X 1 Independently selected from -( C=O)-O-Optionally substituted alkenyl groups, wherein... The labeled atoms and W 1 Connection. In this embodiment, each X 1 Independently selected from -( C=O)-O-optionally substituted (C5-C) 25 )alkenyl, wherein The labeled atoms and W 1 Connection. In this embodiment, each X 1 Independently selected from -( C=O)-O-optionally substituted (C8-C) 20 )alkenyl, wherein The labeled atoms and W 1 connect.

[0196] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When present) Selected independently from: , , , , , , , , ,or .

[0197] In the embodiments, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is In the embodiment, each R 2 Or each R 2A R 2B R 2C and R 2D (When it exists) is .

[0198] In the embodiments, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is In the embodiment, each R 2A (When it exists) is .

[0199] In the embodiments, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is In the embodiment, each R 2B (When it exists) is .

[0200] In the embodiments, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is In the embodiment, each R 2C (When it exists) is .

[0201] In the embodiments, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is In the embodiment, each R 2D (When it exists) is .

[0202] In the embodiments, each R is independently selected. , where each R 3 It is independently selected from optional substituted alkyl, optional substituted alkenyl, and optional substituted alkynyl groups.

[0203] In the embodiments, each R 3 They are the same. In the embodiment, at least one R 3 They are different.

[0204] In the embodiment, R 3A R 3B R 3C and R 3D They are the same. In the embodiment, R 3A and R 3B They are the same. In the embodiment, R 3C and R 3D They are the same. In the embodiment, R 3A and R 3C They are the same. In the embodiment, R 3B and R 3D They are the same.

[0205] In the embodiment, R 3A and R 3B They are the same and R 3C and R 3D They are the same, but R is different. 3A and R 3B With R 3C and R 3D Different. In the embodiments, R 3A and R 3C They are the same and R 3B and R 3D They are the same, but R is different. 3A and R 3C With R 3B and R 3D different.

[0206] In the embodiments, each R 3 Or each R 3A R 3B R 3C and R 3D(When present) Independently selected from optional substituted (C5-C) 25 )alkyl, optionally substituted (C5-C 25 alkenyl and optionally substituted (C5-C) 25 ) yyn group.

[0207] In the embodiments, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) independently selected from optionally substituted alkyl groups. In the examples, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) Independently selected from optional substituted (C5-C) 25 )alkyl. In the examples, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) Independently selected from optional substitutions (C) 10 -C 20 )alkyl.

[0208] In the embodiments, each R 3A (When present) is an optionally substituted alkyl group. In the examples, each R 3A (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 3A (When present) is an optional substitution (C) 10 -C 20 )alkyl.

[0209] In the embodiments, each R 3B (When present) is an optionally substituted alkyl group. In the examples, each R 3B (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 3B (When present) is an optional substitution (C) 10 -C 20 )alkyl.

[0210] In the embodiments, each R 3C (When present) is an optionally substituted alkyl group. In the examples, each R 3C (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 3C(When present) is an optional substitution (C) 10 -C 20 )alkyl.

[0211] In the embodiments, each R 3D (When present) is an optionally substituted alkyl group. In the examples, each R 3D (When present) is an optional substitute (C5-C) 25 )alkyl. In the examples, each R 3D (When present) is an optional substitution (C) 10 -C 20 )alkyl.

[0212] In the embodiments, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) independently selected from optionally substituted alkenyl groups. In the examples, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) Independently selected from optional substituted (C5-C) 25 )alkenyl. In the examples, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) Independently selected from optional substitutions (C) 10 -C 20 )alkenyl.

[0213] In the embodiments, each R 3A (When present) is an optional substituted alkenyl group. In the examples, each R 3A (When present) is an optional substitute (C5-C) 25 )alkenyl. In the examples, each R 3A (When present) is an optional substitution (C) 10 -C 20 )alkenyl.

[0214] In the embodiments, each R 3B (When present) is an optional substituted alkenyl group. In the examples, each R 3B (When present) is an optional substitute (C5-C) 25 )alkenyl. In the examples, each R 3B (When present) is an optional substitution (C) 10 -C 20 )alkenyl.

[0215] In the embodiments, each R 3C (When present) is an optional substituted alkenyl group. In the examples, each R 3C (When present) is an optional substitute (C5-C) 25 )alkenyl. In the examples, each R 3C (When present) is an optional substitution (C) 10 -C 20 )alkenyl.

[0216] In the embodiments, each R 3D (When present) is an optional substituted alkenyl group. In the examples, each R 3D (When present) is an optional substitute (C5-C) 25 )alkenyl. In the examples, each R 3D (When present) is an optional substitution (C) 10 -C 20 )alkenyl.

[0217] In the embodiments, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) independently selected from optionally substituted alkynyl groups. In the examples, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) Independently selected from optional substituted (C5-C) 25 ) ynyl group. In the examples, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) Independently selected from optional substitutions (C) 10 -C 20 ) yyn group.

[0218] In the embodiments, each R 3A (When present) is an optional substituted alkynyl group. In the examples, each R 3A (When present) is an optional substitute (C5-C) 25 ) ynyl group. In the examples, each R 3A (When present) is an optional substitution (C) 10 -C 20 ) yyn group.

[0219] In the embodiments, each R 3B(When present) is an optional substituted alkynyl group. In the examples, each R 3B (When present) is an optional substitute (C5-C) 25 ) ynyl group. In the examples, each R 3B (When present) is an optional substitution (C) 10 -C 20 ) yyn group.

[0220] In the embodiments, each R 3C (When present) is an optional substituted alkynyl group. In the examples, each R 3C (When present) is an optional substitute (C5-C) 25 ) ynyl group. In the examples, each R 3C (When present) is an optional substitution (C) 10 -C 20 ) yyn group.

[0221] In the embodiments, each R 3D (When present) is an optional substituted alkynyl group. In the examples, each R 3D (When present) is an optional substitute (C5-C) 25 ) ynyl group. In the examples, each R 3D (When present) is an optional substitution (C) 10 -C 20 ) yyn group.

[0222] In the embodiments, each R 3 Or each R 3A R 3B R 3C and R 3D (When present) Selected independently from: (i) , (ii) ,or (iii) Optionally, each R 3 Or each R 3A R 3B R 3C and R 3D (When it exists) is option (iii).

[0223] In the embodiments, each R 3 Or each R 3A R 3B R 3C and R 3D (When it exists) is In the embodiment, each R 3 Or each R 3A R3B R 3C and R 3D (When it exists) is In the embodiment, each R 3 Or each R 3A R 3B R 3C and R 3D (When it exists) is .

[0224] In the embodiments, each R 3A (When it exists) is In the embodiment, each R 3A (When it exists) is In the embodiment, each R 3A (When it exists) is .

[0225] In the embodiments, each R 3B (When it exists) is In the embodiment, each R 3B (When it exists) is In the embodiment, each R 3B (When it exists) is .

[0226] In the embodiments, each R 3C (When it exists) is In the embodiment, each R 3C (When it exists) is In the embodiment, each R 3C (When it exists) is .

[0227] In the embodiments, each R 3D (When it exists) is In the embodiment, each R 3D (When it exists) is In the embodiment, each R 3D (When it exists) is .

[0228] In the embodiments, the substituents are not optional substitutions.

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

[0230] In the embodiments, this document provides a composition comprising the cationic lipids 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.

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

[0232] In embodiments, lipid nanoparticles encapsulate nucleic acids, optionally mRNA encoding peptides or proteins. In embodiments, lipid nanoparticles encapsulate mRNA encoding peptides or proteins, optionally for use in vaccines. In embodiments, the peptide is an antigen. As used herein, the phrase "encapsulation percentage" refers to the portion of a therapeutic agent (e.g., mRNA) effectively encapsulated within a liposome-based medium (e.g., lipid nanoparticles) relative to the initial portion of the therapeutic agent present in the lipid phase. In embodiments, the encapsulation percentage of mRNA by the lipid nanoparticles is at least 50%. In embodiments, the encapsulation percentage of mRNA by the lipid nanoparticles is at least 55%. In embodiments, the encapsulation percentage of mRNA by the lipid nanoparticles is at least 60%. In embodiments, the encapsulation percentage of mRNA by the lipid nanoparticles is at least 65%. In embodiments, the encapsulation percentage of mRNA by the lipid nanoparticles is at least 70%. In embodiments, the encapsulation percentage of mRNA by the lipid nanoparticles is at least 75%. In embodiments, the encapsulation percentage of mRNA by the lipid nanoparticles is at least 80%. In embodiments, the encapsulation percentage of mRNA by the lipid nanoparticles is at least 85%. In one embodiment, the encapsulation percentage of the lipid nanoparticles on the mRNA was at least 90%. In another embodiment, the encapsulation percentage of the lipid nanoparticles on the mRNA was at least 95%. In yet another embodiment, the encapsulation percentage was calculated by Ribogreen assay (Invitrogen) with and without 0.1% Triton-X 100.

[0233] In the embodiments, the compositions of the present invention are used in therapeutic applications.

[0234] In the embodiments, the compositions of the present invention are used in a method of treating or preventing a disease that can be treated or prevented by a peptide or protein encoded by the mRNA, optionally wherein the mRNA encodes an antigen, and / or the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lungs, brain or muscles, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

[0235] In an embodiment, a method for treating or preventing a disease is provided, wherein the method comprises administering the composition of the invention to a subject in need, and wherein the disease is treatable or preventable by a peptide or protein encoded by mRNA, optionally wherein the mRNA encodes an antigen, and / or the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lungs, brain or muscles, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.

[0236] In the embodiments, the composition is delivered intravenously, intrathecally, intramuscularly, intranasally, sublingually, or via the lungs, and optionally by nebulization. In the embodiments, the composition is administered intramuscularly. Exemplary compounds

[0237] In the embodiments, the cationic lipids of the present invention comprise compounds selected from those depicted in Table A or Table B, or pharmaceutically acceptable salts thereof.

[0238] Exemplary compounds include those described in Tables A and B, or pharmaceutically acceptable salts thereof.

[0239] Any of the compounds (1-86) identified in Table A or Table B above may be provided in the form of pharmaceutically acceptable salts, and such salts are intended to be covered in this invention.

[0240] The compounds of the present invention as described herein can be prepared according to methods known in the art, including exemplary synthesis of the examples provided herein. Nucleic acid

[0241] The compounds of the present invention, as described herein, can be used to prepare compositions that can be used to deliver nucleic acids. Nucleic acid synthesis

[0242] The nucleic acids according to the invention can be synthesized according to any known method. For example, the mRNA according to the invention can be synthesized via in vitro transcription (IVT). In short, IVT is typically performed using: a linear or circular DNA template containing a promoter, a ribonucleotide triphosphate pool, a buffer system that may include DTT and magnesium ions, and a suitable RNA polymerase (e.g., T3, T7, mutant T7, or SP6 RNA polymerase), DNase I, pyrophosphatase, and / or RNase inhibitors. The exact conditions will vary depending on the specific application.

[0243] In some embodiments, to prepare the mRNA according to the invention, a DNA template is transcribed in vitro. A suitable DNA template typically has a promoter for in vitro transcription (e.g., T3, T7, mutated T7, or SP6 promoter), followed by the desired nucleotide sequence for the desired mRNA and a termination signal.

[0244] One or more desired mRNA sequences according to the invention can be determined and incorporated into a DNA template using standard methods. For example, starting with the desired amino acid sequence (e.g., an enzyme sequence), a virtual reverse translation is performed based on the degenerate genetic code. An optimization algorithm can then be used to select suitable codons. Typically, in one aspect, the G / C content can be optimized to achieve the highest possible G / C content, and in another aspect, the frequency of tRNA can be optimally considered based on codon usage. The optimized RNA sequence can be established and displayed, for example, by means of a suitable display device, and compared with the original (wild-type) sequence. Secondary structures can also be analyzed to calculate stable and unstable properties, or the regions of RNA can be calculated separately. Modified mRNA

[0245] In some embodiments, the mRNA according to the invention can be synthesized as unmodified or modified mRNA. Modified mRNA includes nucleotide modifications in the RNA. Therefore, the modified mRNA according to the invention can include nucleotide modifications, such as backbone modifications, sugar modifications, or base modifications. In some embodiments, the 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 modified nucleotides, purine and pyrimidine analogs or derivatives, such as, for example, 1-methyladenine, 2-methyladenine, 2-methylthio-N-6-isopentene. N-6-methyladenine, N-6-isopentenyladenine, 2-thiocytosine, 3-methylcytosine, 4-acetylcytosine, 5-methylcytosine, 2,6-diaminopurine, 1-methylguanine, 2-methylguanine, 2,2-dimethylguanine, 7-methylguanine, inosine, 1-methylinosine, pseudouracil (5-uracil), dihydrouracil, 2- Thio-uracil, 4-thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio- Uracil, 5'-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 1-methyl-pseudouracil, queuosine, β-D-mannosyl-queuosine, wybutoxosine, and phosphoramide, thiophosphate, peptide nucleotide, methylphosphonate, 7-deazoguanosine, 5-methylcytosine, and inosine. Those skilled in the art will know the preparation of such analogues, for example, from the following documents: U.S. Patent Nos. 4,373,071, 4,401,796, 4,415,732, 4,458,066, 4,500,707, 4,668,777, 4,973,679, 5,047,524, 5,132,418, 5,153,319, 5,262,530, and 5,700,642, the disclosures of which are incorporated herein by reference in their entirety. Pharmaceutical formulations containing cationic lipids and nucleic acids

[0246] In some embodiments, the compounds of the present invention as described herein, as well as pharmaceutical and liposome compositions comprising such lipids, can be used in formulations to facilitate the delivery of encapsulated material (e.g., one or more polynucleotides such as mRNA) to one or more target cells and subsequently transfect one or more target cells. For example, in some embodiments, the cationic lipids (and compositions, such as liposome compositions comprising such lipids) described herein are characterized by causing one or more of the following: receptor-mediated endocytosis, clathrin-mediated and pit-mediated endocytosis, phagocytosis and macropinocytosis, fusogenicity, endosome or lysosomal disruption, and / or releasability, which provides advantages of such compounds relative to other similarly classified lipids.

[0247] According to the present invention, nucleic acids, such as mRNA encoding proteins (e.g., full-length, fragments, or portions of proteins), as described herein, can be delivered via a delivery medium comprising compounds of the present invention as described herein.

[0248] As used herein, the terms “delivery medium,” “transfer medium,” “nanoparticle,” or their grammatical equivalents are used interchangeably.

[0249] For example, the present invention provides a composition (e.g., a pharmaceutical composition) comprising the compounds described herein and one or more polynucleotides. The composition (e.g., a pharmaceutical composition) may further comprise... (i) one or more cationic lipids, (ii) one or more non-cationic lipids, (iii) one or more cholesterol-based lipids, and / or (iv) One or more PEG-modified lipids.

[0250] In some embodiments, the composition exhibits an enhanced (e.g., increased) ability to transfect one or more target cells. Therefore, methods for transfecting one or more target cells are also provided herein. Such methods typically involve contacting the one or more target cells with a cationic lipid and / or pharmaceutical composition disclosed herein (e.g., a liposome formulation comprising a compound described herein encapsulated with one or more polynucleotides), such that the one or more target cells are transfected by the encapsulated material (e.g., one or more polynucleotides). As used herein, the term “transfect” or “transfection” refers to the introduction of one or more encapsulated materials (e.g., nucleic acids and / or polynucleotides) into cells (e.g., into target cells). The introduced polynucleotides may be stably or transiently maintained in the target cells. The term “transfection efficiency” refers to the relative amount of such encapsulated material (e.g., polynucleotides) absorbed, introduced, and / or expressed by the transfected target cells. In practice, transfection efficiency can be estimated by the amount of reporter polynucleotide product produced by the target cells after transfection. In some embodiments, the compounds and pharmaceutical compositions described herein exhibit high transfection efficiency, thereby increasing the likelihood that an appropriate dose of the encapsulated material (e.g., one or more polynucleotides) will be delivered to the pathological site and subsequently expressed, while minimizing potential systemic adverse reactions or toxicities associated with the compound or its encapsulated contents.

[0251] Transfection of one or more target cells with a polynucleotide, for example, encapsulated in one or more lipid nanoparticles containing a drug or liposome composition disclosed herein, can stimulate the production of a product (e.g., a polypeptide or protein) encoded by such polynucleotide and enhance the ability of such target cells to express polynucleotides and produce, for example, the target polypeptide or protein. For example, transfection of target cells with one or more compounds or drug compositions encapsulating mRNA will enhance (i.e., increase) the production of a protein or enzyme encoded by such mRNA.

[0252] Furthermore, the delivery mediators described herein (e.g., liposome delivery mediators) can be prepared for preferential distribution to other target tissues, cells, or organs, such as the heart, lungs, kidneys, and spleen. In embodiments, the delivery mediators described herein (e.g., liposome delivery mediators) can be prepared for preferential distribution to the lungs. In embodiments, the lipid nanoparticles of the present invention can be prepared to achieve enhanced delivery to target cells and tissues. For example, polynucleotides (e.g., mRNA) encapsulated in one or more of the compounds or pharmaceutical and liposome compositions described herein can be delivered to target cells or tissues and / or transfected. In some embodiments, the encapsulated polynucleotides (e.g., mRNA) are capable of being expressed by target cells and producing (and in some cases excreted) functional polypeptide products, thereby conferring, for example, beneficial properties to the target cells or tissues. Such encapsulated polynucleotides (e.g., mRNA) can encode, for example, antigens, hormones, enzymes, receptors, polypeptides, peptides, or other target proteins. Liposome delivery mediators

[0253] In some embodiments, the composition is a suitable delivery medium. In examples, the composition is a liposome delivery medium, such as lipid nanoparticles.

[0254] The terms “liposome delivery medium” and “liposome composition” are used interchangeably.

[0255] Enriching liposome compositions with one or more of the cationic lipids disclosed herein can be used as a means to improve safety or otherwise confer one or more desired properties upon 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 composition). Therefore, pharmaceutical compositions comprising one or more of the cationic lipids disclosed herein, and particularly liposome compositions, are also contemplated.

[0256] Therefore, in some embodiments, the compounds of the present 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 permeation or fusion with the lipid membrane of such target cells).

[0257] As used herein, liposome delivery mediators (e.g., lipid nanoparticles) are typically characterized as microvesicles with an internal aqueous space isolated from an external medium by a membrane having one or more bilayers. The bilayer membrane of a liposome is typically formed from amphiphilic molecules, such as synthetic or naturally derived lipids containing spatially separated hydrophilic and hydrophobic domains (Lasic, Trends Biotechnol. 16: 307-321, 1998). The bilayer membrane of a liposome can also be formed from amphiphilic polymers and surfactants (e.g., polymers, nonionic surfactant vesicles, etc.). In the context of this invention, liposome delivery mediators are typically used to transport desired mRNA to target cells or tissues.

[0258] In some embodiments, such compositions (e.g., liposome compositions) are loaded with or otherwise encapsulated with materials such as, for example, one or more biologically active polynucleotides (e.g., mRNA).

[0259] In examples, the composition (e.g., a pharmaceutical composition) comprises mRNA encoding a peptide or protein encapsulated within liposomes. In examples, the liposomes comprise: (i) one or more cationic lipids, (ii) one or more non-cationic lipids, (iii) One or more cholesterol-based lipids, and (iv) One or more PEG-modified lipids, wherein at least one cationic lipid is a compound of the present invention as described herein.

[0260] In some embodiments, the composition comprises mRNA encoding a peptide or protein (e.g., any peptide or protein described herein). In some embodiments, the composition comprises mRNA encoding a peptide (e.g., any peptide described herein). In some embodiments, the composition comprises mRNA encoding a protein (e.g., any protein described herein).

[0261] In the embodiments, the composition (e.g., a pharmaceutical composition) comprises nucleic acids encapsulated in liposomes, wherein the liposomes contain compounds described herein.

[0262] In some embodiments, the nucleic acid is mRNA encoding a peptide or protein. In some embodiments, the mRNA encodes a peptide or protein for use in the lungs or lung cells of a subject, delivered to or treating the subject. In some embodiments, the mRNA encodes a peptide or protein for use in the liver or hepatocytes of a subject, delivered to or treating the subject. In some embodiments, the mRNA encodes a peptide or protein for use in muscle cells, delivered to or treating the subject. In some embodiments, the mRNA encodes a peptide or protein for use in immune cells, delivered to or treating the subject. Other exemplary mRNAs are also described herein.

[0263] In the embodiments, the liposome delivery medium (e.g., lipid nanoparticles) may have a net positive charge.

[0264] In the embodiments, the liposome delivery medium (e.g., lipid nanoparticles) may have a net negative charge.

[0265] In the embodiments, the liposome delivery medium (e.g., lipid nanoparticles) may have a net neutral charge.

[0266] In the embodiments, the lipid nanoparticles encapsulating nucleic acids (e.g., mRNA encoding peptides or proteins) comprise one or more compounds of the present invention as described herein.

[0267] For example, the amount of the compounds of the present invention as described herein in a composition can be described as a percentage (“wt%”) of the combined dry weight of all lipids in the composition (e.g., the combined dry weight of all lipids present in the liposome composition).

[0268] In the embodiments of the pharmaceutical compositions described herein, the compounds of the invention as described herein are present in an amount of about 0.5 wt% to about 30 wt% (e.g., about 0.5 wt% to about 20 wt%) of the combined dry weight of all lipids present in the composition (e.g., a liposome composition).

[0269] In embodiments, the compounds of the present invention as described herein are present in amounts 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 liposome composition). In embodiments, the compounds of the present invention as described herein are present in amounts 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 liposome delivery medium).

[0270] In the embodiments, the compounds of the present invention as described herein are present in amounts 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 the composition (e.g., a liposome composition).

[0271] In the embodiments, the compounds of the present invention as described herein are present in amounts not exceeding 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 the composition (e.g., liposome composition).

[0272] In examples, the composition (e.g., a liposome delivery medium, such as lipid nanoparticles) comprises about 0.1 wt% to about 20 wt% (e.g., about 0.1 wt% to about 15 wt%) of the compounds described herein. In examples, the delivery medium (e.g., a liposome delivery medium, such as lipid nanoparticles) comprises about 0.5 wt%, about 1 wt%, about 3 wt%, about 5 wt%, or about 10 wt% of the compounds described herein. In examples, the delivery medium (e.g., a liposome delivery medium, such as lipid nanoparticles) comprises up to about 0.5 wt%, about 1 wt%, about 3 wt%, about 5 wt%, about 10 wt%, about 15 wt%, or about 20 wt% of the compounds described herein. In examples, this percentage results in improved beneficial effects (e.g., improved delivery to target tissues such as the liver or lungs).

[0273] The amount of the compounds of the present invention as described herein in the composition may also be described as a percentage (“mol%”) of the total molar amount of lipids in the composition (e.g., the total molar amount of all lipids present in the liposome delivery medium).

[0274] In the embodiments of the pharmaceutical compositions described herein, the compounds of the invention as described herein are present in an amount of about 0.5 mol% to about 50 mol% (e.g., about 0.5 mol% to about 20 mol%) of the combined molar amount of all lipids present in the composition (such as a liposome delivery medium).

[0275] In the embodiments, the compounds of the present invention as described herein are present in amounts 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 a composition (such as a liposome delivery medium). In the embodiments, the compounds of the present invention as described herein are present in amounts 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%.

[0276] In some embodiments, the compounds of the present invention as described herein may comprise from about 0.1 mol% to about 50 mol% of the total lipids in the composition (e.g., a liposome delivery medium), or from about 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%.

[0277] In some embodiments, the compounds of the present invention as described herein may constitute more than about 0.1 mol%, or more than about 0.5 mol%, or more than about 1 mol%, or more than about 5 mol%, or more than about 10 mol%, or more than about 20 mol%, or more than about 30 mol%, or more than about 40 mol% of the total lipids in the lipid nanoparticles.

[0278] In some 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%, or less than about 30 mol%, or less than about 25 mol%, or less than about 10 mol%, or less than about 5 mol%, or less than about 1 mol% of the total lipids in the composition (e.g., a liposome delivery medium).

[0279] In the embodiments, the compounds of the present invention as described herein are present in amounts 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 the composition (e.g., a liposome composition).

[0280] In the embodiments, the compounds of the present invention as described herein are present in amounts not exceeding 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 the composition (e.g., liposome composition).

[0281] In the embodiments, this percentage leads to improved beneficial effects (e.g., improved delivery to target tissues such as the liver, lungs, or muscles).

[0282] In typical embodiments, the compositions of the present invention (e.g., liposome compositions) comprise: (i) one or more cationic lipids, (ii) one or more non-cationic lipids, (iii) One or more cholesterol-based lipids, and (iv) One or more PEG-modified lipids, wherein at least one cationic lipid is a compound of the present invention as described herein.

[0283] For example, compositions suitable for practicing the present invention have four lipid components, which comprise compounds of the present invention as described herein as cationic lipid components, and further comprise: (i) Non-cationic lipids, (ii) Cholesterol-based lipids and (iii) PEG-modified lipids.

[0284] Non-cationic lipids can be DOPE or DEPE. Cholesterol-based lipids can be cholesterol. PEG-modified lipids can be DMG-PEG2K.

[0285] In another embodiment, the pharmaceutical (e.g., liposome) composition comprises one or more of PEG-modified lipids, non-cationic lipids, and cholesterol lipids. 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.

[0286] In the embodiments, the composition (e.g., lipid nanoparticles) encapsulating nucleic acids (e.g., mRNA encoding peptides or proteins) comprises one or more compounds of the present invention as described herein and one or more lipids selected from the group consisting of cationic lipids, non-cationic lipids and PEGylated lipids.

[0287] In embodiments, compositions encapsulating nucleic acids (e.g., mRNA encoding peptides or proteins) (e.g., lipid nanoparticles) comprise 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 comprise cholesterol-based lipids. Typically, such compositions have four lipid components comprising compounds of the present invention as cationic lipid components as described herein, and further comprising: (i) Non-cationic lipids (e.g., DOPE). (ii) Cholesterol-based lipids (e.g., cholesterol) and (iii) PEG-modified lipids (e.g., DMG-PEG2K).

[0288] In the embodiments, the lipid nanoparticles encapsulating nucleic acids (e.g., mRNA encoding peptides or proteins) comprise one or more of the compounds of the present invention as described herein, and one or more lipids selected from the group consisting of: (i) cationic lipids, (ii) Non-cationic lipids, (iii) PEGylated lipids, and (iv) Cholesterol-based lipids.

[0289] According to various embodiments, the selection of cationic lipids, non-cationic lipids, and / or PEG-modified lipids constituting the lipid nanoparticles, and the relative molar ratios of such lipids to each other, are based on the characteristics of one or more selected lipids, the nature of the intended target cells, and the characteristics of the mRNA to be delivered. Other considerations include, for example, the saturation of the alkyl chain and the size, charge, pH, pKa, fusion properties, and toxicity of the selected one or more lipids. Therefore, the molar ratios can be adjusted accordingly. cationic lipids

[0290] In addition to any of the compounds of the present invention as described herein, the composition may contain one or more additional cationic lipids.

[0291] In some embodiments, liposomes may comprise one or more additional cationic lipids. As used herein, the phrase "cationic lipid" refers to any of a variety of lipid substances that have 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.

[0292] Suitable additional cationic lipids for use in the composition include cationic lipids as described in the literature. assist lipids

[0293] Compositions (e.g., liposome compositions) may also contain one or more accessory lipids. Such accessory lipids include noncationic lipids. As used herein, the phrase "noncationic lipid" refers to any neutral, zwitterionic, or anionic lipid. As used herein, the phrase "anionic lipid" refers to any of a variety of lipid substances that carry a net negative charge at a selected pH (e.g., physiological pH). Noncationic lipids include, but are not limited to, distearylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), 1,2-disorcinyl-sn-glycerol-3-phosphate ethanolamine (DEPE), palmitoyloleoylphosphatidylcholine (POPC), and palmitoyloleoylphosphatidylethanolamine. Amines (POPE), dioleoylphosphatidylethanolamine 4-(N-maleimidemethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), distearate-phosphatidylethanolamine (DSPE), 16-O-monomethylPE, 16-O-dimethylPE, 18-1-transPE, 1-stearoyl-2-oleoylphosphatidylethanolamine (SOPE), or mixtures thereof. The non-cationic or co-acting lipid suitable for practicing the present invention is dioleoylphosphatidylethanolamine (DOPE). Alternatively, 1,2-disorcinyl-sn-glycero-3-phosphoethanolamine (DEPE) can be used as a non-cationic or co-acting lipid.

[0294] In some embodiments, the non-cationic lipid is a neutral lipid, i.e., a lipid that does not carry a net charge under the conditions of formulation and / or application of the composition.

[0295] In some embodiments, non-cationic lipids may be present in the following molar ratios (mol%): 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, total non-cationic lipids may be present in the following molar ratios (mol%): 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%. In some embodiments, the percentage of non-cationic lipids in the liposomes may be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage of total non-cationic lipids in liposomes may be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage of non-cationic lipids in liposomes may be no more than about 5 mol%, no more than about 10 mol%, no more than about 20 mol%, no more than about 30 mol%, or no more than about 40 mol%. In some embodiments, the percentage of total non-cationic lipids in liposomes may be no more than about 5 mol%, no more than about 10 mol%, no more than about 20 mol%, no more than about 30 mol%, or no more than about 40 mol%.

[0296] In some embodiments, non-cationic lipids may be present in the following weight percentages (wt%): 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, total non-cationic lipids may be present in the following weight percentages (wt%): 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%. In some embodiments, the percentage of non-cationic lipids in the liposomes 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 total non-cationic lipids in liposomes 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 non-cationic lipids in liposomes 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%. In some embodiments, the percentage of total non-cationic lipids in liposomes 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%. Cholesterol-based lipids

[0297] In some embodiments, compositions comprising the cationic lipids of the present invention (e.g., liposome compositions) further comprise 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-oleoaminopropyl)piperazine (Gao et al. Biochem. Biophys. Res. Comm. 179, 280 (1991); Wolf et al. BioTechniques 23, 139 (1997); U.S. Patent No. 5,744,335), β-sitosterol, or imidazole cholesterol ester (ICE) having the following structure. ("ICE").

[0298] In some embodiments, cholesterol-based lipids may be present in the following molar ratios (mol%): about 1% to about 30% of the total lipids present in the liposomes, or about 5% to about 20%. In some embodiments, the percentage of cholesterol-based lipids in the lipid nanoparticles may be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage of cholesterol-based lipids in the lipid nanoparticles may be no more than about 5 mol%, no more than about 10 mol%, no more than about 20 mol%, no more than about 30 mol%, or no more than about 40 mol%.

[0299] In some embodiments, cholesterol-based lipids may be present in the following weight percentages (wt%): about 1% to about 30% of the total lipids present in the liposomes, or about 5% to about 20%. In some embodiments, the percentage of cholesterol-based lipids in the lipid nanoparticles 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 lipids in the lipid nanoparticles 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

[0300] In some embodiments, the composition (e.g., a liposome composition) comprises one or more additional PEGylated lipids. A suitable PEG-modified or PEGylated lipid for practicing the present invention is 1,2-dimyristoyl-racemic-glycero-3-methoxy polyethylene glycol-2000 (DMG-PEG2K).

[0301] For example, the present invention also envisions the use of polyethylene glycol (PEG) modified phospholipids and derived lipids (such as derived ceramides (PEG-CER), including N-octanoyl-sphingosine-1-[succinyl(methoxypolyethylene glycol)-2000] (C8 PEG-2000 ceramide)) in combination with one or more compounds of the present invention as described herein, and in some embodiments, in combination with other lipids comprising liposomes. In some embodiments, particularly useful exchangeable lipids are those having shorter acyl chains (e.g., (C8 PEG-2000 ceramide)). 14 ) or (C 18 PEG-ceramide.

[0302] Other envisioned PEG-modified lipids (also referred to herein as PEGylated lipids, the term being interchangeable with PEG-modified lipids) include, but are not limited to, those having (C6-C) 20The lipid is a polyethylene glycol chain up to 5 kDa covalently attached to one or more alkyl chains of length 5 kDa. In some embodiments, the PEG-modified or PEGylated lipid is PEGylated cholesterol or PEG-2K. The addition of such components can prevent complex aggregation and can also provide a means of increasing cycle life and enhancing the delivery of lipid-nucleic acid compositions to target cells (Klibanov et al. (1990) FEBS Letters [European Federation of Biochemical Societies Letters], 268(1): 235-237), or they can be selected for rapid in vivo exchange of formulations (see U.S. Patent No. 5,885,613).

[0303] The additional PEG-modified phospholipids and derived lipids of the present invention may be present in the following molar ratios (mol%): about 0% to about 10%, about 0.5% to about 10%, about 1% to about 10%, about 2% to about 10%, about 3% to about 5%, about 1% to about 5%, or about 1.5% to about 3% of the total lipids present in the composition (e.g., liposome composition). Pharmaceutical preparations and therapeutic uses

[0304] The compounds of the present 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 permeation or fusion with the lipid membrane of such target cells).

[0305] For example, when a liposome composition (e.g., lipid nanoparticles) contains or otherwise enriches one or more of the compounds disclosed herein, a phase transition in the lipid bilayer of the one or more target cells can facilitate the delivery of encapsulated material (e.g., one or more therapeutic polynucleotides encapsulated in lipid nanoparticles) to the one or more target cells.

[0306] Similarly, in some embodiments, the compounds of the present invention as described herein can be used to prepare liposomal mediators characterized by their reduced in vivo toxicity. In some embodiments, the reduced toxicity is a function of the high transfection efficiency associated with the compositions disclosed herein, making it possible to administer reduced amounts of such compositions to subjects to achieve the desired therapeutic response or outcome.

[0307] In some embodiments, the compounds of the present invention as described herein can be used to prepare liposomal mediators characterized by effective intranasal delivery of mRNA. In some embodiments, the compounds of the present invention as described herein can be used to prepare liposomal mediators characterized by effective pulmonary delivery of mRNA. In some embodiments, the compounds of the present invention as described herein can be used to prepare liposomal mediators characterized by achieving high levels of expression of said peptide or protein when delivered via intravenous, intrathecal, intramuscular, intranasal, sublingual, or pulmonary delivery (optionally via nebulization). In some embodiments, the compounds of the present invention as described herein can be used to prepare liposomal mediators characterized by achieving high levels of expression of said peptide or protein when delivered via intramuscular delivery of said peptide or protein.

[0308] Therefore, pharmaceutical formulations comprising the compounds described herein and the provided nucleic acids can be used for a variety of therapeutic and / or preventative 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 drug carriers, targeting ligands, or stabilizing agents. In some embodiments, the compounds described herein can be formulated via a premixed lipid solution. In other embodiments, a post-insertion technique can be used to formulate compositions comprising the compounds described herein into lipid membranes of nanoparticles. Pharmaceutical formulation and administration techniques are available in the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.

[0309] Suitable routes of administration include, for example, oral, rectal, vaginal, transmucosal, pulmonary (including tracheal or inhalation), or enteral administration; parenteral delivery, including intradermal, percutaneous (local), intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intravenous, intravenous, intraperitoneal, or intranasal administration. In embodiments, the route of administration is selected from intravenous, intrathecal, intramuscular, intranasal, sublingual, or pulmonary delivery, optionally via nebulization. In embodiments, the route of administration is intramuscular. In specific embodiments, intramuscular administration is directed to muscles selected from the group consisting of skeletal muscle, smooth muscle, and cardiac muscle. In some embodiments, administration results in the delivery of nucleic acids to muscle cells. In some embodiments, administration results in the delivery of nucleic acids to hepatocytes (i.e., liver cells).

[0310] A common route of administration for the liposome compositions of the present invention is intravenous delivery, particularly for the treatment of metabolic disorders, especially those affecting the liver (e.g., ornithine transaminases (OTC) deficiency). Alternatively, depending on the disease or disorder to be treated, the liposome compositions may be administered via pulmonary delivery (e.g., for the treatment of cystic fibrosis). For vaccination, the liposome compositions of the present invention are typically administered intramuscularly. Alternatively, the liposome compositions of the present invention may be administered intranasally for vaccination. Diseases or disorders affecting the eye may be treated by intravitreal administration of the liposome compositions of the present invention.

[0311] Alternatively or additionally, the pharmaceutical formulations of the present invention can be administered locally rather than systemically, for example, by injecting the pharmaceutical formulation directly 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 that can be delivered and / or express mRNA include, but are not limited to, the liver, kidneys, heart, spleen, serum, brain, skeletal muscle, lymph nodes, skin, and / or cerebrospinal fluid. In an example, the targeted tissue 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 the site of injury, disease manifestation, or pain; the composition can be provided in the form of lozenges for oral, tracheal, or esophageal application; can be provided in the form of liquids, tablets, or capsules for gastric or intestinal administration; can be provided in the form of suppositories for rectal or vaginal application; or can even be delivered to the eyes by means of creams, drops, or even injections.

[0312] Alternatively or additionally, the pharmaceutical formulations of the present invention can be administered intranasally. For example, the pharmaceutical formulations of the present invention can be administered via nasal spray. Exemplary tissues that can deliver and / or express mRNA include, but are not limited to, the lungs, heart, liver, spleen, and muscle. In one embodiment, the tissue to be targeted is in the lungs. In another embodiment, the tissue to be targeted is in muscle.

[0313] Alternatively or additionally, the pharmaceutical formulations of the present invention can be administered via pulmonary delivery (optionally via nebulization or dry powder inhalation). In embodiments, the pharmaceutical formulations of the present invention are administered via pulmonary delivery (via nebulization). In embodiments, the pharmaceutical formulations of the present invention are administered via pulmonary delivery (via dry powder inhalation). Exemplary tissues that can deliver and / or express mRNA include, but are not limited to, the lungs, heart, liver, spleen, and muscle. In embodiments, the tissue to be targeted is in the lungs. In embodiments, the tissue to be targeted is in muscle.

[0314] The compositions described herein may contain mRNA encoding peptides, including those described herein (e.g., polypeptides such as proteins).

[0315] In this embodiment, the mRNA encodes a polypeptide. In this embodiment, the mRNA encodes a peptide. In this embodiment, the peptide is an antigen. In this embodiment, the mRNA encodes a peptide for treating influenza. In this embodiment, the mRNA encodes a peptide for treating respiratory syncytial virus (RSV).

[0316] The nucleic acid-encoded antigens disclosed herein may be used to treat or prevent a variety of diseases that may affect humans or animals other than humans.

[0317] Antigens can come from bacteria, viruses, parasites, or cancer cells.

[0318] Viral antigens can be selected from the following groups of viruses: poliovirus, rabies virus, hepatitis A, hepatitis B, hepatitis C, yellow fever virus, varicella-zoster virus (VZV), measles virus, mumps virus, rubella virus, Japanese encephalitis virus, influenza virus, norovirus, rhinovirus, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), SARS-CoV-1, SARS-CoV-2, herpes simplex virus, papillomavirus, cytomegalovirus, rotavirus, West Nile virus, dengue virus, chikungunya virus, HIV (AIDS), and combinations thereof.

[0319] Bacterial antigens can be selected from the following bacterial groups: Acetobacter aurantius, Acinetobacter baumannii, Actinobacter ylangis, Agrobacterium radiata, Agrobacterium tumefaciens, Anaplasma phagocytophilum, Azotobacter azotobacter, Azotobacter browniformis, Bacillus anthracis, Bacillus pumilus, Bacillus cereus, Bacillus fusiformis, Bacillus licheniformis, Bacillus megaterium, Bacillus mycosis fungoides, Bacillus thermophilus, Bacillus subtilis, Bacillus thuringiensis, Bacteroides fragilis, Bacteroides gingivalis, Bacteroides melaninogenica, Bartonella henri, Bartonella pentaphyllum, Bordetella bronchitidis, Bordetella pertussis, and Borrelia burgdorferi. Brucella abortus, Brucella melioides, Brucella swine, Burkholderia melioides, Burkholderia pseudomelioides, Burkholderia cepacia, Campylobacter granulomatosa, Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Campylobacter pylori, Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheriae, Fusobacterium breve, Rickettsia burgdorferi, Propionibacterium acnes, Propionibacterium avidum, Propionibacterium granulosum, Propionibacterium acnes namnetense, Propionibacterium brachii, Ehrlich. chaf., Enterobacter cloacae, Enterococcus avianus, Enterococcus davidianus, Enterococcus faecalis, Enterococcus faecium, Enterococcus maloratus, Escherichia coli, Tula Francisella, Fusobacterium nucleatum, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus pertussis, Haemophilus vaginalis, Helicobacter pylori, Klebsiella pneumoniae, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactococcus lactis, Legionella pneumophila, Listeria monocytogenes, Methanobacterium extroquens, Microbacterium multiforme, Micrococcus luteus, Moraxella catarrhalis, Mycobacterium avianus, Mycobacterium bovis, Mycobacterium diphtheriae Mycobacterium diphtheriae, intracellular mycobacteria, Mycobacterium leprae, Mycobacterium smegmatis, Mycobacterium smegmatisMycobacterium tuberculosis, Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma penetratingis, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Pasteurella tularensis, Peptostreptococcus, Porphyromonas gingivalis, Prevotella melanogaster, Propionibacterium acnes, Pseudomonas aeruginosa, Rhizobium radiophyllum, Rickettsia prowleri, Rickettsia psittaci Rickettsia psittaci), Rickettsia pentadactylae, Rickettsia trachomatis, Rochalimaeahenselae, Rochalimaeahenselae, Rochalimaeahenselae, Rochalimae, Salmonella enteritidis, Salmonella typhi, Salmonella typhimurium, Serratia marcescens, Shigella dysenteriae, Spirospira, Staphylococcus aureus, Staphylococcus epidermidis, Stenotrophomonas maltophilia, Streptococcus agalactiae, Streptococcus avium, Streptococcus bovis, Streptococcus hamsterii, Streptococcus dactylis (faceium), Streptococcus faecalis, Streptococcus pyogenes, Streptococcus spp., Streptococcus lactis, Streptococcus viridans, Streptococcus pyogenes, Streptococcus mutans, Streptococcus stomatitis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus ratis, Streptococcus salivarius, Streptococcus serovars, Streptococcus pyogenes, Treponema pallidum, Treponema denticulatum, Vibrio cholerae, Vibrio comma, Vibrio parahaemolyticus, Vibrio vulnificus, Streptococcus viridans, Wolbachia, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, and combinations thereof.

[0320] Parasite antigens can be selected from the following parasite groups: Plasmodium, Leishmania, Trypanosoma, and Schistosoma.

[0321] Cancer antigens are molecules expressed on the surface of cancer cells or secreted into the bloodstream, which can be recognized and targeted by the immune system. These antigens are usually absent or present at much lower levels on healthy cells.

[0322] Cancer antigens can be selected from the following groups: HER2 / neu, EGFR (epidermal growth factor receptor), BRAF, carcinoembryonic antigen (CEA), MAGE-A, and NY-ESO-1.

[0323] In this embodiment, the mRNA encodes a protein. In this embodiment, the mRNA encodes a protein used to treat influenza. In this embodiment, the mRNA encodes a protein used to treat respiratory syncytial virus (RSV).

[0324] The present invention provides a method for delivering a composition having a full-length mRNA molecule encoding a target peptide or protein for treating a subject, such as a human subject or a cell of a human subject, or for treating and delivering to a cell of a human subject. delivery method

[0325] The delivery routes used in the methods of the present invention allow for non-invasive self-administration of the compounds of the present invention. In some embodiments, the method involves administering a composition containing mRNA encoding a therapeutic peptide or protein (in a suitable transfection or lipocarrier medium as described above) via aerosolization, nebulization, or instillation into the nose, trachea, or lungs. In some embodiments, the method involves administering a composition containing mRNA encoding a therapeutic peptide or protein (in a suitable transfection or lipocarrier medium as described above) via intravenous, intrathecal, intramuscular, intranasal, sublingual, or pulmonary delivery (optionally via nebulization). In some embodiments, the peptide or protein is encapsulated in liposomes. In some embodiments, the liposomes contain lipids that are compounds of the present invention. As used below, administration of the compounds of the present invention includes administration of a composition containing the compounds of the present invention.

[0326] Although local cells and tissues of the lung represent potential targets capable of functioning as biological reservoirs or repositories for the production and secretion of mRNA-encoded proteins, the applicant has found that administration of the compounds of the present invention to the lungs via aerosolization, nebulization, or infusion results in the distribution of even non-secreting proteins outside the lung cells. Without wishing to be bound by any particular theory, it is envisioned that the nanoparticle compositions of the present invention cross the lung airway-blood barrier, resulting in the translocation of intact nanoparticles to non-lung cells and tissues, such as the heart, liver, and spleen, in which encoded peptides or proteins are produced. Therefore, the practicality of the compounds and methods of the present invention extends beyond the production of therapeutic proteins in lung cells and lung tissues and can be used for delivery to non-lung target cells and / or tissues. They are useful for the management and treatment of a variety of diseases. In some embodiments, the compounds of the present invention used in the methods of the present invention result in the distribution of mRNA-encapsulated nanoparticles in the liver, spleen, heart, and / or other non-lung cells, and the production of encoded peptides or proteins. For example, administering the compounds of the present invention to the lungs via aerosolization, nebulization, or infusion will result in the composition itself and its peptide or protein products (e.g., antigens or functional proteins) being detectable in local cells and tissues of the lungs, as well as in peripheral target cells, tissues, and organs (due to the translocation of mRNA and delivery mediators to non-lung cells).

[0327] In some embodiments, the compounds of the present invention can be used in the methods of the present invention to specifically target peripheral cells or tissues. Following pulmonary delivery, it is contemplated that the compounds of the present invention cross the pulmonary airway-blood barrier and distribute to cells other than local lung cells. Therefore, the compounds disclosed herein can be administered to a subject via the pulmonary administration route using a variety of methods known to those skilled in the art (e.g., by inhalation) and distributed to both local target cells and tissues of the lungs and peripheral non-pulmonary cells and tissues (e.g., cells of the liver, spleen, kidneys, heart, skeletal muscle, lymph nodes, brain, cerebrospinal fluid, and plasma). Thus, both local lung cells and peripheral non-pulmonary cells can serve as biological reservoirs or repositories capable of producing and / or secreting translational products encoded by one or more polynucleotides. Therefore, the present invention is not limited to treating lung diseases or conditions, but can be used as a non-invasive means to facilitate the delivery of polynucleotides or the production of peptides or proteins encoded by them in peripheral organs, tissues, and cells (e.g., hepatocytes) that would otherwise only be achieved through systemic administration. Exemplary peripheral non-lung cells include, but are not limited to, hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, osteocytes, stem cells, mesenchymal cells, nerve cells, cardiac cells, adipocytes, vascular smooth muscle cells, cardiomyocytes, skeletal muscle cells, β cells, pituitary cells, synovial lining cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, granulocytes, and tumor cells.

[0328] Following administration of the composition to a subject, at least one to seven days or longer after administration of the compound, a peptide or protein product (e.g., a functional protein or enzyme) encoded by mRNA can be detected in the peripheral target tissue. 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 patient's condition. For example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45 days or longer after administration of the compound to the subject, a peptide or protein product can be detected in peripheral target tissue at a concentration (e.g., therapeutic concentration) of at least 0.025-1.5 µg / ml (e.g., at least 0.050 µg / ml, at least 0.075 µg / ml, at least 0.1 µg / ml, at least 0.2 µg / ml, at least 0.3 µg / ml, at least 0.4 µg / ml, at least 0.5 µg / ml, at least 0.6 µg / ml, at least 0.7 µg / ml, at least 0.8 µg / ml, at least 0.9 µg / ml). 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).

[0329] It has been demonstrated that nucleic acids can be delivered to the lungs via 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 the dry powder device described in U.S. Patent 5,780,014, which is incorporated herein by reference).

[0330] In some embodiments, the compounds of the present invention may be formulated such that they can be aerosolized or otherwise delivered as particulate liquids or solids before or during administration to a subject. Such compounds may be administered with the aid of one or more suitable devices for administering such solid or liquid particulate compositions (e.g., aerosolized aqueous solutions or suspensions) to produce particles easily inhaled or exhaled by the subject. In some embodiments, such devices (e.g., metered-dose inhalers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers, propellant-based inhalers, or blowpipes) facilitate the administration of a predetermined mass, volume, or dose of the composition to a subject (e.g., about 0.5 mg / kg mRNA per dose). For example, in some embodiments, the compounds of the present invention are administered to a subject using a metered-dose inhaler containing a suspension or solution comprising the compound and a suitable propellant. In some embodiments, the compounds of the present invention may be formulated as particulate powders (e.g., inhalable dry granules) intended for inhalation. In some embodiments, the compositions of the invention, formulated as inhalable particles, have a suitable size such 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 smaller). In yet other embodiments, the compounds of the invention are formulated to include one or more pulmonary surfactants (e.g., lamellar bodies). In some embodiments, the compounds of the present invention are administered to a subject such that a single dose is given at least 0.05 mg / kg, at least 0.1 mg / kg, at least 0.5 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0 mg / kg, at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 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. Concentration of mg / kg body weight.In some embodiments, the compounds of the present invention are administered to a subject such that a total amount of at least 0.1 mg, at least 0.5 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 6.0 mg, at least 7.0 mg, at least 8.0 mg, at least 9.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of mRNA is administered in one or more doses. Example

[0331] While certain compounds, compositions, and methods of the present invention have been specifically described according to certain embodiments, the following examples are for illustrative purposes only and are not intended to limit the scope of the invention. List of abbreviations: DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMAP: 4-Dimethylaminopyridine EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc: Ethyl acetate NaHCO3: Sodium bicarbonate Py: Pyridine Na2SO4: Sodium sulfate TEA: Triethylamine TFA: Trifluoroacetic acid MS: Mass Spectrometry ESI-MS: Electrospray ionization mass spectrometry TLC: Thin-layer chromatography Example 1: Synthesis of the compound of the present invention Scheme 1: Synthesis of Compound 24 Step 1: Synthesis of intermediate (3)

[0332] As described in Scheme 1: DIPEA (0.95 mL, 5.47 mmol), DMAP (0.084 g, 0.68 mmol), and EDC (0.393 g, 2.05 mmol) were added to a solution of acid (2) (1.2 g, 1.71 mmol) and isosorbide (1) (0.100 g, 0.68 mmol) in dichloromethane (10 mL). The resulting mixture was stirred overnight at room temperature. After 16 h, MS and TLC (30% EtOAc in hexane) analysis indicated the completion of the reaction. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified, and the desired product was eluted with 6% EtOAc in hexane. The fraction containing the product was concentrated to obtain 0.72 g (69%) of pure product. result: ESI-MS: Calculated value C 86 H 177 N2O 10 Si4, [M + H] + = 1510.25, observed values ​​= 1510.3 and 755.4 [M / 2 + H] + ] Step 2: Synthesis of Compound 24

[0333] As described in Scheme 1: Hydrogen fluoride (70% HF.py complex, 2 mL, 14.298 mmol) was added to a solution of intermediate (3) (0.72 g, 0.476 mmol) in tetrahydrofuran (4 mL) at 0°C, and the mixture was stirred for 5 min at the same temperature. The reaction mixture was then warmed to room temperature and stirred for 16 h. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified, and the desired product was eluted with 65% EtOAc in hexane. The purest fraction was concentrated to obtain 0.120 g (24%) of pure product. result: 1H NMR (400 MHz, CDCl3) δ 5.30 - 5.00 (m, 2H), 4.97 - 4.68 (m, 2H), 4.55 - 3.71 (m, 8H), 3.57 - 2.92 (m, 8H), 2.84 - 2.04 (m, 8H), 1.99 - 1.01 (m, 76H), 0.88 (t, J = 6.8 Hz, 12H). ESI-MS: Calculated value C 62 H 121 N2O 10 [M + H] + [M / 2 + H] = 1053.90, observed values ​​= 1053.2 and 527.3 + ] Scheme 2: Synthesis of Compound 3 Step 1: Synthesis of intermediate (3)

[0334] As described in Scheme 2: DIPEA (3.65 mL, 20.96 mmol), DMAP (0.32 g, 2.62 mmol), and EDC (1.5 g, 7.86 mmol) were added to a solution of acid (2) (4.58 g, 6.55 mmol) and isomannitol (1) (0.38 g, 2.62 mmol) in dichloromethane (40 mL). The resulting mixture was stirred overnight at room temperature. After 16 h, MS and TLC (30% EtOAc in hexane) analysis indicated the completion of the reaction. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified, and the desired product was eluted with 6% EtOAc in hexane. The fraction containing the product was concentrated to obtain 2.58 g (65%) of pure product. result: ESI-MS: Calculated value C 86 H 177 N2O 10 Si4, [M + H] + ] = 1510.25, Observed value = 1510.3 Step 2: Synthesis of Compound 3

[0335] As described in Scheme 2: Hydrogen fluoride (70% HF.py complex, 7 mL, 51.23 mmol) was added to a solution of intermediate (3) (2.58 g, 1.70 mmol) in tetrahydrofuran (14 mL) at 0°C, and the mixture was stirred for 5 min at the same temperature. The reaction mixture was then warmed to room temperature and stirred for 16 h. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified, and the desired product was eluted with 67% EtOAc in hexane. The purest fraction was concentrated to obtain 1.1 g (61%) of pure product. result: 1 H NMR (400 MHz, CDCl3) δ 5.13 - 5.03 (m, 2H), 4.73 - 4.65 (m, 2H), 4.29 - 3.83 (m, 8H), 3.52 - 2.98 (m, 12H), 2.69 - 2.49 (m, 4H), 2.32 - 2.09 (m, 4H), 1.73 - 1.12 (m, 72H), 0.88 (t, J = 6.6 Hz, 12H). ESI-MS: Calculated value C 62 H 121 N2O 10 [M + H] + [M / 2 + H] = 1053.90, observed values ​​= 1053.2 and 527.2 + ] Scheme 3: Synthesis of Compound 40 Step 1: Synthesis of intermediate (4)

[0336] As described in Scheme 3: DMAP (0.033 g, 0.027 mmol) and TEA (0.67 mL, 4.79 mmol) were added to a solution of isosorbide (1) (0.100 g, 0.68 mmol) in anhydrous DCM (3 mL). (2) (0.33 g, 1.64 mmol) was added to the resulting mixture and stirred for 20 min. Alcohol (3) (1.15 g, 1.71 mmol) in DCM (5 mL) was added and stirred for 20 h at room temperature. MS (non-ionized) and TLC analyses indicated product formation. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 8% ethyl acetate in hexane) to give intermediate (4) (1.05 g, quantitative yield). result: ESI-MS: Calculated value C 86 H 177 N2O 12 Si4, [M + H] + = 1542.24, observed value = 771.5 [M / 2 + H] + ] Step 2: Synthesis of Compound 40

[0337] As described in Scheme 3: Hydrogen fluoride (70% HF.py complex, 1 mL, 6.80 mmol) was added to a solution of intermediate (4) (1.05 g, 0.68 mmol) in tetrahydrofuran (4 mL) at 0°C, and the mixture was stirred for 5 min at the same temperature. The reaction mixture was then warmed to room temperature and stirred for 16 h. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified, and the purest fraction was concentrated to obtain 0.154 g (20%) of pure product. result: ESI-MS: Calculated value C 62 H 120 N2O 12 [M + H] + [M / 2 + H] = 1085.89, observed values ​​= 1085.1 and 543.2 + ] Scheme 4: Synthesis of Compound 9 and Compound 19 Step 1: Synthesis of intermediate (2)

[0338] As described in Scheme 4: Isomannitol (144 mg, 0.985 mmol), DMAP (120 mg, 0.978 mmol), and EDC (244 mg, 1.27 mmol) were added to a solution of acid (1) (750 mg, 1.07 mmol) in 8 mL of DCM. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (in 10% ethyl acetate in hexane) to give intermediate (2) (455 mg, 55%). result: ESI-MS: Calculated value C 46 H 94 NO7Si2, [M + H] + = 828.66, observed value = 828.6. Step 2: Synthesis of intermediate (4)

[0339] As described in Scheme 4: DIPEA (0.16 mL, 0.917 mmol), DMAP (0.028 g, 0.229 mmol), and EDC (0.132 g, 0.688 mmol) were added to a solution of acid (with TFA salt) (3) (0.335 g, 0.298 mmol) and isomannitol monoester (2) (0.19 g, 0.229 mmol) in dichloromethane (5 mL). The resulting mixture was stirred overnight at room temperature. After 16 h, MS and TLC (30% EtOAc in hexane) analysis indicated the completion of the reaction. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3 solution, water, and aqueous salt solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified, and the desired product was eluted with 7% EtOAc in hexane. The fraction containing the product was concentrated to obtain intermediate (4) 0.255 g (61%) of pure product. result: ESI-MS: Calculated value C 104 H 209 N2O 14 Si4, [M + H] += 1822.48, observed value = 911.5 [M / 2 + H] + ] Step 3: Synthesis of Compound 9 and Compound 19

[0340] As described in Scheme 4: Hydrogen fluoride (70% HF.py complex, 2 mL, 6.993 mmol) was added to a solution of intermediate (4) (0.255 g, 0.139 mmol) in tetrahydrofuran (2 mL) at 0°C, and the mixture was stirred for 5 min at the same temperature. The reaction mixture was then warmed to room temperature and stirred for 16 h. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified, and the desired product compound 9 was eluted with 70%–97% EtOAc in hexane, and the cyclized product compound 19 was eluted with 97%–100% EtOAc in hexane. The purest fractions were concentrated to obtain 50 mg (26%) of compound 9 and 46 mg (27%) of compound 19. result: ESI-MS of compound 9: Calculated value C 80 H 153 N2O 14 [M + H] + = 1366.13, Observations = 1366.1 and 683.6 [M / 2 + H + ] ESI-MS of compound 19: Calculated C 80 H 153 N2O 14 [M + H] + [M / 2 + H] = 1193.95, observed values ​​= 1193.1 and 597.2 + ] Scheme 5: Synthesis of Compound 1 Step 1: Synthesis of intermediate (2)

[0341] As described in Scheme 5: Isomannitol (0.250 g, 1.711 mmol), 4-dimethylaminopyridine (DMAP) (0.210 g, 1.711 mmol), diisopropylethylamine (DIPEA) (2.4 mL, 14 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.312 g, 6.844 mmol) were added to a solution of acid (1) (3.306 g, 5.132 mmol) in 25 mL of anhydrous dichloromethane (DCM). The resulting mixture was stirred overnight at room temperature. Mass spectrometry (MS) analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (1.493 g, 62%). result: ESI-MS: Calculated value C 78 H 160 N2O 10 Si4, [M + H] + = 1398.12, observed values ​​= 1398.2 and 699.1 [M / 2 + H] + ]. Step 2: Synthesis of Compound 1

[0342] As described in Scheme 5: Pyridine hydrogen fluoride (70% HF, 8.0 mL, 62 mmol) was added to a solution of intermediate (2) (2.471 g, 1.767 mmol) in 16 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 47% ethyl acetate in hexane) to obtain compound 1 (720 mg, 43%). result: 1H NMR (400 MHz, CDCl3) δ 5.12 - 5.02 (m, 2H), 4.74 - 4.66 (m, 2H), 4.28 - 4.11 (m, 2H), 4.10 - 3.98 (m, 4H), 3.97 - 3.71 (m, 2H), 3.43 - 2.90(m, 12H), 2.78 - 2.49 (m, 4H), 2.45 - 2.08 (m, 4H), 1.69 - 1.19 (m, 56H), 0.88 (t, J = 6.6 Hz, 12H). ESI-MS: Calculated value C 54 H 104 N2O 10 [M + H] + [M / 2 +H] = 941.78, observed values ​​= 941.2 and 471.1 + ] Scheme 6: Synthesis of Compound 20 Step 1: Synthesis of intermediate (2)

[0343] As described in Scheme 6: Isosorbide (0.250 g, 1.711 mmol), DMAP (0.210 g, 1.711 mmol), DIPEA (2.4 mL, 14 mmol), and EDC (1.312 g, 6.844 mmol) were added to a solution of acid (1) (3.306 g, 5.132 mmol) in 25 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (1.402 g, 59%). result: ESI-MS: Calculated value C 78 H 160 N2O 10 Si4, [M + H] + = 1398.12, observed values ​​= 1398.2 and 699.2 [M / 2 + H] + ]. Step 2: Synthesis of Compound 20

[0344] As described in Scheme 6: Pyridine hydrogen fluoride (70% HF, 8.0 mL, 62 mmol) was added to a solution of intermediate (2) (2.250 g, 1.609 mmol) in 16 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 37% ethyl acetate in hexane) to obtain compound 20 (366 mg, 24%). result: 1 H NMR (400 MHz, CDCl3) δ 5.22 - 5.13 (m, 2H), 4.89 - 4.82 (m, 2H), 4.52 - 4.45 (m, 2H), 4.24 - 3.77 (m, 8H), 3.41 - 2.57 (m, 12H), 2.58 - 2.27 (m, 4H), 2.22 - 1.95 (m, 2H), 1.70 - 1.16 (m, 56H), 0.88 (t, 12H). ESI-MS: Calculated value C 54 H 104 N2O 10 [M + H] + = 941.78, observed values ​​= 941.1 and 471.1 [M / 2 +H + ] Scheme 7: Synthesis of Compound 33 Step 1: Synthesis of intermediate (2)

[0345] As described in Scheme 7: Isosorbide (38 mg, 0.26 mmol), DMAP (30 mg, 0.24 mmol), DIPEA (0.35 mL, 2.0 mmol), and EDC (190 mg, 0.991 mmol) were added to a solution of acid (1) (751 mg, 0.742 mmol) in 7.5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (266 mg, 48%). result: ESI-MS analysis: Calculated value C 122 H 240 N2O 18 Si4, [M + H] + = 2134.71, observed value = 1067.3 [M / 2+ H + ]. Step 2: Synthesis of Compound 33

[0346] As described in Scheme 7: Pyridine hydrogen fluoride (70% HF, 0.05 mL, 0.4 mmol) was added to a solution of intermediate (2) (583 mg, 0.264 mmol) in 1.5 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 53% ethyl acetate in hexane) to obtain compound 33 (119 mg, 27%). result: 1H NMR (400 MHz, CDCl3) δ 5.21 - 5.17 (m, 2H), 4.90 - 4.79 (m, 2H), 4.51 - 4.46 (m, 6H), 4.29 - 4.23 (m, 2H), 4.09 - 4.01 (m, 4H), 3.97 - 3.88(m, 4H), 3.29 - 3.24 (m, 6H), 3.15 - 3.10 (m, 4H), 2.54 - 2.50 (m, 6H), 2.39- 2.24 (m, 12H), 2.22 - 2.18 (m, 6H), 1.84 - 1.79 (m, 4H), 1.65 - 1.55 (m,12H), 1.55 - 1.45 (m, 12H), 1.41 - 1.33 (m, 4H), 1.33 - 1.27 (m, 18H), 1.27 -1.05 (m, 58H), 0.87 (t, J = 6.6 Hz, 18H). ESI-MS: Calculated value C 98 H 184 N2O 18 [M + H] + [M / 2 + H] = 1678.36, observed values ​​= 1678.2 and 839.3 + ]. Scheme 8: Synthesis of Compound 21 Step 1: Synthesis of intermediate (2)

[0347] As described in Scheme 8: Isosorbide (44 mg, 0.30 mmol), DMAP (37 mg, 0.30 mmol), DIPEA (0.423 mL, 2.43 mmol), and EDC (233 mg, 1.22 mmol) were added to a solution of acid (1) (500 mg, 0.760 mmol) in 5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (265 mg, 24%). result: ESI-MS analysis: Calculated value C80 H 164 N2O 10 Si4, [M + H] + = 1426.15, observed value = 714.0 [M / 2+ H + ]. Step 2: Synthesis of Compound 21

[0348] As described in Scheme 8: Pyridine hydrogen fluoride (70% HF, 0.75 mL, 5.8 mmol) was added to a solution of intermediate (2) (265 mg, 0.186 mmol) in 1 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 47% ethyl acetate in hexane) to obtain compound 21 (64 mg, 36%). result: ESI-MS: Calculated value C 56 H 108 N2O 10 [M + H] + = 969.81, observed values ​​= 969.2 and 485.2 [M / 2 +H + ]. Scheme 9: Synthesis of Compound 35 Step 1: Synthesis of intermediate (2)

[0349] As described in Scheme 9: Isosorbide (42.1 mg, 0.288 mmol), DMAP (35 mg, 0.29 mmol), DIPEA (0.39 mL, 2.2 mmol), and EDC (215 mg, 1.12 mmol) were added to a solution of acid (1) (750 mg, 0.837 mmol) in 7.5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 7% ethyl acetate in hexane) to give intermediate (2) (364 mg, 66%). result: ESI-MS analysis: Calculated value C 106 H 200 N2O 18 Si4, [M + H] + = 1902.40, observed value = 951.2 [M / 2+ H + ]. Step 2: Synthesis of Compound 35

[0350] As described in Scheme 9: Pyridine hydrogen fluoride (70% HF, 0.08 mL, 0.6 mmol) was added to a solution of intermediate (2) (364 mg, 0.191 mmol) in 2.3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 84% ethyl acetate in hexane) to obtain compound 35 (94 mg, 34%). result: 1 H NMR (400 MHz, CDCl3) δ 5.69 - 5.57 (m, 4H), 5.57 - 5.38 (m, 4H), 5.25 - 4.94 (m, 2H), 4.94 - 4.74 (m, 2H), 4.74 - 4.56 (m, 8H), 4.56 - 4.42(m, 1H), 4.42 - 4.32 (m, 1H), 4.32 - 4.00 (m, 4H), 4.00 - 3.65 (m, 2H), 2.86- 2.00 (m, 32H), 1.96 - 1.81 (m, 2H), 1.81 - 1.00 (m, 66H), 0.99 - 0.76 (m, 12H). ESI-MS: Calculated value C 82 H 144 N2O 18 [M + H] + [M / 2 + H] = 1446.05, observed values ​​= 1446.1 and 723.5 + ] Scheme 10: Synthesis of Compound 26 Step 1: Synthesis of intermediate (2)

[0351] As described in Scheme 10: Isosorbide (51 mg, 0.35 mmol), DMAP (44 mg, 0.36 mmol), DIPEA (0.50 mL, 3.0 mmol), and EDC (268 mg, 1.40 mmol) were added to a solution of acid (1) (750 mg, 1.05 mmol) in 7.5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis showed the presence of a monoester. Additional EDC (134 mg, 0.699 mmol) was added to the reactants, and the reaction was allowed to proceed for another 90 minutes. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (166 mg, 31%). result: ESI-MS analysis: Calculated value C 88 H 180 N2O 10 Si4, [M + H] + [M / 2 + H] = 1538.28, observed values ​​= 1538.3 and 769.6 + ]. Step 2: Synthesis of Compound 26

[0352] As described in Scheme 10: Pyridine hydrogen fluoride (70% HF, 0.1 mL, 0.8 mmol) was added to a solution of intermediate (2) (306 mg, 0.200 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 60% ethyl acetate in hexane) to obtain compound 26 (74 mg, 34%). result: 1H NMR (400 MHz, CDCl3) δ 5.26 - 5.10 (m, 2H), 4.92 - 4.76 (m, 2H), 4.32 - 4.15 (m, 2H), 3.98 - 3.79 (m, 2H), 3.35 - 2.99 (m, 16H), 2.67 - 2.17 (m, 4H), 2.06 - 1.90 (m, 4H), 1.79 - 1.18 (m, 76H), 0.88 (t, J = 6.7 Hz, 12H). ESI-MS: Calculated value C 64 H 124 N2O 10 [M + H] + [M / 2 + H] = 1081.93, observed values ​​= 1081.3 and 541.2 + ] Scheme 12: Synthesis of Compound 28 Step 1: Synthesis of intermediate (2)

[0353] As described in Scheme 12: Isosorbide (48 mg, 0.33 mmol), DMAP (41 mg, 0.33 mmol), DIPEA (0.45 mL, 2.6 mmol), and EDC (250 mg, 1.30 mmol) were added to a solution of acid (1) (755 mg, 0.980 mmol) in 7.5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (381 mg, 70%). result: ESI-MS analysis: Calculated value C 96 H 196 N2O 10 Si4, [M + H] + = 1650.40, observed value = 825.8 [M / 2+ H + ]. Step 2: Synthesis of Compound 28

[0354] As described in Scheme 12: Pyridine hydrogen fluoride (70% HF, 0.60 mL, 5.0 mmol) was added to a solution of intermediate (2) (381 mg, 0.231 mmol) in 2 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 65% ethyl acetate in hexane) to obtain compound 28 (174 mg, 63%). result: 1 H NMR (400 MHz, CDCl3) δ 5.26 - 5.02 (m, 2H), 4.96 - 4.75 (m, 2H), 4.31 - 4.14 (m, 2H), 3.93 (d, J = 15.6 Hz, 2H), 3.37 - 2.96 (m, 16H), 2.50 -2.26 (m, 4H), 2.03 - 1.85 (m, 4H), 1.79 - 1.17 (m, 92H), 0.91 - 0.81 (m,12H). ESI-MS: Calculated value C 72 H 140 N2O 10 [M + H] + [M / 2 + H] = 1194.0, observed values ​​= 1193.3 and 597.3 + ]. Scheme 13: Synthesis of Compound 31 Step 1: Synthesis of intermediate (2)

[0355] As described in Scheme 13: Isosorbide (43 mg, 0.29 mmol), DMAP (36 mg, 0.29 mmol), DIPEA (0.40 mL, 2.0 mmol), and EDC (221 mg, 1.15 mmol) were added to a solution of acid (1) (755 mg, 0.855 mmol) in 7.5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis showed the presence of a monoester. Additional EDC (127 mg, 0.66 mmol) was added to the reactants, and the reaction was allowed to proceed for another 90 minutes. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (375 mg, 68%). result: ESI-MS analysis: Calculated value C 112 H 228 N2O 10 Si4, [M + H] + = 1874.65, observed value = 937.8 [M / 2+ H + ]. Step 2: Synthesis of Compound 31

[0356] As described in Scheme 13: Pyridine hydrogen fluoride (70% HF, 0.55 mL, 4.3 mmol) was added to a solution of intermediate (2) (375 mg, 0.200 mmol) in 2 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 40% ethyl acetate in hexane) to obtain compound 31 (172 mg, 61%). result: 1H NMR (400 MHz, CDCl3) δ 5.25 - 5.18 (m, 2H), 4.51 - 4.45 (m, 2H), 4.28 - 4.16 (m, 2H), 3.95 - 3.81 (m, 2H), 3.34 - 3.01 (m, 16H), 2.50 - 2.34(m, 4H), 2.02 - 1.87 (m, 4H), 1.85 - 1.16 (m, 124H), 0.87 (t, 12H). ESI-MS: Calculated value C 88 H 172 N2O 10 [M + H] + = 1418.31, observed values ​​= 1418.3 and 709.3 [M / 2+ H + ] Scheme 14: Synthesis of Compound 29 Step 1: Synthesis of intermediate (2)

[0357] As described in Scheme 14: Isosorbide (45 mg, 0.31 mmol), DMAP (40 mg, 0.33 mmol), DIPEA (0.50 mL, 3.0 mmol), and EDC (237 mg, 1.24 mmol) were added to a solution of acid (1) (758 mg, 0.933 mmol) in 7.5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis showed the presence of a monoester. Additional DMAP (19 mg, 0.15 mmol) was added to the reactants, and the reaction was allowed to proceed for another 2 hours. Mass spectrometry confirmed the presence of a small amount of monoester. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous salt solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (503 mg, 94%). result: ESI-MS analysis: Calculated value C 102 H 208 N2O 10 Si4, [M + H] + = 1734.50, observed value = 867.7 [M / 2+ H + ]. Step 2: Synthesis of Compound 29

[0358] As described in Scheme 14: Pyridine hydrogen fluoride (70% HF, 1.7 mL, 13 mmol) was added to a solution of intermediate (2) (503 mg, 0.290 mmol) in 3.5 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 72% ethyl acetate in hexane) to obtain compound 29 (229 mg, 62%). result: 1 H NMR (400 MHz, CDCl3) δ 5.25 - 5.10 (m, 2H), 4.90 - 4.80 (m, 2H), 4.51 - 4.44 (m, 2H), 4.32 - 4.14 (m, 2H), 4.00 - 3.82 (m, 4H), 3.43 - 3.01 (m, 10H), 2.62 - 2.13 (m, 6H), 1.74 - 1.12 (m, 108H), 0.88 (t, 12H). ESI-MS: Calculated value C 78 H 152 N2O 10 [M + H] + [M / 2 + H] = 1278.15, observed values ​​= 1278.3 and 639.3 + ] Scheme 15: Synthesis of Compound 30 Step 1: Synthesis of intermediate (2)

[0359] As described in Scheme 15: Isosorbide (43 mg, 0.29 mmol), DMAP (39 mg, 0.32 mmol), DIPEA (0.40 mL, 2.0 mmol), and EDC (223 mg, 1.16 mmol) were added to a solution of acid (1) (751 mg, 0.865 mmol) in 7.5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis showed the presence of a monoester. Additional EDC (110 mg, 0.574 mmol) was added to the reactants, and the reaction was allowed to proceed for another 2 hours. Mass spectrometry confirmed the presence of a small amount of monoester. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (214 mg, 39%). result: ESI-MS analysis: Calculated value C 110 H 224 N2O 10 Si4, [M + H] + = 1846.62, observed value = 924.3 [M / 2+ H + ]. Step 2: Synthesis of Compound 30

[0360] As described in Scheme 15: Pyridine hydrogen fluoride (70% HF, 0.90 mL, 7.0 mmol) was added to a solution of intermediate (2) (214 mg, 0.116 mmol) in 1.8 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 61% ethyl acetate in hexane) to obtain compound 30 (87 mg, 54%). result: 1H NMR (400 MHz, CDCl3) δ 5.18 - 5.04 (m, 2H), 4.85 - 4.73 (m, 2H), 4.48 - 4.37 (m, 2H), 4.19 - 4.13 (m, 2H), 3.88 - 3.78 (m, 4H), 3.28 - 3.00(m, 10H), 2.60 - 2.36 (m, 6H), 2.30 - 2.05 (m, 4H), 1.79 - 1.11 (m, 120H), 0.81 (t, J = 6.6 Hz, 12H). ESI-MS: Calculated value C 86 H 168 N2O 10 [M + H] + = 1390.28, observed value = 695.3 [M / 2 + H] + ] Scheme 16: Synthesis of Compound 34 Step 1: Synthesis of intermediate (2)

[0361] As described in Scheme 16: Isosorbide (144 mg, 0.985 mmol), DMAP (120 mg, 0.978 mmol), and EDC (244 mg, 1.27 mmol) were added to a solution of acid (1) (750 mg, 1.07 mmol) in 7.5 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 10% ethyl acetate in hexane) to give intermediate (2) (368 mg, 45%). ekovic, Tokic, Z. Selective esterification of 1,4:3,6-'dianhydro-D-glucitol. Synthesis 1989, 8, 610-612. result: 1H NMR (400 MHz, CDCl3) δ 5.72 - 5.63 (m, 2H), 5.59 - 5.48 (m, 2H), 5.23 - 5.15 (m, 2H), 4.92 - 4.80 (m, 1H), 4.67 - 4.61 (m, 4H), 4.54 - 4.45(m, 1H), 4.45 - 4.30 (m, 1H), 4.30 - 4.01 (m, 3H), 4.01 - 3.76 (m, 4H), 3.51- 2.90 (m, 18H), 2.90 - 2.42 (m, 4H), 2.41 - 2.27 (m, 4H), 2.27 - 2.02 (m,6H), 2.01 - 1.18 (m, 64H), 0.89 (d, J = 6.7 Hz, 12H). ESI-MS analysis: Calculated value C 46 H 93 NO7Si2, [M + H] + = 828.66, observed value = 828.6. Step 2: Synthesis of intermediate (4)

[0362] As described in Scheme 16: Intermediate (2) (368 mg, 0.444 mmol), DMAP (54 mg, 0.44 mmol), and EDC (110 mg, 0.574 mmol) were added to a solution of acid (3) (460 mg, 0.513 mmol) in 6 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 5% ethyl acetate in hexane) to give intermediate (4) (482 mg, 55%). result: ESI-MS analysis: Calculated value C 96 H 188 N2O 14 Si4, [M + H] + = 1706.32, observed value = 854.1 [M / 2+ H + ]. Step 3: Synthesis of Compound 34

[0363] As described in Scheme 16: Pyridine hydrogen fluoride (70% HF, 0.05 mL, 0.4 mmol) was added to a solution of intermediate (4) (482 mg, 0.282 mmol) in 3.5 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 65% ethyl acetate in hexane) to obtain compound 34 (220 mg, 62%). result: 1 H NMR (400 MHz, CDCl3) δ 5.22 - 5.13 (m, 2H), 4.88 - 4.79 (m, 2H), 4.50 - 4.45 (m, 2H), 4.30 - 4.20 (m, 4H), 4.09 - 4.01 (m, 2H), 3.97 - 3.94(m, 0H), 3.94 - 3.90 (m, 4H), 3.03 - 2.98 (m, 4H), 2.51 - 2.46 (m, 6H), 2.39- 2.24 (m, 10H), 2.11 - 2.06 (m, 8H), 1.78 - 1.68 (m, 1H), 1.68 - 1.57 (m,3H), 1.53 - 1.37 (m, 8H), 1.37 - 1.27 (m, 25H), 1.27 - 1.23 (m, 35H), 0.99 -0.91 (m, 1H), 0.94 - 0.80 (m, 11H). ESI-MS: Calculated value C 72 H 132 N2O 14 [M + H] + ] = 1249.98, observed values ​​= 1249.8 and 625.5 [M / 2+ H + ] Scheme 17: Synthesis of Compound 22 Step 1: Synthesis of intermediate A (scaled up for asymmetric ester synthesis)

[0364] As described in Scheme 17: Isosorbide (761 mg, 5.21 mmol), DMAP (638 mg, 5.20 mmol), and EDC (1.296 g, 6.761 mmol) were added to a solution of acid (1) (4.005 g, 5.719 mmol) in 40 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was 4.627 g. This compound was used to produce compounds 22, 32, 27, and 25. It was referred to as crude intermediate A in subsequent procedures. In a later stage, crude intermediate A was purified (SiO2: 10% ethyl acetate in hexane) and used to produce compound 23. result: ESI-MS analysis: Calculated value C 46 H 93 NO7Si2, [M + H] + = 828.66, observed value = 828.6. Step 2: Synthesis of intermediate (4)

[0365] As described in Scheme 17: Crude intermediate (2) (305 mg, 0.368 mmol), DMAP (46 mg, 0.37 mmol), and EDC (91 mg, 0.47 mmol) were added to a solution of acid (3) (260 mg, 0.404 mmol) in 6 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (4) (202 mg, 34%). result: ESI-MS analysis: Calculated value C 82 H 168 N2O 10 Si4, [M + H] + [M / 2 + H] = 1454.19, observed values ​​= 1454.1 and 727.8 + ]. Step 3: Synthesis of Compound 22

[0366] As described in Scheme 17: Pyridine hydrogen fluoride (70% HF, 0.68 mL, 5.3 mmol) was added to a solution of intermediate (4) (202 mg, 0.139 mmol) in 1.4 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 77% ethyl acetate in hexane) to obtain compound 22 (78 mg, 56%). result: 1 H NMR (400 MHz, CDCl3) δ 5.22 - 5.09 (m, 2H), 4.90 - 4.79 (m, 1H), 4.51 - 4.45 (m, 1H), 4.22 - 3.76 (m, 8H), 3.20 - 2.54 (m, 12H), 2.54 - 2.28 (m, 4H), 2.19 - 1.95 (m, 4H), 1.56 - 1.20 (m, 64H), 0.88 (t, J = 6.7 Hz, 12H). ESI-MS: Calculated value C 58 H 112 N2O 10 [M + H] + [M / 2 + H] = 997.84, observed values ​​= 997.8 and 499.5 + ] Scheme 18: Synthesis of Compound 32 Step 1: Synthesis of intermediate (2)

[0367] As described in Scheme 18: Crude intermediate A (prepared as in Scheme 17, step 1) (305 mg, 0.368 mmol), DMAP (47 mg, 0.38 mmol), and EDC (93 mg, 0.49 mmol) were added to a solution of acid (1) (416 mg, 0.411 mmol) in 6 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (318 mg, 42%). result: ESI-MS analysis: Calculated value C 104 H 208 N2O 14 Si4, [M + H] + = 1822.48, observed value = 912.2 [M / 2+ H + ]. Step 2: Synthesis of Compound 32

[0368] As described in Scheme 18: Pyridine hydrogen fluoride (70% HF, 0.16 mL, 1.2 mmol) was added to a solution of intermediate (2) (318 mg, 0.174 mmol) in 2.1 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 65% ethyl acetate in hexane) to obtain compound 32 (88 mg, 37%). result: 1H NMR (400 MHz, CDCl3) δ 5.21 - 5.11 (m, 2H), 4.88 - 4.79 (m, 2H), 4.50 - 4.30 (m, 3H), 4.30 - 4.19 (m, 2H), 4.19 - 3.66 (m, 8H), 3.31 - 2.57(m, 6H), 2.55 - 2.39 (m, 4H), 2.39 - 2.24 (m, 4H), 2.18 - 1.97 (m, 4H), 1.91- 1.00 (m, 98H), 0.88 (t, 15H). ESI-MS: Calculated value C 80 H 152 N2O 14 [M + H] + = 1366.13, observed values ​​= 1365.9 and 683.7 [M / 2+ H + ] Scheme 19: Synthesis of Compound 27 Step 1: Synthesis of intermediate (2)

[0369] As described in Scheme 19: Crude intermediate A (prepared as in Scheme 17, step 1) (354 mg, 0.427 mmol), DMAP (52 mg, 0.42 mmol), and EDC (106 mg, 0.553 mmol) were added to a solution of acid (1) (392 mg, 0.483 mmol) in 6 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (453 mg, 58%). result: ESI-MS analysis: Calculated value C 94 H 192 N2O 10 Si4, [M + H] + = 1622.37, observed value = 812.6 [M / 2+ H + ]. Step 2: Synthesis of Compound 27

[0370] As described in Scheme 19: Pyridine hydrogen fluoride (70% HF, 1.5 mL, 12 mmol) was added to a solution of intermediate (2) (453 mg, 0.279 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 54% ethyl acetate in hexane) to obtain compound 27 (132 mg, 41%). result: 1 H NMR (400 MHz, CDCl3) δ 5.22 - 5.13 (m, 2H), 4.92 - 4.82 (m, 1H), 4.51 - 4.44 (m, 1H), 4.22 - 3.76 (m, 8H), 3.34 - 2.78 (m, 12H), 2.72 - 2.32 (m, 4H), 2.27 - 1.96 (m, 4H), 1.58 - 1.15 (m, 88H), 0.88 (t, J = 6.6 Hz, 12H). ESI-MS: Calculated value C 70 H 136 N2O 10 [M + H] + [M / 2 + H] = 1166.03, observed values ​​= 1165.9 and 583.6 + ] Scheme 20: Synthesis of Compound 25 Step 1: Synthesis of intermediate (2)

[0371] As described in Scheme 20: Crude intermediate A (prepared as in Scheme 17, step 1) (354 mg, 0.427 mmol), DMAP (53 mg, 0.43 mmol), and EDC (105 mg, 0.548 mmol) were added to a solution of acid (1) (349 mg, 0.489 mmol) in 6 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (429 mg, 58%). result: ESI-MS analysis: Calculated value C 87 H 178 N2O 10 Si4, [M + H] + = 1524.26, observed value = 762.2 [M / 2+ H + ]. Step 2: Synthesis of Compound 25

[0372] As described in Scheme 20: Pyridine hydrogen fluoride (70% HF, 1.5 mL, 12 mmol) was added to a solution of intermediate (2) (429 mg, 0.281 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 61% ethyl acetate in hexane) to obtain compound 25 (87 mg, 29%). result: 1H NMR (400 MHz, CDCl3) δ 5.25 - 5.07 (m, 2H), 4.92 - 4.73 (m, 1H), 4.54 - 4.41 (m, 1H), 4.32 - 4.13 (m, 2H), 4.05 - 3.83 (m, 2H), 3.39 - 3.00(m, 12H), 2.83 - 2.30 (m, 8H), 2.28 - 2.11 (m, 2H), 2.07 - 1.88 (m, 2H), 1.81- 1.15 (m, 74H), 0.88 (t, J = 6.6 Hz, 12H). ESI-MS: Calculated value C 63 H 122 N2O 10 [M + H] + [M / 2 + H] = 1067.92, observed values ​​= 1067.8 and 534.5 + ] Scheme 21: Synthesis of Compound 23 Step 1: Synthesis of intermediate (2)

[0373] As described in Scheme 21: Intermediate A (prepared as in Scheme 17, step 1) (368 mg, 0.444 mmol), DMAP (54 mg, 0.44 mmol), and EDC (110 mg, 0.574 mmol) were added to a solution of acid (1) (460 mg, 0.699 mmol) in 6 mL of anhydrous dichloromethane. The resulting mixture was stirred overnight at room temperature. MS analysis showed the presence of intermediate (2) in addition to intermediate A. DIPEA (0.25 mL, 1.4 mmol) was added and the reaction was allowed to proceed for another 24 hours. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (482 mg, 47%). result: ESI-MS analysis: Calculated value C 83 H 170 N2O 10 Si4, [M + H] +[M / 2 + H] = 1468.20, observed values ​​= 1468.1 and 734.8 + ]. Step 2: Synthesis of Compound 23

[0374] As described in Scheme 21: Pyridine hydrogen fluoride (70% HF, 1.8 mL, 14 mmol) was added to a solution of intermediate (2) (694 mg, 0.473 mmol) in 3.5 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 45% ethyl acetate in hexane) to obtain compound 23 (349 mg, 73%). result: 1 H NMR (400 MHz, CDCl3) δ 5.21 - 5.11 (m, 2H), 4.88 - 4.75 (m, 2H), 4.31 - 4.20 (m, 2H), 3.99 - 3.89 (m, 2H), 3.84 - 3.56 (m, 4H), 2.94 - 2.17 (m, 16H), 1.89 - 1.14 (m, 70H), 0.94 - 0.80 (m, 12H). ESI-MS: Calculated value C 59 H 114 N2O 10 [M + H] + [M / 2 + H] = 1011.86, observed values ​​= 1011.8 and 506.5 + ] Scheme 22: Synthesis of Compound 37 Step 1: Synthesis of intermediate (2)

[0375] As described in Scheme 22: DMAP (6 mg, 0.05 mmol) and triethylamine (0.2 mL, 1.0 mmol) were added to a solution of isomannitol (34 mg, 0.23 mmol) in 5.5 mL of anhydrous DCM. NO2PhOCOCl (100 mg, 0.496 mmol) was added to the resulting mixture and the mixture was stirred at room temperature for 20 minutes. Alcohol (1) (376 mg, 0.516 mmol) was added, and the reaction mixture was stirred at room temperature overnight. MS showed small peaks (ionization difference) of the starting material (alcohol (1)) and the desired product. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (225 mg, 58%). result: ESI-MS analysis: Calculated value C 94 H 192 N2O 12 Si4, [M + H] + = 1654.36, observed value = 827.6 [M / 2+ H + ]. Step 2: Synthesis of Compound 37

[0376] As described in Scheme 22: Pyridine hydrogen fluoride (HF 70%, 0.75 mL, 5.8 mmol) was added to a solution of intermediate (2) (225 mg, 0.136 mmol) in 1.5 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C, followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. The organic layer was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 8% methanol in DCM) to obtain compound 37 (35 mg, 21%). result: 1H NMR (400 MHz, CDCl3) δ 5.04 - 4.98 (m, 2H), 4.77 - 4.72 (m, 2H), 4.32 - 4.19 (m, 4H), 4.11 - 4.02 (m, 2H), 3.92 - 3.82 (m, 2H), 3.76 - 3.71(m, 4H), 2.90 - 2.42 (m, 12H), 2.02 - 1.85 (m, 4H), 1.54 - 1.16 (m, 88H), 0.88 (t, J = 6.7 Hz, 12H). ESI-MS: Calculated value C 70 H 136 N2O 12 [M + H] + = 1198.01, observed values ​​= 1197.9 and 599.5 [M / 2+ H + ] Scheme 23: Synthesis of Compound 38 Step 1: Synthesis of intermediate (2)

[0377] As described in Scheme 23: DMAP (5 mg, 0.04 mmol) and triethylamine (0.2 mL, 1.0 mmol) were added to a solution of isomannitol (30 mg, 0.21 mmol) in 3 mL of anhydrous DCM. NO2PhOCOCl (100 mg, 0.496 mmol) was added to the resulting mixture and the mixture was stirred at room temperature for 20 minutes. Alcohol (1) (374 mg, 0.545 mmol) was added, and the reaction mixture was stirred at room temperature overnight. MS showed small peaks (ionization difference) of the starting material (1) and the desired product. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 4% ethyl acetate in hexane) to give intermediate (2) (270 mg, 84%). result: ESI-MS: Calculated value C 88 H 180 N2O 12 Si4, [M + H] + = 1570.26, observed value = 786.1 [M / 2 + H + ]. Step 2: Synthesis of Compound 38

[0378] As described in Scheme 23: Pyridine hydrogen fluoride (HF 70%, 0.90 mL, 7.0 mmol) was added to a solution of intermediate (2) (270 mg, 0.172 mmol) in 2 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. The organic layer was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 8% methanol in DCM) to obtain compound 38 (35 mg, 18%). result: 1 H NMR (400 MHz, CDCl3) δ 5.06 - 4.97 (m, 2H), 4.77 - 4.71 (m, 2H), 4.22 - 4.12 (m, 4H), 4.12 - 3.97 (m, 2H), 3.94 - 3.83 (m, 2H), 3.83 - 3.64(m, 4H), 2.85 - 2.47 (m, 12H), 1.87 - 1.57 (m, 8H), 1.57 - 1.16 (m, 72H), 0.92 - 0.80 (m, 12H). ESI-MS: Calculated value C 64 H 124 N2O 12 [M + H] + = 1113.92, observed values ​​= 1113.8 and 557.5 [M / 2 + H] + ] Scheme 24: Synthesis of Compound 36 Step 1: Synthesis of intermediate (2)

[0379] As described in Scheme 24: DMAP (12 mg, 0.098 mmol) and triethylamine (0.45 mL, 3.2 mmol) were added to a solution of isomannitol (66 mg, 0.41 mmol) in 6 mL of anhydrous DCM. NO2PhOCOCl (215 mg, 1.07 mmol) was added to the resulting mixture and the mixture was stirred at room temperature for 90 minutes. Alcohol (1) (749 mg, 1.11 mmol) was added, and the reaction mixture was stirred at room temperature overnight. MS showed small peaks (ionization difference) of the starting material (alcohol (1)) and the desired product. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 5% ethyl acetate in hexane) to give intermediate (2) (630 mg, quantitative yield). result: ESI-MS analysis: Calculated value C 86 H 176 N2O 12 Si4, [M + H] + = 1542.23, observed value = 772.0 [M / 2 + H + ]. Step 2: Synthesis of Compound 36

[0380] As described in Scheme 24: Pyridine hydrogen fluoride (HF 70%, 0.37 mL, 2.9 mmol) was added to a solution of intermediate (2) (630 mg, 0.408 mmol) in 6 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. The organic layer was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (SiO2: 10% methanol in 1% triethylamine DCM solution) to obtain compound 36 (73 mg, 16%). result: 1H NMR (400 MHz, CDCl3) δ 5.03 - 4.99 (m, 2H), 4.77 - 4.72 (m, 2H), 4.30 - 4.23 (m, 4H), 4.08 - 4.04 (m, 2H), 3.91 - 3.86 (m, 2H), 3.67 - 3.58(m, 4H), 2.98 - 2.43 (m, 12H), 2.00 - 1.93 (m, 4H), 1.49 - 1.22 (m, 72H), 0.87 (t, J = 6.4 Hz, 12H). ESI-MS: Calculated value C 62 H 120 N2O 12 [M + H] + [M / 2 + H] = 1085.88, Observations = 1085.8 and 543.5 + ] Scheme 25: Synthesis of Compound 33 Step 1: Synthesis of intermediate (2)

[0381] As described in Scheme 25: Isosorbide (28.86 mg, 0.2 mmol) and acid (1) (500 mg, 0.49 mmol) were added to 5 mL of DCM in a 20 mL vial. DMAP (419.7 mg, 3.421 mmol), DIPEA (0.275 mL, 1.58 mmol), and EDC (151.42 mg, 0.79 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 16 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (24 g silica column, 7% ethyl acetate-hexane gradient) to give 334 mg (79% yield) of intermediate (2). result ESI-MS: Calculated value C 122 H 240 N2O 18 Si4, [M + H] + = 2135.71, Observed value = 1068.2 [M / 2 + H + ]. Step 2: Synthesis of Compound 33

[0382] As described in Scheme 25: Hydrofluoric acid pyridine (70% HF.py complex, 1 mL) was added to a solution of intermediate (2) (334 mg, 712.7 mmol) in 2 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (12 g, 75% ethyl acetate-hexane gradient) to obtain compound 33 (10.5 mg, 4%). result ESI-MS: Calculated value C 98 H 184 N2O 18 [M + H] + = 1678.36, observed value = 839.9 [M / 2 + H] + ]. 1 H NMR (400 MHz, CDCl3) δ 5.16 - 4.99 (m, 2H), 4.94 - 4.79 (m, 2H), 4.77 - 4.66 (m, 2H), 4.31 - 4.20 (m, 2H), 4.04 (t, J = 6.9 Hz, 8H), 3.20 (d,J = 54.9 Hz, 10H), 2.71 - 2.48 (m, 4H), 2.47 - 2.08 (m, 24H), 1.91 - 1.51 (m,20H), 1.51 - 1.03 (m, 88H), 0.87 (t, J = 6.7 Hz, 18H). Scheme 26: Synthesis of Compound 2 Step 1: Synthesis of intermediate (2)

[0383] As described in Scheme 26: Isomannitol (44 mg, 0.303 mmol) and acid (1) (500 mg, 0.76 mmol) were added to 5 mL of DCM in a 20 mL vial. DMAP (37 mg, 0.303 mmol), DIPEA (0.423 mL, 2.431 mmol), and EDC (233 mg, 1.215 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 16 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (12 g silica column, 4% ethyl acetate-hexane) to give 113 mg (48% yield) of intermediate (2). result ESI-MS: Calculated value C 80 H 164 N2O 10 Si4, [M + H] + = 1426.16, observed value = 713.3 [M / 2 + H] + ]. Step 2: Synthesis of Compound 2

[0384] As described in Scheme 26: Hydrofluoric acid pyridine (70% HF.py complex, 1.5 mL) was added to a solution of intermediate (2) (402.6 mg, 0.282 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (12 g, 45% ethyl acetate-hexane gradient) to obtain compound 2 (130.4 mg, 37%). result ESI-MS: Calculated value C 56 H 108 N2O 10 [M + H] + [M + H] = 969.81, Observed value = 969.2 + ], 485.1 [M / 2 + H + ]. 1H NMR (400 MHz, CDCl3) δ 5.13 - 5.04 (m, 2H), 4.73 - 4.67 (m, 2H), 4.04 (dd, 4H), 4.01 - 3.66 (m, 4H), 3.17 - 2.85 (m, 8H), 2.50 - 2.37 (m, 4H), 1.71 (p, J = 7.5 Hz, 4H), 1.57 - 1.34 (m, 12H), 1.42 - 1.09 (m, 52H), 0.87 (t, J = 6.6 Hz, 12H). Scheme 27: Synthesis of Compound 16 Step 1: Synthesis of intermediate (2)

[0385] As described in Scheme 27: Isomannitol (40.74 mg, 0.279 mmol) and acid (1) (750 mg, 0.837 mmol) were added to 7.5 mL of DCM in a 20 mL vial. DMAP (34.22 mg, 0.279 mmol), DIPEA (0.389 mL, 2.231 mmol), and EDC (213.83 mg, 1,115 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 16 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (24 g silica column, 8% ethyl acetate-hexane gradient) to obtain intermediate (2) (229 mg, 44%). result ESI-MS: Calculated value C 106 H 200 N2O 18 Si4, [M + H] + = 1902.40, observed value = 951.7 [M / 2 + H] + ]. Step 2: Synthesis of Compound 16

[0386] As described in Scheme 27: Hydrofluoric acid pyridine (70% HF.py complex, 0.054 mL) was added to a solution of intermediate (2) (229 mg, 0.12 mmol) in 1.5 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h. MS analysis indicated the reaction was complete. The reaction mixtures were combined and diluted with ethyl acetate, quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by rapid silica gel chromatography (12 g, ethyl acetate gradient in hexane) to obtain compound 16 (95 mg, 55%). result ESI-MS: Calculated value C 82 H 144 N2O 18 [M + H] + = 1446.05, observed value = 724.3 [M / 2 + H] + ]. 1 H NMR (400 MHz, CDCl3) δ 5.79 - 5.27 (m, 8H), 5.27 - 4.96 (m, 2H), 4.71 (s, 2H), 4.62 (d, J = 6.8 Hz, 4H), 4.54 - 3.60 (m, 14H), 3.58 - 2.90 (m,6H), 2.70 - 2.43 (m, 2H), 2.44 - 2.14 (m, 8H), 2.13 - 2.01 (m, 2H), 1.89 -1.47 (m, 24H), 1.40 - 1.06 (m, 56H), 0.89 (t, J = 4.9 Hz, 12H). Scheme 28: Synthesis of Compound 11 Step 1: Synthesis of intermediate (2)

[0387] As described in Scheme 28: Isomannitol (36.07 mg, 0.2469 mmol) and acid (1) (750 mg, 0.741 mmol) were added to 7.5 mL of DCM in a 20 mL vial. DMAP (30.289 mg, 0.2469 mmol), DIPEA (0.344 mL, 1.975 mmol), and EDC (189.29 mg, 0.9874 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 16 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (24 g silica column, 7% ethyl acetate-hexane gradient) to obtain intermediate (2) (389 mg, 74%). result ESI-MS: Calculated value C 122 H 240 N2O 18 Si4, [M + H] + = 2134.71, Observed value = 1068.0 [M / 2 + H + ]. Step 2: Synthesis of Compound 11

[0388] As described in Scheme 28: Hydrofluoric acid pyridine (70% HF.py complex, 0.082 mL) was added to a solution of intermediate (2) (389.9 mg, 0.182 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 17 h. MS analysis indicated the reaction was complete. The reaction mixtures were combined and diluted with ethyl acetate, quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by rapid silica gel chromatography (12 g, ethyl acetate gradient in hexane) to obtain compound 11 (157 mg, 51%). result ESI-MS: Calculated value C 98 H 184 N2O 18 [M + H] + = 1678.36, observed value = 1678.3 [M + H] + ], 839.3 [M / 2 + H + ]. 1 H NMR (400 MHz, CDCl3) δ 5.16 - 4.99 (m, 2H), 4.94 - 4.79 (m, 2H), 4.77 - 4.66 (m, 2H), 4.31 - 4.20 (m, 2H), 4.04 (t, J = 6.9 Hz, 8H), 3.20 (d,J = 54.9 Hz, 10H), 2.71 - 2.48 (m, 4H), 2.47 - 2.08 (m, 24H), 1.91 - 1.51 (m,20H), 1.51 - 1.03 (m, 88H), 0.87 (t, J = 6.7 Hz, 18H). Scheme 29: Synthesis of Compound 4 Step 1: Synthesis of intermediate (2)

[0389] As described in Scheme 29: DMAP (42.9 mg, 0.350 mmol), DIPEA (0.488 mL, 2.8 mmol), and EDC (268.4 mg, 1.4 mmol) were added to a solution of isomannitol (51.2 mg, 0.350 mmol), acid (1) (750 mg, 1.05 mmol) in 7.5 mL of DCM, and the resulting mixture was stirred overnight at room temperature. After 22 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (24 g silica column, 4% ethyl acetate-hexane gradient) to obtain intermediate (2) (344 mg, 64%). result ESI-MS: Calculated value C 88 H 180 N2O 10 Si4, [M + H] + = 1538.28, observed value = 769.7 [M / 2 + H] + ]. Step 2: Synthesis of Compound 4

[0390] As described in Scheme 29: Hydrofluoric acid pyridine (70% HF.py complex, 1.5 mL) was added to a solution of intermediate (2) (340.5 mg, 0.221 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h. MS analysis indicated the reaction was complete. The reaction mixtures were combined and diluted with ethyl acetate, quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (12 g, 38% ethyl acetate-hexane gradient) to obtain compound 4 (124 mg, 52%). result ESI-MS: Calculated value C 64 H 124 N2O 10 [M + H] + [M + H] = 1081.94, observed value = 1081.3 + ],541.4 [M / 2 + H + ]. 1 H NMR (400 MHz, CDCl3) δ 5.20 (s, 4H), 4.97 - 4.42 (m, 2H), 4.33 -4.17 (m, 2H), 4.10 - 3.82 (m, 4H), 3.36 - 3.19 (m, 4H), 3.15 - 3.04 (m, 4H), 2.59 - 2.22 (m, 12H), 2.14 - 1.75 (m, 4H), 1.78 - 1.45 (m, 12H), 1.43 - 0.98 (m, 64H), 0.88 (t, J = 6.7 Hz, 12H). Scheme 30: Synthesis of Compound 5 Step 1: Synthesis of intermediate (2)

[0391] As described in Scheme 30: Isomannitol (47.4 mg, 0.32 mmol) and acid (1) (750 mg, 0.97 mmol) were added to 7.5 mL of DCM in a 20 mL vial. DMAP (39.8 mg, 0.32 mmol), DIPEA (0.45 mL, 2.6 mmol), and EDC (310 mg, 1.3 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 22 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (24 g silica column, 4% ethyl acetate-hexane gradient) to obtain intermediate (2) (352 mg, 66%). result ESI-MS: Calculated value C 96 H 196 N2O 10 Si4, [M + H] + = 1650.41, observed value = 825.3 [M / 2 + H] + ]. Step 2: Synthesis of Compound 5

[0392] As described in Scheme 30: Pyridine hydrogen fluoride (70% HF.py complex, 0.13 mL, 1.49 mmol) was added to a solution of intermediate (2) (351.5 mg, 0.21 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 20 h. MS analysis indicated the reaction was complete. The reaction mixtures were combined and diluted with ethyl acetate, quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (12 g, 55% ethyl acetate-hexane gradient) to obtain compound 5 (82 mg, 32%). result ESI-MS: Calculated value C 72 H 140 N2O 10 [M + H] + = 1194.06, observed value = 597.3 [M / 2 + H + ]. 1H NMR (400 MHz, CDCl3) δ 5.09 (s, 4H), 4.69 (m, 2H), 4.11 - 3.97 (m,2H), 3.89 - 3.65 (m, 4H), 3.25 - 2.78 (m, 4H), 2.86 - 2.53 (m, 4H), 2.50 -2.36 (m, 12H), 1.95 - 1.79 (m, 4H), 1.61 - 1.36 (m, 12H), 1.25 (m, 84H), 0.88 (t, J = 6.7 Hz, 12H). Scheme 31: Synthesis of Compound 6 Step 1: Synthesis of intermediate (2)

[0393] As described in Scheme 31: Isomannitol (45 mg, 0.31 mmol) and acid (1) (750 mg, 0.92 mmol) were added to 7.5 mL of DCM in a 20 mL vial. DMAP (56.6 mg, 0.46 mmol), DIPEA (0.64 mL, 3.69 mmol), and EDC (235.9 mg, 1.23 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 20 hr, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (24 g silica column, 5% ethyl acetate-hexane gradient) to obtain intermediate (2) (230 mg, 44%). result ESI-MS: Calculated value C 102 H 208 N2O 10 Si4, [M + H] + = 1734.50, observed value = 868.4 [M / 2 + H] + ]. Step 2: Synthesis of Compound 6

[0394] As described in Scheme 31: Hydrofluoric acid pyridine (70% HF.py complex, 0.5 mL) was added to a solution of intermediate (2) (230 mg, 0.13 mmol) in 2 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hr. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (12 g, 39% ethyl acetate-hexane gradient) to obtain compound 6 (113 mg, 67%). result ESI-MS: Calculated value C 78 H 152 N2O 10 [M + H] + = 1278.15, observed value = 639.5 [M / 2 + H] + ]. 1 H NMR (400 MHz, CDCl3) δ 5.14 - 5.04 (m, 2H), 4.76 - 4.62 (m, 2H), 4.12 - 3.68 (m, 8H), 3.11 - 2.61 (m, 12H), 2.57 - 2.33 (m, 4H), 2.02 (d, J =14.0 Hz, 4H), 1.64 - 1.36 (m, 12H), 1.46 - 0.99 (m, 96H), 0.85 (d, J = 6.7Hz, 12H). Scheme 32: Synthesis of Compound 7 Step 1: Synthesis of intermediate (2)

[0395] As described in Scheme 32: Isomannitol (42.1 mg, 0.29 mmol) and acid (1) (750 mg, 0.86 mmol) were added to 7.5 mL of DCM in a 20 mL vial. DMAP (35.3 mg, 0.29 mmol), DIPEA (0.4 mL, 2.3 mmol), and EDC (220.7 mg, 1.15 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 16 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (24 g silica column, 2% ethyl acetate-hexane gradient) to obtain intermediate (2) (457 mg, 86%). result ESI-MS: Calculated value C 110 H 224 N2O 10 Si4, [M + H] + = 1846.63, observed value = 924.3 [M / 2 + H] + ]. Step 2: Synthesis of Compound 7

[0396] As described in Scheme 32: Hydrofluoric acid pyridine (70% HF.py complex, 1 mL) was added to a solution of intermediate (2) (457 mg, 0.25 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h. MS analysis indicated the reaction was complete. The reaction mixtures were combined and diluted with ethyl acetate, quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (12 g, 85% ethyl acetate-hexane gradient) to obtain compound 7 (186 mg, 54%). result ESI-MS: Calculated value C 86 H 168 N2O 10 [M + H] + = 1390.28, observed value = 695.3 [M / 2 + H] + ]. 1H NMR (400 MHz, CDCl3) δ 5.15 - 4.96 (m, 2H), 4.80 - 4.61 (m, 2H), 4.24 - 3.67 (m, 8H), 3.35 - 2.56 (m, 12H), 2.59 - 2.34 (m, 4H), 2.24 - 1.82 (m, 4H), 1.65 - 1.35 (m, 12H), 1.67 - 1.00 (m, 112H), 0.88 (t, J = 6.6 Hz, 12H). Scheme 33: Synthesis of Compound 15 Step 1: Synthesis of intermediate (2)

[0397] As described in Scheme 33: Isomannitol (142.3 mg, 0.97 mmol) and acid (1) (750 mg, 1.07 mmol) were added to 7.5 mL of DCM in a 20 mL vial. DMAP (119.5 mg, 0.97 mmol) and EDC (242.6 mg, 1.27 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 16 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue (881.5 mg) was relatively pure and was used for the next step (esterification with acid (3)) without further purification. result ESI-MS: Calculated value C 46 H 93 NO7Si2, [M + H] + = 828.66, Observed value = 828.6 [M + H] + ]. Step 2: Synthesis of intermediate (4)

[0398] As described in Scheme 33: In a 20 mL vial, intermediate (2) (881.5 mg, 1.06 mmol) and acid (3) (1049.3 mg, 1.17 mmol) were added to 9 mL of DCM. DMAP (130.6 mg, 1.06 mmol) and EDC (265.2 mg, 1.38 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 16 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (40 g silica column, 4% ethyl acetate-hexane gradient) to obtain intermediate (4) (652 mg, 36%). result ESI-MS: Calculated value C 96 H 188 N2O 14 Si4, [M + H] + = 1706.32, observed value = 854.0 [M / 2 + H] + ]. Step 3: Synthesis of Compound 15

[0399] As described in Scheme 33: Hydrofluoric acid pyridine (70% HF.py complex, 0.17 mL) was added to a solution of intermediate (4) (652 mg, 0.38 mmol) in 4 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 20 h. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (12 g, 78% ethyl acetate-hexane gradient) to obtain compound 15 (332 mg, 70%). result ESI-MS: Calculated value C 72 H 132 N2O 14 [M + H] + ] = 1249.98, Observed value = 1249.8 [M + H + ], 625.6 [M / 2 + H + ]. 1H NMR (400 MHz, CDCl3) δ 5.68 - 5.46 (m, 4H), 5.13 - 5.05 (m, 2H), 4.75 - 4.65 (m, 2H), 4.61 (d, J = 6.8 Hz, 4H), 3.91 (dt, J = 89.7, 8.6 Hz,4H), 3.64 (s, 4H), 2.72 - 2.50 (m, 6H), 2.53 - 2.36 (m, 10H), 2.31 (t, J =7.5 Hz, 6H), 2.09 (q, J = 7.3 Hz, 4H), 1.87 - 1.78 (m, 4H), 1.63 (p, J = 7.5Hz, 4H), 1.51 - 1.36 (m, 12H), 1.36 - 1.07 (m, 54H), 0.88 (t, J = 6.6 Hz, 12H). Scheme 34: Synthesis of Compound 8 Step 1: Synthesis of intermediate (2)

[0400] As described in Scheme 34: Isomannitol (139.5 mg, 0.95 mmol) and acid (1) (750 mg, 1.05 mmol) were added to 7.5 mL of DCM in a 20 mL vial. DMAP (117.1 mg, 0.95 mmol) and EDC (237.9 mg, 1.24 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 18 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue (884.9 mg) was relatively pure and was used for the next step (esterification with acid (3)) without further purification. result ESI-MS: Calculated value C 47 H 95 NO7Si2, [M + H] + = 842.67, Observed value = 842.6 [M + H] + ]. Step 2: Synthesis of intermediate (4)

[0401] As described in Scheme 34: DMAP (128.9 mg, 1.05 mmol) and EDC (261.8 mg, 1.37 mmol) were added to a solution of intermediate (2) (884.9 mg, 1.05 mmol) and acid (3) (949.2 mg, 1.15 mmol) in 9 mL of DCM, and the resulting mixture was stirred overnight at room temperature. After 18 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (40 g silica column, 4% ethyl acetate-hexane gradient) to obtain intermediate (4) (900 mg, 52%). result ESI-MS: Calculated value C 95 H 194 N2O 10 Si4, [M + H] + = 1636.39, observed value = 818.9 [M / 2 + H] + ]. Step 3: Synthesis of Compound 8

[0402] As described in Scheme 34: Hydrofluoric acid pyridine (70% HF.py complex, 1 mL) was added to a solution of intermediate (4) (900 mg, 0.55 mmol) in 4 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 18 h. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (24 g, 75% ethyl acetate-hexane gradient) to obtain compound 8 (105 mg, 16%). result ESI-MS: Calculated value C 71 H 138 N2O 10 Si4, [M + H] + [M + H] = 1179.05, Observed value = 1179.9 + ], 590.7 [M / 2 + H + ]. 1H NMR (400 MHz, CDCl3) δ 5.21 - 5.01 (m, 2H), 4.75 - 4.65 (m, 2H), 3.91 (dd, J = 91.9, 8.4 Hz, 4H), 3.68 - 3.61 (m, 2H), 2.76 - 2.50 (m, 6H), 2.51 - 2.11 (m, 10H), 1.95 - 1.50 (m, 4H), 1.48 - 1.32 (m, 12H), 1.25 (s, 80H), 0.87 (t, J = 7.1 Hz, 12H). Scheme 35: Synthesis of Compound 14 Step 1: Synthesis of intermediate (2)

[0403] As described in Scheme 35: Isomannitol (154.7 mg, 1.06 mmol) and acid (1) (750 mg, 1.16 mmol) were added to 7.5 mL of DCM in a 20 mL vial. DMAP (129.9 mg, 1.06 mmol) and EDC (263.8 mg, 1.38 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 18 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue (713.9 mg) was relatively pure and was used for the next step (esterification with acid (3)) without further purification. result ESI-MS: Calculated value C 42 H 85 NO7Si2, [M + H] + [M + H] = 772.60, Observed value = 772.5 + ]. Step 2: Synthesis of intermediate (4)

[0404] As described in Scheme 35: In a 20 mL vial, 2 (713.9 mg, 0.92 mmol) and acid (3) (818 mg, 0.91 mmol) were added to 7 mL of DCM. DMAP (113.4 mg, 0.92 mmol) and EDC (230.4 mg, 1.20 mmol) were added to this solution, and the resulting mixture was stirred overnight at room temperature. After 18 h, MS analysis indicated that the reaction was complete. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified (40 g silica column, 6% ethyl acetate-hexane gradient) to obtain intermediate (4) (470 mg, 31%). result ESI-MS: Calculated value C 92 H 180 N2O 14 Si4, [M + H] + = 1650.26, observed value = 826.1 [M / 2 + H] + ]. Step 3: Synthesis of Compound 14

[0405] As described in Scheme 35: Hydrofluoric acid pyridine (70% HF.py complex, 1 mL) was added to a solution of intermediate (4) (470 mg, 0.27 mmol) in 3 mL of anhydrous tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 18 h. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel rapid chromatography (12 g, 88% ethyl acetate-hexane gradient) to obtain compound 14 (291 mg, 89%). result ESI-MS: Calculated value C 68 H 124 N2O 14 Si4, [M + H] + [M + H] = 1193.92, Observed value = 1193.8 + ], 597.5 [M / 2 + H + ]. 1H NMR (400 MHz, CDCl3) δ 5.68 - 5.46 (m, 4H), 5.13 - 5.05 (m, 2H), 4.75 - 4.65 (m, 2H), 4.61 (d, J = 6.8 Hz, 4H), 3.91 (dt, J = 89.7, 8.6 Hz,4H), 3.64 (s, 4H), 2.72 - 2.50 (m, 6H), 2.53 - 2.36 (m, 10H), 2.31 (t, J =7.5 Hz, 6H), 2.09 (q, J = 7.3 Hz, 4H), 1.87 - 1.78 (m, 4H), 1.63 (p, J = 7.5Hz, 4H), 1.51 - 1.36 (m, 12H), 1.36 - 1.07 (m, 46H), 0.88 (t, J = 6.6 Hz, 12H). Scheme 36: Synthesis of Compound 56 Step 1: Synthesis of intermediate (2)

[0406] As described in Scheme 36: Isomannitol (344 mg, 2.35 mmol) was added to a solution of intermediate (1) (1.500 g, 2.142 mmol) in anhydrous DCM (15 mL). DMAP (263 mg, 2.14 mmol) and EDC (534 mg, 2.79 mmol) were then added. The reaction mixture was stirred overnight at room temperature. MS analysis showed the presence of monoesters. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and then with brine. The compounds were extracted from the aqueous layer at each step of the post-treatment. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using a hexane:ethyl acetate solvent system to obtain intermediate (2) (839 mg, 47% yield). result: ESI-MS: Calculated value C46H93NO7Si2, [M + H+] = 828.66, observed value = 828.5 Step 2: Synthesis of intermediate (4)

[0407] As described in Scheme 36: Intermediate (2) (839 mg, 1.01 mmol) was added to a solution of intermediate (3) (797 mg, 1.12 mmol) in anhydrous DCM (6.0 mL). DMAP (125 mg, 1.02 mmol) and EDC (252 mg, 1.32 mmol) were then added. The reaction mixture was stirred overnight at room temperature. MS analysis showed the presence of the expected product. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The compound was extracted from the aqueous layer at each step of the post-treatment. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using an ethyl acetate:hexane solvent system to obtain intermediate (4) (1.070 g, 69% yield). result: ESI-MS: Calculated value C87H178N2O10Si4, [M + H+] = 1524.26, observed value = 763.0 [M / 2 +H+] Step 3: Synthesis of Compound 56

[0408] As described in Scheme 36: HF-pyridine (1.8 mL, 14 mmol, 70% by mass) was added to a solution of intermediate (4) (1.070 g, 0.7018 mmol) in anhydrous THF (4.0 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. MS analysis indicated that the expected product had been produced. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 followed by the addition of a saturated NaHCO3 solution. The reaction was quenched at 0°C. The organic layer was then washed with a saturated NaHCO3 solution, followed by washing with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using a 12 g silica column and a hexane:ethyl acetate solvent system. The purest fraction was collected and concentrated to obtain compound 56 (411 mg, 55% yield). result: 1H NMR (400 MHz, CDCl3) δ 5.14 - 5.05 (m, 2H), 4.74 - 4.65 (m, 2H), 4.07 - 3.99 (m, 2H), 3.84 - 3.75 (m, 2H), 3.69 - 3.56 (m, 4H), 2.63 0.88 (t, 12H). ESI-MS: Calculated value C63H122N2O10, [M + H+] = 1067.92, observed value = 1067.8 Scheme 37: Synthesis of Compound 60 Step 1: Synthesis of intermediate (2)

[0409] As described in Scheme 37: Isosorbide (1.20 g, 8.21 mmol) was added to a solution of intermediate (1) (3.0 g, 4.2 mmol) in anhydrous DCM (30 mL). DMAP (564 mg, 4.62 mmol) and EDC (1.047 g, 5.462 mmol) were then added. The reaction mixture was stirred overnight at room temperature. MS analysis showed the presence of monoesters. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and then with brine. The compounds were extracted from the aqueous layer at each step of the post-treatment. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using a hexane:ethyl acetate solvent system to obtain intermediate (2) (2.348 g, 66% yield). result: ESI-MS: Calculated value C47H95NO7Si2, [M + H+] = 842.67, observed value = 842.6 Step 2: Synthesis of intermediate (4)

[0410] As described in Scheme 37: Intermediate (2) (353 mg, 0.419 mmol) was added to a solution of intermediate (3) (366 mg, 0.523 mmol) in anhydrous DCM (6.0 mL). DMAP (60 mg, 0.49 mmol) and EDC (114 mg, 0.595 mmol) were then added. The reaction mixture was stirred overnight at room temperature. MS analysis showed the presence of the expected product. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The compound was extracted from the aqueous layer at each step of the post-processing. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using an ethyl acetate:hexane solvent system to obtain intermediate (4) (768 mg, quantitative yield). result: ESI-MS: Calculated value C87H178N2O10Si4, [M + H+] = 1524.26, observed value = 763.0 [M / 2 +H+] Step 3: Synthesis of Compound 60

[0411] As described in Scheme 37: HF-pyridine (2.50 mL, 19 mmol, 70% by mass) was added to a solution of intermediate (4) (768 mg, 0.504 mmol) in anhydrous THF (5.00 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using an ethyl acetate:hexane solvent system to obtain compound 60 (284 mg, 53% yield). result: 1H NMR (400 MHz, CDCl3) δ 5.22 - 5.12 (m, 3H), 4.87 - 4.79 (m, 1H), 4.52 - 4.44 (m, 1H), 4.01 - 3.90 (m, 3H), 3.83 - 3.75 (m, 1H), 3.68 - 3.55(m, 4H), 2.62 - 2.52 (m, 4H), 2.50 - 2.29 (m, 12H), 1.84 - 1.76 (m, 2H), 1.48- 1.45 (m, 2H), 1.46 - 1.37 (m, 8H), 1.38 - 1.19 (m, 66H), 0.88 (t, 12H). ESI-MS: Calculated value C63H122N2O10, [M + H+] = 1067.92, observed value = 1067.8 Scheme 38: Synthesis of Compound 66 Step 1: Synthesis of intermediate (2)

[0412] As described in Scheme 38: Isosorbide (216 mg, 1.48 mmol) was added to a solution of intermediate (1) (1.001 g, 0.9884 mmol) in anhydrous DCM (10 mL). DMAP (133 mg, 1.09 mmol) and EDC (246 mg, 1.28 mmol) were then added. The reaction mixture was stirred overnight at room temperature. MS analysis showed the presence of monoesters. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and then with brine. The compounds were extracted from the aqueous layer at each step of the post-treatment. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using a hexane:ethyl acetate solvent system to obtain intermediate (2) (664 mg, 59% yield). result: ESI-MS: Calculated value C64H125NO11Si2, [M + H+] = 1140.89, observed value = 1140.7 Step 2: Synthesis of intermediate (4)

[0413] As described in Scheme 38: IS-E3-001-Mono-TBS (352 mg, 0.309 mmol) was added to a solution of intermediate (3) (434 mg, 0.423 mmol) in anhydrous DCM (8 mL). DMAP (41 mg, 0.34 mmol) and EDC (81 mg, 0.42 mmol) were then added. The reaction mixture was stirred overnight at room temperature. MS analysis showed the presence of the expected product. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The compound was extracted from the aqueous layer at each step of the post-processing. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using an ethyl acetate:hexane solvent system to obtain intermediate (4) (459 mg, 69% yield). result: ESI-MS: Calculated value C123H242N2O18Si4, [M + H+] = 2148.72, observed value = 1075.4 [M / 2 + H+] Step 3: Synthesis of Compound 66

[0414] As described in Scheme 38: HF-pyridine (0.17 mL, 1.3 mmol, 70% by mass) was added to a solution of intermediate (4) (459 mg, 0.214 mmol) in anhydrous THF (3.0 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. MS analysis showed the presence of a single TBS product. 0.17 mL of HF-pyridine was added and the reaction mixture was stirred for another 5 hours. MS analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using an ethyl acetate:hexane solvent system to obtain compound 66 (141 mg, 39% yield). result: 1H NMR (400 MHz, CDCl3) δ 5.23 - 5.11 (m, 2H), 4.87 - 4.82 (m, 2H), 4.51 - 4.45 (m, 1H), 4.10 - 4.01 (m, 4H), 3.98 - 3.94 (m, 3H), 3.83 - 3.75 (m, 1H), 3.67 - 3.61 (m, 3H), 2.68 - 2.22 (m, 29H), 1.83 - 1.20 (m, 119H), 0.88 (t, 18H). ESI-MS: Calculated value C99H186N2O18, [M + H+] = 1692.38, observed value = 847.0 [M / 2 + H+] Scheme 39: Synthesis of Compound 73 Step 1: Synthesis of intermediate (2)

[0415] As described in Scheme 39: Isomannitol diamine salt (537 mg, 2.47 mmol), DMAP (315 mg, 2.57 mmol), DIPEA (3.5 mL, 20 mmol), and EDC (1.894 g, 9.880 mmol) were added to a solution of intermediate (1) (5.498 g, 5.429 mmol) in anhydrous DCM (10 mL). The resulting mixture was stirred overnight at room temperature. MS analysis indicated that the reaction was complete after 16 hours. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water, and aqueous salt solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified using a hexane:ethyl acetate solvent system to give intermediate (2) (3.12 g, 59% yield). result: ESI-MS: Calculated value C122H242N4O16Si4, [M + H+] = 2132.74, observed value = 1067.3 [M / 2 + H+] Step 2: Synthesis of Compound 73

[0416] As described in Scheme 39: HF-pyridine (1.88 mL, 15 mmol, 70% by mass) was added to a solution of intermediate (2) (3.12 g, 1.46 mmol) in anhydrous THF (12.5 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate and quenched by the slow addition of solid NaHCO3 at 0°C followed by the addition of a saturated NaHCO3 solution. The organic layer was washed with a saturated NaHCO3 solution, water, and brine. It was then dried over anhydrous Na2SO4 and concentrated. The crude residue was purified on neutral alumina using a hexane:dichloromethane solvent system to obtain compound 73 (220 mg, 9% yield). result: 1H NMR (400 MHz, CDCl3) δ 4.88 - 4.79 (m, 2H), 4.58 - 4.32 (m, 3H), 4.08 - 3.88 (m, 7H), 3.80 - 3.50 (m, 6H), 2.56 - 2.26 (m, 20H), 1.95 - 1.17(m, 124H), 0.87(t, 18H). ESI-MS: Calculated value C98H186N4O16, [M + H+] = 1676.39, observed value = 839 [M / 2 + H+] Scheme 40: Synthesis of Compound 80 Step 1: Synthesis of intermediate (2)

[0417] As described in Scheme 40: p-(chlorosulfonyl)toluene (26.1 g, 4 equivalents, 137 mmol) was added to a stirred solution of intermediate (1) (5.0 g, 34.2 mmol) in pyridine (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC / LCMS data. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by rapid column chromatography (using 0%-60% ethyl acetate in n-hexane) to give intermediate (2) (10.0 g, 64.3% yield) as a white crystalline solid. result: LCMS analysis: purity 99.08%, calculated value C20H22O8S2 = 454.08, observed value = 455.29 (m / z, M+H+). Step 2: Synthesis of intermediate (3)

[0418] As described in Scheme 40: Under an inert atmosphere, potassium thioacetate (12.8 g, 5 equivalents, 110 mmol) was added to a stirred solution of intermediate (2) (10 g, 22 mmol) in DMF (33.3 mL). The reaction mixture was stirred at 90°C for 16 h. The progress of the reaction was monitored by TLC (SM was completely consumed). After the reaction was complete, the mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give the crude compound. The crude product was purified by rapid chromatography (using 0%–20% ethyl acetate in heptane) to give intermediate (3) (3.5 g, 60.64% yield) as a pale red liquid. result: ELSD analysis: purity 99.64%, calculated value C10H14O4S2 = 262.03, observed value = 263.10 (m / z, M+H+). Step 3: Synthesis of intermediate (4)

[0419] As described in Scheme 40: 4N HCl in dioxane (0.5 mL) was added dropwise to a stirred solution of intermediate (3) (0.8 g, 3.05 mmol) in methanol (10 mL, 247 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was neutralized with triethylamine and evaporated under vacuum to give crude intermediate (4) (0.50 g, 64% yield), which was used immediately as is without further purification. result: 1H-NMR (400MHz, CDCl3)- 4.68 (s, 2H), 4.14-4.09 (dd, J=5.2Hz, 9.6Hz, 2H), 3.81-3.74 (m, 2H), 3.41-3.37 (m, 2H), 1.73-1.72 (d, J=8.0Hz, 2H). Step 4: Synthesis of intermediate (7)

[0420] As described in Scheme 40: Ethylbis(propyl-2-yl)amine (55.2 mL, 2.5 equivalents, 320 mmol) was added to a stirred solution of intermediate (5) (15.0 g, 128 mmol) and intermediate (6) (51.9 g, 2.2 equivalents, 282 mmol) in methanol (0.5 L). The resulting reactants were heated at 90°C for 16 h. After 16 h, the reaction progress was monitored by TLC / ELSD. The reactants were cooled to room temperature. Tetrahydrofuran (60 mL, 737 mmol), water (60 mL, 3.33 mol), and lithium hydroxide (1+) hydrate (2.44 g, 2 equivalents, 58.2 mmol) were added to the RM. After 4 h, the reaction progress was monitored by TLC. The reaction mixture was evaporated under reduced pressure. The pH of the mixture was adjusted to 2.0 using 2N hydrochloric acid (200.0 mL) and extracted with DCM (2 x 250 mL). The organic layer was separated, dried over sodium sulfate, and distilled under reduced pressure to give a crude intermediate (7) (45.0 g, crude product) as a colorless semi-solid. The crude product was used as is in the next step. result: ELSD analysis: purity 99.93%, calculated C29H59NO4 = 485.44, observed value = 486.45 (m / z, M+H+). Step 5: Synthesis of intermediate (8)

[0421] As described in Scheme 40: 1H-imidazolium (21 g, 10.0 equivalent, 309 mmol) and tert-butyl(chloro)dimethylsilane (18.6 g, 4 equivalent, 124 mmol) were added to a stirred solution of intermediate (5) (15 g, 30.9 mmol) in dichloromethane (150.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC / ELSD. After completion, the reaction mixture was diluted with DCM and water and extracted three times with DCM. The organic layer was collected, concentrated under reduced pressure to give a crude product, and purified by rapid column chromatography (SiO2: 0%-30% ethyl acetate in hexane) to obtain intermediate (8) (10 g, 44.89% yield) as a colorless liquid. result: ELSD analysis: purity 99.35%, calculated C41H87NO4Si2 = 713.62, observed = 714.60 (m / z, M+H+). Step 6: Synthesis of intermediate (9)

[0422] As described in Scheme 40: N,N-dimethyl-4-pyridylamine (1.33 g, 4.8 equivalents, 10.8 mmol) and 2-methyl-2,6,8-triaza-6,7-decadiene hydrogen chloride (EDC.HCl) (1.03 g, 2.4 equivalents, 5.38 mmol) were added to a stirred solution of intermediate (8) (3.37 g, 2.1 equivalents, 4.7 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 10 min and intermediate (4) was added under an inert atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by ELSD. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography using 5%–6% EtOAc in heptane. The fraction was evaporated under reduced pressure to give intermediate (9) (0.25 g, 7.0% yield) as a colorless liquid. result: ELSD analysis: purity 97.31%, calculated value C88H180N2O8S2Si4 = 1569.23, observed value = 1569.65 (m / z, M+H+). Step 7: Synthesis of Compound 80

[0423] As described in Scheme 40: A hydrogen fluoride-pyridine complex (70% w / w (473 mg, 30 equivalents, 4.77 mmol)) was added to a stirred solution of intermediate (9) (250 mg, 159 µmol) in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by ELSD. After completion, the reaction mixture was quenched to pH 8 with cold saturated sodium bicarbonate solution and extracted with pentane (3 x 10 mL). The organic layers were combined, dried over sodium sulfate anhydride, and concentrated under reduced pressure to give compound 80 (0.90 g, 50.05% yield) as a pale yellow liquid. result: 1H-NMR (400MHz, CDCl3)- 4.57-4.43 (br, 2H), 4.26-4.20 (m, 2H), 4.14-3.95 (m, 2H), 3.80-3.74 (m, 2H), 3.72-2.60 (m, 4H), 2.60-2.56 (m, 8H), 2.55-2.40 (m, 8H), 1.75-1.60 (m, 4H), 1.48-1.38 (m, 14H), 1.35-1.22 (m, 62H), 0.87(t, J=6.4Hz, 12H). ELSD analysis: purity 96.60%, calculated value C64H124N2O8S2 = 1112.88, observed value = 1113.95 (m / z, M+H+). Scheme 41: Synthesis of Compound 81 Step 1: Synthesis of intermediate (2)

[0424] As described in Scheme 41: p-(chlorosulfonyl)toluene (26.1 g, 4 equivalents, 137 mmol) was added to a stirred solution of intermediate (1) (5 g, 34.2 mmol) in pyridine (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC / LCMS data. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The solid residue was purified by rapid column chromatography (using 0%–60% ethyl acetate in n-hexane) to give intermediate (2) (10 g, 64.3% yield) as a white crystalline solid. result: LCMS analysis: purity 99.08%, calculated value C20H22O8S2 = 454.08, observed value = 455.29 (m / z, M+H+). Step 2: Synthesis of intermediate (3)

[0425] As described in Scheme 41: Under an inert atmosphere, potassium thioacetate (12.8 g, 5 equivalents, 110 mmol) was added to a stirred solution of intermediate (2) (10 g, 22 mmol) in DMF (33.3 mL). The reaction mixture was stirred at 90°C for 16 h. The progress of the reaction was monitored by TLC (SM was completely consumed). After the reaction was...

Claims

1. A compound having a structure according to formula (I): (I) Or its pharmaceutically acceptable salt, wherein: A 1 Selected from -C(=O)O-, -C(=O)S-, -C(=O)NH-, -OC(=O)O-, -OC(=O)NH-, -NHC(=O)O-, -SC(=O)NH-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S-, and -SS-, wherein each of the listed structures is left-handedly bonded to -(CH2). a -; Z 1 The following are selected from -OC(=O)-, -SC(=O)-, -NHC(=O)-, -OC(=O)O-, -NHC(=O)O-, -OC(=O)NH-, -NHC(=O)S-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S-, and -SS-, wherein the right-hand side of each of the listed structures is bonded to -(CH2). a -; Each R is selected independently from: (i) , where each R 1 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; (ii) , where each R 2 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The marked atoms and W 1 connect; (iii) , where each R 3 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; and (iv) , where each R 4 Independently selected from optional substituted cycloalkyl or optional substituted heterocyclic alkyl; At least three of the R's are independently selected from (i). (ii) Or (iii) ; Each 'a' is independently selected from 2, 3, 4, and 5; Each b is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; and Each c is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10.

2. The compound of claim 1, wherein, The compound has a structure according to formula (IB1a): (IB1a) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The marked atoms and W 1 connect; Optionally, each 'a' is independently selected from 3 or 4.

3. The compound of claim 1, wherein, The compound has a structure according to formula (IB1b): (IB1b) Or a pharmaceutically acceptable salt thereof, wherein each R 1A R 1B R 1C and R 1D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, among them, i) Each a is 2, and / or ii) Each b is independently selected from 5 or 7.

4. The compound of claim 1, wherein, The compound has a structure according to formula (IB1c): (IB1c) Or a pharmaceutically acceptable salt thereof, wherein each R 3A R 3B R 3C and R 3D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, among them, i) Each a is 3, and / or ii) Each c is 6.

5. The compound of claim 1, wherein, The compound has a structure according to formula (IB2a): (IB2a) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The marked atoms and W 1 connect; Optionally, each 'a' is independently selected from 3 or 4.

6. The compound of claim 1, wherein, The compound has a structure according to formula (IC1a): (IC1a) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The marked atoms and W 1 connect; Optionally, each 'a' is independently selected from 3 or 4.

7. The compound of claim 1, wherein, The compound has a structure according to formula (IC1b): (IC1b) Or a pharmaceutically acceptable salt thereof, wherein each R 1A R 1B R 1C and R 1D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, among them, Each a is 2, and / or ii) each b is independently selected from 5 or 7.

8. The compound of claim 1, wherein, The compound has a structure according to formula (IC2a): (IC2a) Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The marked atoms and W 1 connect; Optionally, each a is 3.

9. The compound of claim 1, wherein, The compound having formula (I) has a structure according to the following: (a) Equation (ID1): Or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from: (i) , where each R 1 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; (ii) , where each R 2 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The marked atoms and W 1 connect; (iii) , where each R 3 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, (i) each a is 3 or 4, and / or (ii) each b is 5, 6, or 7; (b) Equation (ID2): Or a pharmaceutically acceptable salt thereof, wherein each R 1A R 1B R 1C and R 1D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Optionally, where (i) each a is 4, and / or (ii) each b is independently selected from 5 or 7; (c) Equation (IE1): Or a pharmaceutically acceptable salt thereof, wherein each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The marked atoms and W 1 connect; Optionally, each a is 3 or 4; (d) Equation (IE2): Or its pharmaceutically acceptable salt, wherein d is 0 or 1, and Each R 2A R 2B R 2C and R 2D Independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W 1 -X 1 , Each W 1 Independently selected from optionally substituted alkylene groups and optionally substituted alkenyl groups, and Each X 1 Independently selected from - O-(C=O)-Optional substituted alkyl group, -( C=O)-O-Optional substituted alkyl group, - O-(C=O)-optionally substituted alkenyl groups, and -( C=O)-O-Optionally substituted alkenyl groups, wherein... The marked atoms and W 1 connect; Optionally, each a is 3 or 4.

10. A compound having a structure according to formula (II): (II) Or its pharmaceutically acceptable salt, wherein: Each R is selected independently from: (i) , where each R 1 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; and (ii) , where each R 3 Independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl groups; Each 'a' is independently selected from 2, 3, 4, and 5; Each b is independently selected from 2, 3, 4, 5, 6, and 7; and Each 'c' is independently selected from 2, 3, 4, 5, 6, and 7.

11. The compound of claim 10, wherein, The compound has a structure according to formula (IIA): (IIA) Or a pharmaceutically acceptable salt thereof, wherein each R 3A R 3B R 3C and R 3D It is independently selected from optional substituted alkyl, optional substituted alkenyl, and optional substituted alkynyl groups.

12. The compound of claim 10, wherein, The compound has a structure according to formula (IIB): (IIB) Or a pharmaceutically acceptable salt thereof, wherein each R 1A R 1B R 1C and R 1D It is independently selected from optional substituted alkyl, optional substituted alkenyl, and optional substituted alkynyl groups.

13. A composition comprising the cationic lipid as described in any one of claims 1-12, 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, Optionally, the composition consists of lipid nanoparticles. For example, liposomes.

14. The composition of claim 13, wherein, These lipid nanoparticles encapsulate mRNA encoding peptides or proteins, and can be optionally used in vaccines.

15. The composition of claim 14, for use in a therapeutic context.

16. The composition of claim 14, used in a method of treating or preventing a disease that can be treated or prevented by a peptide or protein encoded by the mRNA, optionally wherein the mRNA encodes an antigen, and / or the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lungs, brain, or muscles, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer, further optionally wherein, The composition can be delivered intravenously, intrathecally, intramuscularly, intranasally, sublingually, or via the lungs, and optionally by nebulization.

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