Pegylated lipid compounds and methods of use thereof

Abstract

The present disclosure relates to PEGylated lipid compounds and pharmaceutically acceptable salts thereof. Such compounds are useful, for example, as constituent parts of lipid nanoparticle (LNP) formulations for delivery of various active agents. The present disclosure further provides LNPs comprising a disclosed compound. Also provided herein are methods of preparing such PEGylated lipid compounds, as well as pharmaceutical compositions comprising an LNP and an active agent; and methods of use thereof.

Description

PEGYLATED LIPID COMPOUNDS AND METHODS OF USE THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 373,649, filed August 26, 2022 and United States Provisional Patent Application serial number 63 / 511,515, filed June 30, 2023; the contents of each of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to PEGylated lipid compounds and pharmaceutically acceptable salts thereof. Such compounds are useful, for example, as constituent parts of lipid nanoparticle (LNP) formulations for delivery of various active agents. The present disclosure further provides LNPs comprising a disclosed compound. Also provided herein are methods of preparing such PEGylated lipid compounds, as well as pharmaceutical compositions comprising an LNP and an active agent; and methods of use thereof.SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on August 23, 2023, is named 203250_seqlist.XML and is 9,675 bytes in size.BACKGROUND

[0004] Lipid nanoparticles (LNPs) are effective drug delivery systems for biologically active compounds, such as therapeutic nucleic acids, proteins, and peptides, which are otherwise cell impermeable. Drugs based on nucleic acids, which include large nucleic acid molecules such as, e.g., in vitro transcribed messenger RNA (mRNA) as well as smaller polynucleotides that interact with a messenger RNA or a gene, have to be delivered to the proper cellular compartment in order to be effective. For example, double-stranded nucleic acids such as double-stranded RNA molecules (dsRNA), including, e.g., siRNAs, suffer from poor physico-chemical properties that render them impermeable to cells. If successful delivery into the proper cellular compartment is achieved, siRNAs block gene expression through a highly conserved regulatory mechanism known as RNA interference (RNAi). Typically, siRNAs are large in size with a molecular weight ranging from 12-17 kDa and are highly anionic due to their phosphate backbone with up to 50 negative charges. In addition, the two complementary RNA strands result in a rigid helix. When administered intravenously, siRNA is rapidly excreted from the body with a typical half-life inthe range of only 10 minutes. Additionally, siRNAs are rapidly degraded by nucleases present in blood and other fluids or in tissues and have been shown to stimulate strong immune responses in vitro and in vivo. These features contribute to siRNAs’ poor drug-like properties. See, e.g., Robbins et al., Oligonucleotides 19:89-102, 2009. mRNA molecules suffer from similar issues.

[0005] Lipid nanoparticle (LNP) formulations have improved nucleic acid delivery in vivo. For example, such formulations can significantly reduce the siRNA doses necessary to achieve target knockdown in vivo. See Zimmermann et al., Nature 441 : 111-114, 2006. Typically, such lipid nanoparticle drug delivery systems are multi-component formulations comprising cationic (or ionizable) lipids, helper lipids, and lipids containing polyethylene glycol (PEG lipids). It should be noted that the terms “cationic” and “ionizable” as they relate to lipids herein, unless otherwise described, are used interchangeably. The positively charged cationic lipids bind to the anionic nucleic acid, while the other components support a stable self-assembly of the lipid nanoparticles. Efforts have been directed toward improving delivery efficacy of lipid nanoparticle formulations. Many such efforts have been aimed toward developing more appropriate cationic lipids. See, e.g., Akinc etal., Nature Biotechnology 26:561-569, 2008; Love et al., Proc. Natl. Acad. Sci. USA 107: 1864-1869, 2010; Baigude et al., Journal of Controlled Release 107:276-287, 2005; Semple et al., Nature Biotechnology 28: 172-176, 2010.

[0006] Further, the PEG lipid PEG2000-C-DMA has been used in LNP formulations that have entered human clinical trials in applications as diverse as oncology, vaccines, antivirals and metabolic diseases. Lipid-containing nanoparticles or lipid nanoparticles, liposomes, and lipoplexes have proven effective as transport vehicles into cells and / or intracellular compartments for biologically active substances such as small molecule drugs, proteins, and nucleic acids. Though a variety of such lipid-containing nanoparticles have been demonstrated, the desired safety, efficacy, and / or specificity are still lacking. For example, there is a need for additional PEG lipids having, e.g., unique or improved properties for use in lipid nanoparticle formulations.

[0007] The present disclosure meets this need and provides additional, related advantages.SUMMARY

[0008] In an aspect of the present disclosure, provided herein is a compound of formula PL-or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0009] In another aspect of the present disclosure, provided herein is a compound of FormulaPL-II:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0010] In another aspect, the present disclosure provides a lipid nanoparticle (LNP) comprising a PEGylated lipid compound described herein, such as a compound of formula PL-I or PL-II, or a pharmaceutically acceptable salt thereof. The present disclosure also provides pharmaceutical compositions comprising such LNPs.

[0011] In another aspect, provided herein is a method of treating a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein. In some embodiments, the subject is suffering from a disease or disorder such as those described herein.DETAILED DESCRIPTION

[0012] In one aspect, the present disclosure provides a compound of formula PL-I:or a pharmaceutically acceptable salt thereof, wherein:A1is a saturated 5-6 membered carbocyclic ring or a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the carbocyclic ring and heterocyclic ring are substituted with t occurrences of R4;X1is -N(H)-, -N(C1-6 alkyl)-, or -O-;L1is -C(O)(C1-6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)-N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)O-, -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)C(O)OCH2-, -C(O)(C1-6 aliphatic)-, -C(O)(C1-6 aliphatic)-N(R)-, or -C(O)-;L2and L3are independently a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O- , -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)- , -C(R5)=N-, or -C(R5)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently a straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R4is Ci-4 alkyl;R5is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or -OC(O)OR; n is an integer from 10-75, inclusive; m is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

[0013] In another aspect, the present disclosure provides a compound of Formula PL-II:or a pharmaceutically acceptable salt thereof, wherein:X1is -N(H)-, -N(C1-6 alkyl)-, or -O-;L1is -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)-, or -C(O)-;L2and L3are a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, - OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R4)=N- , or -C(R4)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R4is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or OC(O)OR; n is an integer from 10-75, inclusive; and m is 0, 1, 2, 3, or 4.

[0014] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof; a pharmaceutical agent; and a carrier, excipient, or adjuvant.

[0015] In another aspect, the present disclosure provides a lipid nanoparticle (LNP) comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, a lipid nanoparticle comprises an ionizable lipid, a structural lipid, a PEGylated lipid, and a phospholipid.A. Definitions

[0016] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0017] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0018] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of up to ±10% from the specified value. This disclosure encompasses embodiments where the value is within ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, or ±9% of the stated value.

[0019] As used herein, the term “biologically active” refers to a characteristic of an agent (e.g., DNA, RNA, or protein) that has activity in a biological system (including in vitro and in vivo biological system), and particularly in a living organism, such as in a mammal, including human and non-human mammals. For instance, an agent when administered to an organism has a biological effect on that organism, is considered to be biologically active.

[0020] As used herein, the term “bulge” refers to a small region of unpaired base(s) that interrupts a “stem” of base-paired nucleotides. The bulge may comprise one or two singlestranded or unbase-paired nucleotides joined at both ends by base-paired nucleotides of the stem. The bulge can be symmetrical (viz., the two unbase-paired single-stranded regions have the same number of nucleotides), or asymmetrical (viz., the unbase-paired single stranded region(s) have different or unequal numbers of nucleotides), or there is only one unbase-paired nucleotide on one strand. A bulge can be described as A / B (such as a “2 / 2 bulge,” or a “1 / 0 bulge”) wherein A represents the number of unpaired nucleotides on the upstream strand of the stem, and B represents the number of unpaired nucleotides on the downstream strand of the stem. Anupstream strand of a bulge is more 5’ to a downstream strand of the bulge in the primary nucleotide sequence.

[0021] The term “recombinant nucleic acid” or “recombinant nucleotide,” as used herein, refers to a molecule that is constructed by joining nucleic acid molecules, which optionally may self-replicate in a live cell.

[0022] The term “synthetic or artificial nucleic acid,” as used herein, refers to nucleic acids that are non-naturally occuring sequences. Such sequences do not originate from, or are not known to be present in any living organism (e.g., based on sequence search in existing sequence databases).

[0023] Recombinant nucleic acids and synthetic nucleic acids also include those molecules that result from the replication of either of the foregoing.

[0024] Engineered nucleic acid constructs of the present disclosure, such as the engineered retron described herein, may be encoded by a single molecule (e.g., encoded by or present on the same plasmid or other suitable vector) or by multiple different molecules (e.g., multiple independently-replicating vectors).

[0025] As used herein, the term “exosomes” refer to small membrane bound vesicles with an endocytic origin. Without wishing to be bound by theory, exosomes are generally released into an extracellular environment from host / progenitor cells post fusion of multivesicular bodies the cellular plasma membrane. As such, exosomes can include components of the progenitor membrane in addition to designed components (e.g. engineered retron). Exosome membranes are generally lamellar, composed of a bilayer of lipids, with an aqueous inter-nanoparticle space.

[0026] As used herein, the term “heterologous nucleic acid” refers to a genotypically distinct entity from that of the rest of the entity to which it is compared or into which it is introduced or incorporated. For example, a polynucleotide introduced by genetic engineering techniques into a different cell type is a heterologous polynucleotide (e.g., DNA or RNA) and, if expressed, can encode a heterologous polypeptide. Similarly, a cellular sequence (e.g., a gene or portion thereof) that is incorporated into a viral vector is a heterologous nucleotide sequence with respect to the vector.

[0027] As used herein, the term “liposomes” refers to small vesicles that contain at least one lipid bilayer membrane surrounding an aqueous inner-nanoparticle space that is generally not derived from a progenitor / host cell.

[0028] As used herein, the term “nanoparticle” refers to any particle ranging in size from 10- 1,000 nm.

[0029] As used herein, the terms “nucleic acid” or “nucleic acid molecule” or “nucleic acid sequence” or “polynucleotide” generally refer to deoxyribonucleic or ribonucleic oligonucleotides in either single- or double-stranded form. The terms may (or may not) encompass oligonucleotides containing known analogues of natural nucleotides. The terms also may (or may not) encompass nucleic acid-like structures with synthetic backbones, see, e.g, Eckstein, 1991; Baserga et ah, 1992; Milligan, 1993; WO 97 / 03211; WO 96 / 39154; Mata, 1997; Strauss-Soukup, 1997; and Samstag, 1996. The terms encompass both ribonucleic acid (RNA) and DNA, including cDNA, genomic DNA, synthetic, synthesized (e.g., chemically synthesized) DNA, and / or DNA (or RNA) containing nucleic acid analogs. The nucleotides Adenine (A), Thymine (T), Guanine (G) and Cytosine (C) also may (or may not) encompass nucleotide modifications, e.g., methylated and / or hydroxylated nucleotides, e.g., Cytosine (C) encompasses 5-methylcytosine and 5- hydroxymethylcytosine.

[0030] As used herein, the term “sequence identity” refers to the overall relatedness between polymeric molecules, e.g. , between polynucleotide molecules (e.g. , DNA molecules and / or RNA molecules) and / or between polypeptide molecules. Calculation of the percent identity of two polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). For example, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux,J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CAB IOS, 1989, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna. CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H. and Lipman, D., SIAM J Applied Math., 48: 1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990).

[0031] As used herein, the term “identical” refers to two or more sequences or subsequences which are the same. In addition, the term “substantially identical,” as used herein, refers to two or more sequences which have a percentage of sequential units which are the same when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using a comparison algorithm or by manual alignment and visual inspection. By way of example only, two or more sequences may be “substantially identical” if the sequential units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. Such percentages to describe the “percent identity” of two or more sequences. The identity of a sequence can exist over a region that is at least about 75-100 sequential units in length, over a region that is about 50 sequential units in length, or, where not specified, across the entire sequence. This definition also refers to the complement of a test sequence.

[0032] As used herein, the term “stem” refers to two or more base pairs, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more base pairs, formed by inverted repeat sequences connected at a “tip,” where the more 5’ or “upstream” strand of the stem bends to allows the more 3’ or “downstream” strand to base-pair with the upstream strand. The number of base pairs in a stem is the “length” of the stem. The tip of the stem is typically at least 3 nucleotides, but can be 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more nucleotides. Larger tips with more than 5 nucleotides are also referred to as a “loop.” An otherwise continuous stem may be interrupted by one or more bulges as defined herein. The number of unpaired nucleotides in the bulge(s) are not included in the length of the stem. The position of a bulge closest to the tipcan be described by the number of base pairs between the bulge and the tip (e.g., the bulge is 4 bps from the tip). The position of the other bulges (if any) further away from the tip can be described by the number of base pairs in the stem between the bulge in question and the tip, excluding any unpaired bases of other bulges in between.

[0033] As used herein, the term “loop” in the polynucleotide refers to a single stranded stretch of one or more nucleotides, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, wherein the most 5’ nucleotide and the most 3’ nucleotide of the loop are each linked to a base-paired nucleotide in a stem.

[0034] As used herein, the term “operably linked” or “under transcriptional control,” when used in conjunction with the description of a promoter, refers to the correct location and orientation in relation to a polynucleotide (e.g., a coding sequence) to control the initiation of transcription by RNA polymerase and expression of the coding sequence, such as one for the msr gene, msd gene, and / or the ret gene.

[0035] As used herein, the term “vector” permits or facilitates the transfer of a polynucleotide from one environment to another. It is a replicon such as a plasmid, phage, or cosmid into which another DNA segment may be inserted so as to bring about the replication of the inserted segment (e.g. , the subj ect engineered retron). Generally, a vector is capable of replication when associated with the proper control elements. The term “vector” may include cloning and expression vectors, as well as viral vectors and integrating vectors.

[0036] As used herein, the term “expression vector” or “expression construct” refers to a vector that includes one or more expression control sequences, and an “expression control sequence” is a DNA sequence that controls and regulates the transcription and / or translation of another DNA sequence. Suitable expression vectors include, without limitation, plasmids and viral vectors derived from, for example, bacteriophage, baculoviruses, tobacco mosaic virus, herpes viruses, cytomegalovirus, retroviruses, vaccinia viruses, adenoviruses, and adeno- associated viruses. Numerous vectors and expression systems are commercially available, such as from Novagen (Madison, WI), Clontech (Palo Alto, CA), Stratagene (La Jolla, CA), and Invitrogen / Life Technologies (Carlsbad, CA). The present invention comprehends recombinant vectors that may include viral vectors, bacterial vectors, protozoan vectors, DNA vectors, or recombinants thereof.

[0037] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and / or triple bonds), having from one to thirty or more carbon atoms (e.g., C1-C24 alkyl), one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (Ci-C8 alkyl) or one to six carbonatoms (C1-C6 alkyl) and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n propyl, 1 -methylethyl (iso propyl), n butyl, n pentyl, 1,1 dimethylethyl (t butyl), 3 methylhexyl, 2 methylhexyl, ethenyl, propyl enyl, but-l-enyl, pent-l-enyl, penta-1, 4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkyl groups that include one or more units of unsaturation (one or more double and / or triple bond) can be C2-C24, C2-C12, C2-C8 or C2-C6 groups, for example. Unless specifically stated otherwise, an alkyl group is optionally substituted. The term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C1-6 means one to six carbon atoms) and includes straight, branched chain, or cyclic substituent groups.

[0038] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double (alkenylene) and / or triple bonds (alkynylene)), and having, for example, from one to thirty or more carbon atoms (e.g., C1-C24 alkylene), one to fifteen carbon atoms (C1-C15 alkylene), one to twelve carbon atoms (C1-C12 alkylene), one to eight carbon atoms (C1-C8 alkylene), one to six carbon atoms (C1-C6 alkylene), two to four carbon atoms (C2-C4 alkylene), one to two carbon atoms (C1-C2 alkylene), e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. Alkylene groups that include one or more units of unsaturation (one or more double and / or triple bond) can be C2-C24, C2-C12, C2-C8 or C2-C6 groups, for example. The alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted.

[0039] “Cycloalkyl” or “carbocyclic ring” refers to a stable non aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbomyl, decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, and the like. Unless specifically stated otherwise, a cycloalkyl group is optionally substituted.

[0040] “Cycloalkylene” is a divalent cycloalkyl group. Unless otherwise stated specifically in the specification, a cycloalkylene group may be optionally substituted.

[0041] As used herein, the term “heteroalkyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two or more heteroatoms typically selected from the group consisting of O, N, Si, P, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be a primary, secondary, tertiary or quaternary nitrogen. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples of heteroalkyl groups include: -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, - CH2-NH-OCH3, or -CH2-CH2-S-S-CH3.

[0042] As used herein, the term “heterocyclyl” or “heterocyclic ring” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms typically selected from the group consisting of N, O, Si, P, and S. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1 -di oxo- thiomorpholinyl. Unless specifically stated otherwise, a heterocyclyl group may be optionally substituted.

[0043] As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n + 2) delocalized p (pi) electrons, where n is an integer.

[0044] As used herein, the term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. Preferred are phenyl and naphthyl, most preferred is phenyl.

[0045] As used herein, the term “heteroaryl” or “heteroaromatic” refers to aryl groups which contain at least one heteroatom typically selected from N, O, Si, P, and S; wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom(s) may be optionally teriatry or quatemized. Heteroaryl groups may be substituted or unsubstituted. A heteroaryl group may be attached to the remainder of the molecule through a heteroatom. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline, 2,3- dihydrobenzofuryl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2 -furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5 -benzothiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3 -dihydrofuran, 2, 5 -dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,2.3 -dihydropyran, tetrahydropyran, 1,4-di oxane, 1,3 -di oxane, homopiperazine, homopiperidine,1.3-dioxepane, 4,7-dihydro-l,3-dioxepin and hexamethyleneoxide. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl. Examples of polycyclic heterocycles include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl), 1, 2,3,4- tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3- dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly 3-, 4-, 5-, 6-, and 7- benzothienyl), benzoxazolyl, benzothiazolyl (particularly 2-benzothiazolyl and 5- benzothiazolyl), purinyl, benzimidazolyl (particularly 2-benzimidazolyl), benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl. The aforementioned listing of heterocyclyl and heteroaryl moieties is intended to be representative and not limiting.

[0046] As used herein, the term “amino aryl” refers to an aryl moiety which contains an amino moiety. Such amino moieties may include, but are not limited to primary amines, secondaryamines, tertiary amines, quaternary amines, masked amines, or protected amines. Such tertiary amines, masked amines, or protected amines may be converted to primary amine or secondary amine moieties. Additionally, the amine moiety may include an amine-like moiety which has similar chemical characteristics as amine moieties, including but not limited to chemical reactivity.

[0047] As used herein, the terms “alkoxy,” “alkylamino” and “alkylthio” are used in their conventional sense, and refer to alkyl groups linked to molecules via an oxygen atom, an amino group, a sulfur atom, respectively.

[0048] For example, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred are (C1-C3) alkoxy, particularly ethoxy and methoxy.

[0049] As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.

[0050] As described herein, compounds of the present disclosure may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0051] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; — (CH2)0-4R°; — (CH2)0-40R°; — 0(CH2)0-4R°, — O— (CH2)0-4C(0)OR°; — (CH2)0-4CH(OR°)2; — (CH2)o.4SR°; — (CH2)0.4Ph, which may be substituted with R°; — (CH2)0-40(CH2)0-iPh which may be substituted with R°; — CH=CHPh, which may be substituted with R°; — (CH2)0-40(CH2)0-i-pyridyl which may be substituted with R°; — NO2; — CN; — N3; — (CH2)0-4N(R°)2; — (CH2)0-4N(R°)C(0)R°; — N(R°)C(S)R°; — (CH2)0-4N(R°)C(O)NR° 2; — N(R°)C(S)NR° 2; — (CH2)0-4N(R°)C(0)OR°; — N(R°)N(R°)C(O)R°; — N(R°)N(R°)C(O)NR° 2; — N(R°)N(R°)C(O)OR°; — (CH2)0-4C(0)R°; — C(S)R°; — (CH2)0-4C(O)OR°; — (CH2)0-4C(0)SR°; — (CH2)0-4C(0)OSiR° 3; — (CH2)0-4OC(0)R°; — OC(0)(CH2)0-4SR°, SC(S)SR°; — (CH2)0-4SC(0)R°; — (CH2)0-4C(0)NR° 2; — C(S)NR° 2; — C(S)SR°; — SC(S)SR°, — (CH2)0-4OC(0)NR° 2; — C(O)N(OR°)R°; — C(O)C(O)R°; — C(O)CH2C(O)R°; — C(NOR°)R°; — (CH2)0-4SSR°; — (CH2)0-4S(0)2R°; — (CH2)0-4S(0)20R°; — (CH2)0-4OS(0)2R°; — S(O)2NR° 2; — (CH2)0-4S(0)R°; — N(R°)S(O)2NR° 2; — N(R°)S(O)2R°; — N(OR°)R°; — C(NH)NR° 2; — P(O)2R°; — P(O)R° 2; — OP(O)R° 2; — 0P(0)(0R°)2; SiR° 3; — (C1-4 straight or branched alkylene)O — N(R°)2; or — (C1-4 straight or branched alkylene)C(O)O — N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1- 6 aliphatic, — CH2Ph, — 0(CH2)0-iPh, — CH2-(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0052] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, — (CH2)0-2R●, -(haloR●), — (CH2)0-2OH, — (CH2)0-20R●, — (CH2)0-2CH(OR●)2; — O(haloR●), — CN, — N3, — (CH2)0-2C(0)R●, — (CH2)0-2C(0)OH, — (CH2)0-2C(0)OR●, — (CH2)0-2SR●, — (CH2)0-2SH, — (CH2)0-2NH2, — (CH2)0-2NHR●, — (CH2)0-2NR● 2, — NO2, — SiR● 3, — OSiR● 3, — C(O)SR●, — (Ci-4 straight or branched alkylene)C(O)OR●, or — SSR● wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, — CH2Ph, — 0(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0053] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*, — O(C(R*2))2-3O— , or — S(C(R*2))2-3S— , wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted”group include: — O(CR*2)2-3O — , wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0054] Suitable substituents on the aliphatic group of R* include halogen, — R●, -(haloR●), —OH, —OR●, — O(haloR●), — CN, — C(O)OH, — C(O)OR●, — NH2, — NHR●, —NR● 2, or — NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, — CH2Ph, — 0(CH2)0-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0055] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include — R†, — NR†2, — C(O)R†, — C(O)OR†, — C(O)C(O)R†, — C(O)CH2C(O)R†, — S(O)2R†, — S(O)2NRb, — CISJNR†N, — C(NH)NR†2, or — N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted — OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0056] Suitable substituents on the aliphatic group of R†are independently halogen, — R●, - (haloR●), —OH, —OR●, — O(haloR●), — CN, — C(O)OH, — C(O)OR●, — NH2, —NHR●, — NR● 2, or — NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, — CH2Ph, — 0(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0057] Heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that "substitution" or "substituted" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, or elimination.

[0058] In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organiccompounds. Illustrative substituents include, for example, those described herein. The permissible substituents can be one or more and the same or different for appropriate organic compounds. The heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.

[0059] In various embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, each of which optionally is substituted with one or more suitable substituents. In some embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, wherein each of the alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone can be further substituted with one or more suitable substituents.

[0060] Examples of substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, thioketone, ester, heterocyclyl, -CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, alkylthio, oxo, acylalkyl, carboxy esters, carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, carboxamidoalkylaryl, carb oxami doaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like. In some embodiments, the substituent is selected from cyano, halogen, hydroxyl, and nitro.

[0061] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0062] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0063] As used herein, the term “antibody” is referred to in the broadest sense and specifically covers various embodiments including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies) so long as they exhibit a desired biological activity (e.g., “functional”). Antibodies are primarily amino-acid based molecules but may also comprise one or more modifications (including, but not limited to the addition of sugar moieties, fluorescent moieties, chemical tags, etc.). Non-limiting examples of antibodies or fragments thereof include VH and VL domains, scFvs, Fab, Fab', F(ab')2, Fv fragment, diabodies, linear antibodies, single chain antibody molecules, multispecific antibodies, bispecific antibodies, intrabodies, monoclonal antibodies, polyclonal antibodies, humanized antibodies, codon- optimized antibodies, tandem scFv antibodies, bispecific T-cell engagers, mAb2 antibodies, chimeric antigen receptors (CAR), tetravalent bispecific antibodies, biosynthetic antibodies, native antibodies, miniaturized antibodies, unibodies, maxibodies, antibodies to senescent cells,antibodies to conformers, antibodies to disease specific epitopes, or antibodies to innate defense molecules.

[0064] As used herein, a “lipid nanoparticle” or “LNP” is a composition comprising one or more lipids. LNPs are typically sized on the order of micrometers or smaller and may include a lipid bilayer, and preferably have an average size of less than 1 micrometer.

[0065] As used herein, a “PEG lipid” or “PEGylated lipid” refers to a lipid comprising a polyethylene glycol component.

[0066] As used herein, the interchangeable terms “ionizable lipid” and “cationic lipid” refer to a lipid capable of being either positively charged or uncharged (neutral), depending on pH. Exemplary ionizable lipids comprise one or more fatty acid or fatty aliphatic chains and one or more moieties capable of bearing a positive charge. In preferred embodiments, the moiety capable of bearing the positive charge is a protonatable amine group. Preferred ionizable or cationic lipids are ionizable such that they can exist in a positively charged or neutral form depending on pH of the surrounding environment. Preferable ionizable lipids are protonated to form a cation at acidic physiological pH (about pH 4) and are neutral at neutral pH (pH 7).

[0067] “Isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.

[0068] An “isolated nucleic acid” refers to a nucleic acid segment or fragment, which has been separated from sequences which flank it in a naturally occurring state, i.e., a DNA fragment, which has been removed from the sequences which are normally adjacent to the fragment, i.e., the sequences adjacent to the fragment in a genome in which it naturally occurs. The term also applies to nucleic acids which have been substantially purified from other components, which naturally accompany the nucleic acid, i.e., RNA or DNA or proteins, which naturally accompany it in the cell. The term therefore includes, for example, a recombinant DNA or RNA, which is incorporated into a vector, into an autonomously replicating plasmid or virus, or into the genomic DNA or RNA of a prokaryote or eukaryote, or which exists as a separate molecule (i.e., as a cDNA or a genomic or cDNA fragment produced by PCR or restriction enzyme digestion) independent of other sequences. It also includes a recombinant DNA or RNA, which is part of a hybrid gene encoding additional polypeptide sequence.

[0069] The term “DNA” is a well-known term of art that refers to deoxyribonucleic acid.

[0070] The term “RNA” is a well-known term of art that refers to ribonucleic acid.

[0071] “Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

[0072] As used herein, the term “homologous” refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. When a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared X 100. For example, if 6 of 10 of the positions in two sequences are matched or homologous then the two sequences are 60% homologous. By way of example, the DNA sequences ATTGCC and TATGGC share 50% homology. Generally, a comparison is made when two sequences are aligned to give maximum homology.

[0073] Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).

[0074] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantiallyhomologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.

[0075] An “effective amount” as used herein, means an amount which provides a therapeutic or prophylactic benefit under the conditions of administration.

[0076] The term “therapeutic” as used herein means a treatment and / or prophylaxis. A therapeutic effect is obtained by suppression, diminution, remission, or eradication of at least one sign or symptom of a disease or disorder state.

[0077] The term “therapeutically effective amount” refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term “therapeutically effective amount” includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the signs or symptoms of the disorder or disease being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.

[0078] By the term “modulating,” as used herein, is meant mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and / or compared with the level of a response in an otherwise identical but untreated subject. The term encompasses perturbing and / or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human.

[0079] To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.

[0080] As used herein, “encapsulation efficiency” (abbreviated as “ee”) refers to the amount of a therapeutic and / or prophylactic that becomes part of a nanoparticle composition, relative to theinitial total amount of therapeutic and / or prophylactic used in the preparation of a nanoparticle composition. For example, if 97 mg of a polynucleotide are encapsulated in a nanoparticle composition out of a total 100 mg of therapeutic and / or prophylactic initially provided to the composition, the encapsulation efficiency may be given as 97%. As used herein, “encapsulation” may refer to complete, substantial, or partial enclosure, confinement, surrounding, or encasement.

[0081] Throughout the disclosure, chemical substituents described in Markush structures are represented by variables. Where a variable is given multiple definitions as applied to differentMarkush formulas in different sections of the disclosure, it is to be understood that each definition should only apply to the applicable formula in the appropriate section of the disclosure.

[0082] The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred materials and methods are now described. Other features, objects and advantages of the disclosure will be apparent from the description. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present description will control.

[0083] As used herein, the following abbreviations and initialisms have the indicated meanings:

[0084] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.B. Exemplary PEGylated Lipid Compounds

[0085] In one aspect, the present disclosure provides a compound of formula PL-I’:or a pharmaceutically acceptable salt thereof, wherein:A1is a saturated 5-6 membered carbocyclic ring or a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the carbocyclic ring and heterocyclic ring are substituted with t occurrences of R4;X1is -N(H)-, -N(C1-6 alkyl)-, -C1-6 aliphatic-N(H)-, -C1-6 aliphatic-N(C1-6 alkyl)-, -O- or -C1-6 aliphatic-O-;L1is -C(O)(C1-6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)-N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)O-, -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)C(O)OCH2-, -C(O)(C1-6 aliphatic)-, -C(O)(C1-6 aliphatic)-N(R)-, or -C(O)-;L2and L3are independently a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O- , -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)- , -C(R5)=N-, or -C(R5)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently a straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R4is Ci-4 alkyl;R5is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or -OC(O)OR; n is an integer from 10-75, inclusive; m is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

[0086] In another aspect, the present disclosure provides a compound of formula PL-I” :or a pharmaceutically acceptable salt thereof, wherein:A1is a saturated 5-6 membered carbocyclic ring or a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the carbocyclic ring and heterocyclic ring are substituted with t occurrences of R4;X1is -C1-8 aliphatic-N(H)-, -C1-8 aliphatic-N(C1-6 alkyl)-, or -C1-8 aliphatic-O-;L1is -C(O)(C1-6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)-N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)O-, -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)C(O)OCH2-, -C(O)(C1-6 aliphatic)-, -C(O)(C1-6 aliphatic)-N(R)-, or -C(O)-;L2and L3are independently a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O- , -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)- , -C(R5)=N-, or -C(R5)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently a straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R4is Ci-4 alkyl;R5is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or -OC(O)OR; n is an integer from 10-75, inclusive; m is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

[0087] In one aspect, the present disclosure provides a compound of formula PL-I:or a pharmaceutically acceptable salt thereof, wherein:A1is a saturated 5-6 membered carbocyclic ring or a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the carbocyclic ring and heterocyclic ring are substituted with t occurrences of R4;X1is -N(H)-, -N(C1-6 alkyl)-, or -O-;L1is -C(O)(C1-6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)-N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)O-, -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)C(O)OCH2-, -C(O)(C1-6 aliphatic)-, -C(O)(C1-6 aliphatic)-N(R)-, or -C(O)-;L2and L3are independently a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O- , -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)- , -C(R5)=N-, or -C(R5)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N2, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently a straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R4is Ci-4 alkyl;R5is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or -OC(O)OR; n is an integer from 10-75, inclusive; m is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.R1

[0088] As defined generally above, R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl. In some embodiments, R1is H. In some embodiments, R1is C1-6 alkyl. In someembodiments, R1is -(C1-6 alkyl)-N3. In some embodiments, R1is -(C1-6 alkyl)-SH. In some embodiments, R1is C3-8 alkynyl. In some embodiments, R1is a C1-3 alkyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is propyl. In some embodiments, R1is -(C1-3 alkyl)-N3. In some embodiments, R1is -CH2N3. In some embodiments, R1is -(C1.3 alkyl)-SH. In some embodiments, R1is -CH2SH. In some embodiments, R1is C3-5 alkynyl. In some embodiments, R1is C3 alkynyl. In some embodiments, R1is C4 alkynyl. In some embodiments, R1is C5 alkynyl. In some embodiments, R1is C5-8 alkynyl. In some embodiments, R1is C5 alkynyl. In some embodiments, R1is C6 alkynyl. In some embodiments, R1is C7 alkynyl. In some embodiments, R1is C8 alkynyl. In some embodiments, R1is not methyl. In some embodiments, R1is selected from those depicted in Table 1, below.R2and R3

[0089] As defined generally above, R2and R3are independently a straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx.

[0090] In some embodiments, R2is a straight or branched C6-30 alkyl. In some embodiments, R2is -(CH2) C6-25. In some embodiments, R2is -(CH2)10-25. In some embodiments, R2is -(CH2)10- 14. In some embodiemtns, R2is -(CH2)14-16. In some embodiments, R2is -(CH2)18-20.

[0091] In some embodiments, R2is a straight or branched C6-30 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-30 alkyl substituted with m instances of Rx.

[0092] In some embodiments, R2is a straight or branched C6-25 alkyl. In some embodiments, R2is a straight or branched C6-25 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-25 alkyl substituted with m instances of Rx.

[0093] In some embodiments, R2is a straight or branched C10-25 alkyl. In some embodiments, R2is a straight or branched C10-25 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-25 alkyl substituted with m instances of Rx.

[0094] In some embodiments, R2is a straight or branched C10-14 alkyl. In some embodiments, R2is a straight or branched C10-14 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-14 alkyl substituted with m instances of Rx.

[0095] In some embodiments, R2is a straight or branched C14-16 alkyl. In some embodiments, R2is a straight or branched C14-16 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C14-16 alkyl substituted with m instances of Rx.

[0096] In some embodiments, R2is a straight or branched C18-20 alkyl. In some embodiments, R2is a straight or branched C18-20 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C18-20 alkyl substituted with m instances of Rx.

[0097] In some embodiments, R2is a straight or branched C6-30 alkenyl. In some embodiments, R2is a straight or branched C6-25 alkenyl. In some embodiments, R2is C10-25 alkenyl. In some embodiments, R2is C10-14 alkenyl. In some embodiments, R2is C14-16 alkenyl. In some embodiments, R2is C18-20 alkenyl.

[0098] In some embodiments, R2includes one, two, three, or four carbon-carbon double bonds.

[0099] In some embodiments, R2is a straight or branched C6-30 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-30 alkenyl substituted with m instances of Rx.

[0100] In some embodiments, R2is a straight or branched C6-25 alkenyl. In some embodiments, R2is a straight or branched C6-25 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-25 alkenyl substituted with m instances of Rx.

[0101] In some embodiments, R2is a straight or branched C10-25 alkenyl. In some embodiments, R2is a straight or branched C10-25 alkenyl; wherein 1, 2, or 3 methylene units areindependently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-25 alkenyl substituted with m instances of Rx.

[0102] In some embodiments, R2is a straight or branched C10-14 alkenyl. In some embodiments, R2is a straight or branched C10-14 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C 10-14 alkenyl substituted with m instances of Rx.

[0103] In some embodiments, R2is a straight or branched C14-16 alkenyl. In some embodiments, R2is a straight or branched C14-16 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C14-16 alkenyl substituted with m instances of Rx.

[0104] In some embodiments, R2is a straight or branched C18-20 alkenyl. In some embodiments, R2is a straight or branched C18-20 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C18-20 alkenyl substituted with m instances of Rx.

[0105] In some embodiments, R2is a straight or branched C6-30 alkynyl. In some embodiments, R2is -(CH2)C6-2.5 In some embodiments R2is -(CH2)10-25. In some embodiments R2is -(CH2)10-14. In some embodiemtns R2is -(CH2)14-16. In some embodiments R2is -(CH2)18-20.

[0106] In some embodiments, R2has one, two, three, four, or more carbon-carbon triple bonds.

[0107] In some embodiments, R2is a straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-30 alkynyl substituted with m instances of Rx.

[0108] In some embodiments, R2is a straight or branched C6-25 alkynyl. In some embodiments, R2is a straight or branched C6-25 alkynyl; wherein 1, 2, or 3 methylene units areindependently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-25 alkynyl substituted with m instances of Rx.

[0109] In some embodiments, R2is a straight or branched C10-25 alkynyl. In some embodiments, R2is a straight or branched C10-25 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-25 alkynyl substituted with m instances of Rx.

[0110] In some embodiments, R2is a straight or branched C10-14 alkynyl. In some embodiments, R2is a straight or branched C10-14 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-14 alkynyl substituted with m instances of Rx.[OlH] In some embodiments, R2is a straight or branched C14-16 alkynyl. In some embodiments, R2is a straight or branched C14-16 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C14-16 alkynyl substituted with m instances of Rx.

[0112] In some embodiments, R2is a straight or branched C18-20 alkynyl. In some embodiments, R2is a straight or branched C18-20 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C18-20 alkynyl substituted with m instances of Rx.

[0001] In some embodiments, R2is selected from those depicted in Table 1, below.

[0113] In some embodiments, R3is a straight or branched C6-30 alkyl. In some embodiments, R3is -(CH2)C6-2.5 In some embodiments R3is -(CH2)10-25. In some embodiments R3is -(CH2)i0-i4. In some embodiemtns R3is -(CH2)14-16. In some embodiments R3is -(CH2)18-20.

[0114] In some embodiments, R3is a straight or branched C6-30 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturatedC3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-30 alkyl substituted with m instances of Rx.

[0115] In some embodiments, R3is a straight or branched C6-25 alkyl. In some embodiments, R3is a straight or branched C6-25 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-25 alkyl substituted with m instances of Rx.

[0116] In some embodiments, R3is a straight or branched C10-25 alkyl. In some embodiments, R3is a straight or branched C10-25 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-25 alkyl substituted with m instances of Rx.

[0117] In some embodiments, R3is a straight or branched C10-14 alkyl. In some embodiments, R3is a straight or branched C10-14 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-14 alkyl substituted with m instances of Rx.

[0118] In some embodiments, R3is a straight or branched C14-16 alkyl. In some embodiments, R3is a straight or branched C14-16 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C14-16 alkyl substituted with m instances of Rx.

[0119] In some embodiments, R3is a straight or branched C18-20 alkyl. In some embodiments, R3is a straight or branched C18-20 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C18-20 alkyl substituted with m instances of Rx.

[0120] In some embodiments, R3is a straight or branched C6-30 alkenyl. In some embodiments, R3is C6-25 alkenyl. In some embodiments, R3is C10-25 alkenyl. In some embodiments, R3is C10-14 alkenyl. In some embodiments, R3is C14-16 alkenyl. In some embodiments, R3is C18-20 alkenyl.

[0121] In some embodiments, R3is a straight or branched C6-30 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturatedC3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-30 alkenyl substituted with m instances of Rx.

[0122] In some embodiments, R3is a straight or branched C6-25 alkenyl. In some embodiments, R3is a straight or branched C6-25 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-25 alkenyl substituted with m instances of Rx.

[0123] In some embodiments, R3is a straight or branched C10-25 alkenyl. In some embodiments, R3is a straight or branched C10-25 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-25 alkenyl substituted with m instances of Rx.

[0124] In some embodiments, R3is a straight or branched C10-14 alkenyl. In some embodiments, R3is a straight or branched C10-14 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C 10-14 alkenyl substituted with m instances of Rx.

[0125] In some embodiments, R3is a straight or branched C14-16 alkenyl. In some embodiments, R3is a straight or branched C14-16 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C14-16 alkenyl substituted with m instances of Rx.

[0126] In some embodiments, R3is a straight or branched C18-20 alkenyl. In some embodiments, R3is a straight or branched C18-20 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C18-20 alkenyl substituted with m instances of Rx.

[0127] In some embodiments, R3is a straight or branched C6-30 alkynyl. In some embodiments, R3is C6-25 alkynyl. In some embodiments R3is C10-25 alkynyl. In some embodiments R3is C10-14 alkynyl. In some embodiemtns R3is C14-16 alkynyl. In some embodiments R3is C18-20 alkynyl.

[0128] In some embodiments, R3has one, two, three, four, or more carbon-carbon triple bonds.

[0129] In some embodiments, R3is a straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-30 alkynyl substituted with m instances of Rx.

[0130] In some embodiments, R3is a straight or branched C6-25 alkynyl. In some embodiments, R3is a straight or branched C6-25 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-25 alkynyl substituted with m instances of Rx.

[0131] In some embodiments, R3is a straight or branched C10-25 alkynyl. In some embodiments, R3is a straight or branched C10-25 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-25 alkynyl substituted with m instances of Rx.

[0132] In some embodiments, R3is a straight or branched C10-14 alkynyl. In some embodiments, R3is a straight or branched C10-14 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-14 alkynyl substituted with m instances of Rx.

[0133] In some embodiments, R3is a straight or branched C14-16 alkynyl. In some embodiments, R3is a straight or branched C14-16 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted withm instances of Rx. In some embodiments, R3is a straight or branched C14-16 alkynyl substituted with m instances of Rx.

[0134] In some embodiments, R3is a straight or branched C18-20 alkynyl. In some embodiments, R3is a straight or branched C18-20 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C18-20 alkynyl substituted with m instances of Rx.

[0135] In some embodiments, R3is selected from those depicted in Table 1, below.

[0136] In some embodiments, R2and R3are the same. In some embodiments R2and R3are different.R4

[0137] As generally defined above, R4is C1-4 alkyl. In some embodiments, R4is C1.3 alkyl. In some embodiments, R4is C1.2 alkyl. In some embodiments, R4is C2-4 alkyl.

[0138] In some embodiments, R4is methyl. In some embodiments R4is ethyl. In some embodiments R4is propyl. In some embodiments R4is isopropyl. In some embodiments R4is butyl. In some embodiments R4is isobutyl.

[0139] In some embodiments, R4is selected from those depicted in Table 1, below.R5

[0140] As generally defined above, R5is C1-6 alkyl. In some embodiments, R5is C1.5 alkyl. In some embodiments, R5is C1.4 alkyl. In some embodiments, R5is C1.3 alkyl. In some embodiments, R5is C1.2 alkyl. In some embodiments, R5is C2-6 alkyl.

[0141] In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R5is propyl. In some embodiments, R5is isopropyl. In some embodiments, R5is butyl. In some embodiments, R5is isobutyl. In some embodiments, R5is pentyl. In some embodiments, R5is hexyl.

[0142] In some embodiments, R5is selected from those depicted in Table 1, below.X1

[0143] As generally defined above, X1is -N(H)-, -N(C1-6 alkyl)-, -C1-6 aliphatic-N(H)-, -C1-6 aliphatic-N(C1-6 alkyl)-, -O- or -C1-6 aliphatic-O-. Alternatively, as generally defined above, X1is -C1-8 aliphatic-N(H)-, -C1-8 aliphatic-N(C1-6 alkyl)-, or -C1-8 aliphatic-O-.

[0144] Alternatively, as generally defined above, X1is -N(H)-, -N(C1-6 alkyl)-, or -O-. In some embodiments, X1is -N(H)-. In some embodiments, X1is -N(C1-6 alkyl)-. In some embodiments, X1is -O-.

[0145] In some embodiments, X1is -C1-6 aliphatic-N(H)-. In some embodiments, X1is -C1-6 alkyl-N(H)-. In some embodiments, X1is -C1-8 aliphatic-N(H)-. In some embodiments, X1is - C1-8 alkyl-N(H)-. In some embodiments, X1is -Ci alkyl-N(H)-. In some embodiments, X1is - C2 alkyl-N(H)-. In some embodiments, X1is -C3 alkyl-N(H)-. In some embodiments, X1is -C4alkyl-N(H)-. In some embodiments, X1is -C5 alkyl-N(H)-. In some embodiments, X1is -C6 alkyl-N(H)-. In some embodiments, X1is -CH2N(H)-. In some embodiments, X1is -(CH2)2N(H)-. In some embodiments, X1is -(CH2)3N(H)-. In some embodiments, X1is -(CH2)4N(H)-. In some embodiments, X1is -(CH2)5N(H)-. In some embodiments, X1is -(CH2)6N(H)-.

[0146] In some embodiments, X1is -C1-6 aliphatic-N(C1-6 alkyl)-. In some embodiments, X1is -C1-6 alkyl-N(C1-6 alkyl)-. In some embodiments, X1is -C1-8 aliphatic-N(C1-6 alkyl)-. In some embodiments, X1is -C1-8 alkyl-N(C1-6 alkyl)-. In some embodiments, X1is -Ci alkyl-N(C1-6 alkyl)-. In some embodiments, X1is -C2alkyl-N(C1-6 alkyl)-. In some embodiments, X1is -C3 alkyl-N(C1-6 alkyl)-. In some embodiments, X1is -C4alkyl-N(C1-6 alkyl)-. In some embodiments, X1is -C5 alkyl-N(C1-6 alkyl)-. In some embodiments, X1is -C6 alkyl-N(C1-6 alkyl)-. In some embodiments, X1is -CH2N(C1-6 alkyl)-. In some embodiments, X1is - (CH2)2N(C1-6 alkyl)-. In some embodiments, X1is -(CH2)3N(C1-6 alkyl)-. In some embodiments, X1is -(CH2)4N(C1-6 alkyl)-. In some embodiments, X1is -(CH2)5N(C1-6 alkyl)-. In some embodiments, X1is -(CH2)6N(C1-6 alkyl)-.

[0147] In some embodiments, X1is -C1-6 aliphatic-O-. In some embodiments, X1is -C1-6 alkyl-O-. In some embodiments, X1is -C1-8 aliphatic-O-. In some embodiments, X1is -C1-8 alkyl- O-. In some embodiments, X1is -Ci alkyl-O-. In some embodiments, X1is -C2alkyl-O-. In some embodiments, X1is -C3 alkyl-O-. In some embodiments, X1is -C4alkyl-O-. In some embodiments, X1is -C5 alkyl-O-. In some embodiments, X1is - C6 alkyl-O-. In some embodiments, X1is -CH2N(H)-. In some embodiments, X1is -(CH2)2O-. In some embodiments, X1is — (CH2)3O-. In some embodiments, X1is -(CH2)4O-. In some embodiments, X1is - (CH2)SO-. In some embodiments, X1is -(CH2)6O-.

[0148] In some embodiments, X1is -N(CI-5 alkyl)-. In some embodiments, X1is -N(CI-4alkyl)-. In some embodiments, X1is -N(CI-3 alkyl)-. In some embodiments, X1is -N(CI-2alkyl)- . In some embodiments, X1is -N(C2-6 alkyl)-.

[0149] In some embodiments, X1is -N(CH3)-. In some embodiments, X1is -N(CH2CH3)-. In some embodiments, X1is -N((CH2)2CH3)-. In some embodiments, X1is -N((CH2)3CH3)-. In some embodiments, X1is -N((CH2)4CH3)-. In some embodiments, X1is -N((CH2)5CH3)-.

[0150] In some embodiments, X1is selected from those depicted in Table 1, below.L1

[0151] As defined generally above, L1is -C(O)(C1-6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)-N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)O-, -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)C(O)OCH2-, -C(O)(C1-6 aliphatic)-, -C(O)(C1-6 aliphatic)-N(R)-, or -C(O)-.

[0152] In some embodiments, L1is -C(O)(C1-6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)- N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)2-, or -C(O)(C1-6 aliphatic)C(O)-.

[0153] In some embodiments, L1is -C(O)(C1-6 aliphatic)C(O)-N(R)-. In some embodiments, L1is -C(O)(C1-6 aliphatic)-N(R)C(O)-. In some embodiments, L1is -C(O)(C1-6 aliphatic)C(O)O- . In some embodiments, L1is -C(O)(C1-6 aliphatic)C(O)-. In some embodiments, L1is -C(O)(Ci- 6 aliphatic)C(O)OCH2-. In some embodiments, L1is -C(O)(C1-6 aliphatic)-. In some embodiments, L1is -C(O)(C1-6 aliphatic)-N(R)-. In some embodiments, L1is-C(O)-.

[0154] In some embodiments, L1is -C(O)(C1-5 aliphatic)C(O)-N(R)-. In some embodiments, L1is -C(O)(Ci-4 aliphatic)C(O)-N(R)-. In some embodiments, L1is -C(O)(C1-3 aliphatic)C(O)- N(R)-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)C(O)-N(R)-.

[0155] In some embodiments, L1is -C(O)(C2-6 aliphatic)C(O)-N(R)-. In some embodiments, L1is -C(O)(C3-6 aliphatic)C(O)-N(R)-. In some embodiments, L1is -C(O)(C4-6 aliphatic)C(O)- N(R)-. In some embodiments, L1is -C(O)(C5-6 aliphatic)C(O)-N(R)-.

[0156] In some embodiments, L1is -C(O)(CH2)C(O)-N(R)-. In some embodiments, L1is - C(O)(CH2CH2)C(O)-N(R)-. In some embodiments, L1is -C(O)(CH2)3C(O)-N(R)-. In some embodiments, L1is -C(O)(CH2)4C(O)-N(R)-. In some embodiments, L1is -C(O)(CH2)5C(O)- N(R)-. In some embodiments, L1is -C(O)(CH2)6C(O)-N(R)-.

[0157] In some embodiments, L1is -C(O)(C1-5 aliphatic)-N(R)C(O)-. In some embodiments, L1is -C(O)(Ci-4 aliphatic)-N(R)C(O)-. In some embodiments, L1is -C(O)(C1-3 aliphatic)- N(R)C(O)-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)-N(R)C(O)-.

[0158] In some embodiments, L1is -C(O)(C2-6 aliphatic)-N(R)C(O)-. In some embodiments, L1is -C(O)(C3-6 aliphatic)-N(R)C(O)-. In some embodiments, L1is -C(O)(C4-6 aliphatic)- N(R)C(O)-. In some embodiments, L1is -C(O)(C5-6 aliphatic)-N(R)C(O)-.

[0159] In some embodiments, L1is -C(O)(CH2)-N(R)C(O)-. In some embodiments, L1is - C(O)(CH2CH2)-N(R)C(O)-. In some embodiments, L1is -C(O)(CH2)3-N(R)C(O)-. In some embodiments, L1is -C(O)(CH2)4-N(R)C(O)-. In some embodiments, L1is -C(O)(CH2)5- N(R)C(O)-. In some embodiments, L1is -C(O)(CH2)6-N(R)C(O)-.

[0160] In some embodiments, L1is -C(O)(C1-5 aliphatic)C(O)O-. In some embodiments, L1is -C(O)(Ci-4 aliphatic)C(O)O-. In some embodiments, L1is -C(O)(C1-3 aliphatic)C(O)O-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)C(O)O-.

[0161] In some embodiments, L1is -C(O)(C2-6 aliphatic)C(O)O-. In some embodiments, L1is -C(O)(C3-6 aliphatic)C(O)O-. In some embodiments, L1is -C(O)(C4-6 aliphatic)C(O)O-. In some embodiments, L1is -C(O)(C5-6 aliphatic)C(O)O-.

[0162] In some embodiments, L1is -C(O)(CH2)C(O)O-. In some embodiments, L1is - C(O)(CH2CH2)C(O)O-. In some embodiments, L1is -C(O)(CH2)3C(O)O-. In some embodiments, L1is -C(O)(CH2)4C(O)O-. In some embodiments, L1is -C(O)(CH2)5C(O)O-. In some embodiments, L1is -C(O)(CH2)6C(O)O-.

[0163] In some embodiments, L1is -C(O)(C1-5 aliphatic)C(O)-. In some embodiments, L1is -C(O)(Ci-4 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C1-3 aliphatic)C(O)-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)C(O)-.

[0164] In some embodiments, L1is -C(O)(C2-6 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C3-6 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C4-6 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C5-6 aliphatic)C(O)-.

[0165] In some embodiments, L1is -C(O)(CH2)C(O)-. In some embodiments, L1is - C(O)(CH2CH2)C(O)-. In some embodiments, L1is -C(O)(CH2)3C(O)-. In some embodiments, L1is -C(O)(CH2)4C(O)-. In some embodiments, L1is -C(O)(CH2)5C(O)-. In some embodiments, L1is -C(O)(CH2)6C(O)-.

[0166] In some embodiments, L1is -C(O)(C1-5 aliphatic)C(O)OCH2-. In some embodiments, L1is -C(O)(Ci-4 aliphatic)C(O)OCH2-. In some embodiments, L1is -C(O)(C1-3 aliphatic)C(O)OCH2-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)C(O)OCH2-.

[0167] In some embodiments, L1is -C(O)(C2-6 aliphatic)C(O)OCH2-. In some embodiments, L1is -C(O)(C3-6 aliphatic)C(O)OCH2-. In some embodiments, L1is -C(O)(C4-6 aliphatic)C(O)OCH2-. In some embodiments, L1is -C(O)(C5-6 aliphatic)C(O)OCH2-.

[0168] In some embodiments, L1is -C(O)(CH2)C(O)OCH2-. In some embodiments, L1is - C(O)(CH2CH2)C(O)OCH2-. In some embodiments, L1is -C(O)(CH2)3C(O)OCH2-. In some embodiments, L1is -C(O)(CH2)4C(O)OCH2-. In some embodiments, L1is C(O)(CH2)5C(O)OCH2-. In some embodiments, L1is -C(O)(CH2)6C(O)OCH2-.

[0169] In some embodiments, L1is -C(O)(C1-5 aliphatic)-. In some embodiments, L1is - C(O)(Ci-4 aliphatic)-. In some embodiments, L1is -C(O)(C1-3 aliphatic)-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)-.

[0170] In some embodiments, L1is -C(O)(C2-6 aliphatic)- . In some embodiments, L1is - C(O)(C3-6 aliphatic)-. In some embodiments, L1is -C(O)(C4-6 aliphatic)-. In some embodiments, L1is -C(O)(C5-6 aliphatic)- .

[0171] In some embodiments, L1is -C(O)(CH2)-. In some embodiments, L1is - C(O)(CH2CH2)-. In some embodiments, L1is -C(O)(CH2)3-. In some embodiments, L1is - C(O)(CH2)4-. In some embodiments, L1is -C(O)(CH2)5-. In some embodiments, L1is - C(O)(CH2)6-.

[0172] In some embodiments, L1is -C(O)(C1-5 aliphatic)-N(R)-. In some embodiments, L1is -C(O)(Ci-4 aliphatic)-N(R)-. In some embodiments, L1is -C(O)(C1-3 aliphatic)-N(R)-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)-N(R)-.

[0173] In some embodiments, L1is -C(O)(C2-6 aliphatic)-N(R)-. In some embodiments, L1is -C(O)(C3-6 aliphatic)-N(R)-. In some embodiments, L1is -C(O)(C4-6 aliphatic)-N(R)-. In some embodiments, L1is -C(O)(C5-6 aliphatic)-N(R)-.

[0174] In some embodiments, L1is -C(O)(CH2)-N(R)-. In some embodiments, L1is - C(O)(CH2CH2)-N(R)-. In some embodiments, L1is -C(O)(CH2)3-N(R)-. In some embodiments, L1is -C(O)(CH2)4-N(R)-. In some embodiments, L1is -C(O)(CH2)5-N(R)-. In some embodiments, L1is -C(O)(CH2)6-N(R)-.

[0175] In some embodiments, L1is selected from those depicted in Table 1, below. L2and L3

[0176] As defined generally above, L2and L3are independently a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R5)=N-, or -C(R5)=N-O-.

[0177] In some embodiments L2is a covalent bond.

[0178] In some embodiments, L2is C1-6 alkylene. In some embodiments, L2is C1.5 alkylene. In some embodiments, L2is C1.4 alkylene. In some embodiments, L2is C1.3 alkylene. In some embodiments, L2is C1.2 alkylene.

[0179] In some embodiments, L2is C2-6 alkylene. In some embodiments, L2is C3-6 alkylene. In some embodiments, L2is C4-6 alkylene. In some embodiments, L2is C5-6 alkylene.

[0180] In some embodiments L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, - OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, - C(R5)=N-, or -C(R5)=N-O-.

[0181] In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0182] In some embodiments, L2is a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or -OC(O)N(R)-.

[0183] In some embodiments, L2is a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, - C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0184] In some embodiments, L2is a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or - OC(O)N(R)-.

[0185] In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -O-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -NR-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S-S-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S(O)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S(O)2-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)O-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)O-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)N(R)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)O-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)N(R)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)N(R)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(R5)=N-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the Ci- 6 alkylene is replaced with -C(R5)=N-O-.

[0186] In some embodiments L2is selected from -O-, -OC(O)-, -C(O)O-, -OC(O)O-, -CH2O- , -CH2OC(O)-, and -CH2OC(O)O-.

[0187] In some embodiments L2is -O-. In some embodiments L2is -OC(O)-. In some embodiments L2is -C(O)O-. In some embodiments L2is -OC(O)O-. In some embodiments L2is -CH2O-. In some embodiments L2is -CH2OC(O)-. In some embodiments L2is -CH2OC(O)O-.

[0188] In some embodiments L3is a covalent bond.

[0189] In some embodiments, L3is C1-6 alkylene. In some embodiments, L3is C1.5 alkylene. In some embodiments, L3is C1.4 alkylene. In some embodiments, L3is C1.3 alkylene. In some embodiments, L3is C1.2 alkylene.

[0190] In some embodiments, L3is C2-6 alkylene. In some embodiments, L3is C3-6 alkylene. In some embodiments, L3is C4-6 alkylene. In some embodiments, L3is C5-6 alkylene.

[0191] In some embodiments L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, - OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, - C(R5)=N-, or -C(R5)=N-O-.

[0192] In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0193] In some embodiments, L3is a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or -OC(O)N(R)-.

[0194] In some embodiments, L3is a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, - C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0195] In some embodiments, L3is a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or - OC(O)N(R)-.

[0196] In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -O-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -NR-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S-S-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S(O)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S(O)2-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)O-. In someembodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)O-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)N(R)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)O-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)N(R)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)N(R)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(R5)=N-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the Ci- 6 alkylene is replaced with -C(R5)=N-O-.

[0197] In some embodiments L3is selected from -O-, -OC(O)-, -C(O)O-, -OC(O)O-, -CH2O- , -CH2OC(O)-, and -CH2OC(O)O-.

[0198] In some embodiments L3is -O-. In some embodiments L3is -OC(O)-. In some embodiments L3is -C(O)O-. In some embodiments L3is -OC(O)O-. In some embodiments L3is -CH2O-. In some embodiments L3is -CH2OC(O)-. In some embodiments L3is -CH2OC(O)O-.

[0199] In some embodiments, L2and L3are a covalent bond.

[0200] In some embodiments, L2and L3are independently a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, - S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -N(R)C(O)N(R)-, -C(R5)=N-, or -C(R5)=N-O-.

[0201] In some embodiments, L2and L3are independently C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, - S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or -N(R)C(O)N(R)-.

[0202] In some embodiments, L2and L3are independently selected from -O-, -OC(O)-, - C(O)O-, -OC(O)O-, -CH2O-, -CH2OC(O)-, and -CH2OC(O)O-.

[0203] In some embodiments, L2and L3are -O-. In some embodiments, L2and L3are -OC(O)- . In some embodiments, L2and L3are -C(O)O-. In some embodiments, L2and L3are -OC(O)O- . In some embodiments, L2and L3are -CH2O-. In some embodiments, L2and L3are -CH2OC(O)- . In some embodiments, L2and L3are -CH2OC(O)O-.

[0204] In some embodiments, L2and L3are independently selected from -O-, -OC(O)-, - C(O)O-, -OC(O)O-, -CH2O-, -CH2OC(O)-, and -CH2OC(O)O-.

[0205] In some embodiments, L2is -OC(O)- and L3is -CH2OC(O)-.

[0206] In some embodiments, L2and L3are the same. In some embodiments, L2and L3are not the same.

[0207] In some embodiments, L2is selected from those depicted in Table 1, below. In some embodiments, L3is selected from those depicted in Table 1, below.A1

[0208] As defined generally above, A1is a saturated 5-6 membered carbocyclic ring or a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the carbocyclic ring and heterocyclic ring are substituted with t occurrences of R4.

[0209] In some embodiments, A1is a saturated 5-6 membered carbocyclic ring substituted with t occurrences of R4. In some embodiments, a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with t occurrences of R4.

[0210] In some embodiments, A1is a saturated 5 membered carbocyclic ring substituted with t occurrences of R4. In some embodiments, A1is a saturated 6 membered carbocyclic ring substituted with t occurrences of R4.

[0211] In some embodiments, A1is cyclopentyl. In some embodiments, A1is cyclohexyl.

[0212] In some embodiments, A1is selected from pyrrolidinylene, tetrahydrofuranylene, tetrahydrothiophenylene, imidazolidinylene, thiazolidinylene, oxazolidinylene, piperidinylene, tetrahydro-2H-pyranylene, tetrahydro-2H-thiopyranylene, piperazinylene, morpholinylene, and hexahydropyrimidinylene.

[0213] In some embodiments, A1is selected from those depicted in Table 1, below.Rx

[0214] As generally defined above, each Rxis independently halogen, -CN, -OR, -SR, - C(O)R, -C(O)OR, or OC(O)OR.

[0215] In some embodiments, Rxis halogen. In some embodiments, Rxis -CN. In some embodiments, Rxis -OR. In some embodiments, Rxis -SR. In some embodiments, Rxis -C(O)R. In some embodiments, Rxis -C(O)OR. In some embodiments, Rxis OC(O)OR.

[0216] In some embodiments, Rxis selected from those depicted in Table 1, below. n

[0217] As defined generally above, n is an integer from 10-75.

[0218] In some embodiments, n is 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, or 70-75. In some embodiments, n is 10-30, 20-40, 30-50, 40-60, or 50-75. In some embodiments, n is 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75. In some embodiments, n is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55.

[0219] In some embodiments, n is an integer from 30-55, inclusive. In some embodiments, n is an integer from 40-50, inclusive. In some embodiments, n is 44, 45, or 46. In some embodiments, n is 44. In some embodiments, n is 45. In some embodiments, n is 46. m

[0220] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. t

[0221] As defined generally above, t is 0, 1, or 2. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 1 or 2.

[0222] In some embodiments, the present invention provides a compound of formula PL-Ia,PL-Ib, or PL-Ic:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0223] In some embodiments, the present invention provides a compound of formula PL-Iaa, PL-Iab, PL-Iac, PL-Iad, PL-Iae, PL-Iaf, PL-Iag, or PL-Iah:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0224] In some embodiments, the present invention provides a compound of formula PL-Iba,PL-Ibb, PL-Ibc, PL-Ibd, PL-Ibe, PL-Ibf, PL-Ibg, or PL-Ibh:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R , R4, R5, X1, L1, L2, L , R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0225] In some embodiments, the present invention provides a compound of formula PL-Ica,PL-Icb, PL-Icc, or PL-Icd:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0226] In some embodiments, the present invention provides a compound of formula PL-Id or PL-Ie:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0227] In some embodiments, the present invention provides a compound of formula PL-If:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0228] In some embodiments, the present invention provides a compound of formula PL-Ig:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, A1, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0229] In some embodiments, the present invention provides a compound of formula PL-Ih, PL-Ii, PL-Iha, PL-Ihb, PL-Ihc, PL-Ihd, PL-Iia, PL-lib, PL-Iic, or PL-Iid:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0230] In some embodiments, the present invention provides a compound of formula PL-Ij or PL-Ik:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0231] In some embodiments, the present invention provides a compound of formula PL-11, PL-Im, or PL-In:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, X1, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0232] In some embodiments, the present invention provides a compound of formula PL-Io,PL-Ip, or PL-Iq:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R,Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0233] In some embodiments, the present invention provides a compound of formula PL-Ioa,PL-Iob, PL-Ioc, PL-Iod, PL-Ioe, PL-Iof, PL-Iog, or PL-Ioh:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0234] In some embodiments, the present invention provides a compound of formula PL-Ipa,PL-Ipb, PL-Ipc, PL-Ipd, PL-Ipe, PL-Ipf, PL-Ipg, or PL-Iph:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0235] In some embodiments, the present invention provides a compound of formula PL-Iqa,PL-Iqb, PL-Iqc, or PL-Iqd:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0236] In some embodiments, the present invention provides a compound of formula PL-Ir or PL-Is:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0237] In some embodiments, the present invention provides a compound of formula PL-It:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0238] In some embodiments, the present invention provides a compound of formula PL-Iu:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0239] In some embodiments, the present invention provides a compound of formula PL-Iv, PL-Iw, PL-Iva, PL-Ivb, PL-Ivc, PL-Ivd, PL-Iwa, PL-Iwb, PL-Iwc, or PL-Iwd:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0240] In some embodiments, the present invention provides a compound of formula PL-Ix or PL-Ixx:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0241] In some embodiments, the present invention provides a compound of formula PL-Iy, PL-Iyy, or PL-Iyyy:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, L1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0242] In some embodiments, the present invention provides a compound of formula PL-Iz, PL-Izz, or PL-Izzz:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0243] In one aspect, the present disclosure provides a compound of formula PL-II’ :or a pharmaceutically acceptable salt thereof, wherein:X1is -N(H)-, -N(C1-6 alkyl)-, -C1-6 aliphatic-N(H)-, -C1-6 aliphatic-N(C1-6 alkyl)-, -O- or -C1-6 aliphatic-O-;L1is -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)-, or -C(O)-;L2and L3are a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, - OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R6)=N- , or -C(R6)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R6is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or OC(O)OR; n is an integer from 10-75, inclusive; and m is 0, 1, 2, 3, or 4.

[0244] In one aspect, the present disclosure provides a compound of formula PL-II”:or a pharmaceutically acceptable salt thereof, wherein:X1is -C1-8 aliphatic-N(H)-, -C1-8 aliphatic-N(C1-6 alkyl)-, or -C1-8 aliphatic-O-;L1is -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)-, or -C(O)-;L2and L3are a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, - OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R6)=N- , or -C(R6)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene;wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R6is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or OC(O)OR; n is an integer from 10-75, inclusive; and m is 0, 1, 2, 3, or 4.

[0245] In one aspect, the present disclosure provides a compound of formula PL-II:or a pharmaceutically acceptable salt thereof, wherein:X1is -N(H)-, -N(C1-6 alkyl)-, or -O-;L1is -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)-, or -C(O)-;L2and L3are a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, - OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R6)=N- , or -C(R6)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R6is C1-6 alkyl or C2-14 alkenyl;each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or OC(O)OR; n is an integer from 10-75, inclusive; and m is 0, 1, 2, 3, or 4.X1

[0246] As generally defined above, X1is -N(H)-, -N(C1-6 alkyl)-, or -O-. In some embodiments, X1is -N(H)-. In some embodiments, X1is -N(C1-6 alkyl)-. In some embodiments, X1is -O-.

[0247] In some embodiments, X1is -N(CI-5 alkyl)-. In some embodiments, X1is -N(CI-4 alkyl)-. In some embodiments, X1is -N(C1-3 alkyl)-. In some embodiments, X1is -N(CI-2 alkyl)- . In some embodiments, X1is -N(C2-6 alkyl)-.

[0248] In some embodiments, X1is -NCH3-. In some embodiments, X1is -NCH2CH3- . In some embodiments, X1is -N(CH2)2CH3-. In some embodiments, X1is -N(CH2)3CH4-. In some embodiments, X1is -N(CH2)4CH5-. In some embodiments, X1is -N(CH2)5CH6-.

[0249] In some embodiments, X1is selected from those depicted in Table 1, below.L1

[0250] As defined generally above, L1is -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)-, or -C(O)-.

[0251] In some embodiments, L1is -C(O)(C1-6 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C1-6 aliphatic)-. In some embodiments, L1is -C(O)-.

[0252] In some embodiments, L1is -C(O)(C1-5 aliphatic)C(O)-. In some embodiments, L1is -C(O)(Ci-4 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C1-3 aliphatic)C(O)-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)C(O)-.

[0253] In some embodiments, L1is -C(O)(C2-6 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C3-6 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C4-6 aliphatic)C(O)-. In some embodiments, L1is -C(O)(C5-6 aliphatic)C(O)-.

[0254] In some embodiments, L1is -C(O)(CH2)C(O)-. In some embodiments, L1is - C(O)(CH2CH2)C(O)-. In some embodiments, L1is -C(O)(CH2)3C(O)-. In some embodiments, L1is -C(O)(CH2)4C(O)-. In some embodiments, L1is -C(O)(CH2)5C(O)-. In some embodiments, L1is -C(O)(CH2)6C(O)-.

[0255] In some embodiments, L1is -C(O)(C1-5 aliphatic)-. In some embodiments, L1is - C(O)(Ci-4 aliphatic)-. In some embodiments, L1is -C(O)(C1-3 aliphatic)-. In some embodiments, L1is -C(O)(Ci-2 aliphatic)-.

[0256] In some embodiments, L1is -C(O)(C2-6 aliphatic)- . In some embodiments, L1is - C(O)(C3-6 aliphatic)-. In some embodiments, L1is -C(O)(C4-6 aliphatic)-. In some embodiments, L1is -C(O)(C5-6 aliphatic)- .

[0257] In some embodiments, L1is -C(O)(CH2)-. In some embodiments, L1is - C(O)(CH2CH2)-. In some embodiments, L1is -C(O)(CH2)3-. In some embodiments, L1is - C(O)(CH2)4-. In some embodiments, L1is -C(O)(CH2)5-. In some embodiments, L1is - C(O)(CH2)6-.

[0258] In some embodiments, L1is selected from those depicted in Table 1, below. L2and L3

[0259] As defined generally above, L2and L3are independently a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R6)=N-, or -C(R6)=N-O-.

[0260] In some embodiments L2is a covalent bond.

[0261] In some embodiments, L2is C1-6 alkylene. In some embodiments, L2is C1.5 alkylene. In some embodiments, L2is C1.4 alkylene. In some embodiments, L2is C1.3 alkylene. In some embodiments, L2is C1.2 alkylene.

[0262] In some embodiments, L2is C2-6 alkylene. In some embodiments, L2is C3-6 alkylene. In some embodiments, L2is C4-6 alkylene. In some embodiments, L2is C5-6 alkylene.

[0263] In some embodiments L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, - OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, - C(R6)=N-, or -C(R6)=N-O-.

[0264] In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0265] In some embodiments, L2is a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or -OC(O)N(R)-.

[0266] In some embodiments, L2is a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, - C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0267] In some embodiments, L2is a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or - OC(O)N(R)-.

[0268] In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -O-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -NR-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S-S-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S(O)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S(O)2-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)O-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)O-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)N(R)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)O-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)N(R)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)N(R)-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(R6)=N-. In some embodiments, L2is C1-6 alkylene wherein one methylene unit of the Ci- 6 alkylene is replaced with -C(R6)=N-O-.

[0269] In some embodiments L2is selected from -O-, -OC(O)-, -C(O)O-, -OC(O)O-, -CH2O- , -CH2OC(O)-, and -CH2OC(O)O-.

[0270] In some embodiments L2is -O-. In some embodiments L2is -OC(O)-. In some embodiments L2is -C(O)O-. In some embodiments L2is -OC(O)O-. In some embodiments L2is -CH2O-. In some embodiments L2is -CH2OC(O)-. In some embodiments L2is -CH2OC(O)O-.

[0271] In some embodiments L3is a covalent bond.

[0272] In some embodiments, L3is C1-6 alkylene. In some embodiments, L3is C1.5 alkylene. In some embodiments, L3is C1.4 alkylene. In some embodiments, L3is C1.3 alkylene. In some embodiments, L3is C1.2 alkylene.

[0273] In some embodiments, L3is C2-6 alkylene. In some embodiments, L3is C3-6 alkylene. In some embodiments, L3is C4-6 alkylene. In some embodiments, L3is C5-6 alkylene.

[0274] In some embodiments L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, - OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, - C(R6)=N-, or -C(R6)=N-O-.

[0275] In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0276] In some embodiments, L3is a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or -OC(O)N(R)-.

[0277] In some embodiments, L3is a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, - C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0278] In some embodiments, L3is a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or - OC(O)N(R)-.

[0279] In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -O-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -NR-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S-S-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S(O)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -S(O)2-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)O-. In someembodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)O-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -OC(O)N(R)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)O-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(O)N(R)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -N(R)C(O)N(R)-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with -C(R6)=N-. In some embodiments, L3is C1-6 alkylene wherein one methylene unit of the Ci- 6 alkylene is replaced with -C(R6)=N-O-.

[0280] In some embodiments L3is selected from -O-, -OC(O)-, -C(O)O-, -OC(O)O-, -CH2O- , -CH2OC(O)-, and -CH2OC(O)O-.

[0281] In some embodiments L3is -O-. In some embodiments L3is -OC(O)-. In some embodiments L3is -C(O)O-. In some embodiments L3is -OC(O)O-. In some embodiments L3is -CH2O-. In some embodiments L3is -CH2OC(O)-. In some embodiments L3is -CH2OC(O)O-.

[0282] In some embodiments, L2and L3are a covalent bond.

[0283] In some embodiments, L2and L3are independently a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, - S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -N(R)C(O)N(R)-, -C(R6)=N-, or -C(R6)=N-O-.

[0284] In some embodiments, L2and L3are independently selected from -O-, -OC(O)-, - C(O)O-, -OC(O)O-, -CH2O-, -CH2OC(O)-, and -CH2OC(O)O-.

[0285] In some embodiments, L2and L3are -O-. In some embodiments, L2and L3are -OC(O)- . In some embodiments, L2and L3are -C(O)O-. In some embodiments, L2and L3are -OC(O)O- . In some embodiments, L2and L3are -CH2O-. In some embodiments, L2and L3are -CH2OC(O)- . In some embodiments, L2and L3are -CH2OC(O)O-.

[0286] In some embodiments, L2and L3are independently selected from -O-, -OC(O)-, - C(O)O-, -OC(O)O-, -CH2O-, -CH2OC(O)-, and -CH2OC(O)O-.

[0287] In some embodiments, L2is -OC(O)- and L3is -CH2OC(O)-.

[0288] In some embodiments, L2and L3are the same. In some embodiments, L2and L3are not the same.

[0289] In some embodiments, L2is selected from those depicted in Table 1, below. In some embodiments, L3is selected from those depicted in Table 1, below.R1

[0290] As defined generally above, R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl. In some embodiments, R1is H. In some embodiments, R1is C1-6 alkyl. In some embodiments, R1is -(C1-6 alkyl)-N3. In some embodiments, R1is -(C1-6 alkyl)-SH. In some embodiments, R1is C3-8 alkynyl. In some embodiments, R1is a C1-3 alkyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is propyl. In some embodiments, R1is -(C1.3 alkyl)-N3. In some embodiments, R1is -CH2N3. In some embodiments, R1is -(C1.3 alkyl)-SH. In some embodiments, R1is -CH2SH. In some embodiments, R1is C3-5 alkynyl. In some embodiments, R1is C3 alkynyl. In some embodiments, R1is C4 alkynyl. In some embodiments, R1is C5 alkynyl. In some embodiments, R1is C5-8 alkynyl. In some embodiments, R1is C5 alkynyl. In some embodiments, R1is C6 alkynyl. In some embodiments, R1is C7 alkynyl. In some embodiments, R1is C8 alkynyl. In some embodiments, R1is not methyl. In some embodiments, R1is selected from those depicted in Table 1, below.R2and R3

[0291] As defined generally above, R2and R3are independently a straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx.

[0292] In some embodiments, R2is a straight or branched C6-30 alkyl. In some embodiments, R2is -(CH2)6-25. In some embodiments, R2is -(CH2)10-25. In some embodiments, R2is -(CH2)10- 14. In some embodiments, R2is -(CH2)14-16. In some embodiments, R2is -(CH2)18-20.

[0293] In some embodiments, R2is a straight or branched C6-30 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-30 alkyl substituted with m instances of Rx.

[0294] In some embodiments, R2is a straight or branched C6-25 alkyl. In some embodiments, R2is a straight or branched C6-25 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-25 alkyl substituted with m instances of Rx.

[0295] In some embodiments, R2is a straight or branched C10-25 alkyl. In some embodiments, R2is a straight or branched C10-25 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-25 alkyl substituted with m instances of Rx.

[0296] In some embodiments, R2is a straight or branched C10-14 alkyl. In some embodiments, R2is a straight or branched C10-14 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-14 alkyl substituted with m instances of Rx.

[0297] In some embodiments, R2is a straight or branched C14-16 alkyl. In some embodiments, R2is a straight or branched C14-16 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C14-16 alkyl substituted with m instances of Rx.

[0298] In some embodiments, R2is a straight or branched C18-20 alkyl. In some embodiments, R2is a straight or branched C18-20 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C18-20 alkyl substituted with m instances of Rx.

[0299] In some embodiments, R2is a straight or branched C6-30 alkenyl. In some embodiments, R2is a straight or branched C6-25 alkenyl. In some embodiments, R2is C10-25 alkenyl. In some embodiments, R2is C10-14 alkenyl. In some embodiments, R2is C14-16 alkenyl. In some embodiments, R2is C18-20 alkenyl.

[0300] In some embodiments, R2includes one, two, three, or four carbon-carbon double bonds.

[0301] In some embodiments, R2is a straight or branched C6-30 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-30 alkenyl substituted with m instances of Rx.

[0302] In some embodiments, R2is a straight or branched C6-25 alkenyl. In some embodiments, R2is a straight or branched C6-25 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclicring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-25 alkenyl substituted with m instances of Rx.

[0303] In some embodiments, R2is a straight or branched C10-25 alkenyl. In some embodiments, R2is a straight or branched C10-25 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-25 alkenyl substituted with m instances of Rx.

[0304] In some embodiments, R2is a straight or branched C10-14 alkenyl. In some embodiments, R2is a straight or branched C10-14 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C 10-14 alkenyl substituted with m instances of Rx.

[0305] In some embodiments, R2is a straight or branched C14-16 alkenyl. In some embodiments, R2is a straight or branched C14-16 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C14-16 alkenyl substituted with m instances of Rx.

[0306] In some embodiments, R2is a straight or branched C18-20 alkenyl. In some embodiments, R2is a straight or branched C18-20 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C18-20 alkenyl substituted with m instances of Rx.

[0307] In some embodiments, R2is a straight or branched C6-30 alkynyl. In some embodiments, R2is -(CH2)C6-2.5 In some embodiments, R2is -(CH2)10-25. In some embodiments, R2is -(CH2)10-14. In some embodiments, R2is -(CH2)14-16. In some embodiments, R2is -(CH2)18- 20.

[0308] In some embodiments, R2has one, two, three, four, or more carbon-carbon triple bonds.

[0309] In some embodiments, R2is a straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-30 alkynyl substituted with m instances of Rx.

[0310] In some embodiments, R2is a straight or branched C6-25 alkynyl. In some embodiments, R2is a straight or branched C6-25 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C6-25 alkynyl substituted with m instances of Rx.

[0311] In some embodiments, R2is a straight or branched C10-25 alkynyl. In some embodiments, R2is a straight or branched C10-25 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-25 alkynyl substituted with m instances of Rx.

[0312] In some embodiments, R2is a straight or branched C10-14 alkynyl. In some embodiments, R2is a straight or branched C10-14 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C10-14 alkynyl substituted with m instances of Rx.

[0313] In some embodiments, R2is a straight or branched C14-16 alkynyl. In some embodiments, R2is a straight or branched C14-16 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R2is a straight or branched C14-16 alkynyl substituted with m instances of Rx.

[0314] In some embodiments, R2is a straight or branched C18-20 alkynyl. In some embodiments, R2is a straight or branched C18-20 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted withm instances of Rx. In some embodiments, R2is a straight or branched C18-20 alkynyl substituted with m instances of Rx.

[0002] In some embodiments, R2is selected from those depicted in Table 1, below.

[0315] In some embodiments, R3is a straight or branched C6-30 alkyl. In some embodiments, R3is -(CH2)6-25. In some embodiments, R3is -(CH2)10-25. In some embodiments, R3is -(CH2)10- 14. In some embodiments, R3is -(CH2)14-16. In some embodiments, R3is -(CH2)18-20.

[0316] In some embodiments, R3is a straight or branched C6-30 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-30 alkyl substituted with m instances of Rx.

[0317] In some embodiments, R3is a straight or branched C6-25 alkyl. In some embodiments, R3is a straight or branched C6-25 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-25 alkyl substituted with m instances of Rx.

[0318] In some embodiments, R3is a straight or branched C10-25 alkyl. In some embodiments, R3is a straight or branched C10-25 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-25 alkyl substituted with m instances of Rx.

[0319] In some embodiments, R3is a straight or branched C10-14 alkyl. In some embodiments, R3is a straight or branched C10-14 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-14 alkyl substituted with m instances of Rx.

[0320] In some embodiments, R3is a straight or branched C14-16 alkyl. In some embodiments, R3is a straight or branched C14-16 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C14-16 alkyl substituted with m instances of Rx.

[0321] In some embodiments, R3is a straight or branched C18-20 alkyl. In some embodiments, R3is a straight or branched C18-20 alkyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene;wherein the alkyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C18-20 alkyl substituted with m instances of Rx.

[0322] In some embodiments, R3is a straight or branched C6-30 alkenyl. In some embodiments, R3is C6-25 alkenyl. In some embodiments, R3is C10-25 alkenyl. In some embodiments, R3is C10-14 alkenyl. In some embodiments, R3is C14-16 alkenyl. In some embodiments, R3is C18-20 alkenyl.

[0323] In some embodiments, R3is a straight or branched C6-30 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-30 alkenyl substituted with m instances of Rx.

[0324] In some embodiments, R3is a straight or branched C6-25 alkenyl. In some embodiments, R3is a straight or branched C6-25 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-25 alkenyl substituted with m instances of Rx.

[0325] In some embodiments, R3is a straight or branched C10-25 alkenyl. In some embodiments, R3is a straight or branched C10-25 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-25 alkenyl substituted with m instances of Rx.

[0326] In some embodiments, R3is a straight or branched C10-14 alkenyl. In some embodiments, R3is a straight or branched C10-14 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C 10-14 alkenyl substituted with m instances of Rx.

[0327] In some embodiments, R3is a straight or branched C14-16 alkenyl. In some embodiments, R3is a straight or branched C14-16 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted withm instances of Rx. In some embodiments, R3is a straight or branched C14-16 alkenyl substituted with m instances of Rx.

[0328] In some embodiments, R3is a straight or branched C18-20 alkenyl. In some embodiments, R3is a straight or branched C18-20 alkenyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkenyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C18-20 alkenyl substituted with m instances of Rx.

[0329] In some embodiments, R3is a straight or branched C6-30 alkynyl. In some embodiments, R3is C6-25 alkynyl. In some embodiments, R3is C10-25 alkynyl. In some embodiments, R3is C10-14 alkynyl. In some embodiments, R3is C14-16 alkynyl. In some embodiments, R3is C18-20 alkynyl.

[0330] In some embodiments, R3has one, two, three, four, or more carbon-carbon triple bonds.

[0331] In some embodiments, R3is a straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-30 alkynyl substituted with m instances of Rx.

[0332] In some embodiments, R3is a straight or branched C6-25 alkynyl. In some embodiments, R3is a straight or branched C6-25 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C6-25 alkynyl substituted with m instances of Rx.

[0333] In some embodiments, R3is a straight or branched C10-25 alkynyl. In some embodiments, R3is a straight or branched C10-25 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-25 alkynyl substituted with m instances of Rx.

[0334] In some embodiments, R3is a straight or branched C10-14 alkynyl. In some embodiments, R3is a straight or branched C10-14 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclicring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C10-14 alkynyl substituted with m instances of Rx.

[0335] In some embodiments, R3is a straight or branched C14-16 alkynyl. In some embodiments, R3is a straight or branched C14-16 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C14-16 alkynyl substituted with m instances of Rx.

[0336] In some embodiments, R3is a straight or branched C18-20 alkynyl. In some embodiments, R3is a straight or branched C18-20 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx. In some embodiments, R3is a straight or branched C18-20 alkynyl substituted with m instances of Rx.

[0337] In some embodiments, R3is selected from those depicted in Table 1, below.

[0338] In some embodiments, R2and R3are the same. In some embodiments R2and R3are different.R6

[0339] As generally defined above, R6is C1-6 alkyl or C2-14 alkenyl. In some embodiments, R6is C1-6 alkyl. In some embodiments, R6is C2-14 alkenyl. In some embodiments, R6is C1.5 alkyl. In some embodiments, R6is C1.4 alkyl. In some embodiments, R6is C1.3 alkyl. In some embodiments, R6is C1.2 alkyl. In some embodiments, R6is C2-6 alkyl. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is propyl. In some embodiments, R6is isopropyl. In some embodiments, R6is butyl. In some embodiments, R6is isobutyl. In some embodiments, R6is pentyl. In some embodiments, R6is hexyl. In some embodiments, R6is C2-14 alkenyl. In some embodiments, R6is C2-10 alkenyl. In some embodiments, R6is C2-8 alkenyl. In some embodiments, R6is C2-6 alkenyl. In some embodiments, R6is C2-4 alkenyl. In some embodiments, R6is selected from those depicted in Table 1, below. Rx

[0340] As generally defined above, each Rxis independently halogen, -CN, -OR, -SR, - C(O)R, -C(O)OR, or OC(O)OR. In some embodiments, Rxis halogen. In some embodiments, Rxis -CN. In some embodiments, Rxis -OR. In some embodiments, Rxis -SR. In someembodiments, Rxis -C(O)R. In some embodiments, Rxis -C(O)OR. In some embodiments, Rxis OC(O)OR. In some embodiments, Rxis selected from those depicted in Table 1, below. n

[0341] As defined generally above, n is an integer from 10-75.

[0342] In some embodiments, n is 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, or 70-75. In some embodiments, n is 10-30, 20-40, 30-50, 40-60, or 50-75. In some embodiments, n is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75. In some embodiments, n is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55.

[0343] In some embodiments, n is an integer from 30-55, inclusive. In some embodiments, n is an integer from 40-50, inclusive. In some embodiments, n is 44, 45, or 46. In some embodiments, n is 44. In some embodiments, n is 45. In some embodiments, n is 46. m

[0344] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3.

[0345] In some embodiments, the present invention provides a compound of formula PL-IIc or PL-IId:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R6, X1, R, Rx, m, and n, is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0346] In some embodiments, the present invention provides a compound of formula PL-IIe:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R6, X1, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0347] In some embodiments, the present invention provides a compound of formula PL-IIf:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R6, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0348] In some embodiments, the present invention provides a compound of formula PL-IIg or PL-IIh:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R6, X1, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, X1is -N(H)-.

[0349] In some embodiments, the present invention provides a compound of formula PL-IIa or PL-IIb:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R6, R, Rx, m, and n, is as defined above and described in embodiments herein, both singly and in combination.

[0350] In some embodiments, the present invention provides a compound of formula PL-IIk:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R6, L2, L3, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0351] In some embodiments, the present invention provides a compound of formula PL-IIm or PL-IIn:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R6, R, Rx, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[0352] In some embodiments, the PEGylated lipid compound is one of those shown in Table1. In some embodiments, the PEGylated lipid compound is selected from Compounds PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7, PL-8, PL-9, PL-10, PL-11, PL-12, PL-13, PL-14, PL-15, and PL-16; or a pharmaceutically acceptable salt thereof.Table 1. Exemplary Compoundsc. Lipid Nanoparticle Compositions

[0353] In one aspect, the present disclosure further provides delivery systems for delivery of a therapeutic payload disclosed herein. In some embodiments, a delivery system suitable for delivery of the therapeutic payload disclosed herein comprises a lipid nanoparticle (LNP) formulation.

[0354] In some embodiments, an LNP of the present disclosure comprises an ionizable lipid, a structural lipid, a PEGylated lipid (aka PEG lipid), and a phospholipid. In alternative embodiments, an LNP comprises an ionizable lipid, a structural lipid, a PEGylated lipid (aka PEG lipid), and a zwitterionic amino acid lipid. In some embodiments, an LNP further comprises a 5thlipid, besides any of the aforementioned lipid components. In some embodiments, the LNP encapsulates one or more elements of the active agent of the present disclosure. In some embodiments, an LNP further comprises a targeting moiety covalently or non-covalently bound to the outer surface of the LNP. In some embodiments, the targeting moiety is a targeting moiety that binds to, or otherwise facilitates uptake by, cells of a particular organ system.

[0355] In some embodiments, an LNP has a diameter of at least about 20nm, 30 nm, 40nm, 50nm, 60nm, 70nm, 80nm, or 90nm. In some embodiments, an LNP has a diameter of less than about lOOnm, HOnm, 120nm, 130nm, 140nm, 150nm, or 160nm. In some embodiments, an LNP has a diameter of less than about lOOnm. In some embodiments, an LNP has a diameter of less than about 90nm. In some embodiments, an LNP has a diameter of less than about 80nm. In some embodiments, an LNP has a diameter of about 60-100nm. In some embodiments, an LNP has a diameter of about 75-80nm.

[0356] In some embodiments, the lipid nanoparticle compositions of the present disclosure are described according to the respective molar ratios of the component lipids in the formulation.As a non-limiting example, the mol-% of the ionizable lipid may be from about 10 mol-% to about 80 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 20 mol-% to about 70 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 30 mol-% to about 60 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 35 mol-% to about 55 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 40 mol-% to about 50 mol-%.

[0357] In some embodiments, the mol-% of the phospholipid may be from about 1 mol-% to about 50 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 2 mol-% to about 45 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 3 mol-% to about 40 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 4 mol-% to about 35 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 5 mol-% to about 30 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 10 mol-% to about 20 mol-%. In some embodiments, the mol- % of the phospholipid may be from about 5 mol-% to about 20 mol-%.

[0358] In some embodiments, the mol-% of the structural lipid may be from about 10 mol-% to about 80 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 20 mol-% to about 70 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 30 mol-% to about 60 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 35 mol-% to about 55 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 40 mol-% to about 50 mol-%.

[0359] In some embodiments, the mol-% of the PEG lipid may be from about 0.1 mol-% to about 10 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 0.2 mol- % to about 5 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 0.5 mol-% to about 3 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 1 mol-% to about 2 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 1.5 mol-%. i. Ionizable lipids

[0360] In some embodiments, an LNP disclosed herein comprises an ionizable lipid. In some embodiments, an LNP comprises two or more ionizable lipids.

[0361] In some embodiments, an ionizable lipid has a dimethylamine or an ethanolamine head. In some embodiments, an ionizable lipid has an alkyl tail. In some embodiments, a tail has one or more ester linkages, which may enhance biodegradability. In some embodiments, a tail is branched, such as with 3 or more branches. In some embodiments, a branched tail mayenhance endosomal escape. In some embodiments, an ionizable lipid has a pKa between 6 and 7, which may be measured, for example, by TNS assay.

[0362] In some embodiments, an ionizable lipid has a structure of any of the formulas disclosed below, and all formulas disclosed in a reference publication and patent application publication cited below. In some embodiments, an ionizable lipid comprises a head group of any structure or formula disclosed below. In some embodiments, an ionizable lipid comprises a bridging moiety of any structure or formula disclosed below. In some embodiments, an ionizable lipid comprises any tail group, or combination of tail groups disclosed below. The present disclosure contemplates all permutations and combinations of head group, bridging moiety and tail group, or tail groups, disclosed herein.

[0363] In some embodiments, a head, tail, or structure of an ionizable lipid is described in US patent application US20170210697A1.

[0364] In some embodiments, a compound has a structure according to formula 1 :wherein:R1is selected from the group consisting of C5-30 alkyl, C5-20 alkenyl, - R*YR", YR", and -R"M'R†; R2and R3are independently selected from the group consisting ofH, Cl-14 alkyl, C2-14 alkenyl, — R*YR", — YR", and — R*OR", or R2and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;R4is selected from the group consisting of a C3-6 carbocycle, — (CH2)nQ, — (CH2)nCHQR, — CHQR, CO(R)2, and unsubstituted C 1-6 alkyl, where Q is selected from a carbocycle, heterocycle, —OR, — O(CH2)nN(R)2, — C(O)OR, — OC(O)R, — CX3, — CX2H, -CXH2, -CN, N(R)2, - C(O)N(R)2, - N(R)C(O)R, -N(R)S(O)2R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, -N(R)R8, - O(CH2)nOR, -N(R)C(=NR9)N(R)2-N(R)C(=CHR9)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, - N(OR)C(O)R, -N(OR)S(O)2R, -N(OR)C(O)OR, -N(OR)C(O)N(R)2, -N(OR)C(S)N(R)2- N(OR)C(— NR)N(R) - N(OR)C(=CHR9)N(R)2, -C(=NR9)N(R)2, — C(=NR9)R, -C(O)N(R)OR, and — C(R)N(R)2, C(O)OR, and each n is independently selected from 1, 2, 3, 4, and 5 or ahead group disclosed in Table 2A; each R5is independently selected from the group consisting of Cl -3 alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of Cl -3 alkyl, C2-3 alkenyl, and H;M and M’ are independently selected from — C(O)O-, -OC(O) — , -C(O)N(R’)-, -N(R')C(O)-, - C(O)—, — C(S)— , — C(S)S-, — SC(S)— , — CH(OH)— , — P(O)(OR’)O-, — S(O)— , — S-S-, an aryl group, and a heteroaryl group;R7is selected from the group consisting of C 1 -3alkyl, C2-3 alkenyl, and H;R8is selected from the group consisting of C3-6 carbocycle and heterocycle;R9is selected from the group consisting of H. CN, NCh, Cl -6 alkyl, -OR, — S(O)2R, — S(O)2N(R)2, C2-6 alkenyl, C3-6 carbocycle and heterocycle; each R is independently selected from the group consisting of Cl -3 alkyl, C2-3 alkenyl, and H; each R’ is independently selected from the group consisting of C1-18 alkyl, C2-18 alkenyl, — R*YR", —YR", and H; each R” is independently selected from the group consisting of C3-14 alkyl, C3-14 alkenyl, and H; each R* is independently selected from the group consisting of Cl-12 alkyl and C2-12 alkenyl: each Y is independently a C3-6 carbocycle; each X is independently selected from the group consisting of F, Cl, Br, and I; each Q is is -OH, -NHC(S)N(R)2, -NHC(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)R8, - NHC(=NR9)N(R)2, -NHC(=CHR9)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, heteroaryl or heterocycloalkyl; and m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13: and wherein when R4is — (CH2)nQ, — (CH2)nCHQR, — CHQR, or — CQ(R)2, then (i) Q is not — N(R), when n is 1, 2, 3, 4 or 5, or (ii) Q is not 5, 6, or 7-membered heterocycloalkyl when n is 1 or 2.

[0365] In some embodiments, R4is in Table 2A.

[0366] In some embodiments, R4in formula 1 is selected from head groups 1-47.Table 2A - Ionizable lipid head groups

[0367] In some embodiments, a subset of the compounds of formula 1 are also described by formula lb:

[0368] Wherein 1 is selected from 1, 2, 3, 4, and 5; M1is a bond or M1; R4is unsubstituted C1- 3 alkyl, or -(CH2)nQ, in which n is 2, 3, or 4, and Q is -OH, -NHC(S)N(R)2, -NHC(O)N(R)2, - N(R)C(O)R, -N(R)S(O)2R, -N(R)R8, -NHC(=NR9)N(R)2, -NHC(=CHR9)N(R)2, -OC(O)N(R)2, - N(R)C(O)OR, heteroaryl or heterocycloalkyl; M and M' are independently selected from - C(O)O-, -OC(O)-, -C(O)N(R')-, -P(O)(OR')O-, -S-S-, an ary l group, and a heteroaryl group; and R2and R3 are independently selected from the group consisting of H, Ci-i4 alkyl, and C2-14 alkenyl.

[0369] In some embodiments, a head, tail, or structure of an ionizable lipid is described in international patent application PCT / US2018 / 058555.

[0370] In some embodiments, an ionizable lipid has a structure according to formula 2:wherein: one of L1or L2is -0(C=0)-, -(C=0)0-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, - NRaC(=0)-, -C(=O)NRa-, -NRaC(=0)NRa-, -0C(=0)NRa- or -NRaC(=O)O-, and the other of L1or L2is -0(C=0)-, -(C=0)0-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=0)-, - C(=O)NRa-, -NRaC(=0)NRa-, -0C(=0)NRa- or -NRaC(=O)O- or a direct bond;Rais H or Ci -C 12 alkyl;Rlaand Rlbare, at each occurrence, independently either (a) H or C1-C12 alkyl, or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond; R2aand R2bare, at each occurrence, independently either (a) H or C1-C12 alkyl, or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;R3aand R3bare, at each occurrence, independently either (a) H or C1-C12 alkyl, or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond; R4aand R4bare, at each occurrence, independently either (a) H or C1-C12 alkyl, or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond; R5and R6are each independently methyl or cycloalkyl;R7is, at each occurrence, independently H or C1-C12 alkyl;R8and R9are each independently unsubstituted C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring comprising one nitrogen atom; a and d are each independently an integer from 0 to 24; b and c are each independently an integer from 1 to 24; e is 1 or 2; and x is 0, 1 or 2.

[0371] In some embodiments, an ionizable lipid has a structure according to formula 3 :wherein: one of L1or L2is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, - NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa- or -NRaC(=O)O-, and the other of L1or L2is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, - C(=O)NRa-, NRaC(=O)NRa-, -OC(=O)NRa- or -NRaC(=O)O- or a direct bond;G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond:G2is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;G3is C1-C6 alkylene;Rais H or C1-C12 alkyl;Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond; R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond; R3aand R3bare, at each occurrence, independently either (a): H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond; R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond; R5and R6are each independently H or methyl;R7is C4-C20 alkyl;R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2.

[0372] In some embodiments, an ionizable lipid has a structure according to formula 4:

[0373] wherein: one of L1or L2is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, - NRaC(=O)-, -C(=O)NRa-, NRaC(=O)NRa-, -OC(=O)NRa- or -NRaC(=O)O-, and the other of L1or L2is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, - C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa- or -NRaC(=O)O- or a direct bond;G1and G2are each independently unsubstituted C1-C12 alkylene or C1-C12 alkenylene;G3is C1-C24 alkylene, C1-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene;Rais H or C1-C12 alkyl;R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4or -NR5C(=O)R4;R4is C1-C12 alkyl;R5is H or C1-C6 alkyl; and x is 0, 1 or 2.

[0374] In some embodiments, an ionizable lipid has a structure according to formula 5:wherein: one of G1or G2is, at each occurrence, -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)y, -S-S-, - C(=O)S-, SC(=O)-, -N(Ra)C(=O)-, -C(=O)N(Ra)-, -N(Ra)C(=O)N(Ra)-, -OC(=O)N(Ra)- or - N(Ra)C(=O)O-, and the other of G1or G2is, at each occurrence, -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)y, -S-S-, -C(=O)S-, -SC(=O)-, -N(Ra)C(=O)-, -C(=O)N(Ra)-, -N(Ra)C(=O)N(Ra)-, - OC(=O)N(Ra)- or -N(Ra)C(=O)O- or a direct bond;L is, at each occurrence, ~O(C=O)-, wherein ~ represents a covalent bond to X;X is CRa;Z is alkyl, cycloalkyl or a monovalent moiety comprising at least one polar functional group when n is 1; or Z is alkylene, cycloalkylene or a polyvalent moiety comprising at least one polar functional group when n is greater than 1;Rais, at each occurrence, independently H, C1-C12 alkyl, C1-C12 hydroxylalkyl, C1-C12 aminoalkyl, C1-C12 alkylaminylalkyl, C1-C12 alkoxyalkyl, C1-C12 alkoxycarbonyl, C1-C12 alkylcarbonyloxy, C1-C12 alkylcarbonyloxyalkyl or C1-C12 alkylcarbonyl;R is, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R together with the carbon atom to which it is bound is taken together with an adjacent R and the carbon atom to which it is bound to form a carbon-carbon double bond;R1and R2have, at each occurrence, the following structure, respectively:a1and a2are, at each occurrence, independently an integer from 3 to 12; b1and b2are, at each occurrence, independently 0 or 1; c1and c2are, at each occurrence, independently an integer from 5 to 10; d1and d2are, at each occurrence, independently an integer from 5 to 10; y is, at each occurrence, independently an integer from 0 to 2; and n is an integer from 1 to 6, wherein each alkyl, alkylene, hydroxylalkyl, aminoalkyl, alkylaminylalkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl and alkylcarbonyl is optionally substituted with one or more substituent.

[0375] In some embodiments, an ionizable lipid has a structure according to formula 6:wherein: one of G1or G2is, at each occurrence, -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)y, -S-S-, - C(=O)S-, SC(=O)-, -N(Ra)C(=O)-, -C(=O)N(Ra)-, -N(Ra)C(=O)N(Ra)-, -OC(=O)N(Ra)- or - N(Ra)C(=O)O-, and the other of G1or G2is, at each occurrence, -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)y-, -S-S-, -C(=O)S-, -SC(=O)-, -N(Ra)C(=O)-, -C(=O)N(Ra)-, -N(Ra)C(=O)N(Ra)-, - OC(=O)N(Ra)- or -N(Ra)C(=O)O- or a direct bond;L is, at each occurrence, ~O(C=O)-, wherein ~ represents a covalent bond to X;X is CRa;Z is alkyl, cycloalkyl or a monovalent moiety comprising at least one polar functional group when n is 1; or Z is alkylene, cycloalkylene or a polyvalent moiety comprising at least one polar functional group when n is greater than 1;Rais, at each occurrence, independently H, C1-C12 alkyl, C1-C12 hydroxylalkyl, C1-C12 aminoalkyl, C1-C12 alkylaminylalkyl, C1-C12 alkoxyalkyl, C1-C12 alkoxycarbonyl, C1-C12 alkylcarbonyloxy, C1-C12 alkylcarbonyloxyalkyl or C1-C12 alkylcarbonyl;R is, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R together with the carbon atom to which it is bound is taken together with an adjacent R and the carbon atom to which it is bound to form a carbon-carbon double bond;R1and R2have, at each occurrence, the following structure, respectively:R' is, at each occurrence, independently H or C1-C12 alkyl; a1and a2are, at each occurrence, independently an integer from 3 to 12; b1and b2are, at each occurrence, independently 0 or 1; c1and c2are, at each occurrence, independently an integer from 2 to 12; d1and d2are, at each occurrence, independently an integer from 2 to 12; y is, at each occurrence, independently an integer from 0 to 2; and n is an integer from 1 to 6, wherein a1, a2, c1, c2, d1and d2are selected such that the sum of a1+c1+d1is an integer from 18 to 30, and the sum of a2+c2+d2is an integer from 18 to 30, and wherein each alkyl, alkylene, hydroxylalkyl, aminoalkyl, alkylaminylalkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl and alkylcarbonyl is optionally substituted with one or more substituent.

[0376] In certain embodiments of Formula (V), G1and G2are each independently -O(C=O)- or -(C=O)O-.

[0377] In some embodiments, an ionizable lipid has a disulfide tail.

[0378] In some embodiments, an ionizable lipid includes short peptides of 12-15 mer length as head groups.

[0379] In some embodiments, the head of an ionizable lipid comprises the structure of Vitamin A, D, E, or K as described in the published Patent Application WO2019232095A1, which is incorporated by herein by reference in its entirety.

[0380] In some embodiments, a lipid is described in international patent applications W02021077067, or WO2019152557, each of which is incorporated herein by reference in its entirety.

[0381] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2019 / 0240354, which is incorporated herein by reference in its entirety.

[0382] In some embodiments, the lipids disclosed in US 2019 / 0240354 are of Formula I:or salts thereof, wherein:R1and R2are either the same or different and are independently hydrogen (H) or an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, or R3and R2may join to form an optionally substituted heterocyclic ring of 4 to 6 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of nitrogen (N), oxygen (O), and mixtures thereof;R3is either absent or is hydrogen (H) or a C1-C6 alkyl to provide a quaternary amine; R4and R5are either the same or different and are independently an optionally substituted C10-C24 alkyl, C10-C24 alkenyl, C10-C24 alkynyl, or C10-C24 acyl, wherein at least one of R4and R5comprises at least two sites of unsaturation; and n is 0, 1, 2, 3, or 4.

[0383] In some embodiments, the lipids disclosed in US 2019 / 0240354 are of Formula II:wherein R1and R2are either the same or different and are independently an optionally substituted C12-C24 alkyl, C12-C24 alkenyl, C12-C24 alkynyl, or C12-C24 acyl; R3and R4are either the same or different and are independently an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2- C6, alkynyl, or R3and R4may join to form an optionally substituted heterocyclic ring of 4 to 6 carbon atoms and 1 or 2 heteroatoms chosen from nitrogen and oxygen; R5is either absent or ishydrogen (H) or a Ci-C6 alkyl to provide a quaternary amine; m, n, and p are either the same or different and are independently either 0, 1, or 2, with the proviso that m, n, and p are not simultaneously 0; q is 0, 1, 2, 3, or 4; and Y and Z are either the same or different and are independently O, S, or NH. In some embodiments, q is 2.

[0384] In some embodiments, the cationic lipid of Formula II is 2,2-dilinoleyl-4-(2- dimethylaminoethyl)-[l,3]-dioxolane, 2,2-dilinoleyl-4-(3-dimethylaminopropyl)-[l,3]- dioxolane, 2,2-dihnoleyl-4-(4-dimethylaminobutyl)-[l,3]-dioxolane, 2,2-dilinoleyl-5- dimethylaminomethyl-[l,3]-dioxane, 2,2-dilinoleyl-4-N-methylpepiazino-[l,3]-dioxolane, 2,2- dilinoleyl-4-dimethylaminomethyl-[l,3]-dioxolane, 2,2-dioleoyl-4-dimethylaminomethyl-[l,3]- dioxolane, 2,2-distearoyl-4-dimethylaminomethyl-[l,3]-dioxolane, 2,2-dilinoleyl-4-N- morpholino-[l,3]-dioxolane, 2,2-Dilinoleyl-4-trimethylamino-[l,3]-dioxolane chloride, 2,2- dilinoleyl-4,5-bis(dimethylaminomethyl)-[l,3]-di oxolane, 2,2-dilinoleyl-4-methylpiperzine- [l,3]-dioxolane, or mixtures thereof In some embodiments, the cationic lipid of Formula II is 2, 2-dilinol ey 1-4 -(2 -dimethylaminoethyl)- [1,3] -di oxolane.

[0385] In some embodiments, the lipids disclosed in US 2019 / 0240354 are of Formula III:

[0386] or salts thereof, wherein: RJ and R2are either the same or different and are independently an optionally substituted Ci-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, or R1and R2may join to form an optionally substituted heterocyclic ring of 4 to 6 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of nitrogen (N), oxygen (0), and mixtures thereof; R3is either absent or is hydrogen (H) or a C1-C6 alkyl to provide a quaternary amine; R4and R5are either absent or present and when present are either the same or different and are independently an optionally substituted C1-C10 alkyl or C2-C10 alkenyl; and n is 0, 1, 2, 3, or 4.

[0387] In some embodiments, the lipids disclosed in US 2019 / 0240354 are of Formula C:X-A-Y — Z1; (Formula C) or salts thereof, wherein:X is — N(H)R or — NR2;A is absent, Ci to C6 alkyl, C2 to C6 alkenyl, or C2 to C6 alkynyl, which Cito C6 alkyl, C2to C6 alkenyl, and C2 to C6 alkynyl is optionally substituted with one or more groups independently selected from oxo, halogen, heterocycle, — CN, — ORX, — NRxRy, — NRxC(=O)Ry, — NRxSO2Ry, — C(=O)RX, — C(=O)ORX, — C(=O)NRxRy, — SOnRx, and — SOnNRxRy, whereinn is 0, 1, or 2, and Rxand Ryare each independently hydrogen, alkyl, or heterocycle, wherein each alkyl and heterocycle of Rxand Rymay be further substituted with one or more groups independently selected from oxo, halogen, — OH, — CN, alkyl, — ORX, heterocycle, — NRxRy, — NRx'C(=O)Ry', — NRXSO2Ry, — C(=O)RX, — C(=O)ORX', — C(=O)NRxRy', — SOnRx', and — SOn'NRxRy, wherein n' is 0, 1, or 2, and Rxand Ryare each independently hydrogen, alkyl, or heterocycle;Y is selected from the group consisting of absent, — C(=O) — , — O — , — OC(=O) — , — C(=O)O— , — N(Rb)C(=O)— , — C(=O)N(Rb)— , — N(Rb)C(=O)O— , and — OC(=O)N(Rb)—Z1is a Ci to C6 alkyl that is substituted with three or four Rxgroups, wherein each Rxis independently selected from C6to C11 alkyl, C6 to C11 alkenyl, and C6to C11 alkynyl, which C6 to C11 alkyl, C6 to C11 alkenyl, and C6to C11 alkynyl is optionally substituted with one or more groups independently selected from oxo, halogen, heterocycle, — CN, — ORX, — NRXRy, — NRxC(=O)Ry, — NRxSO2Ry, — C(=O)RX, — C(=O)ORX, — C(=O)NRxRy, — SOnRx, and — SOnNRxRy, wherein n is 0, 1, or 2, and Rxand Ryare each independently hydrogen, alkyl, or heterocycle, wherein any alkyl and heterocycle of Rxand Rymay be further substituted with one or more groups independently selected from oxo, halogen, — OH, — CN, alkyl, — ORX, heterocycle, — NRxRy, — NRxC(=O)Ry', — NRxSO2Ry', — C(=O)RX', — C(=O)ORX', — C(=O)NRxRy, — SOnRx, and — SOnNRxRy, wherein n' is 0, 1, or 2, and Rxand Ryare each independently hydrogen, alkyl, or heterocycle; each R is independently alkyl, alkenyl, or alkynyl, that is optionally substituted with one or more groups independently selected from oxo, halogen, heterocycle, — CN, — ORX, — NRXRy, — NRxC(=O)Ry, — NRxSO2Ry, — C(=O)RX, — C(=O)ORX, — C(=O)NRxRy, — SOnRx, and — SOnNRxRy, wherein n is 0, 1, or 2, and Rxand Ryare each independently hydrogen, alkyl, or heterocycle, wherein any alkyl and heterocycle of Rxand Rymay be further substituted with one or more groups independently selected from oxo, halogen, — OH, — CN, alkyl, — ORX, heterocycle, — NRxRy, — NRxC(=O)Ry', — NRxSO2Ry', — C(=O)RX', — C(=O)ORX', — C(=O)NRxRy, — SOnRx, and — SOnNRxRy, wherein n' is 0, 1, or 2, and Rxand Ryare each independently hydrogen, alkyl, or heterocycle; and each Rbis H or Ci to C6alkyl.

[0388] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2010 / 0130588, which is incorporated herein by reference in its entirety.

[0389] In some embodiments, the lipids disclosed in US 2010 / 0130588 are of Formula I:wherein R1and R2are independently selected and are H or C1-C3 alkyls, R3and R4are independently selected and are alkyl groups having from about 10 to about 20 carbon atoms, and at least one of R3and R4comprises at least two sites of unsaturation. In some embodiments, R3and R4are both the same, i.e., R3and R4are both linoleyl (C18), etc. In some embodiments, R3and R4are different, i.e., R3is tetradectrienyl (C14) and R4is linoleyl (Cis).

[0390] In some embodiments, the lipid of Formula I is l,2-dilinoleyloxy-N,N- dimethylaminopropane (DLinDMA) or l,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA).

[0391] In some embodiments, the lipids disclosed in US 2010 / 0130588 are of Formula II:wherein R1and R2are independently selected and are H or C1-C3 alkyls, R3and R4are independently selected and are alkyl groups having from about 10 to about 20 carbon atoms, and at least one of R3and R4comprises at least two sites of unsaturation.

[0392] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2021 / 0087135, which is incorporated herein by reference in its entirety.

[0393] In some embodiments, the lipids disclosed in US 2021 / 0087135 are of Formula (A):or its N-oxide, or a salt or isomer thereof, wherein R'ais R'branchedor R'cyclic; wherein R 'branched is :wherein:denotes a point of attachment; wherein Raαis H, and Raβ. Ra γ. and Raδare each independently selected from the group consisting of H, C2-12 alkyl, and C2-12 alkenyl, wherein at least one of Raβ, Ra γ, and Raδis selected from the group consisting of C2-12 alkyl and C2-12 alkenyl;R2and R3are each C1-14 alkyl;R4is selected from the group consisting of — (CH2)2OH, — (CH2)3OH, — (CH2)4OH, — (CH2)5OH and wherein:denotes a point of attachment;R10is N(R)2; each R is independently selected from the group consisting of C 1-6 alkyl, C2- 3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of OH, C1-3 alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of OH, C1-3 alkyl, C2-3 alkenyl, and H;R7is H;M and M' are each independently selected from the group consisting of — C(O)O — and — OC(O)— ;R' is a Ci-i2 alkyl or C2-12 alkenyl;Yais a C3-6 carbocycle;R*ais selected from the group consisting of C145 alkyl and C2-15 alkenyl;1 is selected from the group consisting of 1, 2, 3, 4, and 5; s is 2 or 3; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13.

[0394] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2021 / 0128488, which is incorporated herein by reference in its entirety

[0395] In some embodiments, the lipids disclosed in US 2021 / 0128488 are of structure (I):or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein:L1is — O(C=O)R', — (C=O)OR1, — C(=O)R1, —OR1, — S(O)XR1, — S— SR1, — C('O)SR', — SC(=O)R', — NRaC(=O)R1, — C(=O)NRbRc, — NRaC(=O)NRbRc, — OC(=O)NRbRcor — NRaC(=O)OR1;L2is — O(C=O)R2, — (C=O)OR2, — C(=O)R2, —OR2, — S(O)XR2, — S— SR2, — C(=O)SR2, — SC(=O)R2, — NRdC(=O)R2, — C(=O)NReRf, — NRdC(=O)NReRf, — OC(=O)NReRf; — NRdC(=O)OR2or a direct bond to R2;G1and G2are each independently C2-C12 alkylene or C2-C12 alkenylene;G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene or C3-C8 cycloalkenylene;Ra, Rb, Rdand Reare each independently H or C1-C12 alkyl or C1-C12 alkenyl;Rcand Rfare each independently C1-C12 alkyl or C2-C12 alkenyl;R1and R2are each independently branched C6-C24 alkyl or branched C6-C24 alkenyl;R3is — N(R4)R5;R4is Ci-C 12 alkyl;R5is substituted C1-C12 alkyl; and x is 0, 1 or 2, and wherein each alkyl, alkenyl, alkylene, alkenylene, cycloalkylene, cycloalkenylene, aryl and aralkyl is independently substituted or unsubstituted unless otherwise specified.

[0396] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2020 / 0121809, which is incorporated herein by reference in its entirety.

[0397] In some embodiments the lipids disclosed in US 2020 / 0121809 have a structure of Formula II:or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein: one of L1or L2is — O(C=O)— , — (C=O)O— , — C(=O)— , — O— , — S(O)X— , — S— S— , — C(=O)S— , SC(=O)— , — NRaC(=O)— , — C(=O)NRa— , NRaC(=O)NRa— , — OC(=O)NRa— or — NRaC(=O)O— , and the other of L1or L2is — O(C=O)— , — (C=O)O— , — C(=O)— , — O— , — S(O)X— , — S— S— , — C(=O)S— , SC(=O)— , — NRaC(=O)— , — C(=O)NRa— , NRaC(=O)NRa— , — OC(=O)NRa— or — NRaC(=O)O— or a direct bond;G1is C1-C2 alkylene, — (C=O)— , — O(C=O)— , — SC(=O)— , — NRaC(=O)— or a direct bond;G2is — C(=O)— , — (C=O)O— , — C(=O)S— , — C(=O)NRa— or a direct bond;G3is C1-C6 alkylene;Rais H or C1-C12 alkyl;Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;R3aand R3bare, at each occurrence, independently either (a): H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;R5and R6are each independently H or methyl;R7is C4-C20 alkyl;R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2.

[0398] In some embodiments, the lipids disclosed in US 2020 / 0121809 have a structure of Formula III:or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein: one of L1or L2is — O(C=O)— , — (C=O)O— , — C(=O)— , — O— , — S(O)X— , — S— S— , — C(=O)S— , SC(=O)— , — NRaC(=O)— , — C(=O)NRa— , NRaC(=O)NRa— , — OC(=O)NRa— or — NRaC(=O)O— , and the other of L1or L2is — O(C=O)— , — (C=O)O— , — C(=O)— , — O— , — S(O)X— , — S— S— , — C(=O)S— , SC(=O)— , — NRaC(=O)— , — C(=O)NRa— , NRaC(=O)NRa— , — OC(=O)NRa— or — NRaC(=O)O— or a direct bond;G1and G2are each independently unsubstituted C1-C12 alkylene or C1-C12 alkenylene;G3is C1-C24 alkylene, C1-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene;Rais H or C1-C12 alkyl;R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;R3is H, ORS, CN, — C(=O)OR4, — OC(=O)R4or — NR5C(=O)R4;R4is Ci-C 12 alkyl;R5is H or C1-C6 alkyl; and x is 0, 1 or 2.

[0399] In some embodiments, the lipids disclosed in US 2020 / 0121809 have a structure of Formula (IV):or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein:one of G1or G2is, at each occurrence, — O(C=O) — , — (C=O)O — , — C(=O) — , — O — , — S(O)y— , — S— S— , — C(=O)S— , SC(=O)— , — N(Ra)C(=O)— , — C(=O)N(Ra)— , — N(Ra)C(=O)N(Ra)— , — OC(=O)N(Ra)— or — N(Ra)C(=O)O— , and the other of G1or G2is, at each occurrence, — O(C=O)— , — (C=O)O— , — C(=O)— , — O— , — S(O)y— , — S— S— , — C(=O)S— , — SC(=O)— , — N(Ra)C(=O)— , — C(=O)N(Ra)— , — N(Ra)C(=O)N(Ra)— , — OC(=O)N(Ra) — or — N(Ra)C(=O)O — or a direct bond;L is, at each occurrence, — O(C=O) — , wherein - represents a covalent bond to X;X is CRa;Z is alkyl, cycloalkyl or a monovalent moiety comprising at least one polar functional group when n is 1; or Z is alkylene, cycloalkylene or a polyvalent moiety comprising at least one polar functional group when n is greater than 1;Rais, at each occurrence, independently H, C1-C12 alkyl, Ci-C 12 hydroxylalkyl, Ci- C 12 aminoalkyl, C1-C12 alkylaminylalkyl, C1-C12 alkoxyalkyl, Ci-C 12 alkoxy carbonyl, Ci- C12 alkylcarbonyloxy, C1-C12 alkylcarbonyloxyalkyl or C1-C12 alkylcarbonyl;R is, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R together with the carbon atom to which it is bound is taken together with an adjacent R and the carbon atom to which it is bound to form a carbon-carbon double bond;R1and R2have, at each occurrence, the following structure, respectively:a1and a2are, at each occurrence, independently an integer from 3 to 12; b1and b2are, at each occurrence, independently 0 or 1; c1and c2are, at each occurrence, independently an integer from 5 to 10; d1and d2are, at each occurrence, independently an integer from 5 to 10; y is, at each occurrence, independently an integer from 0 to 2; and n is an integer from 1 to 6, wherein each alkyl, alkylene, hydroxylalkyl, aminoalkyl, alkylaminylalkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl and alkylcarbonyl is optionally substituted with one or more substituent.

[0400] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2013 / 0108685, which is incorporated herein by reference in its entirety.

[0401] In some embodiments, the lipids disclosed in US 2013 / 0108685 are represented by the following formula (I):wherein:R1and R2are, the same or different, each linear or branched alkyl, alkenyl or alkynyl having 12 to 24 carbon atoms, or R1and R2are combined together to form dialkylmethylene, dialkenylmethylene, dialkynylmethylene or alkylalkenylmethylene,X1and X3are hydrogen atoms, or are combined together to form a single bond or alkylene, X3is absent or represents alkyl having 1 to 6 carbon atoms, or alkenyl having 3 to 6 carbon atoms, when X3is absent,Y is absent, a and b are 0, L3is a single bond, R3is alkyl having 1 to 6 carbon atoms, alkenyl having 3 to 6 carbon atoms, pyrrolidin-3-yl, piperi din-3 -yl, piperidin-4-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, and L1and L2are — O — ,Y is absent, a and b are, the same or different, 0 to 3, and are not 0 at the same time, L3is a single bond, R3is alkyl having 1 to 6 carbon atoms, alkenyl having 3 to 6 carbon atoms, pyrrolidin-3- yl, piperi din-3 -yl, piperi din-4-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, L1and L2are, the same or different, — O — , — CO — O — or — O — CO — ,Y is absent, a and b are, the same or different, 0 to 3, L3is a single bond, R3is a hydrogen atom, and L1and L2are, the same or different, — O — , — CO — O — or — O — CO — , orY is absent, a and b are, the same or different, 0 to 3, L3is — CO — or — CO — O — , R3is pyrrolidin-2-yl, pyrrolidin-3-yl, piperi din-2 -yl, piperi din-3 -yl, piperi din-4-yl, morpholin-2-yl, morpholin-3-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atomssubstituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, wherein at least one of the substituents is amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl or morpholinyl, and L1and L2are, the same or different, — O — , — CO — O — or — O — CO — , and when X3is alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms,Y is a pharmaceutically acceptable anion, a and b are, the same or different, 0 to 3, L3is a single bond, R3is alkyl having 1 to 6 carbon atoms, alkenyl having 3 to 6 carbon atoms, pyrrolidin-2- yl, pyrrolidin-3-yl, piperidin-2-yl, piperi din-3 -yl, piperidin-4-yl, morpholin-2-yl, morpholin-3- yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, L1and L2are, the same or different, — O — , — CO — O — or — O— CO— ).

[0402] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2013 / 0195920, which is incorporated herein by reference in its entirety.

[0403] In some embodiments, the lipids disclosed in US 2013 / 0195920 are of formula (I), which has a branched alkyl at the alpha position adjacent to the biodegradable group (between the biodegradable group and the teriary carbon):Formula (I)or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinR' is absent, hydrogen, or alkyl (e.g., C1-C4 alkyl); with respect to R1and R2,(i) R1and R2are each, independently, optionally substituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, heterocycle, or R10;(ii) R1and R2, together with the nitrogen atom to which they are attached, form an optionally substituted heterocylic ring; or(iii) one ofR1and R2is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or heterocycle, and the other forms a 4-10 member heterocyclic ring or heteroaryl (e.g., a 6-member ring) with (a) the adjacent nitrogen atom and (b) the (R)agroup adjacent to the nitrogen atom; each occurrence of R is, independently, — (CR3R4) — ; each occurrence of R3and R4are, independently H, halogen, OH, alkyl, alkoxy, — NH2, R10, alkylamino, or dialkylamino (In some embodiments, each occurrence of R3and R4are, independently H or C1-C4 alkyl); each occurrence of R10is independently selected from PEG and polymers based on poly(oxazoline), poly(ethylene oxide), poly(vinyl alcohol), poly(glycerol), poly(N- vinylpyrrolidone), poly[N-(2-hydroxypropyl)methacrylamide] and poly(amino acid)s, wherein (i) the PEG or polymer is linear or branched, (ii) the PEG or polymer is polymerized by n subunits, (iii) n is a number-averaged degree of polymerization between 10 and 200 units, and (iv) wherein the compound of formula has at most two R10groups (preferably at most one R10group); the dashed line to Q is absent or a bond; when the dashed line to Q is absent then Q is absent or is — O — , — NH — , — S — , — C(O) — , — C(O)O — , — OC(O)— , — C(O)N(R4)— , — N(R5)C(O)— , — S— S— , — OC(O)O— , — O— N=C(R5)— , — C(R5)=N— O— , — OC(O)N(R5)— , — N(R5)C(O)N(R5)— , — N(R5)C(O)O— , — C(O)S— , — C(S)O— or — C(R5)=N— O— C(O)— ; or when the dashed line to Q is a bond then (i) b is 0 and (ii) Q and the tertiary carbon adjacent to it (C*) form a substituted or unsubstituted, mono- or bi-cyclic heterocyclic group having from 5 to 10 ring atoms (e.g., the heteroatoms in the heterocyclic group are selected from O and S, preferably O); each occurrence of R5is, independently, H or alkyl (e.g. C1-C4 alkyl);X and Y are each, independently, alkylene or alkenylene (e.g., C4to C20 alkylene or C4to C20 alkenylene);M1and M2are each, independently, a biodegradable group (e.g., — OC(O) — , — C(O)O — , — SC(O)— , — C(O)S— , — OC(S)— , — C(S)O, — S— S— , C(R5)=N— , — N=C(R5)— , — C(R5)=N— O— , — O— N=C(R5)— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , — OC(O)O— , — OSi(R5)2O— , — C(O)(CR3R4)C(O)O— , — OC(O)(CR3R4)C(O)— , orwherein R11is a C2-C8 alkyl or alkenyl; each occurrence of Rzis, independently, Ci-C8 alkyl (e.g., methyl, ethyl, isopropyl, n-butyl, n- pentyl, or n-hexyl); a is 1, 2, 3, 4, 5 or 6; b is 0, 1, 2, or 3; andZ1and Z2are each, independently, C8-C11 alkyl or C8-C11 alkenyl, wherein the alkenyl group may optionally be substituted with one or two fluorine atoms at the alpha position to a double bond which is between the double bond and the terminus of Z1or Z2.

[0404] In some embodiments, the lipids disclosed in US 2013 / 0195920 are of formula (II), which has a branched alkyl at the alpha position adjacent to the biodegradable group (between the biodegradable group and the terminus of the tail, i.e., Z1or Z2):Formula (It)or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinR' is absent, hydrogen, or alkyl (e.g., C1-C4 alkyl); with respect to R1and R2,(i) R1and R2are each, independently, optionally substituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, heterocycle, or R10;(ii) R1and R2, together with the nitrogen atom to which they are attached, form an optionally substituted heterocylic ring; or(iii) one ofR1and R2is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or heterocycle, and the other forms a 4-10 membered heterocyclic ring or heteroaryl (e.g., a 6- member ring) with (a) the adjacent nitrogen atom and (b) the (R)agroup adjacent to the nitrogen atom; each occurrence of R is, independently, — (CR3R4) — ; each occurrence of R3and R4are, independently H, halogen, OH, alkyl, alkoxy, — NH2, R10, alkylamino, or dialkylamino (In some embodiments, each occurrence of R3and R4are, independently H or C1-C4 alkyl); each occurrence of R10is independently selected from PEG and polymers based on poly(oxazoline), poly(ethylene oxide), poly(vinyl alcohol), poly(glycerol), poly(N- vinylpyrrolidone), poly[N-(2-hydroxypropyl)methacrylamide] and poly(amino acid)s, wherein(i) the PEG or polymer is linear or branched, (ii) the PEG or polymer is polymerized by n subunits, (iii) n is a number-averaged degree of polymerization between 10 and 200 units, and (iv) wherein the compound of formula has at most two R10groups (preferably at most one R10group); the dashed line to Q is absent or a bond; when the dashed line to Q is absent then Q is absent or is — O — , — NH — , — S — , — C(O) — , — C(O)O — , — OC(O)— , — C(O)N(R4)— , — N(R5)C(O)— , — S— S— , — OC(O)O— , — O— N=C(R5)— , — C(R5)=N— O— , — OC(O)N(R5)— , — N(R5)C(O)N(R5)— , — N(R5)C(O)O— , — C(O)S— , — C(S)O— or — C(R5)=N— O— C(O)— ; or when the dashed line to Q is a bond then (i) b is 0 and (ii) Q and the tertiary carbon adjacent to it (C*) form a substituted or unsubstituted, mono- or bi-cyclic heterocyclic group having from 5 to 10 ring atoms (e.g., the heteroatoms in the heterocyclic group are selected from O and S, preferably O); each occurrence of R5is, independently, H or alkyl;X and Y are each, independently, alkylene (e.g., C6-C8 alkylene) or alkenylene, wherein the alkylene or alkenylene group is optionally substituted with one or two fluorine atoms at the alpha position to the M1or M2groupM1and M2are each, independently, a biodegradable group (e.g., — OC(O) — , — C(O)O — , — SC(O)— , — C(O)S— , — OC(S)— , — C(S)O, — S— S— , C(R5)=N— , — N=C(R5)— , — C(R5)=N— O— , — O— N=C(R5)— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , — OC(O)O— , — OSi(R5)2O— , — C(O)(CR3R4)C(O)O— , — OC(O)(CR3R4)C(O)— , orwherein R11is a C2-C8 alkyl or alkenyl; each occurrence of Rzis, independently, Ci-C8 alkyl (e.g., methyl, ethyl, isopropyl); a is 1, 2, 3, 4, 5 or 6; b is 0, 1, 2, or 3; andZ1and Z2are each, independently, C8-C11 alkyl or C8-C11 alkenyl, wherein (i) the alkenyl group may optionally be substituted with one or two fluorine atoms at the alpha position to a double bond which is between the double bond and the terminus of Z1or Z2;and (ii) the terminus of at least one of Z1and Z2is separated from the group M1or M2by at least 8 carbon atoms.

[0405] In some embodiments, the lipids disclosed in US 2013 / 0195920 are of formula (III), which has a branching point at a position that is 2-6 carbon atoms (i.e., at the beta (P), gamma (γ), delta (δ), epsilon (ε) or zeta position (ζ) adjacent to the biodegradable group (between the biodegradable group and the terminus of the tail, i.e., Z1or Z2):Formula (III)or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinR', R1, R2, R, R3, R4, R10, Q, R5, M1, M2, Rz, a, and b are defined as in formula (I);L1and L2are each, independently, C1-C5 alkylene or C2-C5 alkenylene;X and Y are each, independently, alkylene (e.g., CUo C20 alkylene or C6-C8 alkylene) or alkenylene (e.g., C4 to C20 alkenylene); andZ1and Z2are each, independently, C8-C11 alkyl or C8-C11 alkenyl, wherein the alkenyl group may optionally be substituted with one or two fluorine atoms at the alpha position to a double bond which is between the double bond and the terminus of Z1or Z2. and with the proviso that the terminus of at least one of Z1and Z2is separated from the group M1or M2by at least 8 carbon atoms.

[0406] In some embodiments, the cationic lipid disclosed in US 2013 / 0195920 is a compound of formula (IV), which has a branching point at a position that is 2-6 carbon atoms (i.e., at beta (P), gamma (y), delta (5), epsilon (a) or zeta position (Q adjacent to the biodegradable group (between the biodegradable group and the terminus of the tail, i.e., Z1or Z2):Formula (IV)or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinR', R1, R2, R, R3, R4, R10, Q, R5, M2, Rz, a, and b are defined as in formula (I);L1and L2and are each, independently, C1-C5 alkylene or C2-C5 alkenylene;X and Y are each, independently, alkylene or alkenylene (e.g., C12-C 20 alkylene or C12- C20 alkenylene); and each occurrence of Z is independently C1-C4 alkyl (preferably, methyl).

[0407] For example, in some embodiments, -L1-C(Z)3 is — CH2C(CH3)3. In some embodiments, -L1-C(Z)3 is — CH2CH2C(CH3)3.

[0408] In some embodiments, the lipids disclosed in US 2013 / 0195920 are of formula (V), which has an alkoxy or thioalkoxy (i.e., — S-alkyl) group substitution on at least one tail:or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinR', R1, R2, R, R3, R4, R10, Q, R5, M1, M2, a, and b are defined as in formula (I);X and Y are each, independently, alkylene (e.g., C6-C8 alkylene) or alkenylene, wherein the alkylene or alkenylene group is optionally substituted with one or two fluorine atoms at the alpha position to the M1or M2group;Z1and Z2are each, independently, C8-C11 alkyl or C8-C11 alkenyl, wherein (i) the C8-C11 alkyl or Cx-C 14 alkenyl of at least one of Z1and Z2is substituted by one or more alkoxy (e.g., a Ci- C4 alkoxy such as — OCH3) or thioalkoxy (e.g., a C1-C4 thioalkoxy such as — SCH3) groups, and (ii) the alkenyl group may optionally be substituted with one or two fluorine atoms at the alpha position to a double bond which is between the double bond and the terminus of Z1or Z2.

[0409] In some embodiments, the lipids disclosed in US 2013 / 0195920 are of formula (VIA), which has one or more fluoro substituents on at least one tail at a position that is either alpha to a double bond or alpha to a biodegradable group:or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinR1, R2, R, a, and b are as defined with respect to formula (I);Q is absent or is — O— , — NH— , — S— , — C(O)— , — C(O)O— , — OC(O)— , — C(O)N(R4)— , — N(R5)C(O)— , — S— S— , — OC(O)O— , — O— N=C(R5)— , — C(R5)=N— O— , — OC(O)N(R5)— , — N(R5)C(O)N(R5)— , — N(R5)C(O)O — , — C(O)S— , — C(S)O— or — C(R5)=N— O— C(O)— ;R' is absent, hydrogen, or alkyl (e.g., C1-C4 alkyl); and each of R9and R10are independently C12-C24 alkyl (e.g., C12-C20 alkyl), C12-C24 alkenyl (e.g., C12- C20 alkenyl), or C12-C24 alkoxy (e.g., C12-C20 alkoxy) (a) having one or more biodegradable groups and (b) optionally substituted with one or more fluorine atoms at a position which is (i) alpha to a biodegradable group and between the biodegradable group and the tertiary carbon atom marked with an asterisk (*), or (ii) alpha to a carbon-carbon double bond and between the double bond and the terminus of the R9or R10group; each biodegradable group independently interrupts the C 12-C24 alkyl, alkenyl, or alkoxy group or is substituted at the terminus of the C12-C24 alkyl, alkenyl, or alkoxy group, wherein(i) at least one of R9and R10contains a fluoro group;(ii) the compound does not contain the following moiety:wherein - is an optional bond; and(iii) the terminus of R9and R10is separated from the tertiary carbon atom marked with an asterisk (*) by a chain of 8 or more atoms (e.g., 12 or 14 or more atoms).

[0410] In some embodiments, the terminus of R9and R10is separated from the tertiary carbon atom marked with an asterisk (*) by a chain of 18-22 carbon atoms (e.g., 18-20 carbon atoms).

[0411] In some embodiments, the lipids disclosed in US 2013 / 0195920 are of formula (VIB), which has one or more fluoro substituents on at least one tail at a position that is either alpha to a double bond or alpha to a biodegradable group:or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinR', R1, R2, R, R3, R4, R10, Q, R5, M1, M2, a, and b are defined as in formula (I);X and Y are each, independently, alkylene (e.g., C6-C8 alkylene) or alkenylene, wherein the alkylene or alkenylene group is optionally substituted with one or two fluorine atoms at the alpha position to the M1or M2group; andZ1and Z2are each, independently, C8-C11 alkyl or C8-C11 alkenyl, wherein said C8-C11 alkenyl is optionally substituted by one or more fluorine atoms at a position that is alpha to a double bond, wherein at least one of X, Y, Z1, and Z2contains a fluorine atom.

[0412] In some embodiments, the lipids disclosed in US 2013 / 0195920 are of formula (VII), which has an acetal group as a biodegradable group in at least one tail:or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinR', R1, R2, R, R3, R4, R10, Q, R5, a, and b are defined as in formula (I);X and Y are each, independently, alkylene (e.g., C6-C8 alkylene) or alkenylene, wherein the alkylene or alkenylene group is optionally substituted with one or two fluorine atoms at the alpha position to the M1or M2groupM1and M2are each, independently, a biodegradable group (e.g., — OC(O) — , — C(O)O — , — SC(O)— , — C(O)S— , — OC(S)— , — C(S)O, — S— S— , C(R5)=N— , — N=C(R5)— , — C(R5)=N— O— , — O— N=C(R5)— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , — OC(O)O— , — OSi(R5)2O— , — C(O)(CR3R4)C(O)O— , — OC(O)(CR3R4)C(O)— , orwherein R11is a C4-C10 alkyl or C4-C10 alkenyl; with the proviso that at least one of M1and M2is, andZ1and Z2are each, independently, C4-C14 alkyl or C4-C14 alkenyl, wherein the alkenyl group may optionally be substituted with one or two fluorine atoms at the alpha position to a double bond which is between the double bond and the terminus of Z1or Z2.

[0413] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2015 / 0005363, which is incorporated herein by reference in its entirety.

[0414] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2014 / 0308304, which is incorporated herein by reference in its entirety.

[0415] In some embodiments, the lipid disclosed in US 2014 / 0308304 is a compound of formula (I):or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinXaa is a D- or L-amino acid residue having the formula — NRN— CR1R2— (C=O) — , or a peptide of amino acid residues having the formula — {NRN— CR'R2— (C=O)}n— , wherein n is 2 to 20; R1is independently, for each occurrence, a non-hydrogen, substituted or un substituted side chain of an amino acid;R2and RNare independently, for each occurrence, hydrogen, an organic group consisting of carbon, oxygen, nitrogen, sulfur, and hydrogen atoms, or any combination of the foregoing, and having from 1 to 20 carbon atoms, C(1-5)alkyl, cycloalkyl, cycloalkylalkyl, C(3-5)alkenyl, C(3- 5)alkynyl, C(1-5)alkanoyl, C(1-5)alkanoyloxy, C(1-5)alkoxy, C(1-5)alkoxy-C(1-5)alkyl, C(1-5)alkoxy- C(1-5)alkoxy, C(1-5)alkyl-amino-C(1-5)alkyl-, C(1-5)dialkyl-amino-C(1-5)alkyl-, nitro-C(1-5)alkyl, cyano-C(1-5)alkyl, aryl-C(1-5)alkyl, 4-biphenyl-C(1-5)alkyl, carboxyl, or hydroxyl;Z is NH, O, S, — CH2S — , — CH2S(O) — , or an organic linker consisting of 1-40 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms (preferably, Z is NH or O);Rxand Ryare, independently, (i) a lipophilic tail derived from a lipid (which can be naturally- occurring or synthetic), phospholipid, glycolipid, triacylglycerol, glycerophospholipid, sphingolipid, ceramide, sphingomyelin, cerebroside, or ganglioside, wherein the tail optionally includes a steroid; (ii) an amino acid terminal group selected from hydrogen, hydroxyl, amino, and an organic protecting group; or (iii) a substituted or unsubstituted C(3-22)alkyl, C(6- i2)Cycloalkyl, C(6-i2)Cycloalkyl-C(3-22)alkyl, C(3-22)alkenyl, C(3-22)alkynyl, C(3-22)alkoxy, or C(6-i2)- alkoxy-C(3-22)alkyl;one of Rxand Ryis a lipophilic tail as defined above and the other is an amino acid terminal group, or both Rxand Ryare lipophilic tails; at least one of Rxand Ryis interrupted by one or more biodegradable groups (e.g., — OC(O) — , — C(O)O— , — SC(O)— , — C(O)S— , — OC(S)—, — C(S)O— , — S— S— — C(R5)=N— , — N=C(R5)— , — C(R5)=N— O— , — O— N=C(R5)— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)—, — N(R5)C(O)N(R5)— , — OC(O)O— , — OSi(R5)2O— , — C(O)(CR3R4)C(O)O— , — OC(O)(CR3R4)C(O)— or(wherein R11is a C2-C8 alkyl or alkenyl), in which each occurrence of R5is, independently, H or alkyl; and each occurrence of R3and R4are, independently H, halogen, OH, alkyl, alkoxy, — NH2, alkylamino, or dialkylamino; or R3and R4, together with the carbon atom to which they are directly attached, form a cycloalkyl group (in some embodiments, each occurrence of R3and R4are, independently H or C1-C4 alkyl)); andRxand Ryeach, independently, optionally have one or more carbon-carbon double bonds.

[0416] In some embodiments, the lipid disclosed in US 2014 / 0308304 is a compound of formula (IA):or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinZ and Xaa are as defined with respect to formula (I) (the variables which are used in the definition of Xaa, namely RN, R1and R2, are also as defined in formula (I)); each occurrence of R is, independently, — (CR3R4) — ;each occurrence of R3and R4are, independently H, halogen, OH, alkyl, alkoxy, — NH2, alkylamino, or dialkylamino (in some embodiments, each occurrence of R3and R4are, independently H or C1-C4 alkyl); or R3and R4, together with the carbon atom to which they are directly attached, form a cycloalkyl group, wherein no more than three R groups in each chain between the — Z-Xaa-C(O) — and Z2moieties are cycloalkyl (e.g., cyclopropyl);Q1and Q2are each, independently, absent, — O — , — S — , — OC(O) — , — C(O)O — , — SC(O) — , — C(O)S— , — OC(S)— , — C(S)O— , — S— S— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , or — OC(O)O— ;Q3and Q4are each, independently, H, — (CR3R4) — , cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or a cholesterol moiety; each occurrence of A1, A2, A3and A4is, independently, — (CR5R5— CR5=CR5) — ;M1and M2are each, independently, a biodegradable group (e.g., — OC(O) — , — C(O)O — , — SC(O)— , — C(O)S— , — OC(S)— , — C(S)O— , — S— S— , — C(R5)=N— , — N=C(R5)— , — C(R5)=N— O— , — O— N=C(R5)— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , — OC(O)O— , — OSi(R5)2O— , — C(O)(CR3R4)C(O)O— , — OC(O)(CR3R4)C(O)— , or(wherein R11is a C2-C8 alkyl or alkenyl)); each occurrence of R5is, independently, H or alkyl (e.g., C1-C4 alkyl);Z2is absent, alkylene or — O — P(O)(OH) — O — ; each - attached to Z2is an optional bond, such that when Z2is absent, Q3and Q4are not directly covalently bound together; c, d, e, f, i, j, m, n, q and r are each, independently, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; g and h are each, independently, 0, 1 or 2; k and 1 are each, independently, 0 or 1, wherein at least one of k and 1 is 1; o and p are each, independently, 0, 1 or 2; andQ3and Q4are each, independently, separated from the — Z-Xaa-C(O) — moiety by a chain of 8 or more atoms (e.g., 12 or 14 or more atoms).

[0417] In some embodiments the lipids disclosed in US 2014 / 0308304 are of the formula (IC):or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), whereinZ and Xaa are as defined with respect to formula (I) (the variables which are used in the definition of Xaa, namely RN, R1and R2, are also as defined in formula (I)); each of R9and R10are, independently, alkylene or alkenylene; each of Rnand R12are, independently, alkyl or alkenyl, optionally terminated by COOR13wherein each R13is independently unsubstituted alkyl (e.g., C1-C4 alkyl such as methyl or ethyl), substituted alkyl (such as benzyl), or cycloalkyl;M1and M2are each, independently, a biodegradable group (e.g., — OC(O) — , — C(O)O — , — SC(O)— , — C(O)S— , — OC(S)— , — C(S)O— , — S— S— , — C(R5)=N— , — N=C(R5)— , — C(R5)=N— O— , — O— N=C(R5)— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , — OC(O)O— , — OSi(R5)2O— , — C(O)(CR3R4)C(O)O— , — OC(O)(CR3R4)C(O)— , orwherein Rnis a C2-C8 alkyl or alkenyl, in which each occurrence of R5is, independently, H or alkyl; and each occurrence of R3and R4are, independently H, halogen, OH, alkyl, alkoxy, — NH2, alkylamino, or dialkylamino; or R3and R4, together with the carbon atom to which they are directly attached, form a cycloalkyl group (in some embodiments, each occurrence of R3and R4are, independently H or C1-C4 alkyl));R9, M1, and Rnare together at least 8 carbon atoms in length (e.g., 12 or 14 carbon atoms or longer); andR10, M2, and R12are together at least 8 carbon atoms in length (e.g., 12 or 14 carbon atoms or longer).

[0418] In some embodiments, the lipid disclosed in US 2014 / 0308304 is a compound of the formula II:or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), wherein: s is 1, 2, 3 or 4; andR7is selected from lysyl, ornithyl, 2,3-diaminobutyryl, histidyl and an acyl moiety of the formula:t is 1, 2 or 3; the NH3+moiety in the acyl moiety in R7is optionally absent; each occurrence of Y“ is independently a pharmaceutically acceptable anion (e.g., halide, such as chloride);R5and R6are each, independently a lipophilic tail derived from a naturally-occurring or synthetic lipid, phospholipid, glycolipid, triacylglycerol, glycerophospholipid, sphingolipid, ceramide, sphingomyelin, cerebroside, or ganglioside, wherein the tail may contain a steroid; or a substituted or unsubstituted C(3-22)alkyl, C(6-i2)Cycloalkyl, C(6-i2)Cycloalkyl-C(3-22)alkyl, C(3- 22)alkenyl, C(3-22)alkynyl, C(3-22)alkoxy, or C(6-i2)alkoxy-C(3-22)alkyl; at least one of R5and R6is interrupted by one or more biodegradable groups (e.g., — SC(O) — , — C(O)S— , — OC(S)— , — C(S)O— , — S— S— , — C(O)(NRa)— , — N(Ra)C(O)— , — C(S)(NRa)— , — N(Ra)C(O)— , — N(Ra)C(O)N(Ra)— , or — OC(O)O— ); each occurrence of Rais, independently, H or alkyl; andR5and R6each, independently, optionally contain one or more carbon-carbon double bonds.

[0419] In some embodiments, the lipids disclosed in US 2014 / 0308304 are of the formula (IIA):or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), wherein:R7and s are as defined with respect to formula (II); each occurrence of R is, independently, — (CR3R4) — ; each occurrence of R3and R4are, independently H, halogen, OH, alkyl, alkoxy, — NH2, alkylamino, or dialkylamino (in some embodiments, each occurrence of R3and R4are, independently H or C1-C4 alkyl); or R3and R4, together with the carbon atom to which they are directly attached, form a cycloalkyl group, wherein no more than three R groups in each chain attached to the nitrogen N* are cycloalkyl (e.g., cyclopropyl);Q1and Q2are each, independently, absent, — O — , — S — , — OC(O) — , — C(O)O — , — SC(O) — , — C(O)S— , — OC(S)— , — C(S)O— , — S— S— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , or — OC(O)O— ;Q3and Q4are each, independently, H, — (CR3R4) — , aryl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or a cholesterol moiety; each occurrence of A1, A2, A3and A4is, independently, — (CR5R5— CR5=CR5) — ;M1and M2are each, independently, a biodegradable group (e.g., — OC(O) — , — C(O)O — , — SC(O)— , — C(O)S— , — OC(S)— , — C(S)O— , — S— S— , — C(R5)=N— , — N=C(R5)— , — C(R5)=N— O— , — O— N=C(R5)— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , — OC(O)O— , — OSi(R5)2O— , — C(O)(CR3R4)C(O)O— , — OC(O)(CR3R4)C(O)— , orwherein R11is a C2-C8 alkyl or alkenyl; each occurrence of R5is, independently, H or alkyl;Z is absent, alkylene or — O — P(O)(OH) — O — ; each - attached to Z is an optional bond, such that when Z is absent, Q3and Q4are not directly covalently bound together; c, d, e, f, i, j, m, n, q and r are each, independently, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; g and h are each, independently, 0, 1 or 2; k and 1 are each, independently, 0 or 1, where at least one of k and 1 is 1; ando and p are each, independently, 0, 1 or 2.

[0420] In some embodiments the lipid disclosed in US 2014 / 0308304 are of the formula (IIC):or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), wherein:R7and s are as defined with respect to formula (II); each of R9and R10are independently alkyl (e.g., C12-C24 alkyl) or alkenyl (e.g., C12-C24 alkenyl); each of R11and R12are independently alkyl or alkenyl, optionally terminated by COOR13where each R13is independently alkyl (e.g., C1-C4 alkyl such as methyl or ethyl);M1and M2are each, independently, a biodegradable group (e.g., — OC(O) — , — C(O)O — , — SC(O)— , — C(O)S— , — OC(S)— , — C(S)O— , — S— S— , — C(R5)=N— , — N=C(R5)— , — C(R5)=N— O— , — O— N=C(R5)— , — C(O)(NR5)— , — N(R5)C(O)— , — C(S)(NR5)— , — N(R5)C(O)— , — N(R5)C(O)N(R5)— , — OC(O)O— , — OSi(R5)2O— , — C(O)(CR3R4)C(O)O— , — OC(O)(CR3R4)C(O)— , orwherein R11is a C2-C8 alkyl or alkenyl; in which each occurrence of R5is, independently, H or alkyl; and each occurrence of R3and R4are, independently H, halogen, OH, alkyl, alkoxy, — NH2, alkylamino, or dialkylamino; or R3and R4, together with the carbon atom to which they are directly attached, form a cycloalkyl group (in some embodiments, each occurrence of R3and R4are, independently, H or Ci- C4 alkyl));R9, M1, and R11are together at least 8 carbons atoms in length (e.g., 12 or 14 carbon atoms or longer); andR10, M2, and R12are together at least 8 carbons atoms in length (e.g., 12 or 14 carbon atoms or longer).

[0421] In some embodiments, the lipid disclosed in US 2014 / 0308304 is a compound of the formula (4):wherein:X is N or P;R1, R2, R, a, b, M1, and M2are as defined with respect to formula (I);Q is absent or is — O— , — NH— , — S— , — C(O)O— , — OC(O)— , — C(O)N(R4)— , — N(R5)C(O)— , — S— S— , — OC(O)O— , — O— N=C(R5)— , — C(R5)=N— O— , — OC(O)N(R5)— , — N(R5)C(O)N(R5)— , — N(R5)C(O)O— , — C(O)S— , — C(S)O— or — C(R5)=N— O— C(O)— ;R' is absent, hydrogen, or alkyl (e.g., C1-C4 alkyl); each of R9and R10are independently alkylene, or alkenylene; and each of R11and R12are independently alkyl or alkenyl, optionally terminated by COOR13where each R13is independently alkyl (e.g., C1-C4 alkyl such as methyl or ethyl);R9, M1, and R11are together at least 8 carbons atoms in length (e.g., 12 or 14 carbon atoms or longer); andR10, M2, and R12are together at least 8 carbons atoms in length (e.g., 12 or 14 carbon atoms or longer).

[0422] In some embodiments, the lipid disclosed in US 2014 / 0308304 is a compound of the formula (5)wherein:X is N or P;R1, R2, R, a, and b are as defined with respect to formula (I);Q is absent or is — O— , — NH— , — S— , — C(O)O— , — OC(O)— , — C(O)N(R4)— , — N(R5)C(O)— , — S— S— , — OC(O)O— , — O— N=C(R5)— , — C(R5)=N— O— , — OC(O)N(R5)— , — N(R5)C(O)N(R5)— , — N(R5)C(O)O— , — C(O)S— , — C(S)O— or — C(R5)=N — O — C(O) — ;R' is absent, hydrogen, or alkyl (e.g., C1-C4 alkyl);each of R9and R10are independently C12-C24 alkyl or alkenyl substituted at its terminus with a biodegradable group, such as — COOR13where each R13is independently alkyl (preferably Ci- C4 alkyl such as methyl or ethyl).

[0423] In some embodiments the lipids disclosed in US 2014 / 0308304 are of Formula A:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: n is 0-6 (e.g., n is 0, 1 or 2);R1and R2are independently selected from H, (C1-C6)alkyl, heterocyclyl, and a polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one or more sub stituents selected from R', or R1and R2can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 3-7 (e.g., 4-7) members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one or more substituents selected from R';R3is selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from R', or R3can be taken together with R1to form a monocyclic heterocycle with 3-7 (e.g., 4-7) members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one or more substituents selected from R'; each occurrence of R4, R3and R4is independently selected from H, (C1-C6)alkyl and O-alkyl, said alkyl is optionally substituted with one or more substituents selected from R'; or R3and R4when directly bound to the same carbon atom form an oxo (=0) group, cyclopropyl or cyclobutyl; or R3and R4form an oxo (=0) group;R5is selected from H and (C1-C6)alkyl; or R5can be taken together with R1to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one or more substituents selected from R'; each occurrence of R' is independently selected from halogen, R", OR", SR", CN, CO2R" and CON(R")2;each occurrence of R" is selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH;L1is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl is optionally interrupted by or terminated with one or more biodegradable groups; and said alkyl or alkenyl is optionally substituted with one or more sub stituents selected from R'; andL2is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl is optionally interrupted by or terminated with one or more biodegradable groups; and said alkyl or alkenyl is optionally substituted with one or more sub stituents selected from R'; with the proviso that the CR3R4group when present adjacent to the nitrogen atom in formula A is not a ketone ( — C(O) — ).

[0424] In some embodiments the lipids disclosed in US 2014 / 0308304 are of formula B:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: n is 0, 1, 2, 3, 4, or 5;R6and R7are each independently (i) C1-C4 linear or branched alkyl (e.g., methyl or ethyl) optionally substituted with 1-4 R', or (ii) C3-C8 cycloalkyl (e.g., C3-C6 cycloalkyl); or R6and R7together with the nitrogen atom adjacent to them form a 3-6 membered ring;L1is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl optionally interrupted by or terminated with one or more biodegradable groups; and said alkyl or alkenyl is optionally substituted with 1-5 sub stituents selected from R'; andL2is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl optionally interrupted by or terminated with one or more biodegradable groups; and said alkyl or alkenyl is optionally substituted with 1-5 sub stituents selected from R'; each occurrence of R' is independently selected from halogen, R", OR", SR", CN, CO2R" and CON(R")2; and each occurrence of R" is independently selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH.

[0425] In some embodiments, lipids disclosed in US 2014 / 0308304 are of formula C:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: n is 0, 1, 2, 3, 4, or 5;L1is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl optionally has one or more biodegradable groups; each biodegradable group independently interrupts the alkyl or alkenyl group or is substituted at the terminus of the alkyl or alkenyl group, and said alkyl or alkenyl is optionally substituted with 1-5 sub stituents selected from R'; andL2is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl optionally interrupted by or terminated with one or more biodegradable groups; and said alkyl or alkenyl is optionally substituted with 1-5 sub stituents selected from R'; each occurrence of R' is independently selected from halogen, R", OR", SR", CN, CO2R" and CON(R")2; and each occurrence of R" is independently selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH.

[0426] In some embodiments, the lipid disclosed in US 2014 / 0308304 are of formula D:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, or 5;R6and R7are each independently (i) C1-C4 linear or branched alkyl (e.g., methyl or ethyl) optionally substituted with 1-4 R', or (ii) C3-C8 cycloalkyl (e.g., C3-C6 cycloalkyl); or R6and R7together with the nitrogen atom adjacent to them form a 3-6 membered ring;L1is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl optionally interrupted by or terminated with one or more biodegradable groups; and said alkyl or alkenyl is optionally substituted with 1-5 substituents selected from R'; andL2is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl optionally interrupted by or terminated with one or more biodegradable groups; and said alkyl or alkenyl is optionally substituted with 1-5 substituents selected from R'; each occurrence of R' is independently selected from halogen, R", OR", SR", CN, CO2R" and CON(R")2; and each occurrence of R" is independently selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH.

[0427] In some embodiments lipid disclosed in US 2014 / 0308304 are of formula E:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 0, 1, 2, 3, 4, or 5; the group “amino acid” is an amino acid residue;L1is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl optionally interrupted by or terminated with one or more biodegradable groups, and said alkyl or alkenyl is optionally substituted with 1-5 sub stituents selected from R'; andL2is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl or alkenyl optionally interrupted by or terminated with one or more biodegradable groups, and said alkyl or alkenyl is optionally substituted with 1-5 sub stituents selected from R'; each occurrence of R' is independently selected from halogen, R", OR", SR", CN, CO2R" and CON(R")2; and each occurrence of R" is independently selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH.

[0428] The amino acid residue in formula E may have the formula — C(O) — C(R9)(NH2), where R9is an amino acid side chain.

[0429] In some embodiments, the lipid disclosed in US 2014 / 0308304 are of formula F:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R6and R7are independently (i) C1-C4 linear or branched alkyl (e.g., methyl or ethyl) optionally substituted with 1-4 R', or (ii) C3-C8 cycloalkyl (e.g., C3-C6 cycloalkyl); or R6and R7together with the nitrogen atom adjacent to them form a 3-6 membered ring;L1is a C4-C22 alkyl or C4-C22 alkenyl optionally interrupted by or terminated with one or more biodegradable groups, and said alkyl or alkenyl is optionally substituted with 1-5 substituents selected from R'; andL2is a C4-C22 alkyl or C4-C22 alkenyl optionally interrupted by or terminated with one or more biodegradable groups, and said alkyl or alkenyl is optionally substituted with 1-5 substituents selected from R'; each occurrence of R' is independently selected from halogen, R", OR", SR", CN, CO2R" and CON(R")2; each occurrence of R" is independently selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH.

[0430] In some embodiments, the lipid disclosed in US 2014 / 0308304 are of formula G:Formula Gor a pharmaceutically acceptable salt or stereoisomer thereof, wherein: n is 0, 1, 2, 3, 4, or 5; q is 1, 2, 3, or 4R6and R7are independently (i) C1-C4 linear or branched alkyl (e.g., methyl or ethyl) optionally substituted with 1-4 R', or (ii) C3-C8 cycloalkyl (e.g., C3-C6 cycloalkyl);L1is a C4-C22 alkyl or C4-C22 alkenyl optionally interrupted by or terminated with one or more biodegradable groups, and said alkyl or alkenyl is optionally substituted with 1-5 substituents selected from R'; andL2is a C4-C22 alkyl or C4-C22 alkenyl optionally interrupted by or terminated with one or more biodegradable groups, and said alkyl or alkenyl is optionally substituted with 1-5 substituents selected from R'; each occurrence of R' is independently selected from halogen, R", OR", SR", CN, CO2R" and CON(R")2; each occurrence of R" is independently selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH.

[0431] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US 2013 / 0053572, which is incorporated herein by reference in its entirety.

[0432] In some embodiments, the lipids disclosed in US 2013 / 0053572 are of Formula A:wherein: n is 0, 1 or 2;R1and R2are independently selected from H, (C1-C6)alkyl, heterocyclyl, and a polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one or more substituents selected from R', or R1, and R2can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one or more substituents selected from R'; R3is selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from R', or R3can be taken together with R1to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one or more substituents selected from R';R4is selected from H, (C1-C6)alkyl and O-alkyl, said alkyl is optionally substituted with one or more substituents selected from R';R5is selected from H and (C1-C6)alkyl; or R5can be taken together with R1to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one or more substituents selected from R';R' is independently selected from halogen, R", OR", CN, CO2R" and CON(R")2;R" is selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH;Li is a C4-C22 alkenyl, said alkenyl is optionally substituted with one or more substituents selected from R'; andL2 is a C4-C22 alkenyl, said alkenyl is optionally substituted with one or more substituents selected from R'; or any pharmaceutically acceptable salt or stereoisomer thereof.

[0433] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in US Application publication US2017 / 0119904, which is incorporated by reference herein, in its entirety.

[0434] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in PCT Application publication WO2021 / 204179, which is incorporated by reference herein, in its entirety.

[0435] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, disclosed in PCT Application WO2022251665A1, which is incorporated by reference herein, in its entirety.

[0436] In some embodiments, an LNP described herein comprises a lipid, e.g., an ionizable lipid, selected from one of those in Table 2B below, or a pharmaceutically acceptable salt thereof.Table 2B. Exemplary Ionizable Lipids

[0437] In some embodiments, the ionizable lipid is MC3.

[0438] In some embodiments, an LNP of the present disclosure comprises an ionizable lipid disclosed in PCT Application Publication WO2023044343A1, which is incorporated by reference herein, in its entirety.Formula (VII-A)

[0439] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-A):or a pharmaceutically acceptable salt thereof, wherein:A is -N(-X'R')-, -C(R')(-L1-N(R")R6)-, -C(R')(-OR7a)-, -C(R')(-N(R")R8a)- , -C(R')(-C(=O)OR9a)-, -C(R')(-C(=O)N(R")R10a)-, or -C(=N-Rlla)-;T is -X2a-Yla-Qlaor -X3-C(=O)OR4;X1is optionally substituted C2-C6 alkylenyl;R1is -OH, -Rla,Z1is optionally substituted C1-C6 alkyl;Zlais hydrogen or optionally substituted C1-C6 alkyl;X2and X2aare independently optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenyl enyl;X3is optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl;(i) Y1iswherein the bond marked with an is attached to X2a; each Z2is independently H or optionally substituted Ci-C8 alkyl; each Z3is indpendently optionally substituted C1-C6 alkylenyl;Q1is -NR2R3, -CH(OR2)(OR3), -CR2=C(R3)(R12), or -C(R2)(R3)(R12);Qlais -NR2'R3', -CH(OR2')(OR3'), -CR2=C(R3)(R12), or -C(R2')(R3')(R12'); orwherein the bond marked with an "*" is attached to X2;wherein the bond marked with an is attached to X2a; each Z2is independently H or optionally substituted Ci-C8 alkyl; each Z3is independently optionally substituted C1-C6 alkylenyl;Q1is -NR2R3;Qlais -NR2R3;R2, R3, and R12are independently hydrogen, optionally substituted C1-C14 alkyl, optionally substituted C2-C14 alkenylenyl, or -(CH2)m-G-(CH2)nH;R2, R3, and R12' are independently hydrogen, optionally substituted C1-C14 alkyl, optionally substituted C2-C14 alkenylenyl, or -(CH2)m-G-(CH2)nH;G is a C3-C8 cycloalkylenyl; each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;X3is optionally substituted C2-C14 alkylenyl;R4is optionally substituted C4-C14 alkyl;L1is Ci-C8 alkylenyl;R6is C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkylR7ais -C(=O)N(R"')R7b, -C(=S)N(R"')R7b, -N=C(R7b)(R7c), orR7bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl;R7Cis hydrogen or C1-C6 alkyl;R8ais -C(=O)N(R"')R8b, -C(=S)N(R"')R8b, -N=C(R8b)(R8c), orR8bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl;R8Cis hydrogen or C1-C6 alkyl;R9ais -N=C(R9b)(R9c);R9bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)Ci-C6 alkyl;R9Cis hydrogen or C1-C6 alkyl;Ri°ais-N=C(R10b)(R10c);R10bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl;R10cis hydrogen or C1-C6 alkyl;Rllais -ORllb, -N(R")Rllb, -OC(=O)Rllb, or -N(R")C(=O)Rllb;Rllbis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl;R' is hydrogen or C1-C6 alkyl;R" is hydrogen or C1-C6 alkyl; andR'" is hydrogen or C1-C6 alkyl.Formula (VIII- A)

[0440] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-A), wherein the Lipids of the Disclosure have a structure of Formula (VIILA):or a pharmaceutically acceptable salt thereof.Formula (VII-B)

[0441] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B):or a pharmaceutically acceptable salt thereof, wherein:A is -C(R')(-L1-N(R")R6)-, -C(R')(-OR7a)-, -C(R')(-N(R")R8a)-, -C(R')(-C(=O)OR9a)-, -C(R')(-C(=O)N(R")R10a)-, or -C(=N-Rlla)-;T is -X2a-Yla-Qlaor -X3-C(=O)OR4;X2and X2aare independently optionally substituted C2-C14 alkylenyl or optionally subsituted C2-C14 alkenylenyl;X3is optionally substituted C1-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl;Y1iswherein the bond marked with an "*" is attached to X2;Ylaiswherein the bond marked with an is attached to X2a; each Z3is independently optionally substituted C1-C6 alkylenyl or optionally substituted C2-C14 alkenyl enyl;Q1is -NR2R3, -CH(OR2)(OR3), -CR2=C(R3)(R12), or -C(R2)(R3)(R12);Qlais -NR2R3', -CH(OR2')(OR3'), -CR2=C(R3)(R12), or -C(R2')(R3')(R12');R2, R3, and R12are independently hydrogen, optionally substituted C1-C14 alkyl, optionally substituted C2-C14 alkenylenyl, or -(CH2)m-G-(CH2)nH;R2, R3, and R12' are independently hydrogen, optionally substituted C1-C14 alkyl, optionally substituted C2-C14 alkenylenyl, or -(CH2)m-G-(CH2)nH;G is a C3-C8 cycloalkylenyl; each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;X3is optionally substituted C2-C14 alkylenyl;R4is optionally substituted C4-C14 alkyl;L1is Ci-C8 alkylenyl;R6is (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl.R7ais -C(=O)N(R"')R7b, -C(=S)N(R"')R7b, -N=C(R7b)(R7c),Z1is optionally substituted C1-C6 alkyl;R10is C1-C6 alkylenyl;R7bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl;R7Cis hydrogen or C1-C6 alkyl;R8ais -C(=O)N(R"')R8b, -C(=S)N(R"')R8b, -N=C(R8b)(R8c),R8bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)Ci-C6 alkyl;R8Cis hydrogen or C1-C6 alkyl;R9ais -N=C(R9b)(R9c);R9bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl;R9Cis hydrogen or C1-C6 alkyl;Ri°ais-N=C(R10b)(R10c);R10bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl;R10cis hydrogen or C1-C6 alkyl;Rllais -ORllb, -N(R")Rllb, -OC(=O)Rllb, or -N(R")C(=O)Rllb;Rllbis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl;R' is hydrogen or C1-C6 alkyl;R" is hydrogen or C1-C6 alkyl; and R'" is hydrogen or C1-C6 alkyl.

[0442] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein A is -C(R)(-L1-N(R")R6)-.

[0443] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein A is -C(R')(-OR7a)-.

[0444] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein A is -C(R')(-N(R")R8a).

[0445] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein A is -C(R')(-C(=O)OR9a).

[0446] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein A is -C(R')(-C(=O)N(R")R10a)-.

[0447] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein A is -C(=N-Rlla)-.

[0448] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein T is -X2a-Yla-Qla.

[0449] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein T is -X3-C(=O)OR4.

[0450] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein X2and / or X2aare / is optionally substituted C2-C14 alkylenyl (e.g., C2-C10 alkylenyl, C2-C8 alkylenyl, C2, C3, C4, C5, C6, C7, or C8 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein X2is C2-C14 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein X2ais C2- C14 alkylenyl.

[0451] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Y1and / or Ylaare / is

[0452] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Y1is

[0453] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Ylais

[0454] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Y1and / or Ylaare / is

[0455] In some embodiments, Lipids of the Disclosure have structure of Formula (VII-B), wherein Y1is

[0456] In some embodiments, Lipids of the Disclosure have structure of Formula (VII-B), wherein Ylais

[0457] In some embodiments, Lipids of the Disclosure have structure of Formula (VII-B), wherein Y1and / or Ylaare / is

[0458] In some embodiments, Lipids of the Disclosure have structure of Formula (VII-B), wherein Y1is

[0459] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Ylais

[0460] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Y1and / or Ylaare / is

[0461] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Y1is

[0462] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Ylais

[0463] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Q1and / or Qlaare / is -C(R2)(R3)(R12). In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Q1is -C(R2)(R3)(R12). In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Qlais -C(R2)(R3)(R12).

[0464] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein X3is optionally substituted C1-C14 alkylenyl (e.g., C1-C6, C1-C4 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein X3is Ci- C14 alkylenyl.

[0465] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R2, R3, R12, R2, R3, and / or R12are hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R3is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R12ishydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R3is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R12is hydrogen.

[0466] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R2, R3, R12, R2, R3, and / or R12' are optionally substituted C1-C14 alkyl (e.g., C4-C10 alkyl, C5, C6. C7. C8, C9 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R2is C4-C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R3is C4-C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R12is C4-C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R2is C4- C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R3is C4-C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R12is C4-C10 alkyl.

[0467] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R4is optionally substituted C4-C14 alkyl (e.g., C8-C11 alkyl, linear C8-C11 alkyl, C8, C9, C10, C11, C12, C13, or C14 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R4is linear C8-C11 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R4is linear C11 alkyl.

[0468] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein L1is C1-C3 alkylenyl.

[0469] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R6is (hydroxy)C1-C6 alkyl.

[0470] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R7aisIn some embodiments, Lipids of the Disclosure have astructure of Formula (VII-B), wherein R7aisIn some embodiments,Lipids of the Disclosure have a structure of Formula (VII-B), wherein R7ais

[0471] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R7ais selected from the group consisting of -C(=O)N(R"')R7b, -C(=S)N(R"')R7b, and - N=C(R7b)(R7c). In some embodiments, Lipids of the Disclosure have a structure of Formula (VII- B), wherein R7ais -C(=O)N(R"')R7b. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R7ais -C(=S)N(R"')R7b. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R7ais -N=C(R7b)(R7c).

[0472] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R8ais selected from the group consisting of -C(=O)N(R"')R8b, -C(=S)N(R"')R8b, and - N=C(R8b)(R8c). In some embodiments, Lipids of the Disclosure have a structure of Formula (VII- B), wherein R8ais -C(=O)N(R"')R8b. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R8ais -C(=S)N(R"')R8b. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R8ais -N=C(R8b)(R8c).

[0473] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R8ais

[0474] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R9bis (hydroxy)C1-C6 alkyl.

[0475] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein R10bis (amino)C1-C6 alkyl.

[0476] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Rllais -ORllbor -OC(=O)Rllb. In some embodiments, Lipids of the Disclosure have astructure of Formula (VII-B), wherein Rllais -ORllb. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Rllais -OC(=O)Rllb.

[0477] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Rllais -N(R")Rllbor -N(R")C(=O)Rllb. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Rllais -N(R")Rllb. In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Rllais -N(R")C(=O)Rllb.

[0478] In some embodiments, Lipids of the Disclosure have a structure of Formula (VII-B), wherein Rllbis (amino)C1-C6 alkyl.Formula (III-C)

[0479] In some embodiments, Lipids of the Disclosure have a structure of Formula (IILC):or a pharmaceutically acceptable salt thereof, whereinR20is Ci-C6alkylenyl-NR20C(O)OR20;R20' is hydrogen or optionally substituted C1-C6 alkyl;R20" is optionally substituted C1-C6 alkyl, phenyl, or benzyl;Z1is optionally substituted C1-C6 alkyl;X2and X2aare independently optionally substituted C2-C14 alkylenyl;Y1and Ylaare independentlywherein the bond marked with an is attached to X2or X2a;Z3is independently optionally substituted C2-C6 alkylenyl;R2and R3are independently optionally substituted C4-C14 alkyl; and R2' and R3' are independently optionally substituted C4-C14 alkyl.

[0480] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein R20is -CH2CH2CH2NHC(O)O-t-butyl or -CH2CH2CH2NH(O)O-benzyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein R20is - CH2CH2CH2NHC(O)O-t-butyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein R20is -CH2CH2CH2NHC(O)O-benzyl.

[0481] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein X2and X2aare independently C4-C8 alkylenyl (e.g., C5, C6, C7 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein X2is C6 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein X2ais C6 alkyl.

[0482] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein Y1and Ylaarewherein Z3is C2-C4alkylenyl (e.g., C2 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein Y iswherein Z is C2-C4alkylenyl (e.g., C2 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein Ylais wherein Z3is C2-C4alkylenyl (e.g., C2 alkylenyl).

[0483] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein R2, R3, R2' and R3' are independently optionally substituted C4-C10 alkyl (e.g., C6-Cgalkyl, C6, C7, C8, C9 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein R2is C6-Cgalkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein R3is C6-Cgalkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein R2is C6-Cgalkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-C), wherein R3is C6-Cgalkyl.Formula (III-D)

[0484] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D):or a pharmaceutically acceptable salt thereof, wherein R1is -OH; is optionally substituted C4 alkylenyl; and X2aare independently optionally substituted C2-C14 alkylenyl; and Ylaare independentlyZ3is independently optionally substituted C2-C6 alkylenyl;R2and R3are independently optionally substituted C4-C14 alkyl or C1-C2 alkyl substituted with optionally substituted cyclopropyl; orR2' and R3' are independently optionally substituted C4-C14 alkyl or C1-C2 alkyl substituted with optionally substituted cyclopropyl.

[0485] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein X1is C4 alkylenyl.

[0486] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein X2and X2aare independently optionally substituted C4-C10 alkylenyl (e.g., C5, C6, C7, C8, C9, or C10 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein X2is C4-C10 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein X2ais C4-C10 alkylenyl.

[0487] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein Y1and Ylaare independently, wherein Z is independently C2-C4 alkylenyl (e.g., C2, C4 alkylenyl).

[0488] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2, R3, R2' and R3' are independently C6-C11 alkyl (e.g., C6, C7, C8, C9, C10, C11, C12, C13, or C14 alkyl) or C1-C2 alkyl substituted with optionally substituted cyclopropyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2, R3, R2' and R3' are independently C6-C11 alkyl (e.g., C6, C7, C8, C9, C10, C11, C12, C13, or C14 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2is C6-Ci4 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III- D), wherein R3is C6-C11 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2is C6-C11 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R3is C6-C11 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2is C1-C2 alkyl substituted with substituted cyclopropyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R3is C1-C2 alkyl substituted with substituted cyclopropyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2' is C1-C2 alkyl substituted with substituted cyclopropyl. In some embodiments, Lipids of the Disclosurehave a structure of Formula (III-D), wherein R3' is C1-C2 alkyl substituted with substituted cyclopropyl.

[0489] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2, R3, R2' and R3' are independently C1-C2 alkyl substituted with cyclopropylene-(Ci- C6alkylenyl optionally substituted with cyclopropylene substituted with C1-C6alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2is C1-C2 alkyl substituted with cyclopropylene-(Ci-C6alkylenyl optionally substituted with cyclopropylene substituted with C1-C6alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R3is C1-C2 alkyl substituted with cyclopropylene- (Ci-C6alkylenyl optionally substituted with cyclopropylene substituted with C1-C6alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R2' is C1-C2 alkyl substituted with cyclopropylene-(Ci-C6alkylenyl optionally substituted with cyclopropylene substituted with C1-C6alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-D), wherein R3' is C1-C2 alkyl substituted with cyclopropylene- (Ci-C6alkylenyl optionally substituted with cyclopropylene substituted with C1-C6alkyl).Formula (III-E)

[0490] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E):or a pharmaceutically acceptable salt thereof, whereinR1is -OH;X1is branched C2-C8 alkylenylX2and X2aare independently optionally substituted C2-C14 alkylenyl;Y1and Ylaare independentlyZ3is independently optionally substituted C2-C6 alkylenyl;R2and R3are independently optionally substituted C4-C14 alkyl;R2' and R3' are independently optionally substituted C4-C14 alkyl.

[0491] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein X1is branched C6 alkylenyl.

[0492] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein X2and X2aare independently C4-C10 alkylenyl (e.g., C6, C7, C8 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein X2is C4-C10 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein X2ais C4-C 10 alkylenyl.

[0493] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein Y1and Ylaare, wherein Z3is independently optionally substituted C2 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein Y1is, wherein Z3is independently optionally substituted C2 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein Ylais, wherein Z3is independently optionally substituted C2 alkylenyl.

[0494] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R2, R3, R2' and R3' are independently C6-C12 alkyl (e.g., C9 alkyl) or C4-C10 alkyl (e.g.,C4, C6 alkyl) optionally substituted with C2-C8alkenylene (e.g., C4, C6 alkenylene). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R2is C6-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R3is C6-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R2is C6-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R3is C6-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R2is C4-C10 alkyl optionally substituted with C2-C8alkenylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R3is C4-C10 alkyl optionally substituted with C2-C8alkenylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R2is C4-C10 alkyl optionally substituted with C2-C8alkenylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R3is C4-C10 alkyl optionally substituted with C2-C8alkenylene.Formula (IILF)

[0495] In some embodiments, Lipids of the Disclosure have a structure of Formula (IILF):or a pharmaceutically acceptable salt thereof, whereinR1is -OH;X1is optionally substituted C2-C6 alkylenyl;X2and X2aare independently optionally substituted C2-C14 alkylenyl; each of Y1and Ylais a bond;R2and R3are independently optionally substituted C4-C14 alkyl; and R2' and R3' are independently optionally substituted C4-C14 alkyl.

[0496] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein X1is C4 alkylenyl.

[0497] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein X2and X2aare independently C4-C10 alkylenyl (e.g., C6-C8 alkylenyl, C6, C7, C8 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein X2is C4-C10 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein X2ais C4-C10 alkylenyl.

[0498] In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R2, R3, R2' and R3' are independently C6-Cio alkyl (e.g., C7. C8 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R2is C6-Cio alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R3is C6-Cio alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R2is C6-Cio alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (III-E), wherein R3is C6-Cio alkyl.Formula (VIII-B)

[0499] In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B):or a pharmaceutically acceptable salt thereof, wherein:X1is a bond,R1is C1-C6 alkyl,X2is is C2-C6 alkylenyl,X2ais C2-C14 alkylenyl, wherein X2or X2ais substituted with OH or Ci.4alkylenyl-OH,Y1iswherein the bond marked with an is attached to X2;Ylaiswherein the bond marked with an is attached to X2a; each Z3is independently optionally substituted C1-C6 alkylenyl or optionally substituted C2-C14 alkenyl enyl;Q1is -C(R2)(R3)(R12);Qlais -C(R2)(R3)(R12);R2, R3, and R12are independently hydrogen, optionally substituted C1-C14 alkyl, or optionally substituted C2-C14 alkenylenyl, andR2, R3, and R12' are independently hydrogen, optionally substituted C1-C14 alkyl, or optionally substituted C2-C14 alkenylenyl.

[0500] In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R1is methyl.

[0501] In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein X2is C4, C5, or C6 alkylenyl.

[0502] In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein X2ais C4-C8 alkylenyl (e.g., C5, C6, or C7 alkylenyl).

[0503] In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein Y1isorin some embodiments, Lipids of the Disclosure have a structure ofFormula (VIII-B), wherein Y1isIn some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein Y1isIn some embodiments, Lipids of T the Disclosure have a structure of Formula (VIII-B), wherein YlaisIn some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein Ylais

[0504] In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R2, R3, R12, R2, R3, and R12' are independently hydrogen or C5-C12 alkyl (e.g., C6, C7, C8, C9, C10, C11 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R3is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R3is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R2is C5- C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R3is C5-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R2is C5-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (VIII-B), wherein R3is C5-C12 alkyl.Formula (X)

[0505] In some embodiments, Lipids of the Disclosure have a structure of Formula (X):or a pharmaceutically acceptable salt thereof, wherein each cc is independently selected from 3 to 9;R™ is selected from hydrogen and optionally substituted C1-C6 alkyl; and(i) ee is 1, each dd is independently selected from 1 to 4; and each Rwwis independently selected from the group consisting of C4-C14 alkyl, branched C4-C12 alkenyl, C4-C12 alkenyl comprising at least two double bonds, and C9-C12 alkenyl, wherein any -(CH2)2- of the C4-C14 alkyl can be optionally replaced with C2-C6 cycloalkylenyl;(ii) ee is 0, each dd is 1; and each Rwwis linear C4-C12 alkyl.

[0506] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein R™ is H. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein Rxxis optionally substituted C1-C6 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein Rxxis Ci alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein Rxxis C2 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein R™ is C3 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein Rxxis C4 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein Rxxis C5 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein Rxxis C6alkyl.

[0507] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis independently selected from the group consisting of C4-C14 alkyl, branched C4-C12 alkenyl, C4-C12 alkenyl comprising at least two double bonds, and C9-C12 alkenyl, wherein any -(CH2)2- of the C4-C14 alkyl can be optionally replaced with C2-C6 cycloalkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C4- C14 alkyl, wherein any -(CH2)2- of the C4-C14 alkyl can be optionally replaced with C2-C6 cycloalkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C4-C14 alkyl, wherein any -(CH2)2- of the C4-C14 alkyl can be optionally replaced with cyclopropylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis branched C4-C12 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C4-C12 alkenyl comprising at least two double bonds. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C9-C12 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C4-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis independentlyselected from the group consisting of C6-C11 alkyl, branched C8-Ci2 alkenyl, C8-Ci2 alkenyl comprising at least two double bonds, and C9-C12 alkenyl, wherein any -(CH2)2- of the C6-C11 alkyl can be optionally replaced with cyclopropylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C6-C11 alkyl, wherein any - (CH2)2- of the C6-C14 alkyl can be optionally replaced with cyclopropylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis branched C8-C11 alkenyl, e.g., (linear or branched C3-C5 alkylenyl)-(branched C5-C?alkenyl), e.g., (branched C5 alkylenyl)-(branched C8alkenyl), e.g.,

[0508] . In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each R'™ is C8-C11 alkenyl comprising at least two double bonds. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C9-C12 alkenyl.

[0509] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis independently selected from the group consisting of C6-C11 alkyl (e.g., C6, C8, C9, C10, C11, C13 alkyl), wherein any -(CH2)2- of the C6-C11 alkyl can be optionally replaced with cyclopropylene.

[0510] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis independently branched C8-C11 alkenyl (e.g., branched C10 alkenyl).

[0511] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis independently C8-C11 alkenyl comprising at least two double bonds (e.g., C9 or C10 alkenyl comprising two double bonds).

[0512] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis independently (Ci alkylenyl)-(cyclopropylene-C6 alkyl) or (C2 alkylenyl)- (cyclopropylene-C2 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis independently (Ci alkylenyl)-(cyclopropylene-C6 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis independently (C2 alkylenyl)-(cyclopropylene-C2 alkyl).

[0513] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each R'™ is C4 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C5 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C6 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C7 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C8 alkyl. In someembodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C9 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C11 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C13 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C14 alkyl.

[0514] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C9 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each R'™ is C10 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C11 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C12 alkenyl.

[0515] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each R'™ is C8 alkenyl comprising at least two double bonds. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C9 alkenyl comprising at least two double bonds. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C10 alkenyl comprising at least two double bonds. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each R'™ is C11 alkenyl comprising at least two double bonds. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C12 alkenyl comprising at least two double bonds. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C13 alkenyl comprising at least two double bonds. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C14 alkenyl comprising at least two double bonds.

[0516] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C9 alkyl, wherein one -(CH2)2- of the C9 alkyl is replaced with C2-C6 cycloalkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each R'™ is C9 alkyl, wherein one -(CH2)2- of the C9 alkyl is replaced with cyclopropylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C9 alkyl, wherein two -(CH2)2- of the C9 alkyl are replaced with C2-C6 cycloalkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis C9 alkyl, wherein two -(CH2)2- of the C9 alkyl are replaced with cyclopropylene.

[0517] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C4 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C5 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C6 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C7 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C8 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C9 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C11 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C13 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis linear C14 alkyl.

[0518] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis branched C8 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis branched C9 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis branched C10 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis branched C11 alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each Rwwis branched C12 alkenyl.

[0519] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each cc is independently selected from 3 to 7. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each cc is 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each cc is 4. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each cc is 5. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each cc is 6. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each cc is 7. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each cc is 8. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each cc is 9.

[0520] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each dd is independently selected from 1 to 4. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each dd is 1. In some embodiments, Lipidsof the Disclosure have a structure of Formula (X), wherein each dd is 2. In some embodiments,Lipids of the Disclosure have a structure of Formula (X), wherein each dd is 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein each dd is 4.

[0521] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein ee is 1.

[0522] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein ee is 0.Formula (X-A)

[0523] In some embodiments, Lipids of the Disclosure have a structure of Formula (X), wherein the Lipids of the Disclosure have a structure of Formula (X-A):or a pharmaceutically acceptable salt thereof, wherein each cc is independently selected from 3 to 7; each dd is independently selected from 1 to 4;R™ is selected from hydrogen and optionally substituted C1-C6 alkyl; and each Rwwis independently selected from the group consisting of C4-C14 alkyl or (linear or branched C3-C5 alkylenyl)-(branched C8-Cvalkenyl).

[0524] In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein Rxxis hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein Rxxis Ci alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein Rxxis C2 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein Rxxis C3 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein R™ is C4 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein Rxxis C5 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein Rxxis C6alkyl.

[0525] In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each cc is 4, 5, 6, or 7. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each cc is 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each cc is 4. In some embodiments, Lipids of the Disclosurehave a structure of Formula (X-A), wherein each cc is 5. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each cc is 6. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each cc is 7.

[0526] In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each dd is 1 or 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each dd is 1. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each dd is 2. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each dd is 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each dd is 4.

[0527] In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each R'™ is C4-C14 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each R'™ is C4 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each Rwwis C5 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each Rwwis C6 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each R'™ is C7 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each R'™ is C8 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each Rwwis C9 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each Rwwis C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each Rwwis C11 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each R'™ is C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each R'™ is C13 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each Rwwis C14 alkyl.

[0528] In some embodiments, Lipids of the Disclosure have a structure of Formula (X-A), wherein each Rwwis (linear or branched C3-C5 alkylenyl)-(branched C8-Cvalkenyl), e.g., (branched C5 alkylenyl)-(branched C8alkenyl), e.g.,

[0529] In some embodiments, Lipids of the Disclosure comprise an acyclic core. In some embodiments, Lipids of the Disclosure are selected from any lipid in Table (I) below or a pharmaceutically acceptable salt thereof:Table (I). Non-Limiting Examples of Ionizable Lipids with an Acyclic Core

[0530] In some embodiments, an LNP of the present disclosure comprises an ionizable lipid disclosed in PCT Application Publication WO2023044333A1, which is incorporated by reference herein, in its entirety.Formula (CY)

[0531] In some embodiments, an LNP disclosed herein comprises an ionizable lipid of Formula (CY)or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of -OH, -OAc, Rla,Z1is optionally substituted C1-C6 alkyl;X1is optionally substituted C2-C6 alkylenyl;X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-;X2’ is selected from the group consisting of a bond, -CH2- and -CH2CH2-;X'ris selected from the group consisting of a bond, -CH2- and -CH2CH2X1is selected from the group consisting of a bond, -CH2- and -CH2CH2-;X4and X5are independently optionally substituted C2-C14 alkylenyl or optionally substitutedC2-C14 alkenylenyl;Y1and Y2are independently selected from the group consisting ofwherein the bond marked with an is attached to X4or X5; each Z2is independently H or optionally substituted Ci-C8 alkyl; each Z3is indpendently optionally substituted Ci-C8 alkylenyl;R2is selected from the group consisting of optionally substituted C4-C20 alkyl, optionally substituted C2-C14 alkenyl, and -(CH2)pCH(OR6)(OR7);R3is selected from the group consisting of optionally substituted C4-C20 alkyl, optionally substituted C2-C14 alkenyl, or -(CH2)qCH(OR8)(OR9);Riais:R2a, R2b, and R2care independently hydrogen and C1-C6 alkyl;R3a, R3b, and R3care independently hydrogen and C1-C6 alkyl;R4a, R4b, and R4Care independently hydrogen and C1-C6 alkyl;R33, R5b, and R5care independently hydrogen and C1-C6 alkyl;R6, Rz, R8, and R9are independently optionally substituted C1-C14 alkyl, optionally substituted C2-C14 alkenyl, or -(CH2)m-A-(CH2)nH; each A is independently a C3-C8 cycloalkylenyl; each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and 7; and q is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and 7.Formulas (CY-I), (CY-II), (CY-III), (CY-IV), and (CY-V)

[0532] In some embodiments, the present disclosure includes a compound of Formula (CY-I), (CY-II), (CY-III), (CY-IV), or (CY-V):or a pharmaceutically acceptable salt thereof, wherein X1, X2, X2, X3, X3, X4, X5, Y1, Y2, R1, R2, and R3are defined herein.Formulas (CY-VI) and (CY-VII)

[0533] In some embodiments, the present disclosure includes a compound of Formula (CY- VI) or (CY-VII):(CY-VI) (CY-VII) or a pharmaceutically acceptable salt thereof, wherein X1, X4, X5, R1, R2, and R3are defined herein.Formulas (CY-VIII) and (CY-IX)

[0534] In some embodiments, the present disclosure includes a compound of Formula (CY- VIII) or (CY-IX):(CY- VIII) (CY- IX), or pharmaceutically acceptable salt thereof. wherein X1, X4, X5, R1, R2, and R3are defined herein.Formulas (CY-IV-a), (CY-IV-b), and (CY-IV-c)

[0535] In some embodiments, the present disclosure includes a compound of Formula (CY-IV-a), (CY-IV-b), or (CY-IV-c)(CY-IV-a) (CY-IV-b) (CY-IV-c), or pharmaceutically acceptable salt thereof. wherein X1, X4, X5, R2, and R3are defined herein.Formulas (CY-IV-d), (CY-IV-e), and (CY-IV-f)

[0536] In some embodiments, the present disclosure includes a compound of Formula (CY- IV-d), (CY-IV-e), or (CY-IV-f)or pharmaceutically acceptable salt thereof. wherein X1, X4, X5, R2, and R3are defined herein.Formula (CY-IV)

[0537] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-IV’):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5, X1, X2, X’, X4, X5, Y1, andY2are as defined in connection with Formula (CY-F).

[0538] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-IV’), wherein:R1is -OH, Rla,wherein Z1is optionally substituted Ci-C8 alkyl;X1is optionally substituted C2-C6 alkylenyl;X2and X3are independently a bond, -CH2-, or -CH2CH2-;X4and X5are independently optionally substituted C2-C14 alkylenyl;Y1and Y2are independentlyR2and R3 are independently optionally substituted C4-C20 alkyl;Rlais:R2a, R2b, and R2care independently hydrogen and C1-C6 alkyl;R3a, R3b, and R3care independently hydrogen and C1-C6 alkyl;R4a, R4b, and R4care independently hydrogen and C1-C6 alkyl; andR5a, R5b, and R5care independently hydrogen and C1-C6 alkyl

[0539] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-IV’), wherein R1is -OH,

[0540] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-IV’), wherein Y1and Y2are independently:

[0541] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-IV’), wherein R2is -CH(OR6)(OR7).

[0542] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-IV’), wherein R3is -CH(OR8)(OR9).

[0543] Non-limiting examples of lipids having a structure of Formula (CY-IV’) include compounds CY7, CY8, CY19, CY20, CY21, CY28, CY29, CY40, CY41, CY42, CY48, CY49, CY58, CY59, and CY60.Formula (CY-VF)

[0544] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF):or a pharmaceutically acceptable salt thereof, wherein R1, R6, R7, R8, R9, X1, X2, X3, X4, X5, Y1, and Y2are as defined in connection with Formula (CY-F).

[0545] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R1is -OH.

[0546] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein X1is C2-C6 alkylenyl.

[0547] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein X2is -CH2CH2-.

[0548] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein X4is C2-C6 alkylenyl.

[0549] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein X5is C2-C6 alkylenyl.

[0550] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein Y1is:

[0551] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein Y2is:

[0552] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein each Z3is independently optionally substituted C1-C6 alkylenyl.

[0553] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein each Z3is -CH2CH2-.

[0554] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R6is C5-C14 alkyl.

[0555] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R7is C5-C14 alkyl.

[0556] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R6is C6-C11 alkenyl.

[0557] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R7is C6-C11 alkenyl.

[0558] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R8is C5-C16 alkyl.

[0559] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R9is C5-C14 alkyl.

[0560] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R8is C6-C11 alkenyl.

[0561] In some embodiments, Lipids of the Disclosure have a structure of Formula (CY-VF), or a pharmaceutically acceptable salt thereof, wherein R9is C6-C11 alkenyl.

[0562] In some embodiments, Lipids of the Disclosure comprise a heterocyclic core, wherein the heteroatom is nitrogen. In some embodiments, the heterocyclic core comprises pyrrolidine or a derivative thereof. In some embodiments, the heterocyclic core comprises piperidine or a derivative thereof. In some embodiments, Lipids of the Disclosure are selected from any lipid in Table (II) below or a pharmaceutically acceptable salt thereof:R1

[0563] In some embodiments, R1is selected from the group consisting of -OH, -OAc, Rla,and In some embodiments, R1is -OH or -OAc. In someembodiments, R1is OH. In some emobodiments, R1is -OAc. In some embodiments, R1is Rla.In some embodiments, R1is imidazolyl. In some embodiments, R1is.R2

[0564] In some embodiments, R2is selected from the group consisting of optionally substituted C4-C20 alkyl, optionally substituted C2-C14 alkenyl, and -(CH2)PCH(OR6)(OR7).

[0565] In some embodiments, R2is optionally substituted C4-C20 alkyl. In some embodiments, R2is optionally substituted C8-C11 alkyl. In some embodiments, R2is optionally substituted C9-C16 alkyl. In some embodiments, R2is optionally substituted C8-Cio alkyl. In some embodiments, R2is optionally substituted C11-C13 alkyl. In some embodiments, R2is optionally substituted C14-C16 alkyl. In some embodiments, R2is optionally substituted C9 alkyl. In some embodiments, R2is optionally substituted C10 alkyl. In some embodiments, R2is optionally substituted C11 alkyl. In some embodiments, R2is optionally substituted C12 alkyl. In some embodiments, R2is optionally substituted C13 alkyl. In some embodiments, R2is optionally substituted C14 alkyl. In some embodiments, R2is optionally substituted C15 alkyl. In some embodiments, R2is optionally substituted Ci6 alkyl.

[0566] In some embodiments, R2is optionally substituted C2-C14 alkenyl. In some embodiments, R2is optionally substituted C5-C14 alkenyl. In some embodiments, R2is optionallysubstituted C7-C14 alkenyl. In some embodiments, R2is optionally substituted C9-C14 alkenyl. In some embodiments, R2is optionally substituted C10-C14 alkenyl. In some embodiments, R2is optionally substituted C12-C14 alkenyl.

[0567] In some embodiments, R2is -(CH2)PCH(OR6)(OR7). In some embodiments, R2is - CH(OR6)(OR7). In some embodiments, R2is -CH2CH(OR6)(OR7). In some embodiments, R2is -(CH2)2CH(OR6)(OR7). In some embodiments, R2is -(CH2)3CH(OR6)(OR7). In some embodiments, R2is -(CH2)4CH(OR6)(OR7).

[0568] In some embodiments, R2is selected from the group consisting ofR3

[0569] In some embodiments, R3is selected from the group consisting of optionally substituted C4-C20 alkyl, optionally substituted C2-C14 alkenyl, and -(CH2)qCH(OR6)(OR7).

[0570] In some embodiments, R3is optionally substituted C4-C20 alkyl. In some embodiments, R3is optionally substituted C8-C11 alkyl. In some embodiments, R3is optionally substituted C9-C16 alkyl. In some embodiments, R3is optionally substituted C8-Cio alkyl. In some embodiments, R3is optionally substituted C11-C13 alkyl. In some embodiments, R3is optionally substituted C14-C16 alkyl. In some embodiments, R3is optionally substituted C9 alkyl. In some embodiments, R3is optionally substituted C10 alkyl. In some embodiments, R3is optionally substituted C11 alkyl. In some embodiments, R3is optionally substituted C12 alkyl. In some embodiments, R3is optionally substituted C13 alkyl. In some embodiments, R3is optionally substituted C14 alkyl. In some embodiments, R3is optionally substituted C15 alkyl. In some embodiments, R3is optionally substituted Ci6 alkyl.

[0571] In some embodiments, R3is optionally substituted C2-C14 alkenyl. In some embodiments, R3is optionally substituted C5-C14 alkenyl. In some embodiments, R3is optionally substituted C7-C14 alkenyl. In some embodiments, R3is optionally substituted C9-C14 alkenyl. Insome embodiments, R3is optionally substituted C10-C14 alkenyl. In some embodiments, R3is optionally substituted C12-C14 alkenyl.

[0572] In some embodiments, R3is -(CH2)qCH(OR8)(OR9). In some embodiments, R3is -CH(OR8)(OR9). In some embodiments, R3is -CH2CH(OR8)(OR9). In some embodiments, R3is -(CH2)2CH(OR8)(OR9). In some embodiments, R3is -(CH2)3CH(OR8)(OR9). In some embodiments, R3is -(CH2)4CH(OR8)(OR9).

[0573] In some embodiments, R3is selected from the group consisting ofR6, R7, R8, R9

[0574] In some embodiments, R6, R7, R8, and R9are independently optionally substituted Ci- C14 alkyl, optionally substituted C2-C14 alkenyl, or -(CH2)m-A-(CH2)nH. In some embodiments, R6, R7, R8, and R9are independently optionally substituted C1-C14 alkyl. In some embodiments, R6, R7, R8, and R9are independently optionally substituted C2-C14 alkenyl. In some embodiments, R6, R7, R8, and R9are independently -(CH2)m-A-(CH2)nH.

[0575] In some embodiments, R6is optionally substituted C1-C14 alkyl, optionally substituted C2-C14 alkenyl, or -(CH2)m-A-(CH2)nH. In some embodiments, R6is optionally substituted C3- C10 alkyl. In some embodiments, R6is optionally substituted C4-C10 alkyl. In some embodiments, R6is independently optionally substituted C5-C10 alkyl. In some embodiments, R6is optionally substituted C9-C10 alkyl. In some embodiments, R6is optionally substituted C1-C14 alkyl. In some embodiments, R6is optionally substituted C2-C14 alkenyl. In some embodiments, R6is -(CH2)m- A-(CH2)nH.

[0576] In some embodiments, R7is optionally substituted C1-C14 alkyl, optionally substituted C2-C14 alkenyl, or -(CH2)m-A-(CH2)nH. In some embodiments, R7is optionally substituted C3- C10 alkyl. In some embodiments, R7is optionally substituted C4-C10 alkyl. In some embodiments, R7is optionally substituted C5-C10 alkyl. In some embodiments, R7is optionally substituted C9-Cio alkyl. In some embodiments, R7is optionally substituted C1-C14 alkyl. In some embodiments, R7is optionally substituted optionally substituted C2-C14 alkenyl. In some embodiments, R7is - (CH2)m-A-(CH2)nH.

[0577] In some embodiments, R8is optionally substituted C1-C14 alkyl, optionally substituted C2-Ci4 alkenyl, or -(CH2)m-A-(CH2)nH. In some embodiments, R8is optionally substituted C3- C10 alkyl. In some embodiments, R8is optionally substituted C4-C10 alkyl. In some embodiments, R8is optionally substituted C5-C10 alkyl. In some embodiments, R8is optionally substituted C9- C10 alkyl. In some embodiments, R8is optionally substituted C1-C14 alkyl. In some embodiments, R8is optionally substituted C2-Ci4 alkenyl. In some embodiments, R8is -(CH2)m-A-(CH2)nH.

[0578] In some embodiments, R9is optionally substituted C1-C14 alkyl, optionally substituted C2-Ci4 alkenyl, or -(CH2)m-A-(CH2)nH. In some embodiments, R9is optionally substituted C3- C10 alkyl. In some embodiments, R9is optionally substituted C4-C10 alkyl. In some embodiments, R9is optionally substituted C5-C10 alkyl. In some embodiments, R9is optionally substituted C9- C10 alkyl. In some embodiments, R9is optionally substituted C1-C14 alkyl. In some embodiments, R9is optionally substituted C2-Ci4 alkenyl. In some embodiments, R9is -(CH2)m-A-(CH2)nH.

[0579] In some embodiments, each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, each m is 0. In some embodiments, each m is 1. In some embodiments, each m is 2. In some embodiments, each m is 3. In some embodiments, each m is 4. In some embodiments, each m is 5. In some embodiments, each m is 6. In some embodiments, each m is 7. In some embodiments, each m is 8. In some embodiments, each m is 9. In some embodiments, each m is 10. In some embodiments, each m is 11. In some embodiments, each m is 12.

[0580] In some embodiments, each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, each n is 0. In some embodiments, each n is 1. In some embodiments, each n is 2. In some embodiments, each n is 3. In some embodiments, each n is 4. In some embodiments, each n is 5. In some embodiments, each n is 6. In some embodiments, each n is 7. In some embodiments, each n is 8. In some embodiments, each n is 9. In some embodiments, each n is 10. In some embodiments, each n is 11. In some embodiments, each n is 12.

[0581] In some embodiments, each A is independently a C3-C8 cycloalkylenyl. In some embodiments, each A is cyclopropylenyl.X1

[0582] In some embodiments, X1is optionally substituted C2-C6 alkylenyl. In some embodiments, X1is optionally substituted C2-C8 alkylenyl. In some embodiments, X1is optionally substituted C2-C4 alkylenyl. In some embodiments, X1is optionally substituted C2-C3 alkylenyl. In some embodiments, X1is optionally substituted C2alkylenyl. In someembodiments, X1is optionally substituted C3 alkylenyl. In some embodiments, X1is optionally substituted C4 alkylenyl. In some embodiments, X1is optionally substituted C5 alkylenyl. In some embodiments, X1is optionally substituted C6 alkylenyl. In some embodiments, X1is optionally substituted -(CH2)2-. In some embodiments, X1is optionally substituted -(CH2)3-. In some embodiments, X1is optionally substituted -(CH2)4-. In some embodiments, X1is optionally substituted -(CH2)5-. In some embodiments, X1is optionally substituted -(CH2)6-.X2

[0583] In some embodiments, X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-. In some embodiments, X2is a bond. In some embodiments, X2is -CH2-. In some embodiments, X2is -CH2CH2-.X2’

[0584] In some embodiments, X2is...

Claims

CLAIMS1. A compound of formula PL-I’ :PL-F or a pharmaceutically acceptable salt thereof, wherein:A1is a saturated 5-6 membered carbocyclic ring or a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the carbocyclic ring and heterocyclic ring are substituted with t occurrences of R4;X1is -N(H)-, -N(C1-6 alkyl)-, -C1-6 aliphatic-N(H)-, -C1-6 aliphatic-N(C1-6 alkyl)-, -O- or -C1-6 aliphatic-O-;L1is -C(O)(C1-6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)-N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)O-, -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)C(O)OCH2-, -C(O)(C1-6 aliphatic)-, -C(O)(C1-6 aliphatic)-N(R)-, or -C(O)-;L2and L3are independently a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O- , -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)- , -C(R5)=N-, or -C(R5)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N2, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently a straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R4is Ci-4 alkyl;R5is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclicheteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or -OC(O)OR; n is an integer from 10-75, inclusive; m is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

2. The compound of claim 1, wherein X1is -N(H)-, -N(C1-6 alkyl)-, or -O-.

3. The compound of claim 1 or 2, wherein A1is a saturated 5-6 membered carbocyclic ring substituted with t occurrences of R4.

4. The compound of claim 1 or 2, wherein A1is cyclopentyl.

5. The compound of claim 1 or 2, wherein A1is cyclohexyl.

6. The compound of claim 1 or 2, wherein A1is a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is substituted with t occurrences of R4.

7. The compound of claim 1 or 2, wherein A1is selected from pyrrolidinylene, tetrahydrofuranylene, tetrahydrothiophenylene, imidazolidinylene, thiazolidinylene, oxazolidinylene, piperidinylene, tetrahydro-2H-pyranylene, tetrahydro-2H-thiopyranylene, piperazinylene, morpholinylene, and hexahydropyrimidinylene.

8. The compound of claim 1 or 2, wherein the compound is of formula PL-Ia, PL-Ib, or PL-Ic:PL-Ic or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 or 2, wherein the compound is of formula PL-Id or PL-Ie:PL-Ie or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 or 2, wherein the compound is of formula PL-If:PL-If or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 or 2, wherein the compound is of formula PL-Ig:PL-Ig or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 or 2, wherein the compound is of formula PL-Ih or PL-Ii:or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 or 2, wherein the compound is of formula PL-Ij or PL-Ik: / L2-R2PL-Ik or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 or 2, wherein the compound is of formula PL-11, PL-Im, or In:PL-In or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein the compound is of formula PL-Io, PL-Ip, or PL-Iq:PL-Io PL-IpPL-Iq or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein the compound is of formula PL-Ir or PL-Is:PL-Is or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound is of formula PL-It:PL-It or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is of formula PL-Iu:PL-Iu or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is of formula PL-Iv or PL-Iw:PL-Iv PL-Iw or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is of formula PL-Ix or PL-Ixx:PL-Ixx or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is of formula PL-Iy, PL-Iyy, or PL- iyyyPL-IyyPL-Iyyy or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 1-8, 11, 12, 15, 18, 19, or 21, wherein L1is -C(O)(Ci- 6 aliphatic)C(O)-N(R)-, -C(O)(C1-6 aliphatic)-N(R)C(O)-, -C(O)(C1-6 aliphatic)C(O)2-, or - C(O)(C1-6 aliphatic)C(O)-.

23. The compound of any one of claims 1-8, 11, 12, 15, 18, 19, or 21, wherein L1is -C(O)(Ci- 6 aliphatic)C(O)-N(R)-.

24. The compound of any one of claims 1-8, 11, 12, 15, 18, 19, or 21, wherein L1is - C(O)CH2CH2C(O)-N(R)-.

25. The compound of any one of claims 1-8, 11, 12, 15, 18, 19, or 21, wherein L1is -C(O)(Ci- 6 aliphatic)C(O)-.

26. The compound of any one of claims 1-8, 11, 12, 15, 18, 19, or 21, wherein L1is - C(O)CH2CH2C(O)-.

27. The compound of any one of claims 1-8, 11, 12, 15, 18, 19, or 21, wherein L1is -C(O)(Ci- 6 aliphatic)C(O)2-.

28. The compound of any one of claims 1-8, 11, 12, 15, 18, 19, or 21, wherein L1is - C(O)CH2CH2C(O)2-.

29. A compound of Formula PL-II’:PL-II’ or a pharmaceutically acceptable salt thereof, wherein:X1is -N(H)-, -N(C1-6 alkyl)-, -C1-6 aliphatic-N(H)-, -C1-6 aliphatic-N(C1-6 alkyl)-, -O- or -C1-6 aliphatic-O-;L1is -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)-, or -C(O)-;L2and L3are a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, - OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R6)=N- , or -C(R6)=N-O-;R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl;R2and R3are independently straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx;R6is C1-6 alkyl or C2-14 alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or OC(O)OR; n is an integer from 10-75, inclusive; and m is 0, 1, 2, 3, or 4.

30. The compound of claim 29, wherein X1is -N(H)-, -N(C1-6 alkyl)-, or -O-.

31. The compound of claim 29 or 30, wherein L1is -C(O)(C1-6 aliphatic)C(O)-.

32. The compound of claim 29 or 30, wherein L1is -C(O)CH2CH2C(O)-.

33. The compound of claim 29 or 30, wherein L1is -C(O)-.

34. The compound of any one of claims 1-13, 15-20, or 29-33, wherein L2and L3are the same.

35. The compound of any one of claims 1-13, 15-20, or 29-33, wherein L2and L3are independently a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -C(O)O-, -OC(O)-, or -OC(O)N(R)-.

36. The compound of any one of claims 1-13, 15-20, or 29-33, wherein L2and L3are independently a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with - OC(O)-.

37. The compound of any one of claims 1-13, 15-20, or 29-33, wherein L2and L3are independently a C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is replaced with - O-.

38. The compound of any one of claims 1-13, 15-20, or 29-33, wherein L2and L3are independently selected from -O-, -OC(O)-, -C(O)O-, -OC(O)O-, -CH2O-, -CH2OC(O)-, and - CH2OC(O)O-.

39. The compound of any one of claims 1-13, 15-20, or 29-33, wherein L2andL3are -OC(O)-40. The compound of any one of claims 1-13, 15-20, or 29-33, wherein L2and L3are -O-.

41. The compound of any one of claims 1-40, wherein R1is C1-6 alkyl.

42. The compound of any one of claims 1-40, wherein R1is methyl.

43. The compound of any one of claims 1-42, wherein R2and R3are the same.

44. The compound of any one of claims 1-14 or 29-33, wherein X1is -N(H)-.

45. The compound of claim 29, wherein the compound is of formula PL-IIc or PL-IId:PL-IId or a pharmaceutically acceptable salt thereof.

46. The compound of claim 29, wherein the compound is of formula PL-IIe:PL-IIe or a pharmaceutically acceptable salt thereof.

47. The compound of claim 29, wherein the compound is of formula PL-IIf:PL-IIf or a pharmaceutically acceptable salt thereof.

48. The compound of claim 29, wherein the compound is of formula PL-IIg or PL-IIh:PL-IIh or a pharmaceutically acceptable salt thereof.

49. The compound of claim 29, wherein the compound is of formula PL-IIa or PL-IIb:PL-IIaPL-IIb or a pharmaceutically acceptable salt thereof.

50. The compound of claim 29, wherein the compound is of formula PL-IIk:PL-IIk or a pharmaceutically acceptable salt thereof.

51. The compound of claim 29, wherein the compound is of formula PL-IIm or PL-IIn:PL-IIn or a pharmaceutically acceptable salt thereof.

52. The compound of any one of claims 1-51, wherein R2and R3are independently a straight or branched C6-30 alkyl substituted with m instances of Rx.

53. The compound of any one of claims 1-51, wherein R2and R3are independently a straight or branched C6-25 alkyl substituted with m instances of Rx.

54. The compound of any one of claims 1-51, wherein R2and R3are -(CH2)C6-2.

555. The compound of any one of claims 1-51, wherein R2and R3are -(CH2)10-25.

56. The compound of any one of claims 1-51, wherein R2and R3are -(CH2)i0-i4.

57. The compound of any one of claims 1-51, wherein R2and R3are -(CH2)14-16.

58. The compound of any one of claims 1-51, wherein R2and R3are -(CH2)18-20.

59. The compound of any one of claims 1-51, wherein R2and R3are independently a straight or branched C6-30 alkenyl substituted with m instances of Rx.

60. The compound of any one of claims 1-53 or 59, wherein m is 1.

61. The compound of any one of claims 1-53 or 59, wherein m is 0.

62. The compound of any one of claims 1-61, wherein n is an integer from 30-55, inclusive.

63. The compound of any one of claims 1-61, wherein n is an integer from 40-50, inclusive.

64. The compound of any one of claims 1-61, wherein n is 44, 45, or 46.

65. The compound of any one of claims 1-61, wherein n is 45.

66. A compound in Table 1, or a pharmaceutically acceptable salt thereof.

67. A lipid nanoparticle (LNP) comprising a compound of any one of claims 1-66, or a pharmaceutically acceptable salt thereof.

68. The LNP of claim 67, comprising:(a) an ionizable lipid;(b) a structural lipid; and(c) a non-ionizable lipid and / or a zwitterionic lipid.

69. The LNP of claim 68, wherein the ionizable lipid comprises an ionizable amino lipid.

70. The LNP of claim 68, wherein the ionizable lipid is selected from 3-(((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl)oxy)-N,N-dimethylpropan-l-amine;(6Z,9Z,28Z,3 lZ)-heptatriaconta-6,9,28,31-tetraen- 19-yl 4-(dimethylamino)butanoate;(6Z,16Z)- 12-((Z)-dec-4-en-l-yl)docosa-6,16-dien-l 1-yl 5-(dimethylamino)pentanoate;(6Z,16Z)-12-((Z)- dec-4-en-l-yl)docosa-6,16-dien-l l-yl 6-(dimethylamino)hexanoate; N,N- dimethyl-4-(tris(((Z)- dec-4-en-l-yl)oxy)silyl)butan-l -amine; N,N-dimethyl-5-(tris(((Z)-dec-4- en- 1 - yl)oxy)silyl)pentan- 1 -amine; N,N-dimethyl-6-(tris(((Z)-dec-4-en- 1 -yl)oxy)silyl)hexan- 1 -amine; 2-(methyl(4-(tris(((Z)-dec-4-en-l-yl)oxy)silyl)butyl)amino)ethan-l-ol; (6Z,16Z)-12-((6- (dimethylamino)hexanoyl)oxy)docosa-6,16-dien-l 1-yl (Z)-undec-5-enoate; Nl,N3-bis(4- (bis(((Z)-dec-4-en-l-yl)oxy)(methyl)silyl)butyl)-Nl,N3-dimethylpropane-l,3-diamine; N1,N3- dimethyl-Nl,N3-bis(4-(tris(((Z)-hept-3-en-l-yl)oxy)silyl)butyl)propane-l,3-diamine; (lr,4r)- Nl,N4-bis(4-(bis(((Z)-dec-4-en-l-yl)oxy)(methyl)silyl)butyl)-Nl,N4-dimethylcyclohexane- 1,4- diamine; 2,8-bis(4-(bis(((Z)-dec-4-en-l-yl)oxy)(methyl)silyl)butyl)-2,8- diazaspiro[4.5]decane; or bis(2 -butyloctyl) 10-(N-(3-(dimethylamino)propyl) nonanamido)- nonadecanedioate; di(tridecan-7-yl) 10-(N-(3-(dimethylamino)propyl)octanamido)- nonadecanedioate; di (tridecan- 7-yl) 10-(N-decyl-4- (dimethylamino)butanamido)nonadecanedioate; ((4- hydroxybutyl)azanediyl)bis(nonane-9, 1- diyl) bis(2 -butyl octanoate); heptadecan-9-yl 8-((2- hydroxyethyl)(8-(nonyloxy)-8- oxooctyl)amino)octanoate; 3-((4,4-bis(octyloxy)butanoyl)oxy)-2- ((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-di enoate or 3,6- bi s(4-(bi s(2-hy droxy dodecyl)amino)butyl)piperazine-2, 5 -di one; 3 ,6-bi s(4-(bi s((9Z, 12Z)-2- hydroxyoctadeca-9,12-dien-l-yl)amino)butyl)piperazine-2, 5-dione; 1, l'-((2-(l-(2-((2-(bis(2- hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperidin-4- yl)ethyl)azanediyl)bis(dodecan-2-ol); tetratridecyl 3,3',3",3"'-((azanediylbis(propane-3, 1- diyl))bis(azanetriyl))tetrapropionate; nonyl 8-((8,8-bis(octyloxy)octyl)(2- hy droxy ethyl)amino)octanoate; or di((Z)-non-2-en-l-yl) 8,8'-((((2- (dimethylamino)ethyl)thio)carbonyl)azanediyl)dioctanoate.

71. The LNP of claim 68, wherein the ionizable lipid is selected from those compounds disclosed in Table 2B, Table (I), Table (II), Table (III), Table (IV), and Table (V).

72. The LNP of any one of claims 68-71, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, and alpha-tocopherol.

73. The LNP of any one of claims 68-72, wherein the non-ionizable lipid is a phospholipid selected from the group consisting of l,2-dilinoleoyl-sn-glycero-3 -phosphocholine (DLPC), 1,2- dimyristoyl-sn-glycero-phosphocholine (DMPC), l,2-dioleoyl-sn-glycero-3 -phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3 -phosphocholine (DPPC), l,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl-2- oleoyl-sn-glycero-3 -phosphocholine (POPC), l,2-di-O-octadecenyl-sn-glycero-3- phosphocholine (18:0 Diether PC), l-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3- phosphocholine (OChemsPC), l-hexadecyl-sn-glycero-3 -phosphocholine (Cl 6 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3 -phosphocholine, 1 ,2-diarachidonoyl-sn-gly cero-3 -phosphocholine, l,2-didocosahexaenoyl-sn-glycero-3 -phosphocholine, 1,2-dioleoyl-sn-gly cero-3 - phosphoethanolamine (DOPE), l,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1 ,2-distearoyl-sn-gly cero-3 -phosphoethanolamine, 1 ,2-dilinoleoyl-sn-gly cero-3 - phosphoethanolamine, 1,2-dilinolenoyl-sn-gly cero-3 -phosphoethanolamine, 1 ,2- diarachidonoyl-sn-gly cero-3 -phosphoethanolamine, 1,2-didocosahexaenoyl-sn-gly cero-3 - phosphoethanolamine, l,2-dioleoyl-sn-glycero-3-phospho-rac-(l-glycerol) sodium salt (DOPG), and sphingomyelin.

74. The LNP of any one of claims 68-73, further comprising a targeting moiety.

75. The LNP of claim 74, wherein the targeting moiety is an antibody or a fragment thereof.

76. The LNP of any one of claims 68-75, further comprising a PEGylated lipid.

77. The LNP of claim 76, wherein the PEGylated lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG- modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, and a PEG- modified dialkylglycerol.

78. The LNP of any one of claims 67-77, further comprising an active agent.

79. The LNP of claim 78, wherein the active agent is a nucleic acid.

80. The LNP of claim 79, wherein the nucleic acid is a ribonucleic acid.

81. The LNP of claim 80, wherein the ribonucleic acid is at least one ribonucleic acid selected from the group consisting of a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and a long non-coding RNA (IncRNA).

82. The LNP of claim 79, wherein the nucleic acid is a messenger RNA (mRNA) or a circular RNA.

83. The LNP of claim 82, wherein the mRNA includes an open reading frame encoding a cancer antigen.

84. The LNP of claim 82, wherein the mRNA includes an open reading frame encoding an immune checkpoint modulator.

85. The LNP of any one of claims 82-84, wherein the mRNA includes at least one motif selected from the group consisting of a stem loop, a chain terminating nucleoside, a poly A sequence, a polyadenylation signal, and a 5' cap structure.

86. The LNP of claim 79, wherein the nucleic acid is suitable for a genome editing technique.

87. The LNP of claim 86, wherein the genome editing technique is clustered regularly interspaced short palindromic repeats (CRISPR) or transcription activator-like effector nuclease (TALEN).

88. The LNP of claim 87, wherein the nucleic acid is at least one nucleic acid suitable for a genome editing technique selected from the group consisting of a CRISPR RNA (crRNA), a trans-activating crRNA (tracrRNA), a single guide RNA (sgRNA), and a DNA repair template.

89. The LNP of any one of claims 82-88, wherein the mRNA is at least 30 nucleotides in length.

90. The LNP of any one of claims 82-88, wherein the mRNA is at least 300 nucleotides in length.

91. A pharmaceutical composition comprising an LNP of any one of claims 67-90, and a pharmaceutically acceptable carrier.

92. The pharmaceutical composition of claim 91 , formulated for intravenous or intramuscular administration.

93. The pharmaceutical composition of claim 91, which is formulated for intravenous administration.

94. A method for delivering a nucleic acid to a cell comprising contacting the cell with an LNP of any one of claims 79-90.

95. A method for treating a disease characterized by a deficiency of a functional protein, the method comprising administering to a subject having the disease, an LNP formulation comprising an LNP of any one of claims 82-88, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein.

96. A method for treating a disease characterized by overexpression of a polypeptide, comprising administering to a subject having the disease an LNP formulation comprising an LNP of any one of claims 82-88, wherein the siRNA targets expression of the overexpressed polypeptide.

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