Nanomaterials containing ester-linked acetals

Abstract

The present disclosure describes compositions, preparations, nanoparticles (such as lipid nanoparticles), and / or nanomaterials, and methods of using the same.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 128,680, filed December 21, 2020, No. 63 / 223,971, filed July 20, 2021, and No. 63 / 287,390, filed December 8, 2021, each of which is incorporated by reference in its entirety into this specification. [Background technology]

[0002] In chemistry, biology, and medicine, drug delivery systems have been problematic and have been hampered by a lack of understanding of how the molecular properties of the systems control delivery to tissues and confer drug efficacy. Summary of the Invention

[0003] The present invention recognizes the need for compositions, preparations, nanoparticles, and / or nanomaterials, and methods of using them. Among other things, the present disclosure recognizes that the structural features of compositions, preparations, nanoparticles, and / or nanomaterials affect functional responses in vivo, in vitro, and ex vivo. For example, the present disclosure describes, among other things, the selection and combination of one or more components described herein to affect the functional activity of lipid nanoparticles. In some embodiments, for example, functional activity may refer to desired tropism, stabilization, and / or drug delivery efficacy. In some embodiments, among other things, the present disclosure describes the different ratios of one of more components to affect one or more functional activities of compositions, preparations, nanoparticles, and / or nanomaterials described herein.

[0004] Further, among other things, the present disclosure recognizes that the chemical structure of the lipid confers improved properties compared to a reference lipid structure. For example, in some embodiments, the present disclosure provides a compound of formula A': [ka] or its N-oxide, or a pharma- ceutically acceptable salt thereof, 1 , L 2 , L 3 , X, X 2 , R, R”, and R 1 Each of the following is as defined herein:

[0005] In some embodiments, the present disclosure provides a compound of formula II″: [ka] or its N-oxide, or a pharma- ceutically acceptable salt thereof, 1 , L 2 , L 3 , X 2 , R, and R 1 Each of the following is as defined herein:

[0006] In some embodiments, the present disclosure provides a compound of formula III': [ka] or its N-oxide, or a pharma- ceutically acceptable salt thereof, 1 , L 2 , L 3 , X 2 , R, and R 1 Each of the following is as defined herein:

[0007] Among other things, as described herein, the present disclosure demonstrates surprising attributes (e.g., unexpected tropism, stabilization, and delivery efficacy of cargo, such as therapeutic or prophylactic agents) of ionizable lipids comprising an ester-linked acetal feature, and compositions, preparations, nanoparticles, and / or nanomaterials thereof (e.g., LNPs, and / or compositions, preparations, nanoparticles, and / or nanomaterials containing LNPs), and methods of using them. In certain embodiments, the present disclosure demonstrates surprising attributes (e.g., unexpected tropism, stabilization, and delivery efficacy of cargo, such as therapeutic or prophylactic agents) of ionizable lipids comprising at least two ester-linked acetal features, and compositions, preparations, nanoparticles, and / or nanomaterials thereof (e.g., LNPs, and / or compositions, preparations, nanoparticles, and / or nanomaterials containing LNPs), and methods of using them. In some embodiments, the lipids provided comprise two symmetric (e.g., identical) ester-linked acetal features, and in some embodiments, the lipids provided comprise two or more different ester-linked acetal features.

[0008] Among other things, the present disclosure recognizes lipid nanoparticle (LNP) compositions comprising one or more ionizable lipids. For example, the present disclosure provides LNP compositions and / or preparations comprising one or more of the disclosed ionizable lipids that impart unexpected tropism.

[0009] In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials provided are for use in methods of treating a disease or disorder, delivering, producing a polypeptide, or slowing / halting the progression of a disease or disorder.

[0010] In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials provided are for use in a method of manufacturing.

[0011] In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials provided are for use in a characterization method.

[0012] Elements (eg, methods) of embodiments incorporating one aspect of the invention may be applied to embodiments incorporating other aspects of the invention, and vice versa. [Brief description of the drawings]

[0013] [Figure 1] 1 shows an exemplary mRNA screening system for LNP preparations according to an embodiment of the present disclosure.

[0014] [Diagram 2] 1 shows an exemplary siRNA screening system for LNP preparations according to an embodiment of the present disclosure.

[0015] [Diagram 3] A bar graph showing the overall efficacy of three exemplary LNP screens (Screen 33, Screen 35, Screen 36) across various cell types (splenic B cells, splenic T cells, bone marrow B cells, bone marrow T cells, liver endothelial cells, hepatocytes, liver Kupffer cells (liver macrophages)).

[0016] [Figure 4] A bar graph showing the potent delivery of exemplary LNP preparations (exemplary lipid 7, exemplary lipid 5, exemplary lipid 6, exemplary lipid 1, and MC3 control, each characterized as an LNP preparation containing an ester-linked acetal feature) with potent delivery to various cell types, such as splenic B cells and T cells.

[0017] [Diagram 5] 1 shows a bar graph illustrating the potent delivery of exemplary LNP preparations (exemplary lipid 1, exemplary lipid 2, exemplary lipid 3, exemplary lipid 4, and saline control) with potent delivery to various cell types such as bone marrow B cells, bone marrow memory B cells, bone marrow T cells, bone marrow monocytes, splenic monocytes, splenic T cells, splenic B cells, and splenic memory B cells.

[0018] [Figure 6]1 shows a bar graph illustrating functional delivery of hEPO-encoding mRNA payload in vivo in mice using exemplary LNP preparations (Exemplary Lipid 7, Exemplary Lipid 5, Exemplary Lipid 1). Six hours after injection of the exemplary LNP preparations into mice, the amount of hEPO (ng / mL) in plasma was measured.

[0019] [Figure 7] 1 shows a bar graph depicting the tolerability of two exemplary LNP formulations delivering hEPO (Exemplary Lipid 5, Exemplary Lipid 1) in rats 24 hours after injection. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (U / L) were measured 24 hours after injection.

[0020] [Figure 8] 1 shows a bar graph illustrating the tolerability of two exemplary LNP preparations delivering hEPO (Exemplary Lipid 5, Exemplary Lipid 1) in rats. Monocyte chemoattractant protein-1 (MCP-1) (ng / mL) was measured 6 hours after injection.

[0021] [Figure 9] 1 shows a bar graph illustrating the efficacy of two exemplary LNP preparations (Exemplary Lipid 5, Exemplary Lipid 1) in delivering hEPO in a rat model. Plasma hEPO (ng / mL) was measured over various time points (0, 2, 4, 6, 24, 48, and 72 hours).

[0022] [Figure 10]1 shows a bar graph illustrating the functional delivery of reporter-encoding mRNA payload in vivo for each LNP preparation using six exemplary LNP preparations (exemplary lipid 1, exemplary lipid 8, exemplary lipid 4, exemplary lipid 9, exemplary lipid 10, and exemplary lipid 11) containing 1.0 mg / kg reporter mRNA compared to saline control (vehicle) across various HSC cell types (Lin-, Sca-1+, LSK cells, LT-HSC (CD34-Flk2-), and LT-HSC (CD150+CD48-)) in C57BL6 mice.

[0023] [Figure 11] A bar graph showing the functional delivery of reporter-encoding mRNA payload in vivo for each LNP preparation using six exemplary LNP preparations (exemplary lipid 1, exemplary lipid 8, exemplary lipid 4, exemplary lipid 9, exemplary lipid 10, and exemplary lipid 11) containing 1.0 mg / kg reporter mRNA compared to saline control (vehicle) across various bone marrow (BM) cell types (viable cells, T cells, B cells, CD11b, macrophages, NK cells, CD11c) in C57BL6 mice.

[0024] [Figure 12] A bar graph showing the functional delivery of reporter-encoding mRNA payload in vivo of each LNP preparation using six exemplary LNP preparations (exemplary lipid 1, exemplary lipid 8, exemplary lipid 4, exemplary lipid 9, exemplary lipid 10, and exemplary lipid 11) containing 1.0 mg / kg reporter mRNA compared to saline control (vehicle) across various splenic cell types (T cells, B cells, CD11b, macrophages, NK cells, CD11c) to C57BL6 mice.

[0025] [Figure 13]1 shows a bar graph illustrating the functional delivery of reporter-encoding mRNA payload in vivo for each LNP preparation using six exemplary LNP preparations (exemplary lipid 1, exemplary lipid 8, exemplary lipid 4, exemplary lipid 9, exemplary lipid 10, and exemplary lipid 11) containing 1.0 mg / kg reporter mRNA compared to saline control (vehicle) across various liver cell types (CD31, hepatocytes, CD45, CD11b, Kupffer cells, NK cells, T cells, B cells) to C57BL6 mice.

[0026] [Figure 14] 1 shows heat maps depicting the median fluorescence values ​​of various LNP preparations containing different ionizable lipids normalized to the median fluorescence value of LNP preparations containing exemplary lipid 1 across various cell types (myeloid dendritic cells, splenic B cells, and splenic dendritic cells). The bottom left schematic shows the experimental layout of each heat map of various LNP preparations using the exemplary lipids described according to embodiments of the present disclosure. The "X"s in the bottom left schematic represent the various different exemplary lipids tested in various experiments according to embodiments of the present disclosure.

[0027] [Figure 15] Two heat maps are shown showing the normalized mean reporter expression % (left) or normalized mean median fluorescence value (right) of various LNP preparations containing different ionizable lipids. The mean reporter % and median fluorescence value were normalized to the mean reporter expression % or median mean fluorescence value (right) of the LNP preparation containing exemplary lipid 1 delivered to T cells (myeloid cells), respectively. The asterisk indicates the LNP formulation that resulted in a higher mean reporter expression % compared to the mean % reporter expression % using the LNP preparation containing exemplary lipid 1. The design layout of the exemplary LNP preparations tested in various experiments is shown in the schematic diagram in the bottom left of FIG. 14.

[0028] [Figure 16]Two heat maps are shown showing the normalized mean reporter expression % (left) or median mean fluorescence value (right) of various LNP preparations containing different ionizable lipids. The mean reporter % and median mean fluorescence value were normalized to the reporter expression % (left) or median fluorescence value (right), respectively, of the LNP preparation containing exemplary lipid 1 delivered to LSK (Lin-Sca-1+c-Kit+) cells. The asterisks indicate the LNP formulations that produced a higher mean reporter expression % compared to the mean % reporter expression % using the LNP preparation containing exemplary lipid 1. The design layout of the exemplary LNP preparations tested in various experiments is shown in the schematic diagram in the bottom left of FIG. 14.

[0029] [Figure 17] 1 shows plots depicting reporter expression of exemplary lipid 1 compared to exemplary lipid 11 in HSPCs and mouse LT-HSCs.

[0030] [Figure 18] 13A-13C show bar graphs illustrating delivery of mRNA to bone marrow cells (left) and blood cells (right), respectively, in humanized (NSG-CD34+) mice using exemplary LNP preparations described herein.

[0031] [Figure 19] Bar graphs are shown showing delivery of mRNA to blood cells (left), bone marrow (live cells) (center), and bone marrow (LSK cells) in two mouse strains (Balb / C, C57BL6J mice), respectively, using exemplary LNP preparations described herein.

[0032] [Figure 20] A bar graph of relative luminescence intensity after intramuscular administration of various LNP preparations containing Trilink Fluc mRNA is shown. Luminescence intensity images are also shown in FIG.

[0033] [Figure 21]Figures 21-23 show bar graphs showing base editing in bone marrow, spleen, and liver cells using various LNP preparations containing different exemplary lipids described herein. [Figure 22] Figures 21-23 show bar graphs showing base editing in bone marrow, spleen, and liver cells using various LNP preparations containing different exemplary lipids described herein. [Diagram 23] Figures 21-23 show bar graphs showing base editing in bone marrow, spleen, and liver cells using various LNP preparations containing different exemplary lipids described herein.

[0034] [Figure 24] 1 shows a bar graph illustrating dose-dependent delivery of an exemplary LNP preparation comprising exemplary lipid 1 to mouse HSPCs.

[0035] [Diagram 25] Figures 25A and 25B show bar graphs demonstrating the persistence of delivery to mouse HSPCs of an exemplary LNP preparation comprising exemplary lipid 1. Figures 25C and 25D show bar graphs demonstrating reconstitution of immune and hematopoietic lineages by transfected HSPCs.

[0036] [Figure 26] FIG. 26A and FIG. 26B show bar graphs illustrating delivery of an exemplary LNP preparation comprising an exemplary lipid 1 to human CD34+ HSPCs in vitro.

[0037] [Figure 27] 1 shows a bar graph illustrating delivery of an exemplary LNP preparation comprising an exemplary lipid 1 to non-human primate (NHP) HSPCs.

[0038] definition About: As used herein, the term "about" or "approximately" refers to a value that is similar in relation to the referenced value when used herein with respect to a value. In general, a person skilled in the art familiar with the context will understand the relevant degree of difference encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "about" can encompass 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or a range of values ​​that fall in either direction (greater or smaller) of the referenced value, unless otherwise stated or clear from the context (except where such number exceeds 100% of the possible values).

[0039] Administration: As used herein, the term "administration" typically refers to the administration of a composition to a subject or system. Those skilled in the art will recognize the various routes that may be utilized for administration to a subject, e.g., a human, under appropriate circumstances. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, and the like. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (e.g., may include one or more of topical, such as dermal, intradermal, interdermal, transdermal, etc.), enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, and the like. In some embodiments, administration involves administration that is intermittent (e.g., multiple doses spaced apart in time) and / or periodic (e.g., individual doses spaced apart in the same time period) administration. In some embodiments, administration may involve continuous administration (e.g., perfusion) for at least a selected period of time. In some embodiments, pharmaceutical compositions comprising lipid nanoparticles may be formulated for administration by parenteral (intramuscular, intraperitoneal, intravenous (IV), or subcutaneous injection), transdermal (either passively or using iontophoresis or electroporation), or transmucosal (nasal, vaginal, rectal, or sublingual) routes of administration, or by using bioerodible inserts, and may be formulated in dosage forms appropriate for each route of administration.

[0040] Aliphatic: The term "aliphatic" or "aliphatic group," as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle," "carbocyclic," "alicyclic," or "cycloalkyl") and has one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 carbon atoms. In some embodiments, an aliphatic group contains 1-4 carbon atoms. In some embodiments, an aliphatic group contains 1-3 carbon atoms, and in some embodiments, an aliphatic group contains 1-2 carbon atoms. In some embodiments, "carbocyclic" (or "alicyclic," or "carbocycle," or "cycloalkyl") refers to an optionally substituted monocyclic C 3 -C 8 A hydrocarbon or optionally substituted C group that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. 6 -C 12 Refers to a bicyclic hydrocarbon. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, as well as hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0041] Alkenyl: As used herein, the term "alkenyl" refers to an alkyl group, as defined herein, having one or more double bonds. In some embodiments, the term "alkenyl," used alone or as part of a larger moiety, refers to an alkyl group having at least one double bond and (unless otherwise specified) 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C 2-20 , C 2-18 , C 2-16 , C 2-14 , C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ) . Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0042] Alkenylene: The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0043] Alkyl: As used herein, the term "alkyl" is given its ordinary meaning in the art and can include saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, an alkyl has 1-100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C for straight chain). 1 -C 20 , C for branched chains 2 -C 20), or about 1-10 carbon atoms. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure when such rings are monocyclic or bicyclic, or alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group can be a lower alkyl group, where the lower alkyl group has from 1-4 carbon atoms (e.g., C for a straight chain lower alkyl). 1 -C 4 ).

[0044] Alkylenyl: The term "alkylenyl" or "alkylene" refers to a divalent alkyl group (i.e., a divalent saturated hydrocarbon chain) that is straight chain (i.e., unbranched) or branched, substituted or unsubstituted. Any of the monovalent alkyl groups listed above can become alkylenyl by abstracting a second hydrogen atom from the alkyl. In some embodiments, "alkylenyl" refers to a polymethylene group, i.e., -(CH 2 ) n - and n is a positive integer, preferably 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, or 4 to 8. Substituted alkylenyl is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0045] Alkynyl: As used herein, the term "alkynyl" refers to an alkyl group, as defined herein, having one or more triple bonds. In some embodiments, the term "alkynyl," used alone or as part of a larger moiety, refers to an alkyl group, as defined herein, having at least one triple bond and (unless otherwise specified) 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C 2-20 , C 2-18 , C 2-16 , C 2-14 , C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C2-3 ) refers to an optionally substituted straight or branched chain hydrocarbon group having an alkynyl group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0046] Amino Acid: In its broadest sense, as used herein, refers to any compound and / or substance that can be incorporated into a polypeptide chain, for example, through the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H 2 The amino acid has a NC(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a non-natural amino acid, in some embodiments, the amino acid is a D-amino acid, and in some embodiments, the amino acid is an L-amino acid. A "standard amino acid" refers to any of the 20 standard L-amino acids that are typically found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid other than the standard amino acids, whether it is synthetically prepared or obtained from a natural source. In some embodiments, amino acids, including carboxy- and / or amino-terminal amino acids, in a polypeptide may contain structural modifications compared to the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., an amino group, a carboxylic acid group, one or more protons, and / or a hydroxyl group) compared to the general structure. In some embodiments, such modifications may, for example, alter the circulating half-life of a polypeptide containing a modified amino acid compared to a polypeptide containing the same unmodified amino acid. In some embodiments, such modifications do not significantly alter the relevant activity of a polypeptide containing the modified amino acid compared to a polypeptide containing the same unmodified amino acid. As will be clear from the context, in some embodiments, the term "amino acid" may be used to refer to a free amino acid, and in some embodiments, to an amino acid residue of a polypeptide.

[0047] Animal: as used herein refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans of either sex and at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animals are mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cows, primates, and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or parasites. In some embodiments, the animals may be transgenic animals, genetically engineered animals, and / or clones.

[0048] Aptamer: As used herein, the term "aptamer" refers to a macromolecule composed of nucleic acids (e.g., RNA, DNA) that binds tightly to a specific molecular target (e.g., umbrella topology glycans). A particular aptamer can be described by a linear nucleotide sequence and is typically about 15-60 nucleotides in length. Without wishing to be bound by any theory, it is contemplated that the nucleotide chains in an aptamer form intramolecular interactions that fold the molecule into a complex three-dimensional shape that allows the aptamer to bind tightly to the surface of its target molecule. Given the extraordinary diversity of molecular shapes that exist within the field of all possible nucleotide sequences, aptamers can be obtained for a wide range of molecular targets, including proteins and small molecules. In addition to high specificity, aptamers typically have very high affinities for their targets (e.g., picomolar to low nanomolar range affinities for proteins). In many embodiments, aptamers are chemically stable and can be boiled or frozen without loss of activity. Aptamers are synthetic molecules, and therefore amenable to various modifications that can optimize their function for specific applications. For example, aptamers can be modified to dramatically reduce their susceptibility to enzyme degradation in blood for use in in vivo applications. In addition, aptamers can be modified to change their biodistribution or plasma residence time.

[0049] Aryl: The term "aryl" refers to an alkyl group having a total of 6 to 14 ring members, e.g., C 6-14 ), where at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, "aryl" refers to an aromatic ring system, including but not limited to phenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Unless otherwise specified, "aryl" groups are hydrocarbons.

[0050] Associated: As used herein, two events or entities are "associated" with each other when the presence, level, degree, type, and / or form of one correlates with that of the other. For example, a particular entity (e.g., a polypeptide, gene signature, metabolite, microorganism) is considered to be associated with a particular disease, disorder, or condition when its presence, level, and / or form correlates with the incidence and / or susceptibility of the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically "associated" with each other when they directly or indirectly interact with each other such that they are in and / or maintain physical proximity to each other. In some embodiments, two or more entities that are physically associated with each other are covalently bound to each other, and in some embodiments, two or more entities that are physically associated with each other are not covalently bound to each other but are non-covalently associated, for example, by hydrogen bonds, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0051] Biocompatible: The term "biocompatible," as used herein, refers to a material that, when placed in contact with living tissue, e.g., in vivo, does not cause significant harm to such tissue. In certain embodiments, a material is "biocompatible" if it is not toxic to cells. In certain embodiments, materials are "biocompatible" if their addition to cells in vitro results in 20% or less cell death and / or if their administration in vivo does not induce significant inflammation or other such adverse effects.

[0052] Biodegradable: As used herein, the term "biodegradable" refers to a material that, when introduced into a cell, is broken down (e.g., by cellular mechanisms, such as by enzymatic degradation, hydrolysis, and / or a combination thereof) into components that the cell can reuse or dispose of without significant toxic effects on the cell. In certain embodiments, the components produced by the degradation of a biodegradable material are biocompatible and therefore do not induce significant inflammation and / or other adverse effects in vivo. In some embodiments, biodegradable polymeric materials are broken down into their component monomers. In some embodiments, the degradation of a biodegradable material (including, for example, a biodegradable polymeric material) involves hydrolysis of ester bonds. Alternatively or additionally, in some embodiments, the degradation of a biodegradable material (including, for example, a biodegradable polymeric material) involves cleavage of urethane bonds. Exemplary biodegradable polymers include, for example, polymers of hydroxy acids such as lactic acid and glycolic acid, including, but not limited to, poly(hydroxyl acid), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates, poly(lactide-co-caprolactone), blends and copolymers thereof. Also included are, for example, albumin, Many natural polymers are biodegradable, including proteins such as collagen, gelatin, and prolamines, e.g., zein, and polysaccharides such as alginates, cellulose derivatives, and polyhydroxyalkanoates, e.g., polyhydroxybutyrate blends, and copolymers thereof. Those skilled in the art will know or be able to determine when such polymers are their biocompatible and / or biodegradable derivatives (e.g., when related to the parent polymer by substantially identical structure differing only in the substitution or addition of certain chemical groups known in the art).

[0053] Biologically active: as used herein refers to an observable biological effect or result achieved by an agent or entity of interest. For example, in some embodiments, a specific binding interaction is a biological activity. In some embodiments, modulation (e.g., induction, enhancement, or inhibition) of a biological pathway or event is a biological activity. In some embodiments, the presence or degree of biological activity is assessed through detection of a direct or indirect product produced by the biological pathway or event of interest.

[0054] Biological sample: As used herein, the term "biological sample" typically refers to a sample obtained or derived from a biological source of interest (e.g., tissue, or organism, or cell culture) as described herein. In some embodiments, the source of interest includes an organism, such as an animal or human. In some embodiments, the biological sample is or includes a biological tissue or biological fluid. In some embodiments, the biological sample can be or includes bone marrow, blood; blood cells; ascites; tissue or fine needle biopsy sample; cell-containing body fluid; free floating nucleic acid; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluid; skin swab; vaginal swab; oral swab; nasal swab; washing or lavage, such as ductal lavage or bronchoalveolar lavage; aspirate; scraping; bone marrow specimen; tissue biopsy specimen; surgical specimen; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the cells obtained are or comprise cells from the individual from whom the sample is obtained. In some embodiments, the sample is a "primary sample" obtained directly from the source of interest by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, feces, etc.), and the like. In some embodiments, as will be clear from the context, the term "sample" refers to a preparation obtained by processing (e.g., by removing one or more components and / or adding one or more agents) of the primary sample. For example, filtering using a semi-permeable membrane. Such a "processed sample" may include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components.

[0055] Divalent: As used herein, the term "divalent" refers to a chemical moiety that has two points of attachment. For example, a "divalent C 1-8 (or C 1-6) Saturated or unsaturated straight or branched hydrocarbon chain" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0056] Bridged Bicyclic: As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, saturated or partially unsaturated, i.e., carbocyclic or heterocyclic, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, and a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (except hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more of the substituents described for the aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include, but are not limited to, the following: [ka]

[0057] Cancer: The terms "cancer," "malignancy," "neoplasm," "tumor," and "carcinoma" are used herein to refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous proliferation, such that they exhibit an abnormal growth phenotype characterized by a marked loss of control of cell proliferation. In some embodiments, a tumor may be or include cells that are precancerous (e.g., benign), malignant, premetastatic, metastatic, and / or nonmetastatic. The present disclosure specifically identifies certain cancers to which its teachings may be particularly relevant. In some embodiments, the relevant cancer may be characterized as a solid tumor. In some embodiments, the relevant cancer may be characterized as a hematological tumor. In general, examples of different types of cancers known in the art include, for example, hematopoietic cancers including leukemia, lymphoma (Hodgkin's and non-Hodgkin's), myeloma, and myeloproliferative disorders; sarcoma, melanoma, adenoma, cancer of solid tissues, squamous cell carcinoma of the mouth, throat, larynx, and lung, liver cancer, reproductive tract cancers such as prostate, cervical, bladder, uterine, and endometrial cancer, as well as benign lesions such as renal cell carcinoma, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, endocrine system cancer, thyroid cancer, parathyroid cancer, head and neck cancer, breast cancer, gastrointestinal cancer, and nervous system cancers, papilloma, and the like.

[0058] Carrier: as used herein, refers to a diluent, adjuvant, excipient, or vehicle that is administered with the composition. In some exemplary embodiments, the carrier can include sterile liquids such as, for example, water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or includes one or more solid components.

[0059] Carbocyclyl: As used herein, the terms "carbocyclyl", "carbocycle", and "carbocyclic ring" refer to a saturated or partially unsaturated cycloaliphatic monocyclic, bicyclic, or polycyclic ring system as described herein having 3 to 14 members, where the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, "carbocyclyl" (or "alicyclic") refers to an optionally substituted monocyclic C 3 -C 8 A hydrocarbon or optionally substituted C group that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. 6 -C 12 It refers to a bicyclic hydrocarbon. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl group has 3 to 6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0060] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, circumstances, sets of conditions, etc. that may not be identical to each other, but are sufficiently similar to permit a comparison between them, such that a person skilled in the art would understand that a conclusion can be reasonably drawn based on the observed differences or similarities. In some embodiments, a comparable set of conditions, circumstances, individuals, or populations is characterized by a number of substantially identical characteristics and one or a few characteristics that vary. A person skilled in the art will understand what degree of identity is necessary in any given situation for two or more such agents, entities, circumstances, sets of conditions, etc. to be considered comparable, depending on the context. For example, a person skilled in the art will understand that sets of circumstances, individuals, or populations are comparable to each other if the differences in the results obtained or the phenomena observed under or with the different sets of circumstances, individuals, or populations are caused by the variation of those characteristics that vary, or are characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion indicating the variation of the characteristics.

[0061] Component: Those skilled in the art will understand that the term "composition" may be used to refer to a separate physical entity that includes one or more defined components. In general, unless otherwise specified, a composition may be in any form, e.g., gas, gel, liquid, solid, etc.

[0062] Comprising: A composition or method described herein as "comprising" one or more recited elements or steps is open-ended, meaning that the recited elements or steps are essential, but that other elements or steps may be added within the scope of the composition or method. It is also understood that, to avoid redundancy, any composition or method described as "comprising" (or "comprises") one or more recited elements or steps also describes a corresponding, more limited composition or method that "consisting essentially of" (or "consists essentially of") the same recited elements or steps, meaning that the composition or method includes the recited essential elements or steps, and may also include additional elements or steps that do not materially affect the basic and novel characteristics of the composition or method. It is also understood that any composition or method described herein as "comprising" or "consisting essentially of" one or more recited elements or steps also describes a corresponding, more limited, close-ended composition or method that "consisting of" (or "consists of") the recited elements or steps, to the exclusion of any other unrecited elements or steps. In any composition or method disclosed herein, known or disclosed equivalents of any recited essential element or step may be substituted for that element or step.

[0063] "Improve", "Increase", "Inhibit", or "Reduce": As used herein, the terms "improve", "increase", "inhibit", "reduce", or their grammatical equivalents refer to a value compared to a baseline or other reference measurement. In some embodiments, a suitable reference measurement may be or include a measurement in a particular system (e.g., a single individual) under comparable conditions in the absence of a particular agent or treatment (before and / or after), or in the presence of a suitable comparable reference agent. In some embodiments, a suitable reference measurement may be or include a measurement in a comparable system known or expected to respond in a particular manner in the presence of the relevant agent or treatment.

[0064] Determining: Many methodologies described herein include a "determining" step. Upon reading this specification, one of skill in the art will understand that such "determining" may be utilized or accomplished through the use of any of a variety of techniques available to one of skill in the art, including, for example, certain techniques explicitly mentioned herein. In some embodiments, determining involves the manipulation of the physical sample. In some embodiments, determining involves the review and / or manipulation of data or information, for example, using a computer or other processing unit adapted to perform the relevant analysis. In some embodiments, determining involves receiving relevant information and / or materials from a source. In some embodiments, determining involves comparing one or more characteristics of the sample or entity to a comparable reference.

[0065] Encapsulated: The term "encapsulated" is used herein to refer to a substance that is completely surrounded by another material.

[0066] Excipient: as used herein refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0067] Expression: As used herein, the term "expression" of a nucleic acid sequence refers to the generation of any gene product from the nucleic acid sequence. In some embodiments, the gene product can be a transcription product. In some embodiments, the gene product can be a polypeptide. In some embodiments, expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription), (2) processing of the RNA transcript (e.g., by splicing, editing, 5' capping, and / or 3' end formation), (3) translation of the RNA into a polypeptide or protein, and / or (4) post-translational modification of the polypeptide or protein.

[0068] Haloaliphatic: The term "haloaliphatic" refers to an aliphatic group substituted with one or more halogen atoms (e.g., 1, 2, 3, 4, 5, 6, or 7 halo, such as fluoro, iodo, bromo, or chloro). In some embodiments, a haloaliphatic group contains 1-7 halogen atoms. In some embodiments, a haloaliphatic group contains 1-5 halogen atoms. In some embodiments, a haloaliphatic group contains 1-3 halogen atoms.

[0069] Haloalkyl: The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms (e.g., 1, 2, 3, 4, 5, 6, or 7 halo, such as fluoro, iodo, bromo, or chloro). In some embodiments, a haloalkyl group contains 1-7 halogen atoms. In some embodiments, a haloalkyl group contains 1-5 halogen atoms. In some embodiments, a haloalkyl group contains 1-3 halogen atoms.

[0070] Heteroalkylenyl: As used herein, the term "heteroalkylenyl" or "heteroalkylene" refers to an optionally substituted linear (i.e., unbranched) or branched divalent alkyl group (i.e., a divalent saturated hydrocarbon chain) having, in addition to carbon atoms, 1 to 5 heteroatoms. The term "heteroatom" is described below. In some embodiments, a heteroalkylenyl group contains 2 to 10 carbon atoms, with 1 to 3 carbon atoms being optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, a heteroalkylenyl group contains 2 to 8 carbon atoms, with 1 to 3 carbon atoms being optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, a heteroalkylenyl group contains 4 to 8 carbon atoms, with 1 to 3 carbon atoms being optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroalkylenyl groups contain 2-5 carbon atoms with 1-2 carbon atoms being optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroalkylenyl groups contain 1-3 carbon atoms with 1 carbon atom being optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroalkylenyl groups include, but are not limited to, -CH 2 O-, -(CH 2 ) 2 O-, -CH 2 OCH 2 -, -O(CH 2) 2 -, -(CH 2 ) 3 O-, -(CH 2 ) 2 OCH 2 -, -CH 2 O(CH 2 ) 2 -, -O(CH 2 ) 3 -, -(CH 2 ) 4 O-, -(CH 2 ) 3 OCH 2 -, -CH 2 O(CH 2 ) 3 -, -(CH 2 ) 2 O(CH 2 ) 2 -, -O(CH 2 ) 4 - Unless otherwise specified, C x Heteroalkylenyl refers to a heteroalkylenyl having x carbon atoms before being replaced with a heteroatom.

[0071] Heteroaryl: The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5-6 membered monocyclic heteroaryl or 9-10 membered bicyclic heteroaryl), sharing 6, 10, or 14 pi electrons in the cyclic array, and having 1 to 5 heteroatoms in addition to the carbon atoms. Exemplary heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzisoxazolyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzisoxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include optionally substituted rings.

[0072] Heteroatom: The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).

[0073] Heterocycle: The terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably herein and refer to a stable 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-16 membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more heteroatoms, such as 1-4, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiamorpholinyl, and [ka] Heterocyclyl groups can be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl portions are independently and optionally substituted. Bicyclic heterocyclic rings also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or alicyclic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. Bicyclic heterocyclic rings can also be spirocyclic ring systems (e.g., 7-11 membered spirocyclic fused heterocyclic rings having, in addition to carbon atoms, one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) as defined above). Bicyclic heterocyclic rings can also be bridged ring systems (e.g., 7-11 membered bridged heterocyclic rings having 1, 2, or 3 bridging atoms).

[0074] Inhibitor: As used herein, the term "inhibitor" refers to an entity, condition, or event whose presence, level, or extent correlates with a decrease in the level or activity of a target. In some embodiments, an inhibitor may act directly (where it directly affects a target, e.g., by binding to the target), and in some embodiments, an inhibitor may act indirectly (where it affects the target by interacting with and / or altering a regulator of the target such that the level and / or activity of the target is reduced). In some embodiments, an inhibitor is one whose presence or level correlates with a target level or activity that is reduced compared to a particular reference level or activity (e.g., observed under appropriate reference conditions, such as the presence of a known inhibitor or the absence of the inhibitor in question).

[0075] In vitro: As used herein, the term "in vitro" refers to events that take place not within a multicellular organism but in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc.

[0076] Isolated: As used herein, refers to substances and / or entities that are (1) separated from at least some of the components with which they are initially produced (in nature and / or in an experimental setting) and / or (2) designed, produced, prepared, and / or manufactured by the hand of man. Isolated substances and / or entities can be separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% of the other components with which they are initially produced. In some embodiments, an isolated agent is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. In some embodiments, as will be understood by those skilled in the art, a substance may still be considered "isolated" or even "pure" after being combined with certain other components, such as, for example, one or more carriers or excipients (e.g., buffers, solvents, water, etc.), and in such embodiments, the percentage of isolation or purity of the substance is calculated without including such carriers or excipients. By way of example, in some embodiments, a biological polymer, such as a polypeptide or polynucleotide, occurring in nature is considered to be "isolated" if: a) its origin or source is free from association with some or all of the components that accompany it in its natural state in nature; b) it is substantially free of other polypeptides or nucleic acids of the same species from the species that produces it in nature; or c) it is expressed by or associated with components from a cell or other expression system that is not of the species that produces it in nature. Thus, for example, in some embodiments, a polypeptide that is chemically synthesized or synthesized in a cellular system other than the one that produces it in nature is considered to be an "isolated" polypeptide.Alternatively, or in addition, in some embodiments, a polypeptide that has been subjected to one or more purification techniques may be considered to be an "isolated" polypeptide to the extent that it has been separated from a) other components with which it is associated in nature, and / or b) other components with which it was associated when originally produced.

[0077] In vivo: As used herein, refers to events that occur within multicellular organisms, such as humans and non-human animals. In the context of cell-based systems, the term can be used to refer to events that occur within living cells (as opposed to, for example, in vitro systems).

[0078] Linker: As used herein, it is used to refer to that portion of a multi-element agent that connects different elements to one another. For example, one of skill in the art will understand that a polypeptide that includes two or more functional or organizational domains in its structure will often include a stretch of amino acids between such domains that connects them to one another. In some embodiments, a polypeptide that includes a linker element "L" has an overall structure of the general form S1-L'-S2, where S1 and S2 may be the same or different and may represent two domains associated to one another by a linker. In some embodiments, the polypeptide linker is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more amino acids in length. In some embodiments, the linker is characterized in that it does not tend to adopt a rigid three-dimensional structure, but rather provides flexibility to the polypeptide. A variety of different linker elements can be suitably used when engineering polypeptides (e.g., fusion polypeptides) known in the art (e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ, et al. (1994) Structure 2:1 121-1123).

[0079] Nanoparticles: As used herein, the term "nanoparticles" refers to particles having a diameter of less than 1000 nanometers (nm). In some embodiments, nanoparticles have a diameter of less than 300 nm as defined by the National Science Foundation. In some embodiments, nanoparticles have a diameter of less than 100 nm as defined by the National Institutes of Health. In some embodiments, nanoparticles are micelles in that they contain an enclosed compartment separated from the bulk solution by a micellar membrane, typically composed of amphiphilic entities that surround and encapsulate a space or compartment (e.g., to define a lumen). In some embodiments, the micellar membrane is composed of at least one polymer, such as, for example, a biocompatible and / or biodegradable polymer. In some embodiments, the lipid nanoparticles described herein may have an average hydrodynamic diameter of about 30 to about 170 nm. In some embodiments, the lipid nanoparticles described herein may have an average hydrodynamic diameter of about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, or any range having endpoints defined by any two of the foregoing values. For example, in some embodiments, the lipid nanoparticles described herein have an average hydrodynamic diameter of 50 nm to 100 nm.

[0080] Nanoparticle composition: As used herein, the term "nanoparticle composition" refers to a composition containing at least one nanoparticle and at least one additional agent or component. In some embodiments, the nanoparticle composition contains a population of substantially uniform nanoparticles as described herein.

[0081] Nucleic acid: as used herein in its broadest sense refers to any compound and / or substance that is or can be incorporated into an oligonucleotide chain. In some embodiments, a nucleic acid is a compound and / or substance that is or can be incorporated into an oligonucleotide chain via a phosphodiester bond. As will be clear from the context, in some embodiments, a "nucleic acid" refers to an individual nucleic acid residue (e.g., a nucleotide and / or a nucleoside), and in some embodiments, a "nucleic acid" refers to an oligonucleotide chain that includes individual nucleic acid residues. In some embodiments, a "nucleic acid" is or includes RNA, and in some embodiments, a "nucleic acid" is or includes DNA. In some embodiments, a nucleic acid is, includes, or consists of one or more naturally occurring nucleic acid residues. In some embodiments, a nucleic acid is, includes, or consists of one or more nucleic acid analogs. In some embodiments, a nucleic acid analog differs from a nucleic acid in that it does not utilize a phosphodiester backbone. For example, in some embodiments, the nucleic acid is, comprises, or consists of one or more "peptide nucleic acids," which are known in the art and have peptide bonds in the backbone instead of phosphodiester bonds, and are considered within the scope of the present invention. Alternatively or additionally, in some embodiments, the nucleic acid has one or more phosphorothioate and / or 5'-N-phosphoramidite linkages rather than phosphodiester linkages. In some embodiments, the nucleic acid is, comprises, or consists of one or more naturally occurring nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine).In some embodiments, the nucleic acid is, comprises, or consists of one or more nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, the nucleic acid comprises one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) compared to the sugars in naturally occurring nucleic acids. In some embodiments, the nucleic acid has a nucleotide sequence that encodes a functional gene product, such as RNA or a protein. In some embodiments, the nucleic acid comprises one or more introns. In some embodiments, the nucleic acid is prepared by one or more of isolation from a natural source, enzymatic synthesis by polymerization based on a complementary template (in vivo or in vitro), reproduction in a recombinant cell or system, and chemical synthesis. In some embodiments, the nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues in length. In some embodiments, the nucleic acid is partially or completely single-stranded, in some embodiments, the nucleic acid is partially or completely double-stranded, in some embodiments, the nucleic acid has a nucleotide sequence that includes at least one element that encodes a polypeptide or is the complement of a sequence that encodes a polypeptide.In some embodiments, the nucleic acid has enzymatic activity.

[0082] Operably linked: As used herein, refers to a juxtaposition in which the described components are in a relationship permitting them to function in their intended manner. A control element "operably linked" to a functional element is associated with the functional element in a manner such that expression and / or activity of the functional element is achieved under conditions compatible with the control element. In some embodiments, an "operably linked" control element is contiguous (e.g., covalently linked) with a coding element of interest, and in some embodiments, the control element acts in trans or on the functional element of interest.

[0083] For the purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., the entire contents of which are incorporated herein by reference. th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0084] Parenteral: As used herein, the phrases "parenteral administration" and "administered parenterally" have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intraventricular, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0085] Patient: As used herein, the term "patient" refers to any organism to which a provided composition is or can be administered, for example, experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Exemplary patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient is suffering from or susceptible to one or more disorders or conditions. In some embodiments, the patient exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient has been diagnosed as having one or more disorders or conditions. In some embodiments, the disorder or condition is or includes cancer, or one or more tumors. In some embodiments, the patient is undergoing or has undergone a certain therapy to diagnose and / or treat a disease, disorder, or condition.

[0086] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharma- ceutically acceptable carriers. In some embodiments, the active agent is present in an amount of unit doses suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition may be specially formulated for administration in solid or liquid form, including oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., as a sterile solution or suspension, or sustained release formulation, e.g., subcutaneous, intramuscular, intravenous, or epidural injection; topical application, e.g., as a cream, ointment, or controlled release patch, or spray applied to the skin, lungs, or buccal cavity; vaginally or rectally, e.g., as a pessary, cream, or foam; sublingually; ophthalmic; transdermal; or compatible with nasal, pulmonary, and other mucosal surfaces.

[0087] Pharmaceutically acceptable: As used herein, the phrase "pharmacologically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0088] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutical acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a material encapsulating a liquid or solid filler, diluent, excipient, or solvent, involved in carrying or transporting a compound of interest from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials which can function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffer solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical formulations.

[0089] Pharmaceutically acceptable salts: The term "pharmaceutical acceptable salts" as used herein refers to salts of such compounds that are suitable for use in a pharmaceutical context, i.e., salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al., describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutical acceptable salts include non-toxic acid addition salts, which are salts of amino groups 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, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. In some embodiments, pharma- ceutically acceptable salts include, but are not limited to, 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, hydrogen iodide, 2-hydroxybenzoate, benzoic acid salt ... Examples of the salts include hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.In some embodiments, pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0090] Prevent or Prevention: As used herein, when used in relation to the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention may be considered complete if it has delayed the onset of the disease, disorder, or condition for a predefined period of time.

[0091] Protein: As used herein, the term "protein" refers to a polypeptide (i.e., a chain of at least two amino acids linked together by peptide bonds). A protein may contain moieties other than amino acids (e.g., may be a glycoprotein, proteoglycan, etc.) and / or may be processed or modified. Those skilled in the art will understand that a "protein" may be a complete polypeptide chain produced by a cell (with or without a signal sequence) or a characteristic portion thereof. Those skilled in the art will understand that a protein may sometimes include more than one polypeptide chain, for example, linked by one or more disulfide bonds or associated by other means. Polypeptides may contain L-amino acids, D-amino acids, or both, and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, methylation, etc. In some embodiments, a protein may include natural amino acids, unnatural amino acids, synthetic amino acids, and combinations thereof. The term "peptide" is generally used to refer to a polypeptide having a length of less than about 100 amino acids, less than about 50 amino acids, less than 20 amino acids, or less than 10 amino acids. In some embodiments, the protein is an antibody, an antibody fragment, a biologically active portion thereof, and / or a characteristic portion thereof.

[0092] Polypeptide: The term "polypeptide" as used herein generally has its art-recognized meaning of a polymer of at least three amino acids. Those of skill in the art will appreciate that the term "polypeptide" is intended to be general enough to encompass not only polypeptides having the complete sequences listed herein, but also polypeptides that represent functional fragments of such complete polypeptides (i.e., fragments that retain at least one activity). Moreover, those of skill in the art will appreciate that protein sequences generally tolerate some substitutions without destroying activity. Thus, any polypeptide that retains activity and shares one or more highly conserved regions with another polypeptide of the same genus, usually encompassing at least 3-4, and often up to 20 or more amino acids, including at least one region of very high identity, usually at least about 30-40% overall sequence identity, often more than about 50%, 60%, 70%, or 80%, and even usually often more than 90%, or even 95%, 96%, 97%, 98%, or 99%, is encompassed within the related term "polypeptide" as used herein. Polypeptides may contain L-amino acids, D-amino acids, or both, and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, methylation, and the like. In some embodiments, proteins may contain natural amino acids, unnatural amino acids, synthetic amino acids, and combinations thereof. The term "peptide" is generally used to refer to a polypeptide having a length of less than about 100 amino acids, less than about 50 amino acids, less than 20 amino acids, or less than 10 amino acids. In some embodiments, the protein is an antibody, an antibody fragment, a biologically active portion thereof, and / or a characteristic portion thereof.

[0093] Prevention: The term "prevention" as used herein refers to delaying the onset and / or reducing the frequency and / or severity of one or more symptoms of a particular disease, disorder, or condition. In some embodiments, prevention is assessed on a population basis, such that an agent is considered to "prevent" a particular disease, disorder, or condition if a statistically significant reduction in the onset, frequency, and / or intensity of one or more symptoms of the disease, disorder, or condition is observed in a population susceptible to the disease, disorder, or condition. Prevention can be considered complete if it delays the onset of the disease, disorder, or condition for a predefined period of time.

[0094] Protecting group: As used herein, the phrase "protecting group" refers to a temporary substituent that protects a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. "Si-protecting group" is a protecting group that contains a Si atom, such as Si-trialkyl (e.g., trimethylsilyl, tributylsilyl, t-butyldimethylsilyl), Si-triaryl, Si-alkyl-diphenyl (e.g., t-butyldiphenylsilyl), or Si-aryl-dialkyl (e.g., Si-phenyldialkyl). Generally, Si-protecting groups are attached to an oxygen atom. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Such protecting groups (and related protected moieties) are described in detail below.

[0095] Hydroxyl groups that can be protected are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference in its entirety. rdedition, John Wiley & Sons, 1999. Examples of suitable protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formates, acetates, propionates, pentanoates, crotonates, and benzoates. Specific examples of suitable esters include formates, benzoyl formates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4-(ethylenedithio)pentanoates, pivalates (trimethylacetates), crotonates, 4-methoxy-crotonates, benzoates, p-benzylbenzoates, and 2,4,6-trimethylbenzoates. Examples of suitable carbonates include 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl carbonate. Examples of suitable silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl ether, and other trialkylsilyl ethers. Examples of suitable alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, and allyl ethers, or derivatives thereof. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyran-2-yl ether. Examples of suitable arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl ethers.

[0096] Protected amines are well known in the art and include those detailed in Greene (1999). Suitable mono-protected amines further include, but are not limited to, aralkylamines, carbamates, allylamines, amides, and the like. Examples of suitable mono-protected amino moieties include t-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxocarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamide, acetamide, chloroacetamide, dichloroacetamide, trichloroacetamide, phenylacetamide, trifluoroacetamide, benzamide, t-butyldiphenylsilyl, and the like. Suitable di-protected amines include amines substituted with two substituents independently selected from those listed above as mono-protected amines, and further include cyclic imides such as phthalimides, maleimides, succinimides, etc. Suitable di-protected amines also include pyrroles, such as 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine, and azides.

[0097] Protected aldehydes are well known in the art and include those detailed in Greene (1999). Suitable protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, and the like. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxane, 1,3-dioxolane, semicarbazones, and derivatives thereof.

[0098] Protected carboxylic acids are well known in the art and include those detailed in Greene (1999). Suitable protected carboxylic acids include, but are not limited to, optionally substituted C 1-6 Further included are aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, etc. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl esters, each group being optionally substituted. Additional suitable protected carboxylic acids include oxazolines and orthoesters.

[0099] Protected thiols are well known in the art and include those detailed in Greene (1999).Suitably protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates.Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioesters, to name just a few.

[0100] Protein: The term "protein" as used herein refers to one or more polypeptides that function as separate units. When a single polypeptide is a separate functional unit and does not require permanent or temporary physical association with other polypeptides to form a separate functional unit, the terms "polypeptide" and "protein" may be used interchangeably. When a separate functional unit is composed of more than one polypeptide that physically associates with each other, the term "protein" may be used to refer to multiple polypeptides that are physically associated and function together as a separate unit. In some embodiments, a protein may include moieties other than amino acids (e.g., may be a glycoprotein, proteoglycan, etc.) and / or may be processed or modified. One of skill in the art will understand that in some embodiments, the term "protein" may refer to the complete polypeptide chain produced by a cell (e.g., with or without a signal sequence) and / or a form that is active within the cell (e.g., a truncated or complexed form). In some embodiments where a protein is composed of multiple polypeptide chains, such chains may be covalently associated with each other, e.g., by one or more disulfide bonds, or may be associated by other means.

[0101] Pure: As used herein, an agent or entity is "pure" if it is substantially free of other components. For example, a preparation that contains greater than about 90% of a particular agent or entity is typically considered to be a pure preparation. In some embodiments, the agent or entity is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure.

[0102] Reference: as used herein describes a standard or control against which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially simultaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as will be understood by those of skill in the art, a reference or control is determined or characterized under conditions or circumstances equivalent to those being evaluated. Those of skill in the art will understand when there is sufficient similarity to justify reliance and / or comparison on a particular possible reference or control.

[0103] Sample: As used herein, the term "sample" typically refers to an aliquot of material obtained or derived from a source of interest as described herein. In some embodiments, the source of interest is a biological or environmental source. In some embodiments, the source of interest may be or include a cell, or an organism such as a microorganism, a plant, or an animal (e.g., a human). In some embodiments, the source of interest is or includes a biological tissue or fluid. In some embodiments, the biological tissue or fluid may be or include amniotic fluid, aqueous humor, peritoneal fluid, bile, bone marrow, blood, breast milk, cerebrospinal fluid, earwax, chyle, chime, ejaculate, endolymph, exudate, feces, gastric acid, gastric juice, lymph, mucus, pericardial fluid, perilymph, peritoneal fluid, pleural fluid, pus, eye discharge, saliva, sebum, semen, serum, smegma, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vitreous, vomit, and / or combinations or components thereof. In some embodiments, the biological fluid may be or include intracellular fluid, extracellular fluid, intravascular fluid (plasma), interstitial fluid, lymph, and / or intercellular fluid. In some embodiments, the biological fluid may be or include phytoexudates. In some embodiments, the biological tissue or sample may be obtained, for example, by aspiration, biopsy (e.g., fine needle biopsy or tissue biopsy), swab (e.g., oral, nasal, skin, or vaginal swab), scraping, surgery, lavage or washing (e.g., bronchoalveolar, ductal, nasal, ocular, oral, uterine, vaginal, or other lavage or washing). In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the sample is a "primary sample" obtained directly from the source of interest by any suitable means. In some embodiments, as will be clear from the context, the term "sample" refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components and / or adding one or more agents). For example, filtering using a semi-permeable membrane. Such a "processed sample" may comprise, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to one or more techniques, such as amplification or reverse transcription of nucleic acids, isolation and / or purification of certain components.

[0104] Stable nanoparticle compositions: The term "stable" as applied to compositions herein means that the compositions maintain one or more aspects of their physical structure (e.g., particle size range and / or distribution) over a period of time. In some embodiments, a stable nanoparticle composition is one in which the mean particle size, maximum particle size, particle size range, and / or particle size distribution (i.e., percentage of particles above a specified size and / or outside a specified size range) are maintained under defined conditions for a period of time. In some embodiments, a stable provided composition is one in which biologically relevant activity is maintained for a period of time. In some embodiments, the period of time is at least about 1 hour, and in some embodiments, the period of time is about 5 hours, about 10 hours, about one (1) day, about one (1) week, about two (2) weeks, about one (1) month, about two (2) months, about three (3) months, about four (4) months, about five (5) months, about six (6) months, about eight (8) months, about ten (10) months, about twelve (12) months, about twenty-four (24) months, about thirty-six (36) months, or more. In some embodiments, the period of time is within a range of about one (1) day to about twenty-four (24) months, about two (2) weeks to about twelve (12) months, about two (2) months to about five (5) months, etc. For example, a nanoparticle composition is stable if a population of nanoparticles is subjected to storage, temperature changes, and / or pH changes for extended periods of time and the majority of the nanoparticles in the composition maintain diameters within the recited ranges. In some embodiments, the stable composition is stable at ambient conditions. In some embodiments, the stable composition is stable under biological conditions (i.e., in phosphate buffered saline at 37° C.).

[0105] Sterolyl: The term "sterolyl" as used herein refers to a 17-membered fused polycyclic ring moiety that is saturated or partially unsaturated, substituted with at least one hydroxyl group, and has a single point of attachment to the remainder of the molecule at any substitutable carbon or oxygen atom. In some embodiments, the sterolyl group is a cholesterolyl group, or a variant or derivative thereof. In some embodiments, the cholesterolyl group is modified. In some embodiments, the cholesterolyl group is an oxidized cholesterolyl group (e.g., oxidized at the beta ring structure or the hydrocarbon tail structure). In some embodiments, the cholesterolyl group is an esterified cholesterolyl group. In some embodiments, the cholesterolyl group is a phytosterolyl group. Exemplary sterolyl groups include, but are not limited to, 25-hydroxycholesterolyl (25-OH), 20α-hydroxycholesterolyl (20α-OH), 27-hydroxycholesterolyl, 6-keto-5α-hydroxycholesterolyl, 7-ketocholesterolyl, 7β-hydroxycholesterolyl, 7α-hydroxycholesterolyl, 7β-25-dihydroxycholesterolyl, beta-sitosterolyl, stigmasterolyl, brassicasterolyl, and campesterolyl.

[0106] Subject: As used herein, the term "subject" refers to an organism, typically a mammal (e.g., in some embodiments, a human, including prenatal human forms). In some embodiments, the subject suffers from the relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject is one who has one or more characteristics that are susceptible or at risk for being susceptible to the disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual for whom and / or upon whom diagnosis and / or treatment is to be performed.

[0107] Substantially: As used herein, the term "substantially" refers to a qualitative state that indicates the total or nearly total extent or degree of a desired characteristic or property. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, go completely to completion and / or toward complete completion, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0108] Substituted or Optionally Substituted: The compounds of the present disclosure described herein may contain moieties that are optionally substituted and / or substituted. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogens, either explicitly or implicitly from the structure (e.g., [ka] At least [ka] Refers to, [ka] At least [ka] (refers to "optionally substituted"). 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 substituents may be the same or different at all positions. The combinations of substituents envisioned by the present 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 substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. Groups described as "substituted" preferably have 1-4 substituents, more preferably 1-2 substituents. Groups described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0109] Suitable monovalent substituents include halogen; -(CH 2 ) 0-4 R°;-(CH 2 ) 0-4 OR°;-O(CH 2 ) 0-4 R o , -O-(CH 2 ) 0-4 C(O)OR°;-(CH 2 ) 0-4 CH(OR°) 2 ;R° may be substituted with -(CH 2 ) 0-4 Ph; R° may be substituted with -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph; may be substituted with R° -CH=CHPh; may be substituted with R° -(CH 2 ) 0-4 O(CH 2 ) 0-1 -Pyridinyl; -NO 2 ;-CN;-N 3 ;-(CH 2 ) 0-4 N(R°) 2 ;-(CH 2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH 2 ) 0-4 N(R°)C(O)NR° 2 ;-N(R°)C(S)NR° 2 ;-(CH 2 ) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR° 2 ;-N(R°)N(R°)C(O)OR°;-(CH 2 ) 0-4 C(O)R°;-C(S)R°;-(CH 2 ) 0-4 C(O)OR°;-(CH 2 ) 0-4 C(O)SR°;-(CH 2 ) 0-4 C(O)OSiR° 3 ;-(CH 2 ) 0-4 OC(O)R°;-OC(O)(CH 2 ) 0-4 SR°-;-SC(S)SR°;-(CH 2 ) 0-4 SC(O)R°;-(CH 2 ) 0-4 C(O)NR° 2 ;-C(S)NR° 2 ;-C(S)SR°;-SC(S)SR°;-(CH 2 ) 0-4 OC(O)NR° 2 ;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH 2 C(O)R°;-C(NOR°)R°;-(CH 2 ) 0-4 SSR°;-(CH 2 ) 0-4 S(O) 2 R°;-(CH 2 ) 0-4 S(O) 2 OR°;-(CH 2 ) 0-4 OS(O) 2 R°;-S(O) 2 NR° 2 ;-(CH 2 )0-4 S(O)R°;-N(R°)S(O) 2 NR° 2 ;-N(R°)S(O) 2 R°;-N(OR°)R°;-C(NH)NR° 2 ;-P(O) 2 R°;-P(O)R° 2 ;-OP(O)R° 2 ;-OP(O)(OR°) 2 ;-SiR° 3 ;-OSiR° 3 ;-(C 1-4 Linear or branched alkylene)ON(R°) 2 ;or-(C 1-4 Linear or branched alkylene)C(O)ON(R°) 2 wherein each R° can be substituted as defined below and is independently hydrogen, C 1-6 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an aryl ring, as defined above, but where two independent occurrences of R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an aryl monocyclic or bicyclic ring, which may be substituted as defined below.

[0110] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with the intervening atoms) are independently halogen, -(CH 2 ) 0-2 R ● , -(Halo R ● ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR ● , -(CH 2 ) 0-2 CH(OR● ) 2 ;-O(HaloR ● ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R ● , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR ● , -(CH 2 ) 0-2 C(O)NH 2 , -(CH 2 ) 0-2 C(O)NHR ● , -(CH 2 ) 0-2 C(O)NR ● 2 , -(CH 2 ) 0-2 S.R. ● , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR ● , -(CH 2 ) 0-2 NR ● 2 , -NO 2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR ● 、 -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● And each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1Ph or a 5-6 membered saturated, partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an aryl ring. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0111] Suitable divalent substituents include the following: =O, =S, =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2-3 O- or -S(C(R * 2 )) 2-3 S-, each of which is an independent R * occurrences of 1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the proximal substitutable carbon of the "optionally substituted" group include -O(CR * 2 ) 2-3 O-, and each independently R * occurrences of 1-6 It is selected from an aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an aryl ring.

[0112] R * Suitable substituents on the aliphatic group include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 Each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an aryl ring.

[0113] In some embodiments, suitable substituents on a substitutable nitrogen include -R † , -NR † 2 , -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH 2 C(O)R † , -S(O) 2 R † , -S(O) 2 NR † 2 , -C(S)NR † 2 , -C(NH)NR † 2 , or -N(R † )S(O) 2 R † Each R † are independently hydrogen, C which may be substituted as defined below 1-6 an aliphatic, 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 as defined above, but with two independent R †occurrences of, taken together with the intervening atoms, form an unsubstituted 3-12 membered saturated, partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an aryl monocyclic or bicyclic ring.

[0114] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 And each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an aryl ring.

[0115] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E stereoisomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14Within the scope of this invention are compounds having this structure that include a carbon replacement with a C-enriched carbon. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention.

[0116] Susceptible: An individual who is "susceptible" to a disease, disorder, or condition is at risk of developing the disease, disorder, or condition. In some embodiments, an individual who is susceptible to a disease, disorder, or condition does not exhibit any symptoms of the disease, disorder, or condition. In some embodiments, an individual who is susceptible to a disease, disorder, or condition has never been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, or condition is an individual who has been exposed to conditions associated with the development of the disease, disorder, or condition. In some embodiments, the risk of developing a disease, disorder, and / or condition is a population-based risk (e.g., family members of an individual who suffers from the disease, disorder, or condition).

[0117] Systemic: As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" have their art-recognized meanings referring to the administration of a compound or composition so that it enters the system of the recipient.

[0118] Tautomeric forms: As used herein, the phrase "tautomeric forms" is used to describe different isomeric forms of an organic compound that are capable of easy interconversion. Tautomers may be characterized by a topological shift of a hydrogen atom or a proton, accompanied by a switch of a single bond and an adjacent double bond. In some embodiments, tautomers may result from prototropic tautomerism (i.e., rearrangement of a proton). In some embodiments, tautomers may result from valence tautomerism (i.e., rapid rearrangement of bond electrons). All such tautomeric forms are intended to be included within the scope of the present disclosure. In some embodiments, tautomeric forms of a compound exist in transfer equilibrium with one another, such that attempts to prepare separate substances would result in the formation of a mixture. In some embodiments, tautomeric forms of a compound are separable and isolatable compounds. In some embodiments of the present disclosure, chemical compositions may be provided that are or include pure preparations of a single tautomeric form of a compound. In some embodiments, chemical compositions may be provided as mixtures of two or more tautomeric forms of a compound. In certain embodiments, such mixtures contain equal amounts of different tautomeric forms, and in certain embodiments, such mixtures contain unequal amounts of at least two different tautomeric forms of a compound. In some embodiments of the present disclosure, the chemical composition may contain all tautomeric forms of a compound. In some embodiments of the present disclosure, the chemical composition may contain fewer than all tautomeric forms of a compound. In some embodiments of the present disclosure, the chemical composition may contain one or more tautomeric forms of a compound in amounts that vary over time as a result of interconversion. In some embodiments of the present disclosure, the tautomer is keto-enol tautomerism. One of skill in the art will recognize that keto-enol tautomers can be "captured" (i.e., chemically modified to remain in the "enol" form) using any suitable reagent known in the chemical art to provide an enol derivative that can then be isolated using one or more suitable techniques known in the art. Unless otherwise indicated, the present disclosure encompasses all tautomeric forms of the relevant compounds, whether in pure form or mixed with each other.

[0119] Therapeutic Agent: As used herein, the phrase "therapeutic agent" refers to an agent that has a therapeutic effect and / or induces a desired biological and / or pharmacological effect when administered to a subject. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, reduce, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition.

[0120] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that induces a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, inhibit, ameliorate, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be understood by one of skill in the art, the effective amount of a substance can vary depending on such factors as the desired biological endpoint, the substance delivered, the target cell or tissue, and the like. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, ameliorates, relieves, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose, and in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount. The exact dosage will vary depending on a variety of factors, such as subject-specific variables (eg, age, health of the immune system, etc.), the disease, and the treatment being administered.

[0121] "Tissue" and / or "Organ": As used herein, the term "tissue" and / or "organ" refers to viable cellular material in aggregate form, e.g., small portions of organs, and dispersed cells, e.g., cells dispersed, isolated, and / or grown from muscle, cardiac muscle, liver, or kidney, including bone marrow cells and progeny cells, blood-producing stem cells and progeny, and various other blood elements, unless otherwise specified. In some embodiments, tissue and / or organ refers to kidney, heart liver, stomach, spleen, pancreas, lung, brain, eye, intestine, bladder, skin or skin tissue, blood vessels, veins, arteries, heart valves, sperm, and oocytes. As used herein, the term "organ" encompasses both solid organs, e.g., kidney, heart, liver, lung, and functional portions of organs, e.g., portions of skin, arteries, veins, transplantable liver lobes, kidneys, lung sections, etc.

[0122] Treatment: As used herein, the term "treatment" (also "treat" or "treating") refers to the administration of a therapy that partially or completely alleviates, improves, relieves, inhibits, delays the onset, reduces the severity, and / or reduces the incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who is not showing signs of the associated disease, disorder, and / or condition and / or of a subject who is showing only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who shows one or more established signs of the associated disease, disorder, and / or condition. In some embodiments, the treatment may be of a subject who has been diagnosed as suffering from the associated disease, disorder, and / or condition. In some embodiments, the treatment may be of a subject who is known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the associated disease, disorder, and / or condition. Thus, in some embodiments, the treatment may be prophylactic and in some embodiments, therapeutic. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0123] The present disclosure describes how the selection and combination of one or more of the components of the described compositions, preparations, nanoparticles, and / or nanomaterials affects the functional activity of lipid nanoparticles, such as desired tropism, stabilization, and drug delivery efficacy. In particular, the present invention provides compositions, preparations, nanoparticles, and / or nanomaterials for the delivery of therapeutic and / or prophylactic agents to target cells and / or tissues. For example, the present disclosure describes lipid compounds for use in the compositions, preparations, nanoparticles, and / or nanomaterials. In some embodiments, the compositions, preparations, and / or nanomaterials include LNPs that carry cargo to designated target cells, tissues, and / or organs.

[0124] I. Lipid Nanoparticles (LNPs) The present invention provides compositions, preparations, and / or nanomaterials comprising lipid nanoparticles. In some embodiments, the lipid nanoparticles comprise one or more components. In some embodiments, the lipid nanoparticles comprise one or more components, such as a compound, an ionizable lipid, a sterol, a conjugate-linker lipid, and a phospholipid. In particular, the present disclosure describes that the selection and combination of one or more of the components described herein affects the characteristics of lipid nanoparticles, such as diameter, pKa, stabilization, and ionizability.

[0125] In particular, the present disclosure describes that the selection and combination of one or more of the components described herein affects the functional activity of lipid nanoparticles, such as tropism, stabilization, and drug delivery effectiveness.For example, the present disclosure describes that the combination of components may be better suited for the delivery of siRNA.As another example, the present disclosure describes that the combination of components may be better suited for the delivery of mRNA.As another example, the present disclosure describes that the combination of components may be better suited for the delivery of DNA.

[0126] In some embodiments, the lipid nanoparticles comprise one or more compounds as described herein. In some embodiments, the lipid nanoparticles comprise one or more ionizable lipids as described herein. In some embodiments, the lipid nanoparticles comprise one or more sterols as described herein. In some embodiments, the lipid nanoparticles comprise one or more conjugate-linker lipids as described herein. In some embodiments, the lipid nanoparticles comprise one or more phospholipids as described herein.

[0127] A. Compound Among other things, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials that include one or more compounds described herein.

[0128] In some embodiments, the present disclosure provides a compound of formula A': [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein L 1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 is independently an optionally substituted C 2-15 Alkylenyl, or optionally substituted C 3-15 heteroalkylenyl, L is C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-, X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; R” is hydrogen; [ka] Or C 6-20an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R and R a each independently is hydrogen; or C 6-20 an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; L 3 and L 3a each independently being absent or optionally substituted C 1-10 Alkylenyl, or optionally substituted C 2-10 heteroalkylenyl, R 1 is hydrogen; optionally substituted phenyl; optionally substituted 3- to 7-membered alicyclic; optionally substituted 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2 ;-S(O) 2 N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR2 ;-NR 2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2 ;-CR 2 (R 3 ) 2 ;-OP(O)(OR 2 ) 2 、又は-P(O)(OR 2 ) 2 であるか、あるいは R1 but, [ka] or a 3- to 7-membered alicyclic ring, and a 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alicyclic or heterocyclyl ring is selected from 1 to 4 R 2 or R 3 is optionally substituted with a group; Each R 2 are independently hydrogen; oxo; -CN; -NO 2 ;-OR 4 ;-S(O) 2 R 4 ;-S(O) 2 N(R 4 ) 2 ;-(CH 2 ) n -R 4 ; or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered alicyclic, 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 2 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 3 However, independently, -(CH 2 ) n -R 4 or R 3 two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 4 are independently hydrogen, -OR 5 , -N(R 5 )2 , -OC(O)R 5 , -OC(O)OR 5 , -CN, -C(O)N(R 5 ) 2 , -NR 5 C(O)R 5 , -OC(O)N(R 5 ) 2 , -N(R 5 )C(O)OR 5 , -NR 5 S(O) 2 R 5 , -NR 5 C(O)N(R 5 ) 2 , -NR 5 C(S)N(R 5 ) 2 , -NR 5 C(NR 5 )N(R 5 ) 2 or [ka] and Each R 5 are independently hydrogen or optionally substituted C 1-6 aliphatic or R 5 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 6 But independently, C 4-12 It is aliphatic, Each n is independently 0 to 4, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof is provided.

[0129] In some embodiments, the present disclosure provides a compound of formula A: [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein L 1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 But independently, C 2-10 Alkylenyl or C 3-10 heteroalkylenyl, L is C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, Each L 3 But independently, it does not exist or C 1-10 Alkylenyl, or C 2-10 heteroalkylenyl, X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-, X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 an optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; Each L 3a But independently, it does not exist or C 1-10 Alkylenyl, or C 2-10 heteroalkylenyl, Each R a but, independently, hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 an optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; an optionally substituted phenyl; an optionally substituted 3- to 7-membered alicyclic ring; an optionally substituted 3- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 8- to 10-membered bicyclic heteroaryl ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2 ;-S(O) 2 N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR 2 ;-NR 2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 ) OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2 ; [ka] -CR 2 (OR 2 )R 3 ; [ka] or Each R 2 are independently hydrogen; -CN; -NO 2 ;-OR 4 ;-S(O) 2 R 4 ;-S(O) 2 N(R 4 ) 2 ;-(CH 2 ) n -R 4 ; or C 1-6an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered alicyclic ring, a 5- to 6-membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3- to 7-membered heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 2 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 3 However, independently, -(CH 2 ) n -R 4 or R 3 two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 4 are independently hydrogen, -OR 5 , -N(R 5 ) 2 , -OC(O)R 5 , -OC(O)OR 5 , -CN, -C(O)N(R 5 ) 2 , -NR 5 C(O)R 5 , -OC(O)N(R 5 ) 2 , -N(R 5 )C(O)OR 5 , -NR 5 S(O) 2 R 5 , -NR 5 C(O)N(R 5 ) 2 , -NR 5 C(S)N(R 5 ) 2 , -NR 5 C(NR 5 )N(R 5 ) 2 or [ka] and Each R 5 are independently hydrogen, optionally substituted C 1-6 is an aliphatic group, or R 5 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 6 But independently, C 4-12 It is aliphatic, Each n is independently 0 to 4, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof is provided.

[0130] In some embodiments, the present disclosure provides a compound of formula I″: [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein L 1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 is independently an optionally substituted C 2-15 Alkylenyl, or optionally substituted C 3-15 heteroalkylenyl, L is C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-, X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; Each L 3 is independently absent or optionally substituted C 1-10 Alkylenyl, or optionally substituted C2-10 heteroalkylenyl, R” is hydrogen; [ka] Or C 6-20 an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; Each R is independently hydrogen; or C 6-20 an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; optionally substituted phenyl; optionally substituted 3- to 7-membered alicyclic; optionally substituted 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2 ;-S(O) 2 N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR 2 ;-NR2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2 ;-CR 2 (R 3 ) 2 ;-OP(O)(OR 2 ) 2 、又は-P(O)(OR 2 ) 2 であるか、あるいは R 1 が、 [ka] or a ring selected from 3- to 7-membered alicyclic and 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alicyclic or heterocyclyl ring is selected from 1 to 4 R 2 or R 3 is optionally substituted with a group; Each R 2 are independently hydrogen; oxo; -CN; -NO 2 ;-OR 4 ;-S(O) 2 R 4 ;-S(O) 2 N(R 4 ) 2 ;-(CH 2 ) n -R 4 ; or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered alicyclic, 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 2 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 3 However, independently, -(CH 2 ) n -R 4 or R 3 two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 4 are independently hydrogen, -OR 5 , -N(R 5 ) 2 , -OC(O)R5 , -OC(O)OR 5 , -CN, -C(O)N(R 5 ) 2 , -NR 5 C(O)R 5 , -OC(O)N(R 5 ) 2 , -N(R 5 )C(O)OR 5 , -NR 5 S(O) 2 R 5 , -NR 5 C(O)N(R 5 ) 2 , -NR 5 C(S)N(R 5 ) 2 , -NR 5 C(NR 5 )N(R 5 ) 2 or [ka] and Each R 5 are independently hydrogen or optionally substituted C 1-6 aliphatic or R 5 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 6 But independently, C 4-12 It is aliphatic, Each n is independently 0 to 4, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof is provided.

[0131] In some embodiments, the present disclosure provides a compound of formula I': [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein L1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 But independently, C 2-10 Alkylenyl or C 3-10 heteroalkylenyl, L is C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, Each L 3 But independently, it does not exist or C 1-10 Alkylenyl, or C 2-10 heteroalkylenyl, X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-, X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 an optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; an optionally substituted phenyl; an optionally substituted 3- to 7-membered alicyclic ring; an optionally substituted 3- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 8- to 10-membered bicyclic heteroaryl ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R2 ) 2 ;-C(O)N(R 2 ) 2 ;-S(O) 2 N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR 2 ;-NR 2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R2 )N(R 2 ) 2 C(O)OR 2 ; [ka] -CR 2 (OR 2 )R 3 ; [ka] and Each R 2 are independently hydrogen; -CN; -NO 2 ;-OR 4 ;-S(O) 2 R 4 ;-S(O) 2 N(R 4 ) 2 ;-(CH 2 ) n -R 4 ; or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered alicyclic ring, a 5- to 6-membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3- to 7-membered heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 2 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 3 However, independently, -(CH 2 ) n -R 4 or R 3 two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 4 are independently hydrogen, -OR5 , -N(R 5 ) 2 , -OC(O)R 5 , -OC(O)OR 5 , -CN, -C(O)N(R 5 ) 2 , -NR 5 C(O)R 5 , -OC(O)N(R 5 ) 2 , -N(R 5 )C(O)OR 5 , -NR 5 S(O) 2 R 5 , -NR 5 C(O)N(R 5 ) 2 , -NR 5 C(S)N(R 5 ) 2 , -NR 5 C(NR 5 )N(R 5 ) 2 or [ka] and Each R 5 are independently hydrogen, optionally substituted C 1-6 is an aliphatic group, or R 5 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 6 But independently, C 4-12 It is aliphatic, Each n is independently 0 to 4, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof is provided.

[0132] In some embodiments, the present disclosure provides a compound of formula I: [ka] or an N-oxide thereof, or a salt thereof, wherein L 1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 But independently, C 2-10 Alkylenyl or C 3-10 heteroalkylenyl, L is C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, Each L 3 But independently, it does not exist or C 1-10 Alkylenyl, or C 2-10 heteroalkylenyl, X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-, X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 an optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; a 3- to 7-membered alicyclic ring; a 3- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 )2 ;-N(R 2 )C(O)OR 2 ;-NR 2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2 ;

Chem.

[0133] In some embodiments, the present disclosure provides a compound of formula II″: [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein L 1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 is independently an optionally substituted C 2-15 Alkylenyl, or optionally substituted C 3-15heteroalkylenyl, L is C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-, Each L 3 is independently absent or optionally substituted C 1-10 Alkylenyl, or optionally substituted C 2-10 heteroalkylenyl, Each R is independently hydrogen; or C 6-20 an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; optionally substituted phenyl; optionally substituted 3- to 7-membered alicyclic; optionally substituted 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2 ;-S(O) 2 N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR 2 ;-NR2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2 ;-CR 2 (R 3 ) 2 ;-OP(O)(OR 2 ) 2 、 or -P(O)(OR 2 ) 2 and R 1 is [ka] or a ring selected from 3- to 7-membered alicyclic and 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alicyclic or heterocyclyl ring is selected from 1 to 4 R 2 or R 3 is optionally substituted with a group; Each R 2 are independently hydrogen; oxo; -CN; -NO 2 ;-OR 4 ;-S(O) 2 R 4 ;-S(O) 2 N(R 4 ) 2 ;-(CH 2 ) n -R 4 ; or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered alicyclic, 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 2 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 3 However, independently, -(CH 2 ) n -R 4 or R 3 two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 4 are independently hydrogen, -OR 5 , -N(R 5 ) 2 , -OC(O)R5 , -OC(O)OR 5 , -CN, -C(O)N(R 5 ) 2 , -NR 5 C(O)R 5 , -OC(O)N(R 5 ) 2 , -N(R 5 )C(O)OR 5 , -NR 5 S(O) 2 R 5 , -NR 5 C(O)N(R 5 ) 2 , -NR 5 C(S)N(R 5 ) 2 , -NR 5 C(NR 5 )N(R 5 ) 2 or [ka] and Each R 5 are independently hydrogen or optionally substituted C 1-6 aliphatic or R 5 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 6 But independently, C 4-12 It is aliphatic, Each n is independently 0 to 4, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof is provided.

[0134] In some embodiments, the present disclosure provides a compound of formula II': [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein L1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 But independently, C 2-10 Alkylenyl or C 3-10 heteroalkylenyl, L is C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, Each L 3 But independently, it does not exist or C 1-10 Alkylenyl, or C 2-10 heteroalkylenyl, X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-, each R is independently hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 an optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; an optionally substituted phenyl; an optionally substituted 3- to 7-membered alicyclic ring; an optionally substituted 3- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 8- to 10-membered bicyclic heteroaryl ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2;-S(O) 2 N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR 2 ;-NR 2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2; [ka] -CR 2 (OR 2 )R 3 ; [ka] and Each R 2 are independently hydrogen; -CN; -NO 2 ;-OR 4 ;-S(O) 2 R 4 ;-S(O) 2 N(R 4 ) 2 ;-(CH 2 ) n -R 4 ; or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered alicyclic ring, a 5- to 6-membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3- to 7-membered heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 2 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 3 However, independently, -(CH 2 ) n -R 4 or R 3 two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 4 are independently hydrogen, -OR 5 , -N(R 5 ) 2 , -OC(O)R5 , -OC(O)OR 5 , -CN, -C(O)N(R 5 ) 2 , -NR 5 C(O)R 5 , -OC(O)N(R 5 ) 2 , -N(R 5 )C(O)OR 5 , -NR 5 S(O) 2 R 5 , -NR 5 C(O)N(R 5 ) 2 , -NR 5 C(S)N(R 5 ) 2 , -NR 5 C(NR 5 )N(R 5 ) 2 or [ka] and Each R 5 are independently hydrogen, optionally substituted C 1-6 is an aliphatic group, or R 5 two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 6 But independently, C 4-12 It is aliphatic, Each n is independently 0 to 4, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof is provided.

[0135] In some embodiments, the present disclosure provides a compound of formula II: [ka] or an N-oxide thereof, or a salt thereof, wherein L 1But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 But independently, C 2-10 Alkylenyl or C 3-10 heteroalkylenyl, L is C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, Each L 3 But independently, it does not exist or C 1-10 Alkylenyl, or C 2-10 heteroalkylenyl, X 2 is -OC(O)-, -C(O)O-, or -OC(O)O-, each R is independently hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 an optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; a 3- to 7-membered alicyclic ring; a 3- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR 2 ;-NR 2 S(O) 2 R 2 ;-NR2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2 ;

Chem.

Chem.

[0136] In some embodiments, the present disclosure provides a compound of formula III': [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein L 1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 is independently an optionally substituted C 2-15 Alkylenyl, or optionally substituted C 3-15 heteroalkylenyl, Each L is independently C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, each X 2is independently -OC(O)-, -C(O)O-, or -OC(O)O-; Each L 3 is independently absent or optionally substituted C 1-10 Alkylenyl, or optionally substituted C 2-10 heteroalkylenyl, Each R is independently hydrogen; or C 6-20 an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; optionally substituted phenyl; optionally substituted 3- to 7-membered alicyclic; optionally substituted 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2 ;-S(O) 2 N(R 2 ) 2 ;-NR 2 C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR 2 ;-NR 2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2 ;-CR 2 (R 3 ) 2 ;-OP(O)(OR 2 ) 2 、又は-P(O)(OR 2 ) 2 であるか、あるいは R 1 が、

化

[0137] In some embodiments, the present disclosure provides a compound of formula III: [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein L 1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 heteroalkylenyl, Each L 2 But independently, C 2-10 Alkylenyl or C 3-10 heteroalkylenyl, Each L is independently C 1-10 Alkylenyl or C 2-10 heteroalkylenyl, Each L 3 But independently, it does not exist or C 1-10 Alkylenyl, or C 2-10 heteroalkylenyl, each X 2 is independently -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 an optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R 1 is hydrogen; an optionally substituted phenyl; an optionally substituted 3- to 7-membered alicyclic ring; an optionally substituted 3- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 8- to 10-membered bicyclic heteroaryl ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -OR 2 ;-C(O)OR 2 ;-C(O)SR 2 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 ) 2 ;-C(O)N(R 2 ) 2 ;-S(O) 2 N(R 2 ) 2 ;-NR 2C(O)R 2 ;-OC(O)N(R 2 ) 2 ;-N(R 2 )C(O)OR 2 ;-NR 2 S(O) 2 R 2 ;-NR 2 C(O)N(R 2 ) 2 ;-NR 2 C(S)N(R 2 ) 2 ;-NR 2 C(NR 2 )N(R 2 ) 2 ;-NR 2 C(CHR 2 )N(R 2 ) 2 ;-N(OR 2 )C(O)R 2 ;-N(OR 2 )S(O) 2 R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 ) 2 ;-N(OR 2 )C(S)N(R 2 ) 2 ;-N(OR 2 )C(NR 2 )N(R 2 ) 2 ;-N(OR 2 )C(CHR 2 )N(R 2 ) 2 ;-C(NR 2 )N(R 2 ) 2 ;-C(NR 2 )R 2 ;-C(O)N(R 2 )OR 2 ;-C(R 2 )N(R 2 ) 2 C(O)OR 2 ;

Chem.

[0138] As noted above, in some embodiments of any of Formulas A', A, I", I', I, II", II', II, III', and III, L 1 does not exist or C 1-6 Alkylenyl, or C 2-6 In some embodiments, L is heteroalkylenyl. 1 does not exist or C 1-5 Alkylenyl, or C 2-5In some embodiments, L is heteroalkylenyl. 1 does not exist or C 1-4 Alkylenyl, or C 2-4 In some embodiments, L is heteroalkylenyl. 1 In some embodiments, L is absent. 1 is C 1-6 Alkylenyl or C 2-6 In some embodiments, L is heteroalkylenyl. 1 is C 1-5 Alkylenyl or C 2-5 In some embodiments, L is heteroalkylenyl. 1 is C 1-5 In some embodiments, L is alkylenyl. 1 is C 2-5 Alkylenyl or C 2-5 In some embodiments, L is heteroalkylenyl. 1 is C 2-5 In some embodiments, L is alkylenyl. 1 is C 2-5 In some embodiments, L is heteroalkylenyl. 1 is C 1-4 Alkylenyl or C 2-4 In some embodiments, L is heteroalkylenyl. 1 is C 1-4 In some embodiments, L is alkylenyl. 1 is C 2-4 In some embodiments, L is heteroalkylenyl. 1 is C 1 In some embodiments, L is alkylenyl. 1 is C 2 In some embodiments, L is alkylenyl. 1 is C 3 In some embodiments, L is alkylenyl. 1 is C 4 In some embodiments, L is alkylenyl. 1 is C 5 In some embodiments, L is alkylenyl. 1 is C 6 In some embodiments, L is alkylenyl.1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, L 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, L 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 In some embodiments, L 1 is -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 In some embodiments, L 1 is CH 2 CH 2-, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 In some embodiments, L 1 -CH 2 CH 2 -or-CH 2 CH 2 CH 2 In some embodiments, L 1 -CH 2 In some embodiments, L 1 -CH 2 CH 2 In some embodiments, L 1 -CH 2 CH 2 CH 2 In some embodiments, L 1 -CH 2 CH 2 CH 2 CH 2 In some embodiments, L 1 -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, L 1 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, L 1 is C 2 In some embodiments, L is heteroalkylenyl. 1 is C 3 In some embodiments, L is heteroalkylenyl. 1 is C 4 In some embodiments, L is heteroalkylenyl. 1 is C 5 In some embodiments, L is heteroalkylenyl. 1 is C 6In some embodiments, L is heteroalkylenyl. 1 C containing one heteroatom 2 In some embodiments, L is heteroalkylenyl. 1 C containing one heteroatom 3 In some embodiments, L is heteroalkylenyl. 1 C containing one heteroatom 4 In some embodiments, L is heteroalkylenyl. 1 C containing 1-2 heteroatoms 5 In some embodiments, L is heteroalkylenyl. 1 C containing 1-2 heteroatoms 6 In some embodiments, L is heteroalkylenyl. 1 is a C containing one oxygen atom 2 In some embodiments, L is heteroalkylenyl. 1 is a C containing one oxygen atom 3 In some embodiments, L is heteroalkylenyl. 1 is a C containing one oxygen atom 4 In some embodiments, L is heteroalkylenyl. 1 -CH 2 OCH 2 CH 2 In some embodiments, L 1 C containing 1-2 oxygen atoms 5 In some embodiments, L is heteroalkylenyl. 1 C containing 1-2 oxygen atoms 6 It is heteroalkylenyl.

[0139] As noted above, in some embodiments of any of Formulas A', I", II", and III', each L 2 independently represents an optionally substituted C 2-15 Alkylenyl, or optionally substituted C 3-15 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 2-12 Alkylenyl, or optionally substituted C 3-12In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 2-10 Alkylenyl, or optionally substituted C 3-10 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 2-9 Alkylenyl, or optionally substituted C 3-9 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 5-10 Alkylenyl, or optionally substituted C 5-10 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 5-9 Alkylenyl, or optionally substituted C 5-9 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 6-8 Alkylenyl, or optionally substituted C 6-8 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 5-8 Alkylenyl, or optionally substituted C 5-8 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 5-7 Alkylenyl, or optionally substituted C 5-7 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 4-8 Alkylenyl, or optionally substituted C 4-8 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 2-15 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 3-15 In some embodiments, each L is heteroalkylenyl.2 independently represents an optionally substituted C 2-12 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 3-12 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 2-10 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 3-10 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 2-9 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 3-9 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 5-10 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 5-10 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 5-9 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 5-9 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 6-8 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 6-8 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 5-8 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 5-8 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 5-7In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 5-7 In some embodiments, each L is heteroalkylenyl. 2 independently represents an optionally substituted C 4-8 In some embodiments, each L is alkylenyl. 2 independently represents an optionally substituted C 4-8 It is heteroalkylenyl.

[0140] In some embodiments, each L 2 is independently a C substituted with -R° or -OR°; 6-8 In some embodiments, each L is alkylenyl. 2 is independently a C substituted with -R° 6-8 In some embodiments, each L is alkylenyl. 2 is independently a C substituted with -OR° 6-8 In some embodiments, each L is alkylenyl. 2 is independently one or two -R°-substituted C 6-8 In some embodiments, each L is alkylenyl. 2 is independently a C substituted with one -R° 6-8 In some embodiments, each L is alkylenyl. 2 is independently a C substituted with two -R° 6-8 In some embodiments, each L is alkylenyl. 2 is independently a C substituted with one -OR° 6-8 In some embodiments, each L is alkylenyl. 2 is independently one or two C 1-6 Aliphatically substituted C 6-8 In some embodiments, each L is alkylenyl. 2 is independently one C 1-6 Aliphatically substituted C 6-8 In some embodiments, each L is alkylenyl. 2 are independent of each other, 1-6 Aliphatically substituted C 6-8 In some embodiments, each L is alkylenyl.2 is independently one or two methyl-substituted C 6-8 In some embodiments, each L is alkylenyl. 2 independently, one methyl-substituted C 6-8 In some embodiments, each L is alkylenyl. 2 is independently substituted with two methyl groups 6-8 In some embodiments, each L is alkylenyl. 2 independently, C substituted with one -OH 6-8 In some embodiments, each L is alkylenyl. 2 is, independently, [ka] In some embodiments, one L 2 is a C substituted with one -OR° 6-8 Alkylenyl and other L 2 is C 6-8 In some embodiments, one L is alkylenyl. 2 is a C substituted with one -OH 6-8 Alkylenyl and other L 2 is C 6-8 In some embodiments, one L is alkylenyl. 2 is a C substituted with one -OR° 7 Alkylenyl and other L 2 is C 6 In some embodiments, one L is alkylenyl. 2 is a C substituted with one -OH 7 Alkylenyl and other L 2 is C 6 In some embodiments, one L is alkylenyl. 2 teeth, [ka] and other L 2 -CH 2 CH 2 CH 2 CH 2CH 2 CH 2 -It is.

[0141] In some embodiments of any of Formulas A', I", II", and III', each L 2 is independently 2-15 Alkylenyl or C 3-15 In some embodiments, each L is heteroalkylenyl. 2 is independently 2-12 Alkylenyl or C 3-12 In some embodiments, each L is heteroalkylenyl. 2 is independently 2-15 In some embodiments, each L is alkylenyl. 2 is independently 3-15 In some embodiments, each L is heteroalkylenyl. 2 is independently 2-12 In some embodiments, each L is alkylenyl. 2 is independently 3-12 It is heteroalkylenyl.

[0142] In some embodiments of any of Formulas A', A, I", I', I, II", II', II, III', and III, each L 2 is independently 2-10 Alkylenyl or C 3-10 In some embodiments, each L is heteroalkylenyl. 2 is independently 2-9 Alkylenyl or C 3-9 In some embodiments, each L is heteroalkylenyl. 2 is independently 5-10 Alkylenyl or C 5-10 In some embodiments, each L is heteroalkylenyl. 2 is independently 5-9 Alkylenyl or C 5-9 In some embodiments, each L is heteroalkylenyl. 2 is independently 6-8 Alkylenyl or C 6-8 In some embodiments, each L is heteroalkylenyl.2 is independently 5-8 Alkylenyl or C 5-8 In some embodiments, each L is heteroalkylenyl. 2 is independently 4-8 Alkylenyl or C 4-8 In some embodiments, each L is heteroalkylenyl. 2 is independently 2-10 In some embodiments, each L is alkylenyl. 2 is independently 3-10 In some embodiments, each L is heteroalkylenyl. 2 is independently 2-9 In some embodiments, each L is alkylenyl. 2 is independently 3-9 In some embodiments, each L is heteroalkylenyl. 2 is independently 5-10 In some embodiments, each L is alkylenyl. 2 is independently 5-10 In some embodiments, each L is heteroalkylenyl. 2 is independently 5-9 In some embodiments, each L is alkylenyl. 2 is independently 5-9 In some embodiments, each L is heteroalkylenyl. 2 is independently 6-8 In some embodiments, each L is alkylenyl. 2 is independently 6-8 In some embodiments, each L is heteroalkylenyl. 2 is independently 5-8 In some embodiments, each L is alkylenyl. 2 is independently 5-8 In some embodiments, each L is heteroalkylenyl. 2 is independently 4-8 In some embodiments, each L is alkylenyl. 2 is independently 4-8 In some embodiments, each L is heteroalkylenyl. 2 is independently 5-7Alkylenyl or C 5-7 In some embodiments, each L is heteroalkylenyl. 2 is independently 5-7 In some embodiments, each L is alkylenyl. 2 is independently 5-7 It is heteroalkylenyl.

[0143] In some embodiments, each L 2 is independently 2 In some embodiments, each L is alkylenyl. 2 is independently 3 In some embodiments, each L is alkylenyl. 2 is independently 4 In some embodiments, each L is alkylenyl. 2 is independently 5 In some embodiments, each L is alkylenyl. 2 is independently 6 In some embodiments, each L is alkylenyl. 2 is independently 7 In some embodiments, each L is alkylenyl. 2 is independently 8 In some embodiments, each L is alkylenyl. 2 is independently 9 In some embodiments, each L is alkylenyl. 2 is independently 10 In some embodiments, each L is alkylenyl. 2 are independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 2 is, independently, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 are independently -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH2 In some embodiments, each L 2 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -or-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2CH 2 CH 2 In some embodiments, each L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, two L 2 In some embodiments, the two L 2 The groups are the same, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2CH 2 CH 2 CH 2 In some embodiments, two L 2 The groups are the same, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, two L 2 The groups are the same, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, two L 2 The groups are the same, -CH 2 CH 2 CH 2 CH 2 CH 2 - , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, two L 2 The groups are the same, -CH 2 CH 2CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, two L 2 The groups are the same, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, two L 2 In some embodiments, one L 2 -CH 2 CH 2 - and other L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 -CH 2 CH 2 CH 2 - and other L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 -CH2 CH 2 CH 2 CH 2 - and other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 - and other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 - and other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 - and other L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 is -CH 2 CH 2 CH 2 CH 2 CH2 CH 2 - and other L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and other L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and other L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and other L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2In some embodiments, one L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - and other L 2 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 It is.

[0144] In some embodiments, each L 2 is independently 4 In some embodiments, each L is heteroalkylenyl. 2 is independently 5 In some embodiments, each L is heteroalkylenyl. 2 is independently 6 In some embodiments, each L is heteroalkylenyl. 2 is independently 7 In some embodiments, each L is heteroalkylenyl. 2 is independently 8 In some embodiments, each L is heteroalkylenyl. 2 independently, C containing one heteroatom 4 In some embodiments, each L is heteroalkylenyl. 2 independently, C containing one heteroatom 5 In some embodiments, each L is heteroalkylenyl. 2 is independently a C containing one or two heteroatoms 6 In some embodiments, each L is heteroalkylenyl. 2 is independently a C containing one or two heteroatoms 7 In some embodiments, each L is heteroalkylenyl. 2 is independently a C containing one or two heteroatoms 8In some embodiments, each L is heteroalkylenyl. 2 are independently C containing one oxygen atom 4 In some embodiments, each L is heteroalkylenyl. 2 are independently C containing one oxygen atom 5 In some embodiments, each L is heteroalkylenyl. 2 independently, C containing one or two oxygen atoms 6 In some embodiments, each L is heteroalkylenyl. 2 independently, C containing one or two oxygen atoms 7 In some embodiments, each L is heteroalkylenyl. 2 independently, C containing one or two oxygen atoms 8 It is heteroalkylenyl.

[0145] As noted above, in some embodiments of any of formulas A', A, I", I', I, II", II', II, III', and III, each L is independently selected from the group consisting of C 1-10 Alkylenyl, or C 2-10 In some embodiments, each L is independently C 1-8 Alkylenyl or C 2-8 In some embodiments, each L is independently C 1-10 In some embodiments, each L is independently C 2-10 In some embodiments, each L is independently C 1-8 In some embodiments, each L is independently C 2-8 In some embodiments, each L is independently C 1-5 Alkylenyl or C 2-5 In some embodiments, each L is independently C 1-5 In some embodiments, each L is independently C 2-5 In some embodiments, each L is independently C 1-4 Alkylenyl or C 2-4In some embodiments, each L is independently C 1-4 In some embodiments, each L is independently C 2-4 In some embodiments, each L is independently C 1 In some embodiments, each L is independently C 2 In some embodiments, each L is independently C 3 In some embodiments, each L is independently C 4 In some embodiments, each L is independently C 5 In some embodiments, each L is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is independently -CH 2 CH 2 -or-CH2 CH 2 CH 2 In some embodiments, each L is -CH 2 In some embodiments, each L is -CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, one L is -CH 2 CH 2 - and the other L is -CH 2 CH 2 CH 2 In some embodiments, one L is -CH 2 CH 2 - and the other L is -CH 2 CH 2 CH 2 CH 2 In some embodiments, one L is -CH 2 CH 2 CH 2 - and the other L is -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is independently C. 2 In some embodiments, each L is independently C 3 In some embodiments, each L is independently C 4 In some embodiments, each L is independently C 5In some embodiments, each L is independently a C 2 In some embodiments, each L is independently a C 3 In some embodiments, each L is independently a C 4 In some embodiments, each L is independently a C 1 -alkyl group containing one oxygen atom. 2 In some embodiments, each L is independently a C 1 -alkyl group containing one oxygen atom. 3 In some embodiments, each L is independently a C 1 -alkyl group containing one oxygen atom. 4 In some embodiments, each L is independently a C 1 -alkyl group containing one oxygen atom. 5 In some embodiments, each L is independently a C 1 -alkylene group that contains two oxygen atoms. 5 It is heteroalkylenyl.

[0146] In some embodiments, each L is independently C 6-10 Alkylenyl or C 6-10 In some embodiments, each L is independently C 6-10 In some embodiments, each L is independently C 6-10 In some embodiments, each L is independently C 6 In some embodiments, each L is independently C 7 In some embodiments, each L is independently C 8 In some embodiments, each L is independently C 9 In some embodiments, each L is independently C 10 In some embodiments, each L is independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH2 CH 2 CH 2 In some embodiments, each L is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L is independently C. 6 In some embodiments, each L is independently C 7 In some embodiments, each L is independently C 8 In some embodiments, each L is independently C 9 In some embodiments, each L is independently C 10 In some embodiments, each L is independently a C alkyl group containing one or two heteroatoms. 6 In some embodiments, each L is independently a C alkyl group containing 1 to 3 heteroatoms. 7 In some embodiments, each L is independently a C alkyl group containing 1 to 3 heteroatoms. 8 In some embodiments, each L is independently a C alkyl group containing 1 to 3 heteroatoms. 9 In some embodiments, each L is independently a C alkyl group containing 1 to 3 heteroatoms. 10 In some embodiments, each L is independently a C alkyl group containing one or two oxygen atoms. 6 In some embodiments, each L is independently a C alkyl group containing 1 to 3 oxygen atoms. 7 In some embodiments, each L is independently a C alkyl group containing 1 to 3 oxygen atoms. 8 In some embodiments, each L is independently a C alkyl group containing 1 to 3 oxygen atoms. 9In some embodiments, each L is independently a C alkyl group containing 1 to 3 oxygen atoms. 10 It is heteroalkylenyl.

[0147] As noted above, in some embodiments of any of Formulas A', I", II", and III', each L 3 is independently absent or optionally substituted C 1-10 Alkylenyl, or optionally substituted C 2-10 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 1-10 Alkylenyl, or optionally substituted C 2-10 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 1-8 Alkylenyl, or optionally substituted C 2-8 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 1-10 In some embodiments, each L is alkylenyl. 3 independently represents an optionally substituted C 2-10 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 1-8 In some embodiments, each L is alkylenyl. 3 independently represents an optionally substituted C 2-8 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 1-5 Alkylenyl, or optionally substituted C 2-5 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 1-5 In some embodiments, each L is alkylenyl. 3 independently represents an optionally substituted C 2-5 In some embodiments, each L is heteroalkylenyl. 3independently represents an optionally substituted C 1-4 Alkylenyl, or optionally substituted C 2-4 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 1-4 In some embodiments, each L is alkylenyl. 3 independently represents an optionally substituted C 2-4 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 6-10 Alkylenyl, or optionally substituted C 6-10 In some embodiments, each L is heteroalkylenyl. 3 independently represents an optionally substituted C 6-10 In some embodiments, each L is alkylenyl. 3 independently represents an optionally substituted C 6-10 It is heteroalkylenyl.

[0148] In some embodiments of any of Formulas A', A, I", I', I, II", II', II, III', and III, each L 3 is not present or C 1-10 Alkylenyl, or C 2-10 In some embodiments, each L is heteroalkylenyl. 3 In some embodiments, each L 3 is independently 1-10 Alkylenyl or C 2-10 In some embodiments, each L is heteroalkylenyl. 3 is independently 1-8 Alkylenyl or C 2-8 In some embodiments, each L is heteroalkylenyl. 3 is independently 1-10 In some embodiments, each L is alkylenyl. 3 is independently 2-10 In some embodiments, each L is heteroalkylenyl. 3 is independently 1-8In some embodiments, each L is alkylenyl. 3 is independently 2-8 In some embodiments, each L is heteroalkylenyl. 3 is independently 1-5 Alkylenyl or C 2-5 In some embodiments, each L is heteroalkylenyl. 3 is independently 1-5 In some embodiments, each L is alkylenyl. 3 is independently 2-5 In some embodiments, each L is heteroalkylenyl. 3 is independently 1-4 Alkylenyl or C 2-4 In some embodiments, each L is heteroalkylenyl. 3 is independently 1-4 In some embodiments, each L is alkylenyl. 3 is independently 2-4 In some embodiments, each L is heteroalkylenyl. 3 is independently 1 In some embodiments, each L is alkylenyl. 3 is independently 2 In some embodiments, each L is alkylenyl. 3 is independently 3 In some embodiments, each L is alkylenyl. 3 is independently 4 In some embodiments, each L is alkylenyl. 3 is independently 5 In some embodiments, each L is alkylenyl. 3 are independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH2 In some embodiments, each L 3 are independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 are independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 are independently -CH 2 CH 2 -or-CH 2 CH 2 CH 2 In some embodiments, each L 3 is -CH 2 In some embodiments, each L 3 is -CH 2 CH 2 In some embodiments, each L 3 is -CH 2 CH 2 CH 2 In some embodiments, each L 3 is -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 is -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 is independently 2 In some embodiments, each L is heteroalkylenyl. 3 is independently3 In some embodiments, each L is heteroalkylenyl. 3 is independently 4 In some embodiments, each L is heteroalkylenyl. 3 independently, C containing one heteroatom 2 In some embodiments, each L is heteroalkylenyl. 3 independently, C containing one heteroatom 3 In some embodiments, each L is heteroalkylenyl. 3 independently, C containing one heteroatom 4 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing one oxygen atom 2 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing one oxygen atom 3 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing one oxygen atom 4 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing one oxygen atom 5 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing two oxygen atoms 5 It is heteroalkylenyl.

[0149] In some embodiments, each L 3 is independently 6-10 Alkylenyl or C 6-10 In some embodiments, each L is heteroalkylenyl. 3 is independently 6-10 In some embodiments, each L is alkylenyl. 3 is independently 6-10 In some embodiments, each L is heteroalkylenyl. 3 is independently 6 In some embodiments, each L is alkylenyl. 3 is independently 7 In some embodiments, each L is alkylenyl.3 is independently 8 In some embodiments, each L is alkylenyl. 3 is independently 9 In some embodiments, each L is alkylenyl. 3 is independently 10 In some embodiments, each L is alkylenyl. 3 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 is -CH 2 CH 2 CH 2 CH 2 CH2 CH 2 In some embodiments, each L 3 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3 is independently 6 In some embodiments, each L is heteroalkylenyl. 3 is independently 7 In some embodiments, each L is heteroalkylenyl. 3 is independently 8 In some embodiments, each L is heteroalkylenyl. 3 is independently 9 In some embodiments, each L is heteroalkylenyl. 3 is independently 10 In some embodiments, each L is heteroalkylenyl. 3is independently a C containing one or two heteroatoms 6 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing 1 to 3 heteroatoms 7 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing 1 to 3 heteroatoms 8 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing 1 to 3 heteroatoms 9 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing 1 to 3 heteroatoms 10 In some embodiments, each L is heteroalkylenyl. 3 independently, C containing one or two oxygen atoms 6 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing 1 to 3 oxygen atoms 7 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing 1 to 3 oxygen atoms 8 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing 1 to 3 oxygen atoms 9 In some embodiments, each L is heteroalkylenyl. 3 are independently C containing 1 to 3 oxygen atoms 10 It is heteroalkylenyl.

[0150] As noted above, in some embodiments of Formula A', each L 3a is independently absent or optionally substituted C 1-10 Alkylenyl, or optionally substituted C 2-10 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 1-10 Alkylenyl, or optionally substituted C 2-10 In some embodiments, each L is heteroalkylenyl. 3aindependently represents an optionally substituted C 1-8 Alkylenyl, or optionally substituted C 2-8 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 1-10 In some embodiments, each L is alkylenyl. 3a independently represents an optionally substituted C 2-10 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 1-8 In some embodiments, each L is alkylenyl. 3a independently represents an optionally substituted C 2-8 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 1-5 Alkylenyl, or optionally substituted C 2-5 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 1-5 In some embodiments, each L is alkylenyl. 3a independently represents an optionally substituted C 2-5 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 1-4 Alkylenyl, or optionally substituted C 2-4 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 1-4 In some embodiments, each L is alkylenyl. 3a independently represents an optionally substituted C 2-4 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 6-10 Alkylenyl, or optionally substituted C 6-10 In some embodiments, each L is heteroalkylenyl. 3a independently represents an optionally substituted C 6-10In some embodiments, each L is alkylenyl. 3a independently represents an optionally substituted C 6-10 It is heteroalkylenyl.

[0151] In some embodiments of formula A' or A, each L 3a is not present or C 1-10 Alkylenyl, or C 2-10 In some embodiments, each L is heteroalkylenyl. 3a In some embodiments, each L 3a is independently 1-10 Alkylenyl or C 2-10 In some embodiments, each L is heteroalkylenyl. 3a is independently 1-8 Alkylenyl or C 2-8 In some embodiments, each L is heteroalkylenyl. 3a is independently 1-10 In some embodiments, each L is alkylenyl. 3a is independently 2-10 In some embodiments, each L is heteroalkylenyl. 3a is independently 1-8 In some embodiments, each L is alkylenyl. 3a is independently 2-8 In some embodiments, each L is heteroalkylenyl. 3a is independently 1-5 Alkylenyl or C 2-5 In some embodiments, each L is heteroalkylenyl. 3a is independently 1-5 In some embodiments, each L is alkylenyl. 3a is independently 2-5 In some embodiments, each L is heteroalkylenyl. 3a is independently 1-4 Alkylenyl or C 2-4 In some embodiments, each L is heteroalkylenyl. 3a is independently 1-4 In some embodiments, each L is alkylenyl. 3ais independently 2-4 In some embodiments, each L is heteroalkylenyl. 3a is independently 1 In some embodiments, each L is alkylenyl. 3a is independently 2 In some embodiments, each L is alkylenyl. 3a is independently 3 In some embodiments, each L is alkylenyl. 3a is independently 4 In some embodiments, each L is alkylenyl. 3a is independently 5 In some embodiments, each L is alkylenyl. 3a are independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a are independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a are independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3aare independently -CH 2 CH 2 -or-CH 2 CH 2 CH 2 In some embodiments, each L 3a -CH 2 In some embodiments, each L 3a -CH 2 CH 2 In some embodiments, each L 3a -CH 2 CH 2 CH 2 In some embodiments, each L 3a -CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a is independently 2 In some embodiments, each L is heteroalkylenyl. 3a is independently 3 In some embodiments, each L is heteroalkylenyl. 3a is independently 4 In some embodiments, each L is heteroalkylenyl. 3a independently, C containing one heteroatom 2 In some embodiments, each L is heteroalkylenyl. 3a independently, C containing one heteroatom 3 In some embodiments, each L is heteroalkylenyl. 3a independently, C containing one heteroatom 4 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing one oxygen atom 2 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing one oxygen atom 3In some embodiments, each L is heteroalkylenyl. 3a are independently C containing one oxygen atom 4 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing one oxygen atom 5 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing two oxygen atoms 5 It is heteroalkylenyl.

[0152] In some embodiments, each L 3a is independently 6-10 Alkylenyl or C 6-10 In some embodiments, each L is heteroalkylenyl. 3a is independently 6-10 In some embodiments, each L is alkylenyl. 3a is independently 6-10 In some embodiments, each L is heteroalkylenyl. 3a is independently 6 In some embodiments, each L is alkylenyl. 3a is independently 7 In some embodiments, each L is alkylenyl. 3a is independently 8 In some embodiments, each L is alkylenyl. 3a is independently 9 In some embodiments, each L is alkylenyl. 3a is independently 10 In some embodiments, each L is alkylenyl. 3a are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a are independently -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH2 CH 2 CH 2 CH 2 In some embodiments, each L 3a is -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, each L 3a is independently 6 In some embodiments, each L is heteroalkylenyl. 3a is independently 7 In some embodiments, each L is heteroalkylenyl. 3a is independently 8 In some embodiments, each L is heteroalkylenyl. 3a is independently 9 In some embodiments, each L is heteroalkylenyl. 3a is independently 10 In some embodiments, each L is heteroalkylenyl. 3a is independently a C containing one or two heteroatoms 6 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing 1 to 3 heteroatoms 7 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing 1 to 3 heteroatoms 8 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing 1 to 3 heteroatoms 9 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing 1 to 3 heteroatoms 10 In some embodiments, each L is heteroalkylenyl. 3a independently, C containing one or two oxygen atoms 6 In some embodiments, each L is heteroalkylenyl. 3aare independently C containing 1 to 3 oxygen atoms 7 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing 1 to 3 oxygen atoms 8 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing 1 to 3 oxygen atoms 9 In some embodiments, each L is heteroalkylenyl. 3a are independently C containing 1 to 3 oxygen atoms 10 It is heteroalkylenyl.

[0153] As noted above, in some embodiments of any of Formulas A', A, I", I', I, II", I', II, III', and III, each X 2 is independently -OC(O)-, -C(O)O-, or -OC(O)O-. In some embodiments, each X 2 is independently -OC(O)-. In some embodiments, each X 2 is independently -C(O)O-. In some embodiments, each X 2 are independently -OC(O)O-.

[0154] As noted above, in some embodiments of any of formulae A', A, I", I', and I, X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-. In some embodiments, X is absent. In some embodiments, X is -OC(O)-, -C(O)O-, or -OC(O)O-. In some embodiments, X is -OC(O)-. In some embodiments, X is -C(O)O-. In some embodiments, X is -OC(O)O-.

[0155] As noted above, in some embodiments of Formula A', R" is hydrogen; [ka] Or C 6-20R" is an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. In some embodiments of formula I", R" is hydrogen; [ka] Or C 6-20 An optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.

[0156] In some embodiments, R″ is hydrogen; [ka] Or C 6-20 is an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 1-adamantyl, and phenyl. In some embodiments, R″ is hydrogen; [ka] Or C 6-20 An optionally substituted group selected from aliphatic, 3- to 12-membered alicyclic, 1-adamantyl, and phenyl.

[0157] In some embodiments, R″ is hydrogen. In some embodiments, R″ is [ka] In some embodiments, R″ is [ka] It is.

[0158] In some embodiments, R″ is an optionally substituted C 6-20 In some embodiments, R″ is an optionally substituted C 6-12 In some embodiments, R″ is an optionally substituted C 8-11 In some embodiments, R″ is an optionally substituted C 9-10 In some embodiments, R″ is an optionally substituted C 6 In some embodiments, R″ is an optionally substituted C 7 In some embodiments, R″ is an optionally substituted C 8 In some embodiments, R″ is an optionally substituted C 9 In some embodiments, R″ is an optionally substituted C 10 In some embodiments, R″ is an optionally substituted C 11 In some embodiments, R″ is an optionally substituted C 12 In some embodiments, R″ is an optionally substituted C 13-20 In some embodiments, R″ is an optionally substituted C 15-20 In some embodiments, R″ is an optionally substituted C 13 In some embodiments, R″ is an optionally substituted C 14 In some embodiments, R″ is an optionally substituted C 15 In some embodiments, R″ is an optionally substituted C 16 In some embodiments, R″ is an optionally substituted C 17 In some embodiments, R″ is an optionally substituted C 18 In some embodiments, R″ is an optionally substituted C 19 In some embodiments, R″ is an optionally substituted C 20 It is aliphatic.

[0159] In some embodiments, R″ is an optionally substituted linear C 6-20 In some embodiments, R″ is an optionally substituted linear C 6-12 In some embodiments, R″ is an optionally substituted linear C 8-11 In some embodiments, R″ is an optionally substituted linear C 9-10 In some embodiments, R″ is an optionally substituted linear C 6 In some embodiments, R″ is an optionally substituted linear C 7 In some embodiments, R″ is an optionally substituted linear C 8 In some embodiments, R″ is an optionally substituted linear C 9 In some embodiments, R″ is an optionally substituted linear C 10 In some embodiments, R″ is an optionally substituted linear C 11 In some embodiments, R″ is an optionally substituted linear C 12 In some embodiments, R″ is an optionally substituted linear C 13-20 In some embodiments, R″ is an optionally substituted linear C 15-20 In some embodiments, R″ is an optionally substituted linear C 13 In some embodiments, R″ is an optionally substituted linear C 14 In some embodiments, R″ is an optionally substituted linear C 15 In some embodiments, R″ is an optionally substituted linear C 16 In some embodiments, R″ is an optionally substituted linear C 17 In some embodiments, R″ is an optionally substituted linear C 18 In some embodiments, R″ is an optionally substituted linear C 19In some embodiments, R″ is an optionally substituted linear C 20 It is aliphatic.

[0160] In some embodiments, R″ is an optionally substituted branched C 6-20 In some embodiments, R″ is an optionally substituted branched C 6-12 In some embodiments, R″ is an optionally substituted branched C 8-11 In some embodiments, R″ is an optionally substituted branched C 9-10 In some embodiments, R″ is an optionally substituted branched C 6 In some embodiments, R″ is an optionally substituted branched C 7 In some embodiments, R″ is an optionally substituted branched C 8 In some embodiments, R″ is an optionally substituted branched C 9 In some embodiments, R″ is an optionally substituted branched C 10 In some embodiments, R″ is an optionally substituted branched C 11 In some embodiments, R″ is an optionally substituted branched C 12 In some embodiments, R″ is an optionally substituted branched C 13-20 In some embodiments, R″ is an optionally substituted branched C 15-20 In some embodiments, R″ is an optionally substituted branched C 13 In some embodiments, R″ is an optionally substituted branched C 14 In some embodiments, R″ is an optionally substituted branched C 15 In some embodiments, R″ is an optionally substituted branched C 16 In some embodiments, R″ is an optionally substituted branched C 17In some embodiments, R″ is an optionally substituted branched C 18 In some embodiments, R″ is an optionally substituted branched C 19 In some embodiments, R″ is an optionally substituted branched C 20 It is aliphatic.

[0161] In some embodiments, R″ is C 6-20 In some embodiments, R″ is C 6-12 In some embodiments, R″ is C 8-11 In some embodiments, R″ is C 9-10 In some embodiments, R″ is C 6 In some embodiments, R″ is C 7 In some embodiments, R″ is C 8 In some embodiments, R″ is C 9 In some embodiments, R″ is C 10 In some embodiments, R″ is C 11 In some embodiments, R″ is C 12 In some embodiments, R″ is C 13-20 In some embodiments, R″ is C 15-20 In some embodiments, R″ is C 13 In some embodiments, R″ is C 14 In some embodiments, R″ is C 15 In some embodiments, R″ is C 16 In some embodiments, R″ is C 17 In some embodiments, R″ is C 18 In some embodiments, R″ is C 19 In some embodiments, R″ is C 20 It is aliphatic.

[0162] In some embodiments, R″ is a linear C 6-20In some embodiments, R″ is a linear C 6-12 In some embodiments, R″ is a linear C 8-11 In some embodiments, R″ is a linear C 9-10 In some embodiments, R″ is a linear C 6 In some embodiments, R″ is a linear C 7 In some embodiments, R″ is a linear C 8 In some embodiments, R″ is a linear C 9 In some embodiments, R″ is a linear C 10 In some embodiments, R″ is a linear C 11 In some embodiments, R″ is a linear C 12 In some embodiments, R″ is a linear C 13-20 In some embodiments, R″ is a linear C 15-20 In some embodiments, R″ is a linear C 13 In some embodiments, R″ is a linear C 14 In some embodiments, R″ is a linear C 15 In some embodiments, R″ is a linear C 16 In some embodiments, R″ is a linear C 17 In some embodiments, R″ is a linear C 18 In some embodiments, R″ is a linear C 19 In some embodiments, R″ is a linear C 20 It is aliphatic.

[0163] In some embodiments, R″ is a branched C 6-20 In some embodiments, R″ is a branched C 6-12 In some embodiments, R″ is a branched C 8-11 In some embodiments, R″ is a branched C 9-10 In some embodiments, R″ is a branched C 6 In some embodiments, R″ is a branched C7 In some embodiments, R″ is a branched C 8 In some embodiments, R″ is a branched C 9 In some embodiments, R″ is a branched C 10 In some embodiments, R″ is a branched C 11 In some embodiments, R″ is a branched C 12 In some embodiments, R″ is a branched C 13-20 In some embodiments, R″ is a branched C 15-20 In some embodiments, R″ is a branched C 13 In some embodiments, R″ is a branched C 14 In some embodiments, R″ is a branched C 15 In some embodiments, R″ is a branched C 16 In some embodiments, R″ is a branched C 17 In some embodiments, R″ is a branched C 18 In some embodiments, R″ is a branched C 19 In some embodiments, R″ is a branched C 20 It is aliphatic.

[0164] In some embodiments, R″ is an optionally substituted C 6-20 In some embodiments, R″ is an optionally substituted C 6-12 In some embodiments, R″ is an optionally substituted C 8-11 In some embodiments, R″ is an optionally substituted C 9-10 In some embodiments, R″ is an optionally substituted C 6 In some embodiments, R″ is an optionally substituted C 7 In some embodiments, R″ is an optionally substituted C 8 In some embodiments, R″ is an optionally substituted C9 In some embodiments, R″ is an optionally substituted C 10 In some embodiments, R″ is an optionally substituted C 11 In some embodiments, R″ is an optionally substituted C 12 In some embodiments, R″ is an optionally substituted C 13-20 In some embodiments, R″ is an optionally substituted C 15-20 In some embodiments, R″ is an optionally substituted C 13 In some embodiments, R″ is an optionally substituted C 14 In some embodiments, R″ is an optionally substituted C 15 In some embodiments, R″ is an optionally substituted C 16 In some embodiments, R″ is an optionally substituted C 17 In some embodiments, R″ is an optionally substituted C 18 In some embodiments, R″ is an optionally substituted C 19 In some embodiments, R″ is an optionally substituted C 20 It is an alkyl.

[0165] In some embodiments, R″ is C 6-20 In some embodiments, R″ is C 6-12 In some embodiments, R″ is C 8-11 In some embodiments, R″ is C 9-10 In some embodiments, R″ is C 6 In some embodiments, R″ is C 7 In some embodiments, R″ is C 8 In some embodiments, R″ is C 9 In some embodiments, R″ is C 10In some embodiments, R″ is C 11 In some embodiments, R″ is C 12 In some embodiments, R″ is C 13-20 In some embodiments, R″ is C 15-20 In some embodiments, R″ is C 13 In some embodiments, R″ is C 14 In some embodiments, R″ is C 15 In some embodiments, R″ is C 16 In some embodiments, R″ is C 17 In some embodiments, R″ is C 18 In some embodiments, R″ is C 19 In some embodiments, R″ is C 20 It is an alkyl.

[0166] In some embodiments, R″ is a linear C 6-20 In some embodiments, R″ is a straight chain C 6-12 In some embodiments, R″ is a straight chain C 8-11 In some embodiments, R″ is a straight chain C 9-10 In some embodiments, R″ is a straight chain C 6 In some embodiments, R″ is a straight chain C 7 In some embodiments, R″ is a straight chain C 8 In some embodiments, R″ is a straight chain C 9 In some embodiments, R″ is a straight chain C 10 In some embodiments, R″ is a straight chain C 11 In some embodiments, R″ is a straight chain C 12 In some embodiments, R″ is a straight chain C 13-20 In some embodiments, R″ is a straight chain C 15-20 In some embodiments, R″ is a straight chain C 13In some embodiments, R″ is a straight chain C 14 In some embodiments, R″ is a straight chain C 15 In some embodiments, R″ is a straight chain C 16 In some embodiments, R″ is a straight chain C 17 In some embodiments, R″ is a straight chain C 18 In some embodiments, R″ is a straight chain C 19 In some embodiments, R″ is a straight chain C 20 It is an alkyl.

[0167] In some embodiments, R″ is a branched C 6-20 In some embodiments, R″ is a branched C 6-12 In some embodiments, R″ is a branched C 8-11 In some embodiments, R″ is a branched C 9-10 In some embodiments, R″ is a branched C 6 In some embodiments, R″ is a branched C 7 In some embodiments, R″ is a branched C 8 In some embodiments, R″ is a branched C 9 In some embodiments, R″ is a branched C 10 In some embodiments, R″ is a branched C 11 In some embodiments, R″ is a branched C 12 In some embodiments, R″ is a branched C 13-20 In some embodiments, R″ is a branched C 15-20 In some embodiments, R″ is a branched C 13 In some embodiments, R″ is a branched C 14 In some embodiments, R″ is a branched C 15 In some embodiments, R″ is a branched C 16In some embodiments, R″ is a branched C 17 In some embodiments, R″ is a branched C 18 In some embodiments, R″ is a branched C 19 In some embodiments, R″ is a branched C 20 It is an alkyl.

[0168] In some embodiments, R″ is an optionally substituted C 6-20 In some embodiments, R″ is optionally substituted C 6-12 In some embodiments, R″ is optionally substituted C 8-11 In some embodiments, R″ is optionally substituted C 9-10 In some embodiments, R″ is optionally substituted C 6 In some embodiments, R″ is optionally substituted C 7 In some embodiments, R″ is optionally substituted C 8 In some embodiments, R″ is optionally substituted C 9 In some embodiments, R″ is optionally substituted C 10 In some embodiments, R″ is optionally substituted C 11 In some embodiments, R″ is optionally substituted C 12 In some embodiments, R″ is optionally substituted C 13-20 In some embodiments, R″ is optionally substituted C 15-20 In some embodiments, R″ is optionally substituted C 13 In some embodiments, R″ is optionally substituted C 14 In some embodiments, R″ is optionally substituted C 15 In some embodiments, R″ is optionally substituted C16 In some embodiments, R″ is optionally substituted C 17 In some embodiments, R″ is optionally substituted C 18 In some embodiments, R″ is optionally substituted C 19 In some embodiments, R″ is optionally substituted C 20 It is alkenyl.

[0169] In some embodiments, R″ is C 6-20 In some embodiments, R″ is C 6-12 In some embodiments, R″ is C 8-11 In some embodiments, R″ is C 9-10 In some embodiments, R″ is C 6 In some embodiments, R″ is C 7 In some embodiments, R″ is C 8 In some embodiments, R″ is C 9 In some embodiments, R″ is C 10 In some embodiments, R″ is C 11 In some embodiments, R″ is C 12 In some embodiments, R″ is C 13-20 In some embodiments, R″ is C 15-20 In some embodiments, R″ is C 13 In some embodiments, R″ is C 14 In some embodiments, R″ is C 15 In some embodiments, R″ is C 16 In some embodiments, R″ is C 17 In some embodiments, R″ is C 18 In some embodiments, R″ is C 19In some embodiments, R″ is C 20 It is alkenyl.

[0170] In some embodiments, R″ is a linear C 6-20 In some embodiments, R″ is a straight chain C 6-12 In some embodiments, R″ is a straight chain C 8-11 In some embodiments, R″ is a straight chain C 9-10 In some embodiments, R″ is a straight chain C 6 In some embodiments, R″ is a straight chain C 7 In some embodiments, R″ is a straight chain C 8 In some embodiments, R″ is a straight chain C 9 In some embodiments, R″ is a straight chain C 10 In some embodiments, R″ is a straight chain C 11 In some embodiments, R″ is a straight chain C 12 In some embodiments, R″ is a straight chain C 13-20 In some embodiments, R″ is a straight chain C 15-20 In some embodiments, R″ is a straight chain C 13 In some embodiments, R″ is a straight chain C 14 In some embodiments, R″ is a straight chain C 15 In some embodiments, R″ is a straight chain C 16 In some embodiments, R″ is a straight chain C 17 In some embodiments, R″ is a straight chain C 18 In some embodiments, R″ is a straight chain C 19 In some embodiments, R″ is a straight chain C 20 It is alkenyl.

[0171] In some embodiments, R″ is a branched C 6-20In some embodiments, R″ is a branched C 6-12 In some embodiments, R″ is a branched C 8-11 In some embodiments, R″ is a branched C 9-10 In some embodiments, R″ is a branched C 6 In some embodiments, R″ is a branched C 7 In some embodiments, R″ is a branched C 8 In some embodiments, R″ is a branched C 9 In some embodiments, R″ is a branched C 10 In some embodiments, R″ is a branched C 11 In some embodiments, R″ is a branched C 12 In some embodiments, R″ is a branched C 13-20 In some embodiments, R″ is a branched C 15-20 In some embodiments, R″ is a branched C 13 In some embodiments, R″ is a branched C 14 In some embodiments, R″ is a branched C 15 In some embodiments, R″ is a branched C 16 In some embodiments, R″ is a branched C 17 In some embodiments, R″ is a branched C 18 In some embodiments, R″ is a branched C 19 In some embodiments, R″ is a branched C 20 It is alkenyl.

[0172] In some embodiments, R″ is an optionally substituted C 6-20 In some embodiments, R″ is an optionally substituted C 6-12 In some embodiments, R″ is an optionally substituted C 8-11In some embodiments, R″ is an optionally substituted C 9-10 In some embodiments, R″ is an optionally substituted C 6 In some embodiments, R″ is an optionally substituted C 7 In some embodiments, R″ is an optionally substituted C 8 In some embodiments, R″ is an optionally substituted C 9 In some embodiments, R″ is an optionally substituted C 10 In some embodiments, R″ is an optionally substituted C 11 In some embodiments, R″ is an optionally substituted C 12 In some embodiments, R″ is an optionally substituted C 13-20 In some embodiments, R″ is an optionally substituted C 15-20 In some embodiments, R″ is an optionally substituted C 13 In some embodiments, R″ is an optionally substituted C 14 In some embodiments, R″ is an optionally substituted C 15 In some embodiments, R″ is an optionally substituted C 16 In some embodiments, R″ is an optionally substituted C 17 In some embodiments, R″ is an optionally substituted C 18 In some embodiments, R″ is an optionally substituted C 19 In some embodiments, R″ is an optionally substituted C 20 It is alkynyl.

[0173] In some embodiments, R″ is C 6-20 In some embodiments, R″ is C 6-12 In some embodiments, R″ is C8-11 In some embodiments, R″ is C 9-10 In some embodiments, R″ is C 6 In some embodiments, R″ is C 7 In some embodiments, R″ is C 8 In some embodiments, R″ is C 9 In some embodiments, R″ is C 10 In some embodiments, R″ is C 11 In some embodiments, R″ is C 12 In some embodiments, R″ is C 13-20 In some embodiments, R″ is C 15-20 In some embodiments, R″ is C 13 In some embodiments, R″ is C 14 In some embodiments, R″ is C 15 In some embodiments, R″ is C 16 In some embodiments, R″ is C 17 In some embodiments, R″ is C 18 In some embodiments, R″ is C 19 In some embodiments, R″ is C 20 It is alkynyl.

[0174] In some embodiments, R″ is a linear C 6-20 In some embodiments, R″ is a straight chain C 6-12 In some embodiments, R″ is a straight chain C 8-11 In some embodiments, R″ is a straight chain C 9-10 In some embodiments, R″ is a straight chain C 6 In some embodiments, R″ is a straight chain C 7 In some embodiments, R″ is a straight chain C 8In some embodiments, R″ is a straight chain C 9 In some embodiments, R″ is a straight chain C 10 In some embodiments, R″ is a straight chain C 11 In some embodiments, R″ is a straight chain C 12 In some embodiments, R″ is a straight chain C 13-20 In some embodiments, R″ is a straight chain C 15-20 In some embodiments, R″ is a straight chain C 13 In some embodiments, R″ is a straight chain C 14 In some embodiments, R″ is a straight chain C 15 In some embodiments, R″ is a straight chain C 16 In some embodiments, R″ is a straight chain C 17 In some embodiments, R″ is a straight chain C 18 In some embodiments, R″ is a straight chain C 19 In some embodiments, R″ is a straight chain C 20 It is alkynyl.

[0175] In some embodiments, R″ is C 6-20 In some embodiments, R″ is C 6-12 In some embodiments, R″ is C 6-10 In some embodiments, R″ is C 6 In some embodiments, R″ is C 7 In some embodiments, R″ is C 8 In some embodiments, R″ is C 9 In some embodiments, R″ is C 10 In some embodiments, R″ is C 15-20 In some embodiments, R″ is C 15 In some embodiments, R″ is C 16In some embodiments, R″ is C 17 In some embodiments, R″ is C 18 In some embodiments, R″ is C 19 In some embodiments, R″ is C 20 It is haloaliphatic.

[0176] In some embodiments, R″ is a linear C 6-20 In some embodiments, R″ is a linear C 6-12 In some embodiments, R″ is a linear C 6-10 In some embodiments, R″ is a linear C 6 In some embodiments, R″ is a linear C 7 In some embodiments, R″ is a linear C 8 In some embodiments, R″ is a linear C 9 In some embodiments, R″ is a linear C 10 In some embodiments, R″ is a linear C 15-20 In some embodiments, R″ is a linear C 15 In some embodiments, R″ is a linear C 16 In some embodiments, R″ is a linear C 17 In some embodiments, R″ is a linear C 18 In some embodiments, R″ is a linear C 19 In some embodiments, R″ is a linear C 20 It is haloaliphatic.

[0177] In some embodiments, R″ is a C 6-20 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 6-20 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 6-20 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms.6-12 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 6-12 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 6-12 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 6-10 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 6-10 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 6-10 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 6 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 6 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 6 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 7 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 7 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 7 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 8 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 8 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 8 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 9 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 9 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 9 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 10 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 10In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 10 It is haloalkyl.

[0178] In some embodiments, R″ is a C 15-20 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 15-20 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 15-20 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 15 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 15 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 15 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 16 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 16 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 16 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 17 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 17 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 17 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 18 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 18 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 18 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 19 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 19 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms.19 In some embodiments, R″ is a C alkyl group containing 1 to 7 fluorine atoms. 20 In some embodiments, R″ is a C alkyl group containing 1 to 5 fluorine atoms. 20 In some embodiments, R″ is a C alkyl group containing 1 to 3 fluorine atoms. 20 It is haloalkyl.

[0179] In some embodiments, R″ is a linear C 6-20 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 6-20 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 6-20 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 6-12 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 6-12 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 6-12 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 6-10 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 6-10 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 6-10 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 6 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 6 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 6 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 7 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 7 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 7In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 8 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 8 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 8 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 9 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 9 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 9 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 10 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 10 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 10 It is haloalkyl.

[0180] In some embodiments, R″ is a linear C 15-20 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 15-20 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 15-20 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 15 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 15 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 15 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 16 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 16 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 16In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 17 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 17 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 17 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 18 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 18 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 18 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 19 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 19 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 19 In some embodiments, R″ is a linear C alkyl group containing 1 to 7 fluorine atoms. 20 In some embodiments, R″ is a linear C alkyl group containing 1 to 5 fluorine atoms. 20 In some embodiments, R″ is a linear C alkyl group containing 1 to 3 fluorine atoms. 20 It is haloalkyl.

[0181] In some embodiments, R" is an optionally substituted 3-12 membered alicyclic. In some embodiments, R" is an optionally substituted 3-7 membered alicyclic. In some embodiments, R" is an optionally substituted 4-7 membered alicyclic. In some embodiments, R" is an optionally substituted 5-7 membered alicyclic. In some embodiments, R" is an optionally substituted 6-7 membered alicyclic. In some embodiments, R" is an optionally substituted cyclopentyl. In some embodiments, R" is an optionally substituted cyclohexyl. In some embodiments, R" is a cyclohexyl substituted with R°. In some embodiments, R" is a cyclohexyl substituted with a 5 or 6 membered saturated, partially unsaturated ring or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and is substituted with -(CH 2 ) 0-2 R ● In some embodiments, R″ is cyclohexyl substituted with cyclohexyl, C 1-6 It is further substituted with an aliphatic. In some embodiments, R″ is an optionally substituted cycloheptyl.

[0182] In some embodiments, R″ is an optionally substituted 7-12 membered bridged bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R″ is optionally substituted 1-adamantyl. In some embodiments, R″ is optionally substituted 2-adamantyl. In some embodiments, R″ is optionally substituted sterolyl. In some embodiments, R″ is optionally substituted cholesterolyl. In some embodiments, R″ is optionally substituted phenyl. In some embodiments, R″ is phenyl substituted with R°. In some embodiments, R″ is C 1-6 It is an aliphatically substituted phenyl.

[0183] As noted above, in some embodiments of formulae A', I", II", and III', each R is independently hydrogen; or C6-20 R is an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. In some embodiments of Formula A, each R is independently hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 In some embodiments of Formulae I', I, II', II, and III, each R is independently selected from hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 An optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.

[0184] In some embodiments, each R is independently hydrogen; or C 6-20 In some embodiments, each R is independently selected from hydrogen; [ka] Or C 6-20 In some embodiments, each R is independently selected from hydrogen; [ka] Or C 6-20An optionally substituted group selected from aliphatic, 3- to 7-membered alicyclic, 1-adamantyl, and phenyl.

[0185] In some embodiments, each R is hydrogen. In some embodiments, each R is independently [ka] In some embodiments, each R is independently [ka] It is.

[0186] In some embodiments, each R is independently an optionally substituted C 6-20 In some embodiments, each R is independently an optionally substituted C 6-12 In some embodiments, each R is independently an optionally substituted C 8-11 In some embodiments, each R is independently an optionally substituted C 9-10 In some embodiments, each R is independently an optionally substituted C 6 In some embodiments, each R is independently an optionally substituted C 7 In some embodiments, each R is independently an optionally substituted C 8 In some embodiments, each R is independently an optionally substituted C 9 In some embodiments, each R is independently an optionally substituted C 10 In some embodiments, each R is independently an optionally substituted C 11 In some embodiments, each R is independently an optionally substituted C 12 In some embodiments, each R is independently an optionally substituted C 13-20 In some embodiments, each R is independently an optionally substituted C15-20 In some embodiments, each R is independently an optionally substituted C 13 In some embodiments, each R is independently an optionally substituted C 14 In some embodiments, each R is independently an optionally substituted C 15 In some embodiments, each R is independently an optionally substituted C 16 In some embodiments, each R is independently an optionally substituted C 17 In some embodiments, each R is independently an optionally substituted C 18 In some embodiments, each R is independently an optionally substituted C 19 In some embodiments, each R is independently an optionally substituted C 20 It is aliphatic.

[0187] In some embodiments, each R is independently an optionally substituted linear C 6-20 In some embodiments, each R is independently an optionally substituted linear C 6-12 In some embodiments, each R is independently an optionally substituted linear C 8-11 In some embodiments, each R is independently an optionally substituted linear C 9-10 In some embodiments, each R is independently an optionally substituted linear C 6 In some embodiments, each R is independently an optionally substituted linear C 7 In some embodiments, each R is independently an optionally substituted linear C 8 In some embodiments, each R is independently an optionally substituted linear C 9 In some embodiments, each R is independently an optionally substituted linear C 10 In some embodiments, each R is independently an optionally substituted linear C 11In some embodiments, each R is independently an optionally substituted linear C 12 In some embodiments, each R is independently an optionally substituted linear C 13-20 In some embodiments, each R is independently an optionally substituted linear C 15-20 In some embodiments, each R is independently an optionally substituted linear C 13 In some embodiments, each R is independently an optionally substituted linear C 14 In some embodiments, each R is independently an optionally substituted linear C 15 In some embodiments, each R is independently an optionally substituted linear C 16 In some embodiments, each R is independently an optionally substituted linear C 17 In some embodiments, each R is independently an optionally substituted linear C 18 In some embodiments, each R is independently an optionally substituted linear C 19 In some embodiments, each R is independently an optionally substituted linear C 20 It is aliphatic.

[0188] In some embodiments, each R is independently an optionally substituted branched C 6-20 In some embodiments, each R is independently an optionally substituted branched C 6-12 In some embodiments, each R is independently an optionally substituted branched C 8-11 In some embodiments, each R is independently an optionally substituted branched C 9-10 In some embodiments, each R is independently an optionally substituted branched C 6 In some embodiments, each R is independently an optionally substituted branched C 7 In some embodiments, each R is independently an optionally substituted branched C8 In some embodiments, each R is independently an optionally substituted branched C 9 In some embodiments, each R is independently an optionally substituted branched C 10 In some embodiments, each R is independently an optionally substituted branched C 11 In some embodiments, each R is independently an optionally substituted branched C 12 In some embodiments, each R is independently an optionally substituted branched C 13-20 In some embodiments, each R is independently an optionally substituted branched C 15-20 In some embodiments, each R is independently an optionally substituted branched C 13 In some embodiments, each R is independently an optionally substituted branched C 14 In some embodiments, each R is independently an optionally substituted branched C 15 In some embodiments, each R is independently an optionally substituted branched C 16 In some embodiments, each R is independently an optionally substituted branched C 17 In some embodiments, each R is independently an optionally substituted branched C 18 In some embodiments, each R is independently an optionally substituted branched C 19 In some embodiments, each R is independently an optionally substituted branched C 20 It is aliphatic.

[0189] In some embodiments, each R is independently C 6-20 In some embodiments, each R is independently C 6-12 In some embodiments, each R is independently C 8-11 In some embodiments, each R is independently C 9-10In some embodiments, each R is independently C 6 In some embodiments, each R is independently C 7 In some embodiments, each R is independently C 8 In some embodiments, each R is independently C 9 In some embodiments, each R is independently C 10 In some embodiments, each R is independently C 11 In some embodiments, each R is independently C 12 In some embodiments, each R is independently C 13-20 In some embodiments, each R is independently C 15-20 In some embodiments, each R is independently C 13 In some embodiments, each R is independently C 14 In some embodiments, each R is independently C 15 In some embodiments, each R is independently C 16 In some embodiments, each R is independently C 17 In some embodiments, each R is independently C 18 In some embodiments, each R is independently C 19 In some embodiments, each R is independently C 20 It is aliphatic.

[0190] In some embodiments, each R is independently a linear C 6-20 In some embodiments, each R is independently a linear C 6-12 In some embodiments, each R is independently a linear C 8-11 In some embodiments, each R is independently a linear C 9-10 In some embodiments, each R is independently a linear C 6 In some embodiments, each R is independently a linear C 7 In some embodiments, each R is independently a linear C8 In some embodiments, each R is independently a linear C 9 In some embodiments, each R is independently a linear C 10 In some embodiments, each R is independently a linear C 11 In some embodiments, each R is independently a linear C 12 In some embodiments, each R is independently a linear C 13-20 In some embodiments, each R is independently a linear C 15-20 In some embodiments, each R is independently a linear C 13 In some embodiments, each R is independently a linear C 14 In some embodiments, each R is independently a linear C 15 In some embodiments, each R is independently a linear C 16 In some embodiments, each R is independently a linear C 17 In some embodiments, each R is independently a linear C 18 In some embodiments, each R is independently a linear C 19 In some embodiments, each R is independently a linear C 20 It is aliphatic.

[0191] In some embodiments, each R is independently a branched C 6-20 In some embodiments, each R is independently a branched C 6-12 In some embodiments, each R is independently a branched C 8-11 In some embodiments, each R is independently a branched C 9-10 In some embodiments, each R is independently a branched C 6 In some embodiments, each R is independently a branched C 7 In some embodiments, each R is independently a branched C 8 In some embodiments, each R is independently a branched C 9In some embodiments, each R is independently a branched C 10 In some embodiments, each R is independently a branched C 11 In some embodiments, each R is independently a branched C 12 In some embodiments, each R is independently a branched C 13-20 In some embodiments, each R is independently a branched C 15-20 In some embodiments, each R is independently a branched C 13 In some embodiments, each R is independently a branched C 14 In some embodiments, each R is independently a branched C 15 In some embodiments, each R is independently a branched C 16 In some embodiments, each R is independently a branched C 17 In some embodiments, each R is independently a branched C 18 In some embodiments, each R is independently a branched C 19 In some embodiments, each R is independently a branched C 20 It is aliphatic.

[0192] In some embodiments, each R is independently an optionally substituted C 6-20 In some embodiments, each R is independently an optionally substituted C alkyl. 6-12 In some embodiments, each R is independently an optionally substituted C alkyl. 8-11 In some embodiments, each R is independently an optionally substituted C alkyl. 9-10 In some embodiments, each R is independently an optionally substituted C alkyl. 6 In some embodiments, each R is independently an optionally substituted C alkyl. 7 In some embodiments, each R is independently an optionally substituted C alkyl. 8In some embodiments, each R is independently an optionally substituted C alkyl. 9 In some embodiments, each R is independently an optionally substituted C alkyl. 10 In some embodiments, each R is independently an optionally substituted C alkyl. 11 In some embodiments, each R is independently an optionally substituted C alkyl. 12 In some embodiments, each R is independently an optionally substituted C alkyl. 13-20 In some embodiments, each R is independently an optionally substituted C alkyl. 15-20 In some embodiments, each R is independently an optionally substituted C alkyl. 13 In some embodiments, each R is independently an optionally substituted C alkyl. 14 In some embodiments, each R is independently an optionally substituted C alkyl. 15 In some embodiments, each R is independently an optionally substituted C alkyl. 16 In some embodiments, each R is independently an optionally substituted C alkyl. 17 In some embodiments, each R is independently an optionally substituted C alkyl. 18 In some embodiments, each R is independently an optionally substituted C alkyl. 19 In some embodiments, each R is independently an optionally substituted C alkyl. 20 It is an alkyl.

[0193] In some embodiments, each R is independently C 6-20 In some embodiments, each R is independently C 6-12 In some embodiments, each R is independently C 8-11 In some embodiments, each R is independently C 9-10 In some embodiments, each R is independently C 6 In some embodiments, each R is independently C7 In some embodiments, each R is independently C 8 In some embodiments, each R is independently C 9 In some embodiments, each R is independently C 10 In some embodiments, each R is independently C 11 In some embodiments, each R is independently C 12 In some embodiments, each R is independently C 13-20 In some embodiments, each R is independently C 15-20 In some embodiments, each R is independently C 13 In some embodiments, each R is independently C 14 In some embodiments, each R is independently C 15 In some embodiments, each R is independently C 16 In some embodiments, each R is independently C 17 In some embodiments, each R is independently C 18 In some embodiments, each R is independently C 19 In some embodiments, each R is independently C 20 It is an alkyl.

[0194] In some embodiments, each R is independently a linear C 6-20 In some embodiments, each R is independently a straight chain C alkyl. 6-12 In some embodiments, each R is independently a straight chain C alkyl. 8-11 In some embodiments, each R is independently a straight chain C alkyl. 9-10 In some embodiments, each R is independently a straight chain C alkyl. 6 In some embodiments, each R is independently a straight chain C alkyl. 7 In some embodiments, each R is independently a straight chain C alkyl. 8 In some embodiments, each R is independently a straight chain C alkyl.9 In some embodiments, each R is independently a straight chain C alkyl. 10 In some embodiments, each R is independently a straight chain C alkyl. 11 In some embodiments, each R is independently a straight chain C alkyl. 12 In some embodiments, each R is independently a straight chain C alkyl. 13-20 In some embodiments, each R is independently a straight chain C alkyl. 15-20 In some embodiments, each R is independently a straight chain C alkyl. 13 In some embodiments, each R is independently a straight chain C alkyl. 14 In some embodiments, each R is independently a straight chain C alkyl. 15 In some embodiments, each R is independently a straight chain C alkyl. 16 In some embodiments, each R is independently a straight chain C alkyl. 17 In some embodiments, each R is independently a straight chain C alkyl. 18 In some embodiments, each R is independently a straight chain C alkyl. 19 In some embodiments, each R is independently a straight chain C alkyl. 20 It is an alkyl.

[0195] In some embodiments, each R is independently a branched C 6-20 In some embodiments, each R is independently a branched C alkyl. 6-12 In some embodiments, each R is independently a branched C alkyl. 8-11 In some embodiments, each R is independently a branched C alkyl. 9-10 In some embodiments, each R is independently a branched C alkyl. 6 In some embodiments, each R is independently a branched C alkyl. 7 In some embodiments, each R is independently a branched C alkyl. 8 In some embodiments, each R is independently a branched C alkyl. 9 In some embodiments, each R is independently a branched C alkyl.10 In some embodiments, each R is independently a branched C alkyl. 11 In some embodiments, each R is independently a branched C alkyl. 12 In some embodiments, each R is independently a branched C alkyl. 13-20 In some embodiments, each R is independently a branched C alkyl. 15-20 In some embodiments, each R is independently a branched C alkyl. 13 In some embodiments, each R is independently a branched C alkyl. 14 In some embodiments, each R is independently a branched C alkyl. 15 In some embodiments, each R is independently a branched C alkyl. 16 In some embodiments, each R is independently a branched C alkyl. 17 In some embodiments, each R is independently a branched C alkyl. 18 In some embodiments, each R is independently a branched C alkyl. 19 In some embodiments, each R is independently a branched C alkyl. 20 It is an alkyl.

[0196] In some embodiments, each R is independently an optionally substituted C 6-20 In some embodiments, each R is independently optionally substituted C 6-12 In some embodiments, each R is independently optionally substituted C 8-11 In some embodiments, each R is independently optionally substituted C 9-10 In some embodiments, each R is independently optionally substituted C 6 In some embodiments, each R is independently optionally substituted C 7 In some embodiments, each R is independently optionally substituted C 8 In some embodiments, each R is independently optionally substituted C9 In some embodiments, each R is independently optionally substituted C 10 In some embodiments, each R is independently optionally substituted C 11 In some embodiments, each R is independently optionally substituted C 12 In some embodiments, each R is independently optionally substituted C 13-20 In some embodiments, each R is independently optionally substituted C 15-20 In some embodiments, each R is independently optionally substituted C 13 In some embodiments, each R is independently optionally substituted C 14 In some embodiments, each R is independently optionally substituted C 15 In some embodiments, each R is independently optionally substituted C 16 In some embodiments, each R is independently optionally substituted C 17 In some embodiments, each R is independently optionally substituted C 18 In some embodiments, each R is independently optionally substituted C 19 In some embodiments, each R is independently optionally substituted C 20 It is alkenyl.

[0197] In some embodiments, each R is independently C 6-20 In some embodiments, each R is independently C 6-12 In some embodiments, each R is independently C 8-11 In some embodiments, each R is independently C 9-10 In some embodiments, each R is independently C 6 In some embodiments, each R is independently C 7In some embodiments, each R is independently C 8 In some embodiments, each R is independently C 9 In some embodiments, each R is independently C 10 In some embodiments, each R is independently C 11 In some embodiments, each R is independently C 12 In some embodiments, each R is independently C 13-20 In some embodiments, each R is independently C 15-20 In some embodiments, each R is independently C 13 In some embodiments, each R is independently C 14 In some embodiments, each R is independently C 15 In some embodiments, each R is independently C 16 In some embodiments, each R is independently C 17 In some embodiments, each R is independently C 18 In some embodiments, each R is independently C 19 In some embodiments, each R is independently C 20 It is alkenyl.

[0198] In some embodiments, each R is independently a linear C 6-20 In some embodiments, each R is independently a linear C 6-12 In some embodiments, each R is independently a linear C 8-11 In some embodiments, each R is independently a linear C 9-10 In some embodiments, each R is independently a linear C 6 In some embodiments, each R is independently a linear C 7 In some embodiments, each R is independently a linear C 8In some embodiments, each R is independently a linear C 9 In some embodiments, each R is independently a linear C 10 In some embodiments, each R is independently a linear C 11 In some embodiments, each R is independently a linear C 12 In some embodiments, each R is independently a linear C 13-20 In some embodiments, each R is independently a linear C 15-20 In some embodiments, each R is independently a linear C 13 In some embodiments, each R is independently a linear C 14 In some embodiments, each R is independently a linear C 15 In some embodiments, each R is independently a linear C 16 In some embodiments, each R is independently a linear C 17 In some embodiments, each R is independently a linear C 18 In some embodiments, each R is independently a linear C 19 In some embodiments, each R is independently a linear C 20 It is alkenyl.

[0199] In some embodiments, each R is independently a branched C 6-20 In some embodiments, each R is independently a branched C 6-12 In some embodiments, each R is independently a branched C 8-11 In some embodiments, each R is independently a branched C 9-10 In some embodiments, each R is independently a branched C 6 In some embodiments, each R is independently a branched C 7 In some embodiments, each R is independently a branched C 8In some embodiments, each R is independently a branched C 9 In some embodiments, each R is independently a branched C 10 In some embodiments, each R is independently a branched C 11 In some embodiments, each R is independently a branched C 12 In some embodiments, each R is independently a branched C 13-20 In some embodiments, each R is independently a branched C 15-20 In some embodiments, each R is independently a branched C 13 In some embodiments, each R is independently a branched C 14 In some embodiments, each R is independently a branched C 15 In some embodiments, each R is independently a branched C 16 In some embodiments, each R is independently a branched C 17 In some embodiments, each R is independently a branched C 18 In some embodiments, each R is independently a branched C 19 In some embodiments, each R is independently a branched C 20 It is alkenyl.

[0200] In some embodiments, each R is independently an optionally substituted C 6-20 In some embodiments, each R is independently an optionally substituted C 6-12 In some embodiments, each R is independently an optionally substituted C 8-11 In some embodiments, each R is independently an optionally substituted C 9-10 In some embodiments, each R is independently an optionally substituted C 6 In some embodiments, each R is independently an optionally substituted C 7In some embodiments, each R is independently an optionally substituted C 8 In some embodiments, each R is independently an optionally substituted C 9 In some embodiments, each R is independently an optionally substituted C 10 In some embodiments, each R is independently an optionally substituted C 11 In some embodiments, each R is independently an optionally substituted C 12 In some embodiments, each R is independently an optionally substituted C 13-20 In some embodiments, each R is independently an optionally substituted C 15-20 In some embodiments, each R is independently an optionally substituted C 13 In some embodiments, each R is independently an optionally substituted C 14 In some embodiments, each R is independently an optionally substituted C 15 In some embodiments, each R is independently an optionally substituted C 16 In some embodiments, each R is independently an optionally substituted C 17 In some embodiments, each R is independently an optionally substituted C 18 In some embodiments, each R is independently an optionally substituted C 19 In some embodiments, each R is independently an optionally substituted C 20 It is alkynyl.

[0201] In some embodiments, each R is independently C 6-20 In some embodiments, each R is independently C 6-12 In some embodiments, each R is independently C 8-11 In some embodiments, each R is independently C 9-10In some embodiments, each R is independently C 6 In some embodiments, each R is independently C 7 In some embodiments, each R is independently C 8 In some embodiments, each R is independently C 9 In some embodiments, each R is independently C 10 In some embodiments, each R is independently C 11 In some embodiments, each R is independently C 12 In some embodiments, each R is independently C 13-20 In some embodiments, each R is independently C 15-20 In some embodiments, each R is independently C 13 In some embodiments, each R is independently C 14 In some embodiments, each R is independently C 15 In some embodiments, each R is independently C 16 In some embodiments, each R is independently C 17 In some embodiments, each R is independently C 18 In some embodiments, each R is independently C 19 In some embodiments, each R is independently C 20 It is alkynyl.

[0202] In some embodiments, each R is independently a linear C 6-20 In some embodiments, each R is independently a straight chain C 6-12 In some embodiments, each R is independently a straight chain C 8-11 In some embodiments, each R is independently a straight chain C 9-10 In some embodiments, each R is independently a straight chain C 6In some embodiments, each R is independently a straight chain C 7 In some embodiments, each R is independently a straight chain C 8 In some embodiments, each R is independently a straight chain C 9 In some embodiments, each R is independently a straight chain C 10 In some embodiments, each R is independently a straight chain C 11 In some embodiments, each R is independently a straight chain C 12 In some embodiments, each R is independently a straight chain C 13-20 In some embodiments, each R is independently a straight chain C 15-20 In some embodiments, each R is independently a straight chain C 13 In some embodiments, each R is independently a straight chain C 14 In some embodiments, each R is independently a straight chain C 15 In some embodiments, each R is independently a straight chain C 16 In some embodiments, each R is independently a straight chain C 17 In some embodiments, each R is independently a straight chain C 18 In some embodiments, each R is independently a straight chain C 19 In some embodiments, each R is independently a straight chain C 20 It is alkynyl.

[0203] In some embodiments, each R is independently an optionally substituted C 6-20 In some embodiments, each R is independently an optionally substituted C 6-12 In some embodiments, each R is independently an optionally substituted C 6-10 In some embodiments, each R is independently an optionally substituted C 6 In some embodiments, each R is independently an optionally substituted C7 In some embodiments, each R is independently an optionally substituted C 8 In some embodiments, each R is independently an optionally substituted C 9 In some embodiments, each R is independently an optionally substituted C 10 In some embodiments, each R is independently an optionally substituted C 15-20 In some embodiments, each R is independently an optionally substituted C 15 In some embodiments, each R is independently an optionally substituted C 16 In some embodiments, each R is independently an optionally substituted C 17 In some embodiments, each R is independently an optionally substituted C 18 In some embodiments, each R is independently an optionally substituted C 19 In some embodiments, each R is independently an optionally substituted C 20 It is haloaliphatic.

[0204] In some embodiments, each R is independently an optionally substituted linear C 6-20 In some embodiments, each R is independently an optionally substituted linear C 6-12 In some embodiments, each R is independently an optionally substituted linear C 6-10 In some embodiments, each R is independently an optionally substituted linear C 6 In some embodiments, each R is independently an optionally substituted linear C 7 In some embodiments, each R is independently an optionally substituted linear C 8 In some embodiments, each R is independently an optionally substituted linear C 9In some embodiments, each R is independently an optionally substituted linear C 10 In some embodiments, each R is independently an optionally substituted linear C 15-20 In some embodiments, each R is independently an optionally substituted linear C 15 In some embodiments, each R is independently an optionally substituted linear C 16 In some embodiments, each R is independently an optionally substituted linear C 17 In some embodiments, each R is independently an optionally substituted linear C 18 In some embodiments, each R is independently an optionally substituted linear C 19 In some embodiments, each R is independently an optionally substituted linear C 20 It is haloaliphatic.

[0205] In some embodiments, each R is independently an optionally substituted branched C 6-20 In some embodiments, each R is independently an optionally substituted branched C 6-12 In some embodiments, each R is independently an optionally substituted branched C 6-10 In some embodiments, each R is independently an optionally substituted branched C 6 In some embodiments, each R is independently an optionally substituted branched C 7 In some embodiments, each R is independently an optionally substituted branched C 8 In some embodiments, each R is independently an optionally substituted branched C 9 In some embodiments, each R is independently an optionally substituted branched C 10 In some embodiments, each R is independently an optionally substituted branched C 15-20In some embodiments, each R is independently an optionally substituted branched C 15 In some embodiments, each R is independently an optionally substituted branched C 16 In some embodiments, each R is independently an optionally substituted branched C 17 In some embodiments, each R is independently an optionally substituted branched C 18 In some embodiments, each R is independently an optionally substituted branched C 19 In some embodiments, each R is independently an optionally substituted branched C 20 It is haloaliphatic.

[0206] In some embodiments, each R is independently C 6-20 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 6-12 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 6-10 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 6 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 7 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 8 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 9 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 10 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 15-20 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 15 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 16 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 17 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 18 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C 19 In some embodiments, each R is independently selected from the group consisting of haloaliphatic and C20 It is haloaliphatic.

[0207] In some embodiments, each R is independently a linear C 6-20 In some embodiments, each R is independently a linear C 6-12 In some embodiments, each R is independently a linear C 6-10 In some embodiments, each R is independently a linear C 6 In some embodiments, each R is independently a linear C 7 In some embodiments, each R is independently a linear C 8 In some embodiments, each R is independently a linear C 9 In some embodiments, each R is independently a linear C 10 In some embodiments, each R is independently a linear C 15-20 In some embodiments, each R is independently a linear C 15 In some embodiments, each R is independently a linear C 16 In some embodiments, each R is independently a linear C 17 In some embodiments, each R is independently a linear C 18 In some embodiments, each R is independently a linear C 19 In some embodiments, each R is independently a linear C 20 It is haloaliphatic.

[0208] In some embodiments, each R is independently an optionally substituted C 6-20 In some embodiments, each R is independently an optionally substituted C 6-20 In some embodiments, each R is independently an optionally substituted C 6-20In some embodiments, each R is independently an optionally substituted C 6-12 In some embodiments, each R is independently an optionally substituted C 6-12 In some embodiments, each R is independently an optionally substituted C 6-12 In some embodiments, each R is independently an optionally substituted C 6-10 In some embodiments, each R is independently an optionally substituted C 6-10 In some embodiments, R is independently an optionally substituted C alkyl group containing 1 to 3 fluorine atoms. 6-10 In some embodiments, each R is independently an optionally substituted C 6 In some embodiments, each R is independently an optionally substituted C 6 In some embodiments, each R is independently an optionally substituted C 6 In some embodiments, each R is independently an optionally substituted C 7 In some embodiments, each R is independently an optionally substituted C 7 In some embodiments, each R is independently an optionally substituted C 7 In some embodiments, each R is independently an optionally substituted C 8 In some embodiments, each R is independently an optionally substituted C 8In some embodiments, each R is independently an optionally substituted C 8 In some embodiments, each R is independently an optionally substituted C 9 In some embodiments, each R is independently an optionally substituted C 9 In some embodiments, each R is independently an optionally substituted C 9 In some embodiments, each R is independently an optionally substituted C 10 In some embodiments, each R is independently an optionally substituted C 10 In some embodiments, each R is independently an optionally substituted C 10 It is haloalkyl.

[0209] In some embodiments, each R is independently an optionally substituted C 15-20 In some embodiments, each R is independently an optionally substituted C 15-20 In some embodiments, each R is independently an optionally substituted C 15-20 In some embodiments, each R is independently an optionally substituted C 15 In some embodiments, each R is independently an optionally substituted C 15 In some embodiments, each R is independently an optionally substituted C 15 In some embodiments, each R is independently an optionally substituted C 16In some embodiments, each R is independently an optionally substituted C 16 In some embodiments, each R is independently an optionally substituted C 16 In some embodiments, each R is independently an optionally substituted C 17 In some embodiments, each R is independently an optionally substituted C 17 In some embodiments, each R is independently an optionally substituted C 17 In some embodiments, each R is independently an optionally substituted C 18 In some embodiments, each R is independently an optionally substituted C 18 In some embodiments, each R is independently an optionally substituted C 18 In some embodiments, each R is independently an optionally substituted C 19 In some embodiments, each R is independently an optionally substituted C 19 In some embodiments, each R is independently an optionally substituted C 19 In some embodiments, each R is independently an optionally substituted C 20 In some embodiments, each R is independently an optionally substituted C 20 In some embodiments, each R is independently an optionally substituted C 20 It is haloalkyl.

[0210] In some embodiments, each R is independently a C 6-20 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 6-20 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 6-20 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 6-12 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 6-12 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 6-12 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 6-10 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 6-10 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 6-10 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 6 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 6 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 6 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 7 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 7 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 7 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 8 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 8 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 8In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 9 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 9 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 9 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 10 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 10 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 10 It is haloalkyl.

[0211] In some embodiments, each R is independently a C 15-20 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 15-20 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 15-20 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 15 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 15 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 15 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 16 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 16 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 16 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 17 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 17In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 17 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 18 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 18 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 18 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 19 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 19 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 19 In some embodiments, each R is independently a C alkyl group containing 1 to 7 fluorine atoms. 20 In some embodiments, each R is independently a C alkyl group containing 1 to 5 fluorine atoms. 20 In some embodiments, each R is independently a C alkyl group containing 1 to 3 fluorine atoms. 20 It is haloalkyl.

[0212] In some embodiments, each R is independently a linear C 6-20 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 6-20 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 6-20 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 6-12 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 6-12 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 6-12 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms.6-10 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 6-10 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 6-10 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 6 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 6 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 6 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 7 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 7 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 7 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 8 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 8 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 8 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 9 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 9 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 9 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 10 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 10 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 10It is haloalkyl.

[0213] In some embodiments, each R is independently a linear C 15-20 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 15-20 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 15-20 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 15 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 15 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 15 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 16 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 16 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 16 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 17 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 17 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 17 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 18 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 18 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 18 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 19In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 19 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 19 In some embodiments, each R is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 20 In some embodiments, each R is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 20 In some embodiments, each R is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 20 It is haloalkyl.

[0214] In some embodiments, each R is independently an optionally substituted 3-12 membered alicyclic. In some embodiments, each R is independently an optionally substituted 3-7 membered alicyclic. In some embodiments, each R is independently an optionally substituted 4-7 membered alicyclic. In some embodiments, each R is independently an optionally substituted 5-7 membered alicyclic. In some embodiments, each R is independently an optionally substituted 6-7 membered alicyclic. In some embodiments, each R is independently an optionally substituted cyclopentyl. In some embodiments, each R is independently an optionally substituted cyclohexyl. In some embodiments, each R is independently a cyclohexyl substituted with R°. In some embodiments, each R is independently a cyclohexyl substituted with a 5 or 6 membered saturated, partially unsaturated ring or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and is substituted with -(CH 2 ) 0-2 R ● In some embodiments, each R is independently cyclohexyl substituted with cyclohexyl, C 1-6 Further substituted with an aliphatic. In some embodiments, each R is independently an optionally substituted cycloheptyl.

[0215] In some embodiments, each R is independently an optionally substituted 7-12 membered bridged bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each R is independently an optionally substituted 1-adamantyl. In some embodiments, each R is independently an optionally substituted 2-adamantyl. In some embodiments, each R is independently an optionally substituted sterolyl. In some embodiments, each R is independently an optionally substituted cholesterolyl. In some embodiments, each R is independently an optionally substituted phenyl. In some embodiments, each R is independently a phenyl substituted with R°. In some embodiments, each R is independently a C 1-6 It is an aliphatically substituted phenyl.

[0216] In some embodiments of any of formulas A', A, I", I', and I, two R are optionally substituted C 6-20 alkyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkenyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkenyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C alkyl. 6-20 alkynyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C alkyl. 6-20 aliphatic, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C6-20 haloaliphatic, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkenyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkynyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 haloalkyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C alkyl. 6-20 haloalkyl, and the third R is optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 haloalkyl, and the third R is optionally substituted C 6-20 It is alkynyl.

[0217] In some embodiments of any of formulas II", II', II, III', and III, two R are optionally substituted C 6-20 alkyl, and the other two R are optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkenyl, and the other two R are optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkyl, and the other two R are optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20aliphatic, and the other two R are optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkyl, and the other two R are optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkenyl, and the other two R are optionally substituted C 6-20 In some embodiments, two R are optionally substituted C 6-20 alkynyl, and the other two R are optionally substituted C 6-20 It is haloalkyl.

[0218] As noted above, in some embodiments of Formula A′, each R a are independently hydrogen; or C 6-20 In some embodiments of Formula A, each R is an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. a are independently hydrogen; [ka] Or C 6-20 aliphatic, C 6-20 An optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic ring, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.

[0219] In some embodiments, each R a are independently hydrogen; or C 6-20 is an optionally substituted group selected from aliphatic, 3- to 12-membered alicyclic, 1-adamantyl, and phenyl. a are independently hydrogen; [ka] Or C 6-20 An optionally substituted group selected from aliphatic, 3- to 7-membered alicyclic, 1-adamantyl, and phenyl.

[0220] In some embodiments, each R a is hydrogen. In some embodiments, each R a is, independently, [ka] It is.

[0221] In some embodiments, each R a independently represents an optionally substituted C 6-20 In some embodiments, each R a independently represents an optionally substituted C 6-12 In some embodiments, each R a independently represents an optionally substituted C 8-11 In some embodiments, each R a independently represents an optionally substituted C 9-10 In some embodiments, each R a independently represents an optionally substituted C 6 In some embodiments, each R a independently represents an optionally substituted C 7 In some embodiments, each R a independently represents an optionally substituted C 8 In some embodiments, each R a independently represents an optionally substituted C 9 In some embodiments, each R a independently represents an optionally substituted C 10 In some embodiments, each R a independently represents an optionally substituted C 11 In some embodiments, each R aindependently represents an optionally substituted C 12 In some embodiments, each R a independently represents an optionally substituted C 13-20 In some embodiments, each R a independently represents an optionally substituted C 15-20 In some embodiments, each R a independently represents an optionally substituted C 13 In some embodiments, each R a independently represents an optionally substituted C 14 In some embodiments, each R a independently represents an optionally substituted C 15 In some embodiments, each R a independently represents an optionally substituted C 16 In some embodiments, each R a independently represents an optionally substituted C 17 In some embodiments, each R a independently represents an optionally substituted C 18 In some embodiments, each R a independently represents an optionally substituted C 19 In some embodiments, each R a independently represents an optionally substituted C 20 It is aliphatic.

[0222] In some embodiments, each R a independently represents an optionally substituted linear C 6-20 In some embodiments, each R a independently represents an optionally substituted linear C 6-12 In some embodiments, each R a independently represents an optionally substituted linear C 8-11 In some embodiments, each R a independently represents an optionally substituted linear C 9-10 In some embodiments, each Ra independently represents an optionally substituted linear C 6 In some embodiments, each R a independently represents an optionally substituted linear C 7 In some embodiments, each R a independently represents an optionally substituted linear C 8 In some embodiments, each R a independently represents an optionally substituted linear C 9 In some embodiments, each R a independently represents an optionally substituted linear C 10 In some embodiments, each R a independently represents an optionally substituted linear C 11 In some embodiments, each R a independently represents an optionally substituted linear C 12 In some embodiments, each R a independently represents an optionally substituted linear C 13-20 In some embodiments, each R a independently represents an optionally substituted linear C 15-20 In some embodiments, each R a independently represents an optionally substituted linear C 13 In some embodiments, each R a independently represents an optionally substituted linear C 14 In some embodiments, each R a independently represents an optionally substituted linear C 15 In some embodiments, each R a independently represents an optionally substituted linear C 16 In some embodiments, each R a independently represents an optionally substituted linear C 17 In some embodiments, each R a independently represents an optionally substituted linear C 18 In some embodiments, each R aindependently represents an optionally substituted linear C 19 In some embodiments, each R a independently represents an optionally substituted linear C 20 It is aliphatic.

[0223] In some embodiments, each R a independently, optionally substituted branched C 6-20 In some embodiments, each R a independently, optionally substituted branched C 6-12 In some embodiments, each R a independently, optionally substituted branched C 8-11 In some embodiments, each R a independently, optionally substituted branched C 9-10 In some embodiments, each R a independently, optionally substituted branched C 6 In some embodiments, each R a independently, optionally substituted branched C 7 In some embodiments, each R a independently, optionally substituted branched C 8 In some embodiments, each R a independently, optionally substituted branched C 9 In some embodiments, each R a independently, optionally substituted branched C 10 In some embodiments, each R a independently, optionally substituted branched C 11 In some embodiments, each R a independently, optionally substituted branched C 12 In some embodiments, each R a independently, optionally substituted branched C 13-20 In some embodiments, each R aindependently, optionally substituted branched C 15-20 In some embodiments, each R a independently, optionally substituted branched C 13 In some embodiments, each R a independently, optionally substituted branched C 14 In some embodiments, each R a independently, optionally substituted branched C 15 In some embodiments, each R a independently, optionally substituted branched C 16 In some embodiments, each R a independently, optionally substituted branched C 17 In some embodiments, each R a independently, optionally substituted branched C 18 In some embodiments, each R a independently, optionally substituted branched C 19 In some embodiments, each R a independently, optionally substituted branched C 20 It is aliphatic.

[0224] In some embodiments, each R a is independently 6-20 In some embodiments, each R a is independently 6-12 In some embodiments, each R a is independently 8-11 In some embodiments, each R a is independently 9-10 In some embodiments, each R a is independently 6 In some embodiments, each R a is independently 7 In some embodiments, each R a is independently 8In some embodiments, each R a is independently 9 In some embodiments, each R a is independently 10 In some embodiments, each R a is independently 11 In some embodiments, each R a is independently 12 In some embodiments, each R a is independently 13-20 In some embodiments, each R a is independently 15-20 In some embodiments, each R a is independently 13 In some embodiments, each R a is independently 14 In some embodiments, each R a is independently 15 In some embodiments, each R a is independently 16 In some embodiments, each R a is independently 17 In some embodiments, each R a is independently 18 In some embodiments, each R a is independently 19 In some embodiments, each R a is independently 20 It is aliphatic.

[0225] In some embodiments, each R a are independently linear C 6-20 In some embodiments, each R a are independently linear C 6-12 In some embodiments, each R a are independently linear C 8-11 In some embodiments, each R a are independently linear C 9-10In some embodiments, each R a are independently linear C 6 In some embodiments, each R a are independently linear C 7 In some embodiments, each R a are independently linear C 8 In some embodiments, each R a are independently linear C 9 In some embodiments, each R a are independently linear C 10 In some embodiments, each R a are independently linear C 11 In some embodiments, each R a are independently linear C 12 In some embodiments, each R a are independently linear C 13-20 In some embodiments, each R a are independently linear C 15-20 In some embodiments, each R a are independently linear C 13 In some embodiments, each R a are independently linear C 14 In some embodiments, each R a are independently linear C 15 In some embodiments, each R a are independently linear C 16 In some embodiments, each R a are independently linear C 17 In some embodiments, each R a are independently linear C 18 In some embodiments, each R a are independently linear C 19 In some embodiments, each R a are independently linear C 20 It is aliphatic.

[0226] In some embodiments, each Ra is an independent, branched C 6-20 In some embodiments, each R a is an independent, branched C 6-12 In some embodiments, each R a is an independent, branched C 8-11 In some embodiments, each R a is an independent, branched C 9-10 In some embodiments, each R a is an independent, branched C 6 In some embodiments, each R a is an independent, branched C 7 In some embodiments, each R a is an independent, branched C 8 In some embodiments, each R a is an independent, branched C 9 In some embodiments, each R a is an independent, branched C 10 In some embodiments, each R a is an independent, branched C 11 In some embodiments, each R a is an independent, branched C 12 In some embodiments, each R a is an independent, branched C 13-20 In some embodiments, each R a is an independent, branched C 15-20 In some embodiments, each R a is an independent, branched C 13 In some embodiments, each R a is an independent, branched C 14 In some embodiments, each R a is an independent, branched C 15 In some embodiments, each R a is an independent, branched C 16 In some embodiments, each R a is an independent, branched C17 In some embodiments, each R a is an independent, branched C 18 In some embodiments, each R a is an independent, branched C 19 In some embodiments, each R a is an independent, branched C 20 It is aliphatic.

[0227] In some embodiments, each R a independently represents an optionally substituted C 6-20 In some embodiments, each R a independently represents an optionally substituted C 6-12 In some embodiments, each R a independently represents an optionally substituted C 8-11 In some embodiments, each R a independently represents an optionally substituted C 9-10 In some embodiments, each R a independently represents an optionally substituted C 6 In some embodiments, each R a independently represents an optionally substituted C 7 In some embodiments, each R a independently represents an optionally substituted C 8 In some embodiments, each R a independently represents an optionally substituted C 9 In some embodiments, each R a independently represents an optionally substituted C 10 In some embodiments, each R a independently represents an optionally substituted C 11 In some embodiments, each R a independently represents an optionally substituted C 12 In some embodiments, each R a independently represents an optionally substituted C 13-20In some embodiments, each R a independently represents an optionally substituted C 15-20 In some embodiments, each R a independently represents an optionally substituted C 13 In some embodiments, each R a independently represents an optionally substituted C 14 In some embodiments, each R a independently represents an optionally substituted C 15 In some embodiments, each R a independently represents an optionally substituted C 16 In some embodiments, each R a independently represents an optionally substituted C 17 In some embodiments, each R a independently represents an optionally substituted C 18 In some embodiments, each R a independently represents an optionally substituted C 19 In some embodiments, each R a independently represents an optionally substituted C 20 It is an alkyl.

[0228] In some embodiments, each R a is independently 6-20 In some embodiments, each R a is independently 6-12 In some embodiments, each R a is independently 8-11 In some embodiments, each R a is independently 9-10 In some embodiments, each R a is independently 6 In some embodiments, each R a is independently 7 In some embodiments, each R a is independently 8In some embodiments, each R a is independently 9 In some embodiments, each R a is independently 10 In some embodiments, each R a is independently 11 In some embodiments, each R a is independently 12 In some embodiments, each R a is independently 13-20 In some embodiments, each R a is independently 15-20 In some embodiments, each R a is independently 13 In some embodiments, each R a is independently 14 In some embodiments, each R a is independently 15 In some embodiments, each R a is independently 16 In some embodiments, each R a is independently 17 In some embodiments, each R a is independently 18 In some embodiments, each R a is independently 19 In some embodiments, each R a is independently 20 It is an alkyl.

[0229] In some embodiments, each R a are independently linear C 6-20 In some embodiments, each R a are independently linear C 6-12 In some embodiments, each R a are independently linear C 8-11 In some embodiments, each R aare independently linear C 9-10 In some embodiments, each R a are independently linear C 6 In some embodiments, each R a are independently linear C 7 In some embodiments, each R a are independently linear C 8 In some embodiments, each R a are independently linear C 9 In some embodiments, each R a are independently linear C 10 In some embodiments, each R a are independently linear C 11 In some embodiments, each R a are independently linear C 12 In some embodiments, each R a are independently linear C 13-20 In some embodiments, each R a are independently linear C 15-20 In some embodiments, each R a are independently linear C 13 In some embodiments, each R a are independently linear C 14 In some embodiments, each R a are independently linear C 15 In some embodiments, each R a are independently linear C 16 In some embodiments, each R a are independently linear C 17 In some embodiments, each R a are independently linear C 18 In some embodiments, each R a are independently linear C 19 In some embodiments, each R a are independently linear C 20 It is an alkyl.

[0230] In some embodiments, each R a is an independent, branched C 6-20 In some embodiments, each R a is an independent, branched C 6-12 In some embodiments, each R a is an independent, branched C 8-11 In some embodiments, each R a is an independent, branched C 9-10 In some embodiments, each R a is an independent, branched C 6 In some embodiments, each R a is an independent, branched C 7 In some embodiments, each R a is an independent, branched C 8 In some embodiments, each R a is an independent, branched C 9 In some embodiments, each R a is an independent, branched C 10 In some embodiments, each R a is an independent, branched C 11 In some embodiments, each R a is an independent, branched C 12 In some embodiments, each R a is an independent, branched C 13-20 In some embodiments, each R a is an independent, branched C 15-20 In some embodiments, each R a is an independent, branched C 13 In some embodiments, each R a is an independent, branched C 14 In some embodiments, each R a is an independent, branched C 15 In some embodiments, each R a is an independent, branched C 16In some embodiments, each R a is an independent, branched C 17 In some embodiments, each R a is an independent, branched C 18 In some embodiments, each R a is an independent, branched C 19 In some embodiments, each R a is an independent, branched C 20 It is an alkyl.

[0231] In some embodiments, each R a independently represents an optionally substituted C 6-20 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 6-12 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 8-11 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 9-10 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 6 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 7 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 8 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 9 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 10 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 11 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 12alkenyl. In some embodiments, each R a independently represents an optionally substituted C 13-20 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 15-20 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 13 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 14 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 15 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 16 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 17 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 18 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 19 alkenyl. In some embodiments, each R a independently represents an optionally substituted C 20 It is alkenyl.

[0232] In some embodiments, each R a is independently 6-20 alkenyl. In some embodiments, each R a is independently 6-12 alkenyl. In some embodiments, each R a is independently 8-11 alkenyl. In some embodiments, each R a is independently 9-10 alkenyl. In some embodiments, each R a is independently 6 alkenyl. In some embodiments, each Ra is independently 7 alkenyl. In some embodiments, each R a is independently 8 alkenyl. In some embodiments, each R a is independently 9 alkenyl. In some embodiments, each R a is independently 10 alkenyl. In some embodiments, each R a is independently 11 alkenyl. In some embodiments, each R a is independently 12 alkenyl. In some embodiments, each R a is independently 13-20 alkenyl. In some embodiments, each R a is independently 15-20 alkenyl. In some embodiments, each R a is independently 13 alkenyl. In some embodiments, each R a is independently 14 alkenyl. In some embodiments, each R a is independently 15 alkenyl. In some embodiments, each R a is independently 16 alkenyl. In some embodiments, each R a is independently 17 alkenyl. In some embodiments, each R a is independently 18 alkenyl. In some embodiments, each R a is independently 19 alkenyl. In some embodiments, each R a is independently 20 It is alkenyl.

[0233] In some embodiments, each R a are independently linear C 6-20 alkenyl. In some embodiments, each R a are independently linear C6-12 alkenyl. In some embodiments, each R a are independently linear C 8-11 alkenyl. In some embodiments, each R a are independently linear C 9-10 alkenyl. In some embodiments, each R a are independently linear C 6 alkenyl. In some embodiments, each R a are independently linear C 7 alkenyl. In some embodiments, each R a are independently linear C 8 alkenyl. In some embodiments, each R a are independently linear C 9 alkenyl. In some embodiments, each R a are independently linear C 10 alkenyl. In some embodiments, each R a are independently linear C 11 alkenyl. In some embodiments, each R a are independently linear C 12 alkenyl. In some embodiments, each R a are independently linear C 13-20 alkenyl. In some embodiments, each R a are independently linear C 15-20 alkenyl. In some embodiments, each R a are independently linear C 13 alkenyl. In some embodiments, each R a are independently linear C 14 alkenyl. In some embodiments, each R a are independently linear C 15 alkenyl. In some embodiments, each R a are independently linear C 16 alkenyl. In some embodiments, each R a are independently linear C 17 alkenyl. In some embodiments, each R a are independently linear C 18 alkenyl. In some embodiments, each Ra are independently linear C 19 alkenyl. In some embodiments, each R a are independently linear C 20 It is alkenyl.

[0234] In some embodiments, each R a is an independent, branched C 6-20 alkenyl. In some embodiments, each R a is an independent, branched C 6-12 alkenyl. In some embodiments, each R a is an independent, branched C 8-11 alkenyl. In some embodiments, each R a is an independent, branched C 9-10 alkenyl. In some embodiments, each R a is an independent, branched C 6 alkenyl. In some embodiments, each R a is an independent, branched C 7 alkenyl. In some embodiments, each R a is an independent, branched C 8 alkenyl. In some embodiments, each R a is an independent, branched C 9 alkenyl. In some embodiments, each R a is an independent, branched C 10 alkenyl. In some embodiments, each R a is an independent, branched C 11 alkenyl. In some embodiments, each R a is an independent, branched C 12 alkenyl. In some embodiments, each R a is an independent, branched C 13-20 alkenyl. In some embodiments, each R a is an independent, branched C 15-20 alkenyl. In some embodiments, each R a is an independent, branched C 13 alkenyl. In some embodiments, each R ais an independent, branched C 14 alkenyl. In some embodiments, each R a is an independent, branched C 15 alkenyl. In some embodiments, each R a is an independent, branched C 16 alkenyl. In some embodiments, each R a is an independent, branched C 17 alkenyl. In some embodiments, each R a is an independent, branched C 18 alkenyl. In some embodiments, each R a is an independent, branched C 19 alkenyl. In some embodiments, each R a is an independent, branched C 20 It is alkenyl.

[0235] In some embodiments, each R a independently represents an optionally substituted C 6-20 In some embodiments, each R a independently represents an optionally substituted C 6-12 In some embodiments, each R a independently represents an optionally substituted C 8-11 In some embodiments, each R a independently represents an optionally substituted C 9-10 In some embodiments, each R a independently represents an optionally substituted C 6 In some embodiments, each R a independently represents an optionally substituted C 7 In some embodiments, each R a independently represents an optionally substituted C 8 In some embodiments, each R a independently represents an optionally substituted C 9 In some embodiments, each R a independently represents an optionally substituted C10 In some embodiments, each R a independently represents an optionally substituted C 11 In some embodiments, each R a independently represents an optionally substituted C 12 In some embodiments, each R a independently represents an optionally substituted C 13-20 In some embodiments, each R a independently represents an optionally substituted C 15-20 In some embodiments, each R a independently represents an optionally substituted C 13 In some embodiments, each R a independently represents an optionally substituted C 14 In some embodiments, each R a independently represents an optionally substituted C 15 In some embodiments, each R a independently represents an optionally substituted C 16 In some embodiments, each R a independently represents an optionally substituted C 17 In some embodiments, each R a independently represents an optionally substituted C 18 In some embodiments, each R a independently represents an optionally substituted C 19 In some embodiments, each R a independently represents an optionally substituted C 20 It is alkynyl.

[0236] In some embodiments, each R a is independently 6-20 In some embodiments, each R a is independently 6-12 In some embodiments, each R a is independently8-11 In some embodiments, each R a is independently 9-10 In some embodiments, each R a is independently 6 In some embodiments, each R a is independently 7 In some embodiments, each R a is independently 8 In some embodiments, each R a is independently 9 In some embodiments, each R a is independently 10 In some embodiments, each R a is independently 11 In some embodiments, each R a is independently 12 In some embodiments, each R a is independently 13-20 In some embodiments, each R a is independently 15-20 In some embodiments, each R a is independently 13 In some embodiments, each R a is independently 14 In some embodiments, each R a is independently 15 In some embodiments, each R a is independently 16 In some embodiments, each R a is independently 17 In some embodiments, each R a is independently 18 In some embodiments, each R a is independently 19 In some embodiments, each R a is independently 20It is alkynyl.

[0237] In some embodiments, each R a are independently linear C 6-20 In some embodiments, each R a are independently linear C 6-12 In some embodiments, each R a are independently linear C 8-11 In some embodiments, each R a are independently linear C 9-10 In some embodiments, each R a are independently linear C 6 In some embodiments, each R a are independently linear C 7 In some embodiments, each R a are independently linear C 8 In some embodiments, each R a are independently linear C 9 In some embodiments, each R a are independently linear C 10 In some embodiments, each R a are independently linear C 11 In some embodiments, each R a are independently linear C 12 In some embodiments, each R a are independently linear C 13-20 In some embodiments, each R a are independently linear C 15-20 In some embodiments, each R a are independently linear C 13 In some embodiments, each R a are independently linear C 14 In some embodiments, each R a are independently linear C 15 In some embodiments, each R a are independently linear C16 In some embodiments, each R a are independently linear C 17 In some embodiments, each R a are independently linear C 18 In some embodiments, each R a are independently linear C 19 In some embodiments, each R a are independently linear C 20 It is alkynyl.

[0238] In some embodiments, each R a independently represents an optionally substituted C 6-20 In some embodiments, each R a independently represents an optionally substituted C 6-12 In some embodiments, each R a independently represents an optionally substituted C 6-10 In some embodiments, each R a independently represents an optionally substituted C 6 In some embodiments, each R a independently represents an optionally substituted C 7 In some embodiments, each R a independently represents an optionally substituted C 8 In some embodiments, each R a independently represents an optionally substituted C 9 In some embodiments, each R a independently represents an optionally substituted C 10 In some embodiments, each R a independently represents an optionally substituted C 15-20 In some embodiments, each R a independently represents an optionally substituted C 15 In some embodiments, each R a independently represents an optionally substituted C16 In some embodiments, each R a independently represents an optionally substituted C 17 In some embodiments, each R a independently represents an optionally substituted C 18 In some embodiments, each R a independently represents an optionally substituted C 19 In some embodiments, each R a independently represents an optionally substituted C 20 It is haloaliphatic.

[0239] In some embodiments, each R a independently represents an optionally substituted linear C 6-20 In some embodiments, each R a independently represents an optionally substituted linear C 6-12 In some embodiments, each R a independently represents an optionally substituted linear C 6-10 In some embodiments, each R a independently represents an optionally substituted linear C 6 In some embodiments, each R a independently represents an optionally substituted linear C 7 In some embodiments, each R a independently represents an optionally substituted linear C 8 In some embodiments, each R a independently represents an optionally substituted linear C 9 In some embodiments, each R a independently represents an optionally substituted linear C 10 In some embodiments, each R a independently represents an optionally substituted linear C 15-20 In some embodiments, each R a independently represents an optionally substituted linear C 15In some embodiments, each R a independently represents an optionally substituted linear C 16 In some embodiments, each R a independently represents an optionally substituted linear C 17 In some embodiments, each R a independently represents an optionally substituted linear C 18 In some embodiments, each R a independently represents an optionally substituted linear C 19 In some embodiments, each R a independently represents an optionally substituted linear C 20 It is haloaliphatic.

[0240] In some embodiments, each R a independently, optionally substituted branched C 6-20 In some embodiments, each R a independently, optionally substituted branched C 6-12 In some embodiments, each R a independently, optionally substituted branched C 6-10 In some embodiments, each R a independently, optionally substituted branched C 6 In some embodiments, each R a independently, optionally substituted branched C 7 In some embodiments, each R a independently, optionally substituted branched C 8 In some embodiments, each R a independently, optionally substituted branched C 9 In some embodiments, each R a independently, optionally substituted branched C 10 In some embodiments, each R a independently, optionally substituted branched C15-20 In some embodiments, each R a independently, optionally substituted branched C 15 In some embodiments, each R a independently, optionally substituted...

Claims

1. Compound of formula A': 【Chemistry 1】 or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein: L １ But it doesn't exist, or C １－６ Alkylenyl, or C ２－６ heteroalkylenyl, Each L ２ is independently an optionally substituted C ２－１５ Alkylenyl, or optionally substituted C ３－１５ heteroalkylenyl, L is C １－１０ Alkylenyl or C ２－１０ heteroalkylenyl, X ２ is —OC(O)—, —C(O)O—, or —OC(O)O—, X is absent, —OC(O)—, —C(O)O—, or —OC(O)O—; R" is hydrogen, 【Chemistry 2】 Or C ６－２０ an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R and R ａ Each of is independently hydrogen or C ６－２０ an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; L ３ and L ３ａ Each of １－１０ Alkylenyl, or optionally substituted C ２－１０ heteroalkylenyl, R １ is selected from hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered alicyclic, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR ２ , -C(O)OR ２ , -C(O)SR ２ , -OC(O)R ２ , -OC(O)OR ２ , -CN, -N(R ２ ) ２ , -C(O)N(R ２ ) ２ , -S(O) ２ N (R ２ ) ２ , -NR ２ C(O)R ２ , -OC(O)N(R ２ ) ２ , -N(R ２ ) C(O)OR ２ , -NR ２ S (O) ２ R ２ , -NR ２ C(O)N(R ２ ) ２ , -NR ２ C(S)N(R ２ ) ２ , -NR ２ C (NR ２ ) N (R ２ ) ２ , -NR ２ C(CHR ２ ) N (R ２ ) ２ , -N(OR ２ ) C(O)R ２ , -N(OR ２ ) S (O) ２ R ２ , -N(OR ２ ) C(O)OR ２ , -N(OR ２ )C(O)N(R ２ ) ２ 、 -N(OR ２ )C(S)N(R ２ ) ２ 、 -N(OR ２ )C(NR ２ )N(R ２ ) ２ 、 -N(OR ２ )C(CHR ２ )N(R ２ ) ２ 、 -C(NR ２ )N(R ２ ) ２ 、 -C(NR ２ )R ２ 、 -C(O)N(R ２ )OR ２ 、 -C(R ２ )N(R ２ ) ２ C(O)OR ２ 、 -CR ２ (R ３ ) ２ 、 -OP(O)(OR ２ ) ２ 、 or -P(O)(OR ２ ) ２ is, or R １ but, 【Chemistry 3】 or a 3- to 7-membered alicyclic, and a 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alicyclic or heterocyclyl ring is selected from 1 to 4 R ２ Or R ３ is optionally substituted with a group; Each R ２ are independently hydrogen, oxo, -CN, -NO ２ , -OR ４ , -S(O) ２ R ４ , -S(O) ２ N (R ４ ) ２ , -(CH ２ ) ｎ -R ４ , or C １－６ an optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered alicyclic, 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ２ two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ３ are independently -(CH ２ ) ｎ -R ４ or R ３ two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ４ are independently hydrogen, -OR ５ , -N(R ５ ) ２ , -OC(O)R ５ , -OC(O)OR ５ , -CN, -C(O)N(R ５ ) ２ , -NR ５ C(O)R ５ , -OC(O)N(R ５ ) ２ , -N(R ５ ) C(O)OR ５ , -NR ５ S (O) ２ R ５ , -NR ５ C(O)N(R ５ ) ２ , -NR ５ C(S)N(R ５ ) ２ , -NR ５ C (NR ５ ) N (R ５ ) ２ or 【Chemistry 4】 and Each R ５ are independently hydrogen or optionally substituted C １－６ aliphatic or R ５ two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ６ But independently, C ４－１２ It is aliphatic, A compound or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein each n is independently 0 to 4.

2. Compound of formula I": 【Chemistry 5】 or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein: L １ But it doesn't exist, or C １－６ Alkylenyl, or C ２－６ heteroalkylenyl, Each L ２ is independently an optionally substituted C ２－１５ Alkylenyl, or optionally substituted C ３－１５ heteroalkylenyl, L is C １－１０ Alkylenyl or C ２－１０ heteroalkylenyl, X ２ is —OC(O)—, —C(O)O—, or —OC(O)O—, X is absent, —OC(O)—, —C(O)O—, or —OC(O)O—; Each L ３ is independently absent or optionally substituted C １－１０ Alkylenyl, or optionally substituted C ２－１０ heteroalkylenyl, R" is hydrogen, 【Chemistry 6】 Or C ６－２０ an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; Each R is independently hydrogen or C ６－２０ an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R １ is selected from hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered alicyclic, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR ２ , -C(O)OR ２ , -C(O)SR ２ , -OC(O)R ２ , -OC(O)OR ２ , -CN, -N(R ２ ) ２ , -C(O)N(R ２ ) ２ , -S(O) ２ N (R ２ ) ２ , -NR ２ C(O)R ２ , -OC(O)N(R ２ ) ２ , -N(R ２ ) C(O)OR ２ , -NR ２ S (O) ２ R ２ , -NR ２ C(O)N(R ２ ) ２ , -NR ２ C(S)N(R ２ ) ２ , -NR ２ C (NR ２ ) N (R ２ ) ２ , -NR ２ C(CHR ２ ) N (R ２ ) ２ , -N(OR ２ ) C(O)R ２ , -N(OR ２ ) S (O) ２ R ２ , -N(OR ２ ) C(O)OR ２ , -N(OR ２ )C(O)N(R ２ ) ２ 、 -N(OR ２ )C(S)N(R ２ ) ２ 、 -N(OR ２ )C(NR ２ )N(R ２ ) ２ 、 -N(OR ２ )C(CHR ２ )N(R ２ ) ２ 、 -C(NR ２ )N(R ２ ) ２ 、 -C(NR ２ )R ２ 、 -C(O)N(R ２ )OR ２ 、 -C(R ２ )N(R ２ ) ２ C(O)OR ２ 、 -CR ２ (R ３ ) ２ 、 -OP(O)(OR ２ ) ２ 、 or -P(O)(OR ２ ) ２ is, or R １ but, 【Chemistry 7】 or a 3- to 7-membered alicyclic, and a 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alicyclic or heterocyclyl ring is selected from 1 to 4 R ２ Or R ３ is optionally substituted with a group; Each R ２ are independently hydrogen, oxo, -CN, -NO ２ , -OR ４ , -S(O) ２ R ４ , -S(O) ２ N (R ４ ) ２ , -(CH ２ ) ｎ -R ４ , or C １－６ an optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered alicyclic, 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ２ two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ３ are independently -(CH ２ ) ｎ -R ４ or R ３ two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ４ are independently hydrogen, -OR ５ , -N(R ５ ) ２ , -OC(O)R ５ , -OC(O)OR ５ , -CN, -C(O)N(R ５ ) ２ , -NR ５ C(O)R ５ , -OC(O)N(R ５ ) ２ , -N(R ５ ) C(O)OR ５ , -NR ５ S (O) ２ R ５ , -NR ５ C(O)N(R ５ ) ２ , -NR ５ C(S)N(R ５ ) ２ , -NR ５ C (NR ５ ) N (R ５ ) ２ or 【Chemistry 8】 and Each R ５ are independently hydrogen or optionally substituted C １－６ aliphatic or R ５ two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ６ But independently, C ４－１２ It is aliphatic, A compound or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein each n is independently 0 to 4.

3. Compound of Formula II": 【Chemistry 9】 or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein: L １ But it doesn't exist, or C １－６ Alkylenyl, or C ２－６ heteroalkylenyl, Each L ２ is independently an optionally substituted C ２－１５ Alkylenyl, or optionally substituted C ３－１５ heteroalkylenyl, L is C １－１０ Alkylenyl or C ２－１０ heteroalkylenyl, X ２ is —OC(O)—, —C(O)O—, or —OC(O)O—, Each L ３ is independently absent or optionally substituted C １－１０ Alkylenyl, or optionally substituted C ２－１０ heteroalkylenyl, Each R is independently hydrogen or C ６－２０ an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R １ is selected from hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered alicyclic, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR ２ , -C(O)OR ２ , -C(O)SR ２ , -OC(O)R ２ , -OC(O)OR ２ , -CN, -N(R ２ ) ２ , -C(O)N(R ２ ) ２ , -S(O) ２ N (R ２ ) ２ , -NR ２ C(O)R ２ , -OC(O)N(R ２ ) ２ , -N(R ２ ) C(O)OR ２ , -NR ２ S (O) ２ R ２ , -NR ２ C(O)N(R ２ ) ２ , -NR ２ C(S)N(R ２ ) ２ , -NR ２ C (NR ２ ) N (R ２ ) ２ , -NR ２ C(CHR ２ ) N (R ２ ) ２ , -N(OR ２ ) C(O)R ２ , -N(OR ２ ) S (O) ２ R ２ , -N(OR ２ ) C(O)OR ２ , -N(OR ２ )C(O)N(R ２ ) ２ 、 -N(OR ２ )C(S)N(R ２ ) ２ 、 -N(OR ２ )C(NR ２ )N(R ２ ) ２ 、 -N(OR ２ )C(CHR ２ )N(R ２ ) ２ 、 -C(NR ２ )N(R ２ ) ２ 、 -C(NR ２ )R ２ 、 -C(O)N(R ２ )OR ２ 、 -C(R ２ )N(R ２ ) ２ C(O)OR ２ 、 -CR ２ (R ３ ) ２ 、 -OP(O)(OR ２ ) ２ 、 or -P(O)(OR ２ ) ２ is, R １ but, 【Chemistry 10】 or a 3- to 7-membered alicyclic, and a 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alicyclic or heterocyclyl ring is selected from 1 to 4 R ２ Or R ３ is optionally substituted with a group; Each R ２ are independently hydrogen, oxo, -CN, -NO ２ , -OR ４ , -S(O) ２ R ４ , -S(O) ２ N (R ４ ) ２ , -(CH ２ ) ｎ -R ４ , or C １－６ an optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered alicyclic, 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ２ two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ３ are independently -(CH ２ ) ｎ -R ４ or R ３ two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ４ are independently hydrogen, -OR ５ , -N(R ５ ) ２ , -OC(O)R ５ , -OC(O)OR ５ , -CN, -C(O)N(R ５ ) ２ , -NR ５ C(O)R ５ , -OC(O)N(R ５ ) ２ , -N(R ５ ) C(O)OR ５ , -NR ５ S (O) ２ R ５ , -NR ５ C(O)N(R ５ ) ２ , -NR ５ C(S)N(R ５ ) ２ , -NR ５ C (NR ５ ) N (R ５ ) ２ or 【Chemistry 11】 and Each R ５ are independently hydrogen or optionally substituted C １－６ aliphatic or R ５ two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ６ But independently, C ４－１２ It is aliphatic, A compound or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein each n is independently 0 to 4.

4. Compound of formula III': 【Chemistry 12】 or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein: L １ But it doesn't exist, or C １－６ Alkylenyl, or C ２－６ heteroalkylenyl, Each L ２ is independently an optionally substituted C ２－１５ Alkylenyl, or optionally substituted C ３－１５ heteroalkylenyl, Each L is independently C １－１０ Alkylenyl or C ２－１０ heteroalkylenyl, each X ２ is independently —OC(O)—, —C(O)O—, or —OC(O)O—; Each L ３ is independently absent or optionally substituted C １－１０ Alkylenyl, or optionally substituted C ２－１０ heteroalkylenyl, Each R is independently hydrogen; or C ６－２０ an optionally substituted group selected from aliphatic, 3-12 membered alicyclic, 7-12 membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; R １ is selected from hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered alicyclic, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR ２ , -C(O)OR ２ , -C(O)SR ２ , -OC(O)R ２ , -OC(O)OR ２ , -CN, -N(R ２ ) ２ , -C(O)N(R ２ ) ２ , -S(O) ２ N (R ２ ) ２ , -NR ２ C(O)R ２ , -OC(O)N(R ２ ) ２ , -N(R ２ ) C(O)OR ２ , -NR ２ S (O) ２ R ２ , -NR ２ C(O)N(R ２ ) ２ , -NR ２ C(S)N(R ２ ) ２ , -NR ２ C (NR ２ ) N (R ２ ) ２ , -NR ２ C(CHR ２ ) N (R ２ ) ２ , -N(OR ２ ) C(O)R ２ , -N(OR ２ ) S (O) ２ R ２ , -N(OR ２ ) C(O)OR ２ , -N(OR ２ )C(O)N(R ２ ) ２ 、 -N(OR ２ )C(S)N(R ２ ) ２ 、 -N(OR ２ )C(NR ２ )N(R ２ ) ２ 、 -N(OR ２ )C(CHR ２ )N(R ２ ) ２ 、 -C(NR ２ )N(R ２ ) ２ 、 -C(NR ２ )R ２ 、 -C(O)N(R ２ )OR ２ 、 -C(R ２ )N(R ２ ) ２ C(O)OR ２ 、 -CR ２ (R ３ ) ２ 、 -OP(O)(OR ２ ) ２ 、 or -P(O)(OR ２ ) ２ is, or R １ but, 【Chemistry 13】 or a 3- to 7-membered alicyclic, and a 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alicyclic or heterocyclyl ring is selected from 1 to 4 R ２ Or R ３ is optionally substituted with a group; Each R ２ are independently hydrogen, oxo, -CN, -NO ２ , -OR ４ , -S(O) ２ R ４ , -S(O) ２ N (R ４ ) ２ , -(CH ２ ) ｎ -R ４ , or C １－６ an optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered alicyclic, 5- to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ２ two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ３ are independently -(CH ２ ) ｎ -R ４ or R ３ two occurrences of together with the atom to which they are attached form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ４ are independently hydrogen, -OR ５ , -N(R ５ ) ２ , -OC(O)R ５ , -OC(O)OR ５ , -CN, -C(O)N(R ５ ) ２ , -NR ５ C(O)R ５ , -OC(O)N(R ５ ) ２ , -N(R ５ ) C(O)OR ５ , -NR ５ S (O) ２ R ５ , -NR ５ C(O)N(R ５ ) ２ , -NR ５ C(S)N(R ５ ) ２ , -NR ５ C (NR ５ ) N (R ５ ) ２ or 【Chemistry 14】 and Each R ５ are independently hydrogen or optionally substituted C １－６ aliphatic or R ５ two occurrences of together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R ６ But independently, C ４－１２ It is aliphatic, A compound or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, wherein each n is independently 0 to 4.

5. The compound is a compound of formula I"-a: 【Chemistry 15】 or The compound is a compound of formula I"-b: 【Chemistry 16】 or The compound is a compound of formula I"-c: 【Chemistry 17】 or The compound is a compound of formula III-a: 【Chemistry 18】 3. The compound according to claim 1 or 2, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof:

6. each X ２ is -OC(O)-, and / or L 1 is absent, C 1-5 alkylenyl, or C 2-5 heteroalkylenyl, in particular L 1 is C 1-5 alkylenyl; and / or each L 2 is independently optionally substituted C 2-9 alkylenyl or optionally substituted C 3-9 heteroalkylenyl, in particular each L 2 is independently optionally substituted C 2-9 alkylenyl; and / or each L is independently C 1-5 alkylenyl or C 2-5 heteroalkylenyl, in particular each L is independently C 1-5 alkylenyl; and / or each of L 3 and L 3a is absent; and / or each of L 3 and L 3a is independently C 1-5 alkylenyl or C 2-5 heteroalkylenyl, in particular each of L 3 and L 3a is independently C 1-5 alkylenyl; and / or R" is hydrogen, 【Chemistry 19】 or an optionally substituted group selected from C 6-20 aliphatic, 3-12 membered alicyclic, 1-adamantyl, and phenyl, particularly where R″ is hydrogen or R″ is 【Chemistry 20】 or R" is optionally substituted C6-20 aliphatic, in particular R" is C6-20 haloaliphatic, or R" is optionally substituted 3-7 membered alicyclic, or R" is optionally substituted 1-adamantyl, or R" is optionally substituted phenyl, and / or each of R and R a is independently hydrogen; or an optionally substituted group selected from C 6-20 aliphatic, 3-12 membered alicyclic, 1-adamantyl, and phenyl, in particular each of R and R a is hydrogen, or each of R and R a is independently optionally substituted C 6-20 aliphatic, in particular C 6-20 haloaliphatic, or each of R and R a is independently optionally substituted 3-7 membered alicyclic, or each of R and R a is independently optionally substituted 1-adamantyl, or each of R and R a is independently optionally substituted phenyl; and / or Each of -L 3 -R″, -L 3 -R, and -L 3a -R a is independently 【Chemistry 21】 【change】 and / or 【Chemical 22】 Each of the following may be independently 【Chemistry 23】 【change】 and / or R 1 is hydrogen; optionally substituted phenyl; optionally substituted 3-7 membered alicyclic; optionally substituted 3-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -NR 2 S(O) 2 R 2 , -NR 2 -C(O)N(R 2 ) 2 , -CR 2 (R 3 ) 2 , -OP(O)(OR 2 ) 2 , or -P(O)(OR 2 ) 2 , and / or R 1 is hydrogen, optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-10 membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 ) 2 , -C(O)N(R 2 ) 2 , -S(O) 2 N(R 2 ) 2 , -NR 2 C(O)R 2 , -NR 2 S(O) 2 R 2 , -NR 2 C(O)N(R 2 ) 2 , -CR 2 (R 3 ) 2 , -OP(O)(OR 2 ) 2 , -P(O)(OR 2 ) 2 or a 3- to 7-membered alicyclic and a 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said alicyclic or heterocyclyl ring being optionally substituted with 1 to 4 R 2 or R 3 groups; and / or each R 2 is independently hydrogen, —(CH 2 ) n —R 4 , or an optionally substituted group selected from phenyl and a 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R 2 together with the atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; and / or each R 3 is independently —(CH 2 ) n —R 4 ; and / or each R 4 is independently -OR 5 or -N(R 5 ) 2 ; and / or each R 5 is independently hydrogen or an optionally substituted C 1-6 aliphatic; and / or each R 6 is independently C 6-8 aliphatic; and / or R 1 is 【Chemistry 24】 The compound according to any one of claims 1 to 4, selected from the group consisting of:

7. 2. The compound of claim 1, wherein the compound is selected from Table 1 or a pharma- ceutically acceptable salt thereof.

8. A lipid nanoparticle (LNP) preparation comprising a compound according to any one of claims 1 to 4 and 7, or a pharma- ceutically acceptable salt thereof.

9. A phospholipid, Sterols and 9. The lipid nanoparticle (LNP) preparation of claim 8, further comprising a conjugate-linker lipid (e.g., a polyethylene glycol lipid).

10. and / or a therapeutic and / or prophylactic agent, in particular the therapeutic and / or prophylactic agent is or comprises one or more nucleic acids, in particular the one or more nucleic acids is or comprises RNA or DNA, and / or 9. The LNP preparation of claim 8, wherein the LNP preparation is formulated for delivering the therapeutic and / or prophylactic agent to a target cell, particularly wherein the target cell is or comprises a spleen cell (e.g., a splenic B cell, a splenic T cell, a splenic monocyte), a liver cell (e.g., a hepatocyte), a bone marrow cell (e.g., a bone marrow monocyte), an immune cell, a kidney cell, a muscle cell, a cardiac cell, or a cell in the central nervous system, particularly wherein the target cell is or comprises a hematopoietic stem cell (HSC).

11. A pharmaceutical composition comprising the LNP preparation of claim 8 and a pharma- ceutically acceptable excipient.

12. A method for administering a therapeutic and / or prophylactic agent to a subject in need thereof, comprising administering to said subject a pharmaceutical composition according to claim 11; or A method for treating a disease or disorder in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition according to claim 11, wherein said therapeutic and / or prophylactic agent is effective in treating said disease; or A method for slowing and / or halting the progression of a disease or disorder in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition according to claim 11, wherein said therapeutic and / or prophylactic agent is effective in treating said disease; or A method of delivering a therapeutic and / or prophylactic agent to a mammalian cell derived from a subject, comprising administering to said subject a pharmaceutical composition according to claim 11, wherein said therapeutic and / or prophylactic agent is effective in treating said disease; or 12. A method of producing a polypeptide of interest in a mammalian cell, said method comprising contacting said cell with the pharmaceutical composition of claim 11, wherein said therapeutic and / or prophylactic agent is or comprises an mRNA, said mRNA encoding said polypeptide of interest, whereby said mRNA is capable of being translated in said cell to produce said polypeptide of interest, or A method of inhibiting the production of a polypeptide of interest in a mammalian cell, said method comprising contacting said cell with the pharmaceutical composition of claim 11, wherein said therapeutic and / or prophylactic agent is or comprises an RNA, whereby said RNA is capable of inhibiting the production of said polypeptide of interest, or 12. A method for specifically delivering a therapeutic and / or prophylactic agent to a mammalian organ, said method comprising contacting a mammalian organ with the pharmaceutical composition of claim 11, whereby said therapeutic and / or prophylactic agent is delivered to said organ, in particular said method comprising administering to a subject the pharmaceutical composition of claim 11.

12. The pharmaceutical composition of claim 11 for use in 13. The pharmaceutical composition of claim 11 for use in a method of vaccination comprising administering the pharmaceutical composition of claim 11.

14. 12. The pharmaceutical composition of claim 11, for use in a method of inducing an adaptive immune response in a subject, the method comprising administering to the subject an effective amount of the composition comprising at least one RNA, the composition comprising the LNP preparation comprising a compound according to any one of claims 1 to 4 and 7, or a pharma- ceutically acceptable salt thereof.

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