Acetal-containing nanomaterials

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 / 128,682, filed December 21, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] In the fields of chemistry, biology, and medicine, drug delivery systems have been problematic, hindering progress due to a limited understanding of how the molecular properties of the systems control tissue delivery and confer drug efficacy. Summary of the Invention

[0003] The present invention recognizes the need for compositions, preparations, nanoparticles, and / or nanomaterials, as well as methods of using them. Among other things, the present disclosure recognizes that the structural characteristics 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 affecting 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 varying the ratio of one of more components to affect one or more functional activities of the 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 I': [ka] or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , L 3 , X, R, R', and R 1

[0023] The present invention describes a compound or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein each of the following is as defined herein:

[0005] 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 acetal feature containing one or more unsaturated and / or halogenated (e.g., fluorinated) units, 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.

[0006] 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.

[0007] In some embodiments, the provided compositions, preparations, nanoparticles, and / or nanomaterials are for use in methods of treating a disease or disorder, delivering or producing a polypeptide, or slowing / halting the progression of a disease or disorder.

[0008] In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials provided are for use in a method of manufacturing.

[0009] In some embodiments, provided compositions, preparations, nanoparticles, and / or nanomaterials are for use in characterization methods.

[0010] 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 explanation of the drawings]

[0011] [Figure 1] 1 shows an exemplary mRNA screening system for LNP preparations according to an embodiment of the present disclosure.

[0012] [Figure 2] 1 shows an exemplary siRNA screening system for LNP preparations, according to an embodiment of the present disclosure.

[0013] [Figure 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)).

[0014] [Figure 4] 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.

[0015] [Figure 5] 1 shows a bar graph illustrating the robust delivery of exemplary LNP preparations (exemplary lipid 8, exemplary lipid 4, exemplary lipid 1, and saline control) with delivery to various liver cell types, such as CD31 cells, CD11b cells, and stellate cells.

[0016] definition About: As used herein, the terms "about" or "approximately," when used herein with respect to a value, refer to a value that is similar in relation to the referenced value. Generally, a person of ordinary skill 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 a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less) of the referenced value (except where such number exceeds 100% of possible values), unless otherwise stated or apparent from the context.

[0017] Administration: As used herein, the term "administration" typically refers to the administration of a composition to a subject or system. Those of skill in the art will recognize 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, etc. In certain embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (e.g., may be or include one or more of topical, such as dermal, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, 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, etc. 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.

[0018] Aliphatic: The terms "aliphatic" or "aliphatic group," as used herein, refer 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 rest 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 C3-C8 hydrocarbon or an optionally substituted C6-C6 hydrocarbon 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 rest of the molecule. 12 "Cycloalkyl" refers to a bicyclic hydrocarbon. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0019] 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 , C2-16 , C 2-14 , C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ) refers to an optionally substituted straight or branched hydrocarbon chain having an alkyl group. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0020] 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 have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0021] 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., C1-C for a straight chain). 20 , C2-C for branched chains 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, alkyl groups can be lower alkyl groups having from 1-4 carbon atoms (e.g., C1-C4 for a straight chain lower alkyl).

[0022] 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., -(CH2) 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. A 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.

[0023] 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 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 C 2-3 ) refers to an optionally substituted straight or branched chain hydrocarbon group having an alkyl group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0024] Amino acid: In the 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 HN-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid, in some embodiments, an amino acid is a D-amino acid, and in some embodiments, an amino acid is an L-amino acid. A "standard amino acid" refers to any of the 20 standard L-amino acids typically found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid other than the standard amino acids, regardless of whether it is synthetically prepared or obtained from a natural source. In some embodiments, amino acids, including the 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., of 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 the 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.

[0025] Animal: As used herein, refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human of either sex and at any stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or parasites. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0026] Aptamer: As used herein, the term "aptamer" refers to a macromolecule composed of nucleic acids (e.g., RNA, DNA) that tightly binds to a specific molecular target (e.g., umbrella topology glycans). A particular aptamer can be described by its 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, allowing the aptamer to tightly bind to the surface of its target molecule. Given the extraordinary diversity of molecular shapes that exist within the realm 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 affinity for their targets (e.g., picomolar to low nanomolar affinity for proteins). In many embodiments, aptamers are chemically stable and can be boiled or frozen without loss of activity. Because aptamers are synthetic molecules, they are amenable to a variety of modifications that can optimize their function for specific applications. For example, for in vivo applications, aptamers can be modified to dramatically reduce their susceptibility to degradation by enzymes in the blood. In addition, aptamers can be modified to alter their biodistribution or plasma residence time.

[0027] Aryl: The term "aryl" refers to an alkyl group having a total of 6 to 14 ring members (e.g., C 6-14 "aryl" refers to monocyclic and bicyclic ring systems having a cyclic ring structure, wherein 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 aromatic ring systems, 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.

[0028] Associated: As used herein, two events or entities are "associated" with one another 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 one another when they interact directly or indirectly, such that they are in and / or maintain physical proximity to one another. In some embodiments, two or more entities that are physically associated with one another are covalently bound to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently bound to one another, but are non-covalently associated, e.g., by hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0029] 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.

[0030] Biodegradable: As used herein, the term "biodegradable" refers to a material that, when introduced into a cell, breaks 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 to 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 break down into their component monomers. In some embodiments, the degradation of biodegradable materials (e.g., including biodegradable polymeric materials) involves hydrolysis of ester bonds. Alternatively or additionally, in some embodiments, the degradation of biodegradable materials (e.g., including biodegradable polymeric materials) 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, polymers of hydroxy acids such as hydroxypropyl methylcellulose, hydroxypropyl ... 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 the same structure differing only in the substitution or addition of certain chemical groups known in the art).

[0031] 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.

[0032] 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., a tissue, or organism, or cell culture) as described herein. In some embodiments, the source of interest includes an organism, such as an animal or a 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 include bone marrow, blood; blood cells; ascites; tissue or fine needle biopsy sample; cell-containing body fluids; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural effusion; feces; lymph; gynecological fluid; skin swab; vaginal swab; oral swab; nasal swab; washings or lavage such as ductal lavage or bronchoalveolar lavage; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, the obtained cells are or comprise cells derived from the individual from whom the sample is obtained. In some embodiments, a sample is a "primary sample" obtained directly from a source of interest by any suitable means. For example, in some embodiments, a 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, stool, etc.), etc. In some embodiments, as will be clear from the context, the term "sample" refers to a preparation obtained by processing a primary sample (e.g., by removing one or more components and / or adding one or more agents), such as by filtration 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, etc.

[0033] 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.

[0034] Bridged Bicyclic: As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic ring system, i.e., carbocyclic or heterocyclic, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or a single 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 (excluding hydrogen). In some embodiments, bridged bicyclic groups have 7 to 12 ring members and 0 to 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, bridged bicyclic groups are optionally substituted with one or more substituents described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include, but are not limited to, the following: [ka]

[0035] Cancer: The terms "cancer," "malignancy," "neoplasm," "tumor," and "carcinoma" are used herein to refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, 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 non-metastatic. 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 hematologic tumor. In general, examples of different types of cancer 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 tissue, squamous cell carcinoma of the mouth, throat, larynx, and lung, liver cancer, reproductive 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, etc.

[0036] Carrier: As used herein, refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, the carrier can include sterile liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or includes one or more solid components.

[0037] Carbocyclyl: As used herein, the terms "carbocyclyl," "carbocycle," "carbocyclic ring," and "alicyclic ring" refer to a saturated or partially unsaturated alicyclic monocyclic, bicyclic, or polycyclic ring system as described herein having 3 to 14 members, where the alicyclic 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 C3-C8 hydrocarbon or an optionally substituted C6-C8 hydrocarbon 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 rest of the molecule. 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.

[0038] 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 one another, but that are sufficiently similar to permit a comparison between them, so that a person of ordinary skill in the art would understand that conclusions could be reasonably drawn based on the observed differences or similarities. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by several substantially identical characteristics and one or a few varying characteristics. A person of ordinary skill 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 of ordinary skill in the art will understand that sets of circumstances, individuals, or populations are comparable to one another if they are characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by variations in those varying characteristics, or that variations in characteristics are indicative of variations in characteristics.

[0039] Component: Those skilled in the art will understand that the term "composition" can be used to refer to a separate physical entity that includes one or more defined components. Generally, unless otherwise specified, a composition can be in any form, e.g., gas, gel, liquid, solid, etc.

[0040] Comprising: Compositions or methods described herein as "comprising" one or more recited elements or steps are 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 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.

[0041] "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 drug or treatment (before and / or after), or in the presence of a suitable comparable reference drug. 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 way in the presence of the relevant drug or treatment.

[0042] Determining: Many methodologies described herein include a "determining" step. Those skilled in the art will understand, upon reading this specification, that such "determining" can be utilized or accomplished through the use of any of a variety of techniques available to those skilled in the art, including, for example, the specific techniques explicitly mentioned herein. In some embodiments, determining involves physical manipulation of the sample. In some embodiments, determining involves reviewing and / or manipulating 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.

[0043] Encapsulated: The term "encapsulated" is used herein to refer to a substance that is completely surrounded by another material.

[0044] 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, etc.

[0045] Expression: As used herein, the term "expression" of a nucleic acid sequence refers to the production 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.

[0046] 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, e.g., 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.

[0047] 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 to 7 halogen atoms. In some embodiments, a haloalkyl group contains 1 to 5 halogen atoms. In some embodiments, a haloalkyl group contains 1 to 3 halogen atoms.

[0048] Heteroalkylenyl: As used herein, the terms "heteroalkylenyl" or "heteroalkylene" refer to an optionally substituted straight-chain (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 optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, a heteroalkylenyl group contains 2 to 8 carbon atoms, with 1 to 3 carbon atoms optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, a heteroalkylenyl group contains 4 to 8 carbon atoms, with 1 to 3 carbon atoms optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroalkylenyl groups contain 2 to 5 carbon atoms, with 1 to 2 carbon atoms optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroalkylenyl groups contain 1 to 3 carbon atoms, with 1 carbon atom optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroalkylenyl groups include, but are not limited to, -CHO-, -(CH)O-, -CHOCH-, -O(CH)-, -(CH)O-, -(CH)OCH-, -CHO(CH)-, -O(CH)-, -(CH)O-, -(CH)OCH-, -CHO(CH)-, -(CH)O(CH)-, and -O(CH)-. Unless otherwise specified, C x Heteroalkylenyl refers to a heteroalkylenyl having x carbon atoms before being replaced with a heteroatom.

[0049] 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.

[0050] 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).

[0051] Heterocycle: The terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably herein and refer to a stable 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 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 to 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 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl). A 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, and more preferably monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a 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).

[0052] 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 the target, e.g., by binding to the target), while in some embodiments, an inhibitor may act indirectly (where it affects its effect 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).

[0053] 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.

[0054] 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 more than about 99% of the other components with which they are initially associated. 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 greater 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 one of skill 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 percent isolation or purity of the substance is calculated without including such carriers or excipients. For example, in some embodiments, a naturally occurring biopolymer, such as a polypeptide or polynucleotide, is considered "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 different from that which 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.

[0055] 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).

[0056] 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 polypeptides that include two or more functional or organizational domains in their structure 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 represent two domains associated with one another by the 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 by not tending to adopt a rigid three-dimensional structure, but rather providing 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).

[0057] Nanoparticle: As used herein, the term "nanoparticle" refers to a particle having a diameter of less than 1000 nanometers (nm). In some embodiments, a nanoparticle has a diameter of less than 300 nm, as defined by the National Science Foundation. In some embodiments, a nanoparticle has a diameter of less than 100 nm, as defined by the National Institutes of Health. In some embodiments, a nanoparticle is a micelle in that it contains 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 can 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.

[0058] 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.

[0059] 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, nucleic acids are compounds and / or substances that are or can be incorporated into an oligonucleotide chain via a phosphodiester bond. As will be clear from the context, in some embodiments, "nucleic acid" refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides), and in some embodiments, "nucleic acid" refers to an oligonucleotide chain comprising individual nucleic acid residues. In some embodiments, "nucleic acid" is or comprises RNA, and in some embodiments, "nucleic acid" is or comprises DNA. In some embodiments, a nucleic acid is, comprises, or consists of one or more naturally occurring nucleic acid residues. In some embodiments, a nucleic acid is, comprises, 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, nucleic acids comprise one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) compared to sugars in naturally occurring nucleic acids. In some embodiments, nucleic acids have a nucleotide sequence that encodes a functional gene product such as RNA or a protein. In some embodiments, nucleic acids comprise one or more introns. In some embodiments, nucleic acids are 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, and in some embodiments, the nucleic acid is partially or completely double-stranded, hi 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.

[0060] Operably linked: As used herein, refers to a juxtaposition wherein 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 such a manner 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 with or on the functional element of interest.

[0061] 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 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 Edition, The University of California, San Diego, CA, USA, 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.

[0062] 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.

[0063] Patient: As used herein, the term "patient" refers to any organism to which provided compositions are or can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is 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 with 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 particular therapy to diagnose and / or treat the disease, disorder, or condition.

[0064] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose amount suitable for administration in a treatment regimen that, when administered to a relevant population, exhibits a statistically significant probability of achieving a predetermined therapeutic effect. 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 oral cavity; vaginal or rectal administration, e.g., as a pessary, cream, or foam; sublingual; ophthalmic; transdermal; or compatible with the nose, lungs, and other mucosal surfaces.

[0065] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically 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.

[0066] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, which is involved in carrying or transporting a compound of interest from one organ or part of the body to another. 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 that can function as pharmaceutically 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.

[0067] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of such compounds that are suitable for use in pharmaceutical contexts, i.e., salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically 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, pharmaceutically 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, ... Representative salts of alkali or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, and the like.In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates, as appropriate.

[0068] Prevent or Prevention: As used herein, when used in reference 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 the onset of the disease, disorder, or condition has been delayed for a predefined period of time.

[0069] 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). Proteins may contain moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and / or may be processed or modified. Those of skill in the art will understand that a "protein" may be an entire polypeptide chain produced by a cell (with or without a signal sequence), or a characteristic portion thereof. Those of skill in the art will understand that a protein may sometimes comprise two or more polypeptide chains, 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, proteins may comprise 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.

[0070] Polypeptide: As used herein, the term "polypeptide" generally has its art-recognized meaning of a polymer of at least three amino acids. Those of skill in the art will understand that the term "polypeptide" is intended to be general enough to encompass not only polypeptides having the complete sequences recited herein, but also polypeptides representing functional fragments of such complete polypeptides (i.e., fragments that retain at least one activity). Furthermore, those of skill in the art will understand 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 three to four, 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 greater than about 50%, 60%, 70%, or 80%, and even more usually often greater 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 polypeptides 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.

[0071] Prevention: As used herein, the term "prevention" 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 the onset of the disease, disorder, or condition is delayed for a predefined period of time.

[0072] 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. A "Si-protecting group" is a protecting group containing 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). Typically, 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.

[0073] Protected hydroxyl groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, 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-methoxycrotonates, 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. Examples of 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.

[0074] Protected amines are well known in the art and include those described in detail 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 described above as mono-protected amines, and further include cyclic imides such as phthalimide, maleimide, succinimide, etc. Suitable di-protected amines also include pyrroles, 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine, etc., and azides.

[0075] 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.

[0076] 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 examples include 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.

[0077] Protected thiols are well known in the art and include those described in detail in Greene (1999). Suitable 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.

[0078] Protein: As used herein, the term "protein" refers to one or more polypeptides that function as a separate unit. 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 two or more polypeptides that are physically associated with each other, the term "protein" may be used to refer to the 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 in which 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.

[0079] Pure: As used herein, an agent or entity is "pure" if it is substantially free of other components. For example, a preparation containing 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.

[0080] 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 contemporaneously 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 one of skill in the art, a reference or control is determined or characterized under conditions or circumstances comparable to those being evaluated. One of skill in the art will understand when sufficient similarity exists to justify reliance on and / or comparison to a particular possible reference or control.

[0081] Sample: As used herein, the term "sample" typically refers to an aliquot of material obtained from 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, plant, or animal (e.g., 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 can 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 wash (e.g., bronchoalveolar, mammary ductal, nasal, ocular, oral, uterine, vaginal, or other lavage or wash). 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, by filtration using a semi-permeable membrane. Such a "processed sample" can include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to one or more techniques, such as nucleic acid amplification or reverse transcription, isolation and / or purification of certain components, etc.

[0082] Stable Nanoparticle Composition: 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., the 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 is at least about 1 hour, and in some embodiments, the period is about 5 hours, about 10 hours, about 1 (1) day, about 1 (1) week, about 2 (2) weeks, about 1 (1) month, about 2 (2) months, about 3 (3) months, about 4 (4) months, about 5 (5) months, about 6 (6) months, about 8 (8) months, about 10 (10) months, about 12 (12) months, about 24 (24) months, about 36 (36) months, or more. In some embodiments, the period is within a range of about 1 (1) day to about 24 (24) months, about 2 (2) weeks to about 12 (12) months, about 2 (2) months to about 5 (5) months, etc. For example, a nanoparticle composition is stable if a population of nanoparticles is subjected to extended storage, temperature changes, and / or pH changes, 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).

[0083] 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 hydrocarbon tail structure). In some embodiments, the cholesterolyl group is an esterified cholesterolyl group. In some embodiments, the sterolyl 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.

[0084] 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 is suffering from the relevant disease, disorder, or condition. In some embodiments, the subject is predisposed 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 possesses one or more characteristics that make them susceptible to, or at risk for, a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual for whom diagnosis and / or treatment is to be and / or has been performed.

[0085] Substantially: As used herein, the term "substantially" refers to a qualitative condition indicating 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 progress toward complete completion, or achieve or avoid an absolute result. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0086] Substituted or Optionally Substituted: The compounds of the present disclosure described herein may contain optionally substituted and / or substituted moieties. 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 explicit or implied 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 if 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. 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 remain substantially unchanged when subjected to conditions that enable 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 one to four substituents, more preferably one to two substituents. Groups described as "optionally substituted" may be unsubstituted or "substituted," as described above.

[0087] Suitable monovalent substituents include halogen; -(CH2) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2; R° can be substituted with -(CH2) 0-4 Ph; R° may be substituted with -(CH2) 0-4 O(CH2) 0-1 Ph; -CH=CHPh, which may be substituted with R°; -(CH2), which may be substituted with R° 0-4 O(CH2) 0-1 -pyridinyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 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°;-(CH2) 0-4C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°-;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-OSiR°3;-(C 1-4 Linear or branched alkylene)ON(R°)2; or -(C 1-4 and alkylene)C(O)ON(R°), where each R° can be substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 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, or as defined above but which, taken together with the 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, as defined above but with two independent occurrences of R°, which may be substituted as defined below.

[0088] Suitable monovalent substituents on R° (or the ring formed, together with the intervening atoms, by two independent occurrences of R°) are independently halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 C(O)NH2, -(CH2) 0-2 C(O)NHR ● , -(CH2) 0-2 C(O)NR ● 2, -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -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, -CH2Ph, -O(CH2) 0-1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0089] Suitable divalent substituents include the following: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, and each R * occurrences of C which may be substituted as defined below 1-6 A 5- to 6-membered, saturated, partially unsaturated, or aryl ring is selected from aliphatic or unsubstituted rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the proximal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2-3 O-, and each independent R * occurrences of C which may be substituted as defined below 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or aryl rings.

[0090] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 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.

[0091] 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)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † are listed, and 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 ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an aryl ring, or as defined above but which, together with the intervening atoms, form two independent R † The occurrence of forms an unsubstituted 3-12 membered saturated, partially unsaturated ring or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C1-4 Aliphatic, -CH2Ph, -O(CH2) 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.

[0093] 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. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant 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 14 Compounds having this structure including a carbon replacement with a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention.

[0094] 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 with a disease, disorder, or condition).

[0095] 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.

[0096] Tautomeric Forms: As used herein, the phrase "tautomeric forms" is used to describe different isomeric forms of an organic compound that are readily interconvertible. Tautomers can be characterized by a geometrical shift of a hydrogen atom or proton, accompanied by a switch of a single bond and an adjacent double bond. In some embodiments, tautomers can result from prototropic tautomerism (i.e., relocation of a proton). In some embodiments, tautomers can result from valence tautomerism (i.e., rapid reorganization of bond electrons). All such tautomeric forms are intended to be included within the scope of this disclosure. In some embodiments, tautomeric forms of a compound exist in a dispersive equilibrium with one another, such that attempts to prepare separate substances result in the formation of mixtures. 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 pure preparations of or contain a single tautomeric form of a compound. In some embodiments, a chemical composition may be provided as a mixture 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 the compound. In some embodiments of the present disclosure, a chemical composition may contain all tautomeric forms of a compound. In some embodiments of the present disclosure, a chemical composition may contain fewer than all tautomeric forms of a compound. In some embodiments of the present disclosure, a 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. Those skilled 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 arts to provide enol derivatives 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.

[0097] 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, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition.

[0098] 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, when administered as part of a treatment regimen, elicits a desired biological response. 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 being delivered, and the target cell or tissue. 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; 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, including subject-specific variables (eg, age, health of the immune system, etc.), the disease, and the treatment being administered.

[0099] "Tissue" and / or "Organ": As used herein, unless otherwise specified, the terms "tissue" and / or "organ" refer to viable cellular material in aggregate form, e.g., small portions of an organ, and dispersed cells, e.g., cells dispersed, isolated, and / or grown from muscle, cardiac muscle, liver, or kidney, including bone marrow cells and progeny, blood-producing stem cells and progeny, and various other blood elements. 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.

[0100] 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 of, reduces the severity of, 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 treatment of subjects who do not show signs of the associated disease, disorder, and / or condition and / or who show only early signs of the disease, disorder, and / or condition. Alternatively, or additionally, such treatment may be of subjects who show one or more established signs of the associated disease, disorder, and / or condition. In some embodiments, treatment may be treatment of subjects who have been diagnosed with the associated disease, disorder, and / or condition. In some embodiments, treatment may be treatment of subjects who are known to have one or more susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition. Thus, in some embodiments, treatment may be prophylactic, and in some embodiments, therapeutic. DETAILED DESCRIPTION OF THE INVENTION

[0101] The present disclosure describes how the selection and combination of one or more components of the compositions, preparations, nanoparticles, and / or nanomaterials described herein influences the functional activity of lipid nanoparticles, such as desired tropism, stabilization, and drug delivery efficacy. Among other things, the present disclosure 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 comprise LNPs that carry cargo to designated target cells, tissues, and / or organs.

[0102] 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 how the selection and combination of one or more of the components described herein affects lipid nanoparticle characteristics, such as diameter, pKa, stabilization, and ionizability.

[0103] In particular, the present disclosure describes how 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 efficacy. For example, the present disclosure describes how the combination of components may be better suited to the delivery of siRNA. As another example, the present disclosure describes how the combination of components may be better suited to the delivery of mRNA. As another example, the present disclosure describes how the combination of components may be better suited to the delivery of DNA.

[0104] In some embodiments, the lipid nanoparticles comprise one or more compounds described herein. In some embodiments, the lipid nanoparticles comprise one or more ionizable lipids described herein. In some embodiments, the lipid nanoparticles comprise one or more sterols described herein. In some embodiments, the lipid nanoparticles comprise one or more conjugate-linker lipids described herein. In some embodiments, the lipid nanoparticles comprise one or more phospholipids described herein.

[0105] A. Compound Among other things, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials that include one or more compounds described herein.

[0106] In some embodiments, the present disclosure provides a compound of formula I': [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 But it doesn't exist or C 1-6 Alkylenyl, or C 2-6 is heteroalkylenyl, Each L 2 are independently optionally substituted C 2-15 alkylenyl, or optionally substituted C 3-15 is heteroalkylenyl, L 3 is absent or optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 is heteroalkylenyl, X is absent, —OC(O)—, —C(O)O—, or —OC(O)O—; Each R' is independently C 4-12an 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 is hydrogen; [ka] ; or C 6-20 an optionally substituted group selected from aliphatic, 3- to 12-membered alicyclic, 7- to 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 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)2N(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)2R 2 ;-NR 2 C(O)N(R 2 )2;-NR 2 C(S)N(R 2 )2;-NR 2C(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)2R 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 )2C(O)OR 2 ;-CR 2 (R 3 )2;-OP(O)(OR 2 )2, or -P(O)(OR 2 )2 or R 1 but, [ka] 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 optionally substituted with a group, Each R 2 are independently hydrogen; oxo; -CN; -NO2; -OR 4 ;-S(O)2R 4;-S(O)2N(R 4 )2;-(CH2) 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 Together with the bonded atom, R 2 two occurrences form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 3 But independently, -(CH2) n -R 4 or Together with the bonded atom, R 3 two occurrences 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)2R 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 Together with the bonded atom, R 5 two occurrences 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 is aliphatic, Provided is a compound or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein each n is independently 0 to 4.

[0107] 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 is heteroalkylenyl, Each L 2 But independently, C 2-10 Alkylenyl or C 3-10 is heteroalkylenyl, L 3 But it doesn't exist or C 1-10 Alkylenyl, or C 2-10 is heteroalkylenyl, X is absent, —OC(O)—, —C(O)O—, or —OC(O)O—; Each R' is independently C 4-12 Alkenyl, C 4-12 Alkynyl, or C 4-12 is a haloaliphatic, R is 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)2R 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)2R 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(NR2 )N(R 2 )2;-C(NR 2 )R 2 ;-C(O)N(R 2 ) OR 2 ;-C(R 2 )N(R 2 )2C(O)OR 2 ; [ka] ;-CR 2 (OR 2 )R 3 ; [ka] and Each R 2 are independently hydrogen; -CN; -NO2; -OR 4 ;-S(O)2R 4 ;-S(O)2N(R 4 )2;-(CH2) n -R 4 ; or C 1-6 an optionally substituted group selected from an aliphatic, a 3- to 7-membered alicyclic ring, and a 3- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Together with the bonded atom, R 2 two occurrences form an optionally substituted 4-7 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 3 But independently, -(CH2) n -R 4 or Together with the bonded atom, R 3 two occurrences 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(R5 )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)2R 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 an aliphatic group, or Together with the bonded atom, R 5 two occurrences 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 is aliphatic, Provided is a compound or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein each n is independently 0 to 4.

[0108] As noted above, in some embodiments of either of Formulas I′ and I, 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 2-5 In some embodiments, L is heteroalkylenyl. 1does not exist or C 1-4 Alkylenyl, or C 2-4 In some embodiments, L is heteroalkylenyl. 1 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 alkylenyl. In some embodiments, L 1 is C alkylenyl. In some embodiments, L 1 is C alkylenyl. In some embodiments, L 1 is C4 alkylenyl. In some embodiments, L 1 is C5 alkylenyl. In some embodiments, L 1 is C alkylenyl. In some embodiments, L 1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, L1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-. In some embodiments, L 1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L 1 is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L 1 is —CH2CH2—, —CH2CH2CH2—, or —CH2CH2CH2CH2—. In some embodiments, L 1 is —CH2CH2— or —CH2CH2CH2—. In some embodiments, L 1 is -CH-. In some embodiments, L 1 is -CHCH-. In some embodiments, L 1 is -CH2CH2CH2-. In some embodiments, L 1 is -CH2CH2CH2CH2-. In some embodiments, L 1 is -CH2CH2CH2CH2CH2-. In some embodiments, L 1 is -CH2CH2CH2CH2CH2CH2-. In some embodiments, L 1 is C heteroalkylenyl. 1 is C heteroalkylenyl. In some embodiments, L 1 is C4 heteroalkylenyl. In some embodiments, L 1 is a C5 heteroalkylenyl. 1 is C6 heteroalkylenyl. In some embodiments, L 1 is a C2 heteroalkylenyl containing one heteroatom. 1 is a C heteroalkylenyl containing one heteroatom. 1 is a C4 heteroalkylenyl containing one heteroatom. 1is a C5 heteroalkylenyl containing 1 to 2 heteroatoms. 1 is a C6 heteroalkylenyl containing 1 to 2 heteroatoms. 1 is a C2 heteroalkylenyl containing one oxygen atom. 1 is a C heteroalkylenyl containing one oxygen atom. 1 is a C4 heteroalkylenyl containing one oxygen atom. 1 is —CH2OCH2CH2—. In some embodiments, L 1 is a C5 heteroalkylenyl containing 1 to 2 oxygen atoms. 1 is a C6 heteroalkylenyl containing 1 to 2 oxygen atoms.

[0109] As noted above, in some embodiments of Formula I′, 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 3-12 In 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 C5-9 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 2-10 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 C5-9 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 5-7 In 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.

[0110] In some embodiments, each L 2 C independently substituted with -R° or -OR° 6-8 In some embodiments, each L is alkylenyl. 2 are independently -R°-substituted C 6-8 In some embodiments, each L is alkylenyl. 2 are independently substituted with -OR° 6-8 In some embodiments, each L is alkylenyl. 2 is independently a C substituted with one or two -R°; 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 substituted with one -OR° 6-8 In some embodiments, each L is alkylenyl. 2 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 independently two C 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 are independently one methyl-substituted C 6-8 In some embodiments, each L is alkylenyl. 2 is independently two methyl-substituted C 6-8 In some embodiments, each L is alkylenyl. 2 are 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. 2is a C7 alkylenyl substituted with one -OR° and the other L 2 is C alkylenyl. In some embodiments, one L 2 is a C7 alkylenyl substituted with one -OH and the other L 2 is C alkylenyl. In some embodiments, one L 2 teeth, [ka] and other L 2 is -CH2CH2CH2CH2CH2CH2-.

[0111] In some embodiments of Formula I', each L 2 independently, C 2-15 Alkylenyl or C 3-15 In some embodiments, each L is heteroalkylenyl. 2 independently, C 2-12 Alkylenyl or C 3-12 In some embodiments, each L is heteroalkylenyl. 2 independently, C 2-15 In some embodiments, each L is alkylenyl. 2 independently, C 3-15 In some embodiments, each L is heteroalkylenyl. 2 independently, C 2-12 In some embodiments, each L is alkylenyl. 2 independently, C 3-12 It is heteroalkylenyl.

[0112] In some embodiments of either of Formulas I' and I, each L 2 independently, C 2-10 Alkylenyl or C 3-10 In some embodiments, each L is heteroalkylenyl. 2 independently, C 2-9 Alkylenyl or C 3-9 In some embodiments, each L is heteroalkylenyl. 2 independently, C 5-10Alkylenyl or C 5-10 In some embodiments, each L is heteroalkylenyl. 2 independently, C 5-9 Alkylenyl or C 5-9 In some embodiments, each L is heteroalkylenyl. 2 independently, C 6-8 Alkylenyl or C 6-8 In some embodiments, each L is heteroalkylenyl. 2 independently, C 5-8 Alkylenyl or C 5-8 In some embodiments, each L is heteroalkylenyl. 2 independently, C 4-8 Alkylenyl or C 4-8 In some embodiments, each L is heteroalkylenyl. 2 independently, C 2-10 In some embodiments, each L is alkylenyl. 2 independently, C 3-10 In some embodiments, each L is heteroalkylenyl. 2 independently, C 2-9 In some embodiments, each L is alkylenyl. 2 independently, C 3-9 In some embodiments, each L is heteroalkylenyl. 2 independently, C 5-10 In some embodiments, each L is alkylenyl. 2 independently, C 5-10 In some embodiments, each L is heteroalkylenyl. 2 independently, C 5-9 In some embodiments, each L is alkylenyl. 2 independently, C 5-9 In some embodiments, each L is heteroalkylenyl. 2 independently, C 6-8 In some embodiments, each L is alkylenyl. 2 independently, C 6-8 In some embodiments, each L is heteroalkylenyl. 2 independently, C 5-8In some embodiments, each L is alkylenyl. 2 independently, C 5-8 In some embodiments, each L is heteroalkylenyl. 2 independently, C 4-8 In some embodiments, each L is alkylenyl. 2 independently, C 4-8 In some embodiments, each L is heteroalkylenyl. 2 independently, C 5-7 Alkylenyl or C 5-7 In some embodiments, each L is heteroalkylenyl. 2 independently, C 5-7 In some embodiments, each L is alkylenyl. 2 independently, C 5-7 It is heteroalkylenyl.

[0113] In some embodiments, each L 2 is independently a C alkylenyl. 2 is independently a C alkylenyl. 2 is independently a C alkylenyl. 2 is independently a C alkylenyl. 2 is independently a C alkylenyl. 2 is independently a C alkylenyl. 2 is independently C alkylenyl. 2 is independently a C alkylenyl. 2 independently, C 10 In some embodiments, each L is alkylenyl. 2is independently -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2 is independently -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2 is independently -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2 is independently -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2 is independently -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2is independently -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, each L 2 is independently -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, each L 2 is independently -CH2CH2CH2CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, each L 2 is -CH2CH2CH2CH2-. In some embodiments, each L 2 is -CH2CH2CH2CH2CH2-. In some embodiments, each L 2 is -CH2CH2CH2CH2CH2CH2-. In some embodiments, each L 2 is -CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, each L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, each L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, each L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, two L 2 In some embodiments, the two L groups are the same. 2 groups are the same and are selected from the group consisting of -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2The groups are the same and are selected from the group consisting of -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2 groups are the same and are selected from the group consisting of -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2 The groups are the same, -CH2CH2CH2CH2CH2- , -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, two L 2 The groups are the same and are selected from the group consisting of -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2 groups are the same and are selected from the group consisting of -CH2CH2CH2CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 2 In some embodiments, one L 2 is -CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2-. In some embodiments, one L 2 is -CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2. In some embodiments, one L 2is -CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2CH2. In some embodiments, one L 2 is -CH2CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2. In some embodiments, one L 2 is -CH2CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2CH2. In some embodiments, one L 2 is -CH2CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2. In some embodiments, one L 2 is -CH2CH2CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2CH2. In some embodiments, one L 2 is -CH2CH2CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2. In some embodiments, one L 2 is -CH2CH2CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2. In some embodiments, one L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2. In some embodiments, one L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2-, and other L 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2.

[0114] In some embodiments, each L 2 is independently a C heteroalkylenyl. 2 is independently a C5 heteroalkylenyl.2 is independently a C heteroalkylenyl. 2 is independently a C7 heteroalkylenyl. 2 is independently C heteroalkylenyl. 2 is independently a C4 heteroalkylenyl containing one heteroatom. 2 is independently a C5 heteroalkylenyl containing one heteroatom. 2 is independently a C6 heteroalkylenyl containing one or two heteroatoms. 2 is independently a C7 heteroalkylenyl containing one or two heteroatoms. 2 is independently a C heteroalkylenyl containing one or two heteroatoms. 2 is independently a C4 heteroalkylenyl containing one oxygen atom. 2 is independently a C5 heteroalkylenyl containing one oxygen atom. 2 is independently a C6 heteroalkylenyl containing one or two oxygen atoms. 2 is independently a C7 heteroalkylenyl containing one or two oxygen atoms. 2 is independently a C8 heteroalkylenyl containing one or two oxygen atoms.

[0115] As noted above, in some embodiments of Formula I′, L 3 is absent or optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 In some embodiments, L is heteroalkylenyl. 3is an optionally substituted C 1-8 alkylenyl, or optionally substituted C 2-8 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 1-10 In some embodiments, L is alkylenyl. 3 is an optionally substituted C 2-10 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 1-8 In some embodiments, L is alkylenyl. 3 is an optionally substituted C 2-8 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 1-5 alkylenyl, or optionally substituted C 2-5 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 1-5 In some embodiments, L is alkylenyl. 3 is an optionally substituted C 2-5 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 1-4 alkylenyl, or optionally substituted C 2-4 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 1-4 In some embodiments, L is alkylenyl. 3 is an optionally substituted C 2-4 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 6-10 alkylenyl, or optionally substituted C 6-10 In some embodiments, L is heteroalkylenyl. 3 is an optionally substituted C 6-10 In some embodiments, L is alkylenyl. 3 is an optionally substituted C 6-10 It is heteroalkylenyl.

[0116] In some embodiments of either of Formulas I' and I, L 3 does not exist or C 1-10 Alkylenyl, or C 2-10 In some embodiments, L is heteroalkylenyl. 3 is absent. 3 is C 1-10 Alkylenyl or C 2-10 In some embodiments, L is heteroalkylenyl. 3 is C 1-8 Alkylenyl or C 2-8 In some embodiments, L is heteroalkylenyl. 3 is C 1-10 In some embodiments, L is alkylenyl. 3 is C 2-10 In some embodiments, L is heteroalkylenyl. 3 is C 1-8 In some embodiments, L is alkylenyl. 3 is C 2-8 In some embodiments, L is heteroalkylenyl. 3 is C 1-5 Alkylenyl or C 2-5 In some embodiments, L is heteroalkylenyl. 3 is C 1-5 In some embodiments, L is alkylenyl. 3 is C 2-5 In some embodiments, L is heteroalkylenyl. 3 is C 1-4 Alkylenyl or C 2-4 In some embodiments, L is heteroalkylenyl. 3 is C 1-4 In some embodiments, L is alkylenyl. 3 is C 2-4 In some embodiments, L is heteroalkylenyl. 3 is C alkylenyl. In some embodiments, L 3 is C alkylenyl. In some embodiments, L 3is C alkylenyl. In some embodiments, L 3 is C4 alkylenyl. In some embodiments, L 3 is C5 alkylenyl. In some embodiments, L 3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-. In some embodiments, L 3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L 3 is —CH2CH2—, —CH2CH2CH2—, or —CH2CH2CH2CH2—. In some embodiments, L 3 is —CH2CH2— or —CH2CH2CH2—. In some embodiments, L 3 is -CH-. In some embodiments, L 3 is -CHCH-. In some embodiments, L 3 is -CH2CH2CH2-. In some embodiments, L 3 is -CH2CH2CH2CH2-. In some embodiments, L 3 is -CH2CH2CH2CH2CH2-. In some embodiments, L 3 is C heteroalkylenyl. 3 is C heteroalkylenyl. In some embodiments, L 3 is C4 heteroalkylenyl. In some embodiments, L 3 is a C2 heteroalkylenyl containing one heteroatom. 3 is a C heteroalkylenyl containing one heteroatom. 3 is a C4 heteroalkylenyl containing one heteroatom. 3 is a C2 heteroalkylenyl containing one oxygen atom. 3 is a C heteroalkylenyl containing one oxygen atom. 3is a C4 heteroalkylenyl containing one oxygen atom. 3 is a C5 heteroalkylenyl containing one oxygen atom. 3 is a C5 heteroalkylenyl containing two oxygen atoms.

[0117] In some embodiments, L 3 is C 6-10 Alkylenyl or C 6-10 In some embodiments, L is heteroalkylenyl. 3 is C 6-10 In some embodiments, L is alkylenyl. 3 is C 6-10 In some embodiments, L is heteroalkylenyl. 3 is C alkylenyl. In some embodiments, L 3 is C alkylenyl. In some embodiments, L 3 is C alkylenyl. In some embodiments, L 3 is C alkylenyl. In some embodiments, L 3 is C 10 In some embodiments, L is alkylenyl. 3 is -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. 3 is -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, L 3 is —CH2CH2CH2CH2CH2CH2CH2CH2CH2— or —CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2—. In some embodiments, L 3is -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, L 3 is -CH2CH2CH2CH2CH2CH2-. In some embodiments, L 3 is -CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, L 3 is -CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, L 3 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, L 3 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, L 3 is C6 heteroalkylenyl. In some embodiments, L 3 is a C7 heteroalkylenyl. 3 is C heteroalkylenyl. In some embodiments, L 3 is C heteroalkylenyl. In some embodiments, L 3 is C 10 In some embodiments, L is heteroalkylenyl. 3 is a C6 heteroalkylenyl containing one or two heteroatoms. 3 is a C7 heteroalkylenyl containing 1 to 3 heteroatoms. 3 is a C heteroalkylenyl containing 1 to 3 heteroatoms. 3 is a C9 heteroalkylenyl containing 1 to 3 heteroatoms. 3 C containing 1 to 3 heteroatoms 10 In some embodiments, L is heteroalkylenyl. 3 is a C6 heteroalkylenyl containing one or two oxygen atoms. 3 is a C7 heteroalkylenyl containing 1 to 3 oxygen atoms. 3is a C8 heteroalkylenyl containing 1 to 3 oxygen atoms. 3 is a C9 heteroalkylenyl containing 1 to 3 oxygen atoms. 3 is a C containing 1 to 3 oxygen atoms 10 It is heteroalkylenyl.

[0118] As noted above, in some embodiments of any of Formulas 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-. In some embodiments, X is -OC(O)O-.

[0119] As noted above, in some embodiments of Formula I′, each R′ is independently C 4-12 In some embodiments, each R' is independently an optionally substituted group selected from an aliphatic, a 3- to 12-membered alicyclic, a 7- to 12-membered bridged bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. 4-12 aliphatic, and each R' is independently an optionally substituted C 4-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 4-12 In some embodiments, each R' is independently an optionally substituted C 4-12 Alkyl, optionally substituted C 4-12 alkenyl, or optionally substituted C 4-12 In some embodiments, each R' is independently an optionally substituted C 4-12 Alkyl, optionally substituted C 4-12 alkenyl, or optionally substituted C 4-12alkynyl, and each R' is independently an optionally substituted C 4-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 4-12 Alkyl, C 4-12 Alkenyl, C 4-12 Alkynyl, or C 4-12 haloaliphatic, and each R' is independently selected from the group consisting of C 4-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 4-12 Alkyl, C 4-12 Alkenyl, or C 4-12 alkynyl, and each R' is independently C 4-12 When alkyl, X is -OC(O)O-. In some embodiments of any of formulas I' and I, each R' is independently C 4-12 Alkenyl, C 4-12 Alkynyl, or C 4-12 In some embodiments, the two R' groups are the same. In some embodiments, the two R' groups are different.

[0120] In some embodiments, each R' is independently an optionally substituted C 4-12 aliphatic, and each R' is independently an optionally substituted C 4-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 6-12 aliphatic, and each R' is independently an optionally substituted C 6-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 8-12 aliphatic, and each R' is independently an optionally substituted C 8-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 4-10 aliphatic, and each R' is independently an optionally substituted C 4-10When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 6-10 aliphatic, and each R' is independently an optionally substituted C 6-10 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 7-9 aliphatic, and each R' is independently an optionally substituted C 7-9 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 7-8 aliphatic, and each R' is independently an optionally substituted C 7-8 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 8-9 aliphatic, and each R' is independently an optionally substituted C 8-9In some embodiments, when each R' is independently an optionally substituted C4 aliphatic, and each R' is independently an optionally substituted C4 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently an optionally substituted C5 aliphatic, and each R' is independently an optionally substituted C5 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently an optionally substituted C6 aliphatic, and each R' is independently an optionally substituted C6 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently an optionally substituted C7 aliphatic, and each R' is independently an optionally substituted C7 alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C8 aliphatic, and when each R' is independently an optionally substituted C8 alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C9 aliphatic, and when each R' is independently an optionally substituted C9 alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C9 alkyl. 10 aliphatic, and each R' is independently an optionally substituted C 10 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 11 aliphatic, and each R' is independently an optionally substituted C 11 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C 12 aliphatic, and each R' is independently an optionally substituted C 12 When alkyl, X is -OC(O)O-.

[0121] In some embodiments, each R' is independently C 4-12 aliphatic, and each R' is independently C 4-12When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 6-12 aliphatic, and each R' is independently C 6-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 8-12 aliphatic, and each R' is independently C 8-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 4-10 aliphatic, and each R' is independently C 4-10 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 6-10 aliphatic, and each R' is independently C 6-10 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 7-9 aliphatic, and each R' is independently C 7-9 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 7-8 aliphatic, and each R' is independently C 7-8 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 8-9 aliphatic, and each R' is independently C 8-9In some embodiments, when each R' is independently C4 aliphatic and each R' is independently C4 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently C5 aliphatic and each R' is independently C5 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently C6 aliphatic and each R' is independently C6 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently C7 aliphatic and each R' is independently C7 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently C8 aliphatic and each R' is independently C8 alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C9 aliphatic, and when each R' is independently C9 alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 10 aliphatic, and each R' is independently C 10 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 11 aliphatic, and each R' is independently C 11 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently C 12 aliphatic, and each R' is independently C 12 When alkyl, X is -OC(O)O-.

[0122] In some embodiments, each R' is independently a linear C 4-12 aliphatic, and each R' is independently a straight-chain C 4-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 6-12 aliphatic, and each R' is independently a straight-chain C 6-12 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 8-12 aliphatic, and each R' is independently a straight-chain C 8-12When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 4-10 aliphatic, and each R' is independently a straight-chain C 4-10 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 6-10 aliphatic, and each R' is independently a straight-chain C 6-10 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 7-9 aliphatic, and each R' is independently a straight-chain C 7-9 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 7-8 aliphatic, and each R' is independently a straight-chain C 7-8 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 8-9 aliphatic, and each R' is independently a straight-chain C 8-9 In some embodiments, when each R' is independently a straight chain C4 aliphatic, and each R' is independently a straight chain C4 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently a straight chain C5 aliphatic, and each R' is independently a straight chain C5 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently a straight chain C6 aliphatic, and each R' is independently a straight chain C6 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently a straight chain C7 aliphatic, and each R' is independently a straight chain C7 alkyl, X is -OC(O)O-. In some embodiments, when each R' is independently a straight chain C8 aliphatic, and each R' is independently a straight chain C8 alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C9 aliphatic, and when each R' is independently a straight chain C9 alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C9 alkyl. 10 aliphatic, and each R' is independently a straight-chain C 10When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 11 aliphatic, and each R' is independently a straight-chain C 11 When alkyl, X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 12 aliphatic, and each R' is independently a straight-chain C 12 When alkyl, X is -OC(O)O-.

[0123] In some embodiments, each R' is independently an optionally substituted C 4-12 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 6-12 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 8-12 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 4-10 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 6-10 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 7-9 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 7-8 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 8-9In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 10 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 11 In some embodiments, each R' is independently an optionally substituted C alkyl and X is -OC(O)O-. 12 alkyl and X is -OC(O)O-.

[0124] In some embodiments, each R' is independently C 4-12 In some embodiments, each R' is independently C 6-12 In some embodiments, each R' is independently C 8-12 In some embodiments, each R' is independently C 4-10 In some embodiments, each R' is independently C 6-10 In some embodiments, each R' is independently C 7-9 In some embodiments, each R' is independently C 7-8In some embodiments, each R' is independently C 8-9 In some embodiments, each R' is independently a C4 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a C5 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a C6 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a C7 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a C8 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a C9 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a C 10 In some embodiments, each R' is independently C 11 In some embodiments, each R' is independently C 12 alkyl and X is -OC(O)O-.

[0125] In some embodiments, each R' is independently a linear C 4-12 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; 8-12 In some embodiments, each R' is independently a straight chain C alkyl; 4-10 In some embodiments, each R' is independently a straight chain C alkyl; 6-10 In some embodiments, each R' is independently a straight chain C alkyl; 7-9 In some embodiments, each R' is independently a straight chain C alkyl; 7-8 In some embodiments, each R' is independently a straight chain C alkyl;8-9 In some embodiments, each R' is independently a straight chain C4 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C5 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C6 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C7 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C8 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C9 alkyl and X is -OC(O)O-. In some embodiments, each R' is independently a straight chain C 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 alkyl and X is -OC(O)O-.

[0126] In some embodiments, each R' is independently an optionally substituted C 4-12 In some embodiments, each R' is independently an optionally substituted C alkenyl. 6-12 In some embodiments, each R' is independently an optionally substituted C alkenyl. 8-12 In some embodiments, each R' is independently an optionally substituted C alkenyl. 4-10 In some embodiments, each R' is independently an optionally substituted C alkenyl. 6-10 In some embodiments, each R' is independently an optionally substituted C alkenyl. 7-9 In some embodiments, each R' is independently an optionally substituted C alkenyl. 7-8 In some embodiments, each R' is independently an optionally substituted C alkenyl. 8-9In some embodiments, each R' is independently an optionally substituted C4 alkenyl. In some embodiments, each R' is independently an optionally substituted C5 alkenyl. In some embodiments, each R' is independently an optionally substituted C6 alkenyl. In some embodiments, each R' is independently an optionally substituted C7 alkenyl. In some embodiments, each R' is independently an optionally substituted C8 alkenyl. In some embodiments, each R' is independently an optionally substituted C9 alkenyl. In some embodiments, each R' is independently an optionally substituted C 10 In some embodiments, each R' is independently an optionally substituted C alkenyl. 11 In some embodiments, each R' is independently an optionally substituted C alkenyl. 12 It is alkenyl.

[0127] In some embodiments, each R' is independently C 4-12 In some embodiments, each R' is independently C 6-12 In some embodiments, each R' is independently C 8-12 In some embodiments, each R' is independently C 4-10 In some embodiments, each R' is independently C 6-10 In some embodiments, each R' is independently C 7-9 In some embodiments, each R' is independently C 7-8 In some embodiments, each R' is independently C 8-9In some embodiments, each R' is independently a C4 alkenyl. In some embodiments, each R' is independently a C5 alkenyl. In some embodiments, each R' is independently a C6 alkenyl. In some embodiments, each R' is independently a C7 alkenyl. In some embodiments, each R' is independently a C8 alkenyl. In some embodiments, each R' is independently a C9 alkenyl. In some embodiments, each R' is independently a C 10 In some embodiments, each R' is independently C 11 In some embodiments, each R' is independently C 12 It is alkenyl.

[0128] In some embodiments, each R' is independently a linear C 4-12 In some embodiments, each R' is independently a straight-chain C 6-12 In some embodiments, each R' is independently a straight-chain C 8-12 In some embodiments, each R' is independently a straight-chain C 4-10 In some embodiments, each R' is independently a straight-chain C 6-10 In some embodiments, each R' is independently a straight-chain C 7-9 In some embodiments, each R' is independently a straight-chain C 7-8 In some embodiments, each R' is independently a straight-chain C 8-9 In some embodiments, each R' is independently a straight chain C4 alkenyl. In some embodiments, each R' is independently a straight chain C5 alkenyl. In some embodiments, each R' is independently a straight chain C6 alkenyl. In some embodiments, each R' is independently a straight chain C7 alkenyl. In some embodiments, each R' is independently a straight chain C8 alkenyl. In some embodiments, each R' is independently a straight chain C9 alkenyl. In some embodiments, each R' is independently a straight chain C 10 In some embodiments, each R' is independently a straight-chain C 11In some embodiments, each R' is independently a straight-chain C 12 It is alkenyl.

[0129] In some embodiments, each R' is independently an optionally substituted C 4-12 In some embodiments, each R' is independently an optionally substituted C 6-12 In some embodiments, each R' is independently an optionally substituted C 8-12 In some embodiments, each R' is independently an optionally substituted C 4-10 In some embodiments, each R' is independently an optionally substituted C 6-10 In some embodiments, each R' is independently an optionally substituted C 7-9 In some embodiments, each R' is independently an optionally substituted C 7-8 In some embodiments, each R' is independently an optionally substituted C 8-9 In some embodiments, each R' is independently an optionally substituted C4 alkynyl. In some embodiments, each R' is independently an optionally substituted C5 alkynyl. In some embodiments, each R' is independently an optionally substituted C6 alkynyl. In some embodiments, each R' is independently an optionally substituted C7 alkynyl. In some embodiments, each R' is independently an optionally substituted C8 alkynyl. In some embodiments, each R' is independently an optionally substituted C9 alkynyl. 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 It is alkynyl.

[0130] In some embodiments, each R' is independently C4-12 In some embodiments, each R' is independently C 6-12 In some embodiments, each R' is independently C 8-12 In some embodiments, each R' is independently C 4-10 In some embodiments, each R' is independently C 6-10 In some embodiments, each R' is independently C 7-9 In some embodiments, each R' is independently C 7-8 In some embodiments, each R' is independently C 8-9 In some embodiments, each R' is independently a C4 alkynyl. In some embodiments, each R' is independently a C5 alkynyl. In some embodiments, each R' is independently a C6 alkynyl. In some embodiments, each R' is independently a C7 alkynyl. In some embodiments, each R' is independently a C8 alkynyl. In some embodiments, each R' is independently a C9 alkynyl. In some embodiments, each R' is independently a C 10 In some embodiments, each R' is independently C 11 In some embodiments, each R' is independently C 12 It is alkynyl.

[0131] In some embodiments, each R' is independently a linear C 4-12 In some embodiments, each R' is independently a straight-chain C 6-12 In some embodiments, each R' is independently a straight-chain C 8-12 In some embodiments, each R' is independently a straight-chain C 4-10 In some embodiments, each R' is independently a straight-chain C 6-10 In some embodiments, each R' is independently a straight-chain C 7-9 In some embodiments, each R' is independently a straight-chain C 7-8In some embodiments, each R' is independently a straight-chain C 8-9 In some embodiments, each R' is independently a straight chain C4 alkynyl. In some embodiments, each R' is independently a straight chain C5 alkynyl. In some embodiments, each R' is independently a straight chain C6 alkynyl. In some embodiments, each R' is independently a straight chain C7 alkynyl. In some embodiments, each R' is independently a straight chain C8 alkynyl. In some embodiments, each R' is independently a straight chain C9 alkynyl. 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 It is alkynyl.

[0132] In some embodiments, each R' is independently an optionally substituted C 4-12 In some embodiments, each R' is independently an optionally substituted C 6-12 In some embodiments, each R' is independently an optionally substituted C 8-12 In some embodiments, each R' is independently an optionally substituted C 4-10 In some embodiments, each R' is independently an optionally substituted C 6-10 In some embodiments, each R' is independently an optionally substituted C 7-9 In some embodiments, each R' is independently an optionally substituted C 7-8 In some embodiments, each R' is independently an optionally substituted C 8-9In some embodiments, each R' is independently an optionally substituted C4 haloaliphatic. In some embodiments, each R' is independently an optionally substituted C5 haloaliphatic. In some embodiments, each R' is independently an optionally substituted C6 haloaliphatic. In some embodiments, each R' is independently an optionally substituted C7 haloaliphatic. In some embodiments, each R' is independently an optionally substituted C8 haloaliphatic. In some embodiments, each R' is independently an optionally substituted C9 haloaliphatic. 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 It is a haloaliphatic.

[0133] In some embodiments, each R' is independently C 4-12 In some embodiments, each R' is independently C 6-12 In some embodiments, each R' is independently C 8-12 In some embodiments, each R' is independently C 4-10 In some embodiments, each R' is independently C 6-10 In some embodiments, each R' is independently C 7-9 In some embodiments, each R' is independently C 7-8 In some embodiments, each R' is independently C 8-9In some embodiments, each R' is independently a C4 haloaliphatic. In some embodiments, each R' is independently a C5 haloaliphatic. In some embodiments, each R' is independently a C6 haloaliphatic. In some embodiments, each R' is independently a C7 haloaliphatic. In some embodiments, each R' is independently a C8 haloaliphatic. In some embodiments, each R' is independently a C9 haloaliphatic. In some embodiments, each R' is independently a C 10 In some embodiments, each R' is independently C 11 In some embodiments, each R' is independently C 12 It is a haloaliphatic.

[0134] In some embodiments, each R' is independently a linear C 4-12 In some embodiments, each R' is independently a straight chain C 6-12 In some embodiments, each R' is independently a straight chain C 8-12 In some embodiments, each R' is independently a straight chain C 4-10 In some embodiments, each R' is independently a straight chain C 6-10 In some embodiments, each R' is independently a straight chain C 7-9 In some embodiments, each R' is independently a straight chain C 7-8 In some embodiments, each R' is independently a straight chain C 8-9 In some embodiments, each R' is independently a straight chain C4 haloaliphatic. In some embodiments, each R' is independently a straight chain C5 haloaliphatic. In some embodiments, each R' is independently a straight chain C6 haloaliphatic. In some embodiments, each R' is independently a straight chain C7 haloaliphatic. In some embodiments, each R' is independently a straight chain C8 haloaliphatic. In some embodiments, each R' is independently a straight chain C9 haloaliphatic. In some embodiments, each R' is independently a straight chain C 10 In some embodiments, each R' is independently a straight chain C 11In some embodiments, each R' is independently a straight chain C 12 It is a haloaliphatic.

[0135] In some embodiments, each R' is independently an optionally substituted C 4-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 4-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 4-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 6-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 6-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 6-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 8-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 8-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 8-12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 4-10 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 4-10 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 4-10 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 6-10In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 6-10 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 6-10 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 7-9 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 7-9 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 7-9 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 7-8 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 7-8 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 7-8 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 8-9 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 8-9 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 8-9haloalkyl. In some embodiments, each R' is independently an optionally substituted C4 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C4 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C4 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C5 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C5 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C5 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C6 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C6 haloalkyl having 1 to 5 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C6 haloalkyl having 1 to 3 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C7 haloalkyl having 1 to 7 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C7 haloalkyl having 1 to 5 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C7 haloalkyl having 1 to 3 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C8 haloalkyl having 1 to 7 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C8 haloalkyl having 1 to 5 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C8 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C9 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C9 haloalkyl containing 1 to 5 fluorine atoms.In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 10 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 10 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 10 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 11 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 11 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 11 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 12 In some embodiments, each R' is independently an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 12 It is haloalkyl.

[0136] In some embodiments, each R' is independently a C 4-12 In some embodiments, each R' is independently a C alkyl group containing 1 to 5 fluorine atoms. 4-12 In some embodiments, each R' is independently a C alkyl group containing 1 to 3 fluorine atoms. 4-12 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. 6-12In 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. 8-12 In some embodiments, each R' is independently a C alkyl group containing 1 to 5 fluorine atoms. 8-12 In some embodiments, each R' is independently a C alkyl group containing 1 to 3 fluorine atoms. 8-12 In some embodiments, each R' is independently a C alkyl group containing 1 to 7 fluorine atoms. 4-10 In some embodiments, each R' is independently a C alkyl group containing 1 to 5 fluorine atoms. 4-10 In some embodiments, each R' is independently a C alkyl group containing 1 to 3 fluorine atoms. 4-10 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. 7-9 In some embodiments, each R' is independently a C alkyl group containing 1 to 5 fluorine atoms. 7-9 In some embodiments, each R' is independently a C alkyl group containing 1 to 3 fluorine atoms. 7-9 In some embodiments, each R' is independently a C alkyl group containing 1 to 7 fluorine atoms. 7-8 In some embodiments, each R' is independently a C alkyl group containing 1 to 5 fluorine atoms. 7-8 In some embodiments, each R' is independently a C alkyl group containing 1 to 3 fluorine atoms. 7-8 In some embodiments, each R' is independently a C alkyl group containing 1 to 7 fluorine atoms. 8-9In some embodiments, each R' is independently a C alkyl group containing 1 to 5 fluorine atoms. 8-9 In some embodiments, each R' is independently a C alkyl group containing 1 to 3 fluorine atoms. 8-9 haloalkyl. In some embodiments, each R' is independently a C4 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a C4 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a C4 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a C5 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a C5 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a C5 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a C6 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a C6 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a C6 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a C7 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a C7 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a C7 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a C8 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a C8 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a C8 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a C9 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a C9 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a C9 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a C9 haloalkyl containing 1 to 7 fluorine atoms. 10In 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 In some embodiments, each R' is independently a C alkyl group containing 1 to 7 fluorine atoms. 11 In some embodiments, each R' is independently a C alkyl group containing 1 to 5 fluorine atoms. 11 In some embodiments, each R' is independently a C alkyl group containing 1 to 3 fluorine atoms. 11 In some embodiments, each R' is independently a C alkyl group containing 1 to 7 fluorine atoms. 12 In some embodiments, each R' is independently a C alkyl group containing 1 to 5 fluorine atoms. 12 In some embodiments, each R' is independently a C alkyl group containing 1 to 3 fluorine atoms. 12 It is haloalkyl.

[0137] In some embodiments, each R' is independently a linear C 4-12 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 4-12 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 4-12 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. 8-12 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 8-12In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 8-12 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 4-10 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 4-10 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 4-10 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. 7-9 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 7-9 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 7-9 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 7-8 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 7-8 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 7-8 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 8-9 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 8-9 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 8-9haloalkyl. In some embodiments, each R' is independently a straight-chain C4 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a straight-chain C4 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a straight-chain C4 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a straight-chain C5 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a straight-chain C5 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a straight-chain C5 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a straight-chain C6 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a straight-chain C6 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a straight-chain C6 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a straight-chain C7 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a straight-chain C7 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a straight-chain C7 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a straight-chain C8 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a straight-chain C8 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a straight-chain C8 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a straight-chain C9 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, each R' is independently a straight-chain C9 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, each R' is independently a straight-chain C haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, each R' is independently a straight-chain C haloalkyl 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. 10In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 10 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 11 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 11 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 11 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 7 fluorine atoms. 12 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 5 fluorine atoms. 12 In some embodiments, each R' is independently a linear C alkyl group containing 1 to 3 fluorine atoms. 12 It is haloalkyl.

[0138] In some embodiments, each R' is independently an optionally substituted 3- to 12-membered alicyclic. In some embodiments, each R' is independently an optionally substituted 3- to 7-membered alicyclic. In some embodiments, each R' is independently an optionally substituted 4- to 7-membered alicyclic. In some embodiments, each R' is independently an optionally substituted 5- to 7-membered alicyclic. In some embodiments, each R' is independently an optionally substituted 6- to 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 5-6 membered saturated, partially unsaturated, substituted cyclohexyl or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and is selected from -(CH) 0-2 R ● In some embodiments, each R' is independently selected from the group consisting of: 1-6and cyclohexyl substituted with cyclohexyl further substituted with an aliphatic. In some embodiments, each R' is independently an optionally substituted cycloheptyl.

[0139] 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 aliphatic substituted phenyl.

[0140] In some embodiments, each R' is [ka] are independently selected from the group consisting of:

[0141] As noted above, in some embodiments of either of Formulas I' and I, each [ka] teeth, [ka] are independently selected from the group consisting of:

[0142] As noted above, in some embodiments of Formula I', R is hydrogen; [ka] ; or C 6-20 In some embodiments of Formula I, 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 I, R is hydrogen; [ka] ; or C 6-20 aliphatic, C 6-20 is an optionally substituted group selected from haloaliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.

[0143] In some embodiments of either of Formulas I' and I, R is hydrogen; or C 6-20 In some embodiments, R is an optionally substituted group selected from aliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. [ka] ; or C 6-20 In some embodiments, R is an optionally substituted group selected from aliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. 6-20 In some embodiments, R is an optionally substituted group selected from aliphatic, 3- to 7-membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl. In some embodiments, R is hydrogen; [ka] ; or C 6-20 In some embodiments, R is an optionally substituted group selected from aliphatic, 3- to 7-membered alicyclic, 1-adamantyl, and phenyl.6-20 is an optionally substituted group selected from aliphatic and 1-adamantyl.

[0144] In some embodiments, R is hydrogen. In some embodiments, R is [ka] is.

[0145] In some embodiments, R is 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 C6 aliphatic. In some embodiments, R is an optionally substituted C7 aliphatic. In some embodiments, R is an optionally substituted C8 aliphatic. In some embodiments, R is an optionally substituted C9 aliphatic. In some embodiments, R is an optionally substituted C 10 In some embodiments, R is an optionally substituted C 15-20 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.

[0146] In some embodiments, R is C 6-20In 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 a C6 aliphatic. In some embodiments, R is a C7 aliphatic. In some embodiments, R is a C8 aliphatic. In some embodiments, R is a C9 aliphatic. In some embodiments, R is a C 10 In some embodiments, R is C 15-20 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.

[0147] 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 8-11 In some embodiments, R is a linear C 9-10 In some embodiments, R is a straight chain C6 aliphatic. In some embodiments, R is a straight chain C7 aliphatic. In some embodiments, R is a straight chain C8 aliphatic. In some embodiments, R is a straight chain C9 aliphatic. In some embodiments, R is a straight chain 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 19In some embodiments, R is a linear C 20 It is aliphatic.

[0148] 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 C6 aliphatic. In some embodiments, R is a branched C7 aliphatic. In some embodiments, R is a branched C8 aliphatic. In some embodiments, R is a branched C9 aliphatic. In some embodiments, R is a branched C 10 In some embodiments, R is a branched C 15-20 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.

[0149] In some embodiments, R is optionally substituted C 6-20 In some embodiments, R is optionally substituted C alkyl. 6-12 In some embodiments, R is optionally substituted C alkyl. 8-11 In some embodiments, R is optionally substituted C alkyl. 9-10In some embodiments, R is an optionally substituted C alkyl. In some embodiments, R is an optionally substituted C alkyl. In some embodiments, R is an optionally substituted C alkyl. In some embodiments, R is an optionally substituted C alkyl. In some embodiments, R is an optionally substituted C alkyl. In some embodiments, R is an optionally substituted C alkyl. 10 In some embodiments, R is optionally substituted C alkyl. 15-20 In some embodiments, R is optionally substituted C alkyl. 15 In some embodiments, R is optionally substituted C alkyl. 16 In some embodiments, R is optionally substituted C alkyl. 17 In some embodiments, R is optionally substituted C alkyl. 18 In some embodiments, R is optionally substituted C alkyl. 19 In some embodiments, R is optionally substituted C alkyl. 20 It is alkyl.

[0150] 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 a C alkyl. In some embodiments, R is a C alkyl. In some embodiments, R is a C alkyl. In some embodiments, R is a C alkyl. In some embodiments, R is a C alkyl. In some embodiments, R is a C 10 In some embodiments, R is C 15-20 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 18In some embodiments, R is C 19 In some embodiments, R is C 20 It is alkyl.

[0151] In some embodiments, R is a linear C 6-20 In some embodiments, R is a straight chain C alkyl. 6-12 In some embodiments, R is a straight chain C alkyl. 8-11 In some embodiments, R is a straight chain C alkyl. 9-10 In some embodiments, R is a straight chain C alkyl. In some embodiments, R is a straight chain C alkyl. In some embodiments, R is a straight chain C alkyl. In some embodiments, R is a straight chain C alkyl. In some embodiments, R is a straight chain C alkyl. In some embodiments, R is a straight chain C alkyl. 10 In some embodiments, R is a straight chain C alkyl. 15-20 In some embodiments, R is a straight chain C alkyl. 15 In some embodiments, R is a straight chain C alkyl. 16 In some embodiments, R is a straight chain C alkyl. 17 In some embodiments, R is a straight chain C alkyl. 18 In some embodiments, R is a straight chain C alkyl. 19 In some embodiments, R is a straight chain C alkyl. 20 It is alkyl.

[0152] In some embodiments, R is optionally substituted C 6-20 In some embodiments, R is optionally substituted C alkenyl. 6-12 In some embodiments, R is optionally substituted C alkenyl. 8-11 In some embodiments, R is optionally substituted C alkenyl. 9-10In some embodiments, R is an optionally substituted C alkenyl. In some embodiments, R is an optionally substituted C alkenyl. In some embodiments, R is an optionally substituted C alkenyl. In some embodiments, R is an optionally substituted C alkenyl. In some embodiments, R is an optionally substituted C alkenyl. In some embodiments, R is an optionally substituted C alkenyl. In some embodiments, R is an optionally substituted C alkenyl. 10 In some embodiments, R is optionally substituted C alkenyl. 15-20 In some embodiments, R is optionally substituted C alkenyl. 15 In some embodiments, R is optionally substituted C alkenyl. 16 In some embodiments, R is optionally substituted C alkenyl. 17 In some embodiments, R is optionally substituted C alkenyl. 18 In some embodiments, R is optionally substituted C alkenyl. 19 In some embodiments, R is optionally substituted C alkenyl. 20 It is alkenyl.

[0153] 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 alkenyl. In some embodiments, R is C alkenyl. In some embodiments, R is C alkenyl. In some embodiments, R is C alkenyl. In some embodiments, R is C alkenyl. In some embodiments, R is C alkenyl. In some embodiments, R is C alkenyl. 10 In some embodiments, R is C 15-20 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 C18 In some embodiments, R is C 19 In some embodiments, R is C 20 It is alkenyl.

[0154] 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 C6 alkenyl. In some embodiments, R is a straight chain C7 alkenyl. In some embodiments, R is a straight chain C8 alkenyl. In some embodiments, R is a straight chain C9 alkenyl. In some embodiments, R is a straight chain C 10 In some embodiments, R is a straight chain C 15-20 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.

[0155] In some embodiments, R is 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 9-10In some embodiments, R is an optionally substituted C alkynyl. In some embodiments, R is an optionally substituted C alkynyl. In some embodiments, R is an optionally substituted C alkynyl. In some embodiments, R is an optionally substituted C alkynyl. In some embodiments, R is an optionally substituted C alkynyl. In some embodiments, R is an optionally substituted C alkynyl. In some embodiments, R is an optionally substituted C alkynyl. 10 In some embodiments, R is optionally substituted C 15-20 In some embodiments, R is optionally substituted C 15 In some embodiments, R is optionally substituted C 16 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 alkynyl.

[0156] 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 alkynyl. In some embodiments, R is C alkynyl. In some embodiments, R is C alkynyl. In some embodiments, R is C alkynyl. In some embodiments, R is C alkynyl. In some embodiments, R is C alkynyl. 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 16 In some embodiments, R is C 17 In some embodiments, R is C18 In some embodiments, R is C 19 In some embodiments, R is C 20 It is alkynyl.

[0157] 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 C6 alkynyl. In some embodiments, R is a straight chain C7 alkynyl. In some embodiments, R is a straight chain C8 alkynyl. In some embodiments, R is a straight chain C9 alkynyl. In some embodiments, R is a straight chain C 10 In some embodiments, R is a straight chain C 15-20 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.

[0158] In some embodiments, R is 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 6-10In some embodiments, R is an optionally substituted C haloaliphatic. In some embodiments, R is an optionally substituted C haloaliphatic. In some embodiments, R is an optionally substituted C haloaliphatic. In some embodiments, R is an optionally substituted C haloaliphatic. In some embodiments, R is an optionally substituted C haloaliphatic. In some embodiments, R is an optionally substituted C haloaliphatic. In some embodiments, R is an optionally substituted C haloaliphatic. 10 In some embodiments, R is an optionally substituted C 15-20 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 a haloaliphatic.

[0159] 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 a C haloaliphatic. In some embodiments, R is a C haloaliphatic. In some embodiments, R is a C haloaliphatic. In some embodiments, R is a C haloaliphatic. In some embodiments, R is a C haloaliphatic. In some embodiments, R is a C haloaliphatic. In some embodiments, R is a C haloaliphatic. 10 In some embodiments, R is C 15-20 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 C19 In some embodiments, R is C 20 It is a haloaliphatic.

[0160] 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 straight chain C haloaliphatic. In some embodiments, R is a straight chain C haloaliphatic. In some embodiments, R is a straight chain C haloaliphatic. In some embodiments, R is a straight chain C haloaliphatic. In some embodiments, R is a straight chain C haloaliphatic. In some embodiments, R is a straight chain C haloaliphatic. In some embodiments, R is a straight chain C haloaliphatic. In some embodiments, R is a straight chain C haloaliphatic. 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 a haloaliphatic.

[0161] In some embodiments, R is an optionally substituted C 6-20 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 6-20 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 6-20 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 6-12 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 6-12In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 6-12 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 6-10 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 6-10 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 6-10 haloalkyl. In some embodiments, R is an optionally substituted C6 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is an optionally substituted C6 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is an optionally substituted C6 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is an optionally substituted C7 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is an optionally substituted C7 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is an optionally substituted C7 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is an optionally substituted C8 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is an optionally substituted C8 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is an optionally substituted C8 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is an optionally substituted C9 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is an optionally substituted C9 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is an optionally substituted C9 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is an optionally substituted C9 haloalkyl containing 1 to 7 fluorine atoms. 10 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 10In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 10 It is haloalkyl.

[0162] In some embodiments, R is an optionally substituted C 15-20 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 15-20 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 15-20 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 15 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 15 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 15 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 16 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 16 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 16 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 17 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 17 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 17 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 18 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 18In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 18 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 19 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 19 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 19 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 7 fluorine atoms. 20 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 5 fluorine atoms. 20 In some embodiments, R is an optionally substituted C haloalkyl containing 1 to 3 fluorine atoms. 20 It is haloalkyl.

[0163] 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. 6-10haloalkyl. In some embodiments, R is a C6 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is a C6 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is a C6 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is a C7 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is a C7 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is a C7 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is a C8 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is a C8 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is a C8 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is a C9 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is a C9 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is a C9 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is a C 10 In some embodiments, R is a C alkyl group containing 1 to 5 fluorine atoms. 10 In some embodiments, R is a C alkyl group containing 1 to 3 fluorine atoms. 10 It is haloalkyl.

[0164] 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. 16In 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.

[0165] 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. 6-12In 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 haloalkyl. In some embodiments, R is a linear C6 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is a linear C6 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is a linear C6 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is a linear C7 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is a linear C7 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is a linear C7 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is a linear C8 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is a linear C8 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is a linear C8 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is a linear C9 haloalkyl containing 1 to 7 fluorine atoms. In some embodiments, R is a straight chain C9 haloalkyl containing 1 to 5 fluorine atoms. In some embodiments, R is a straight chain C9 haloalkyl containing 1 to 3 fluorine atoms. In some embodiments, R is a straight chain C9 haloalkyl 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.

[0166] 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. 15-20In 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. 16 In 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.

[0167] 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 an optionally substituted cycloheptyl.

[0168] 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 an optionally substituted 1-adamantyl. In some embodiments, R is an optionally substituted 2-adamantyl. In some embodiments, R is an optionally substituted sterolyl. In some embodiments, R is an optionally substituted cholesterolyl. In some embodiments, R is an optionally substituted phenyl.

[0169] As noted above, in some embodiments of either of Formulas I′ and I, -L 3 -R is [ka] is.

[0170] In some embodiments, R 7 is an optionally substituted C 4-10 Aliphatic or C 4-10 In some embodiments, R 7 is an optionally substituted C 4-10 In some embodiments, R 7 is an optionally substituted C4-8 In some embodiments, R 7 is an optionally substituted C 4-6 In some embodiments, R 7 is an optionally substituted C4 aliphatic. In some embodiments, R 7 is an optionally substituted C5 aliphatic. In some embodiments, R 7 is an optionally substituted C6 aliphatic. In some embodiments, R 7 is an optionally substituted C7 aliphatic. In some embodiments, R 7 is an optionally substituted C8 aliphatic. In some embodiments, R 7 is an optionally substituted C9 aliphatic. In some embodiments, R 7 is an optionally substituted C 10 It is aliphatic.

[0171] In some embodiments, R 7 is an optionally substituted C 4-10 In some embodiments, R 7 is an optionally substituted C 4-8 In some embodiments, R 7 is an optionally substituted C 4-6 In some embodiments, R 7 is an optionally substituted C haloaliphatic. In some embodiments, R 7 is an optionally substituted C haloaliphatic. In some embodiments, R 7 is an optionally substituted C haloaliphatic. In some embodiments, R 7 is an optionally substituted C7 haloaliphatic. In some embodiments, R 7 is an optionally substituted C haloaliphatic. In some embodiments, R 7 is an optionally substituted C haloaliphatic. In some embodiments, R 7 is an optionally substituted C 10 It is a haloaliphatic.

[0172] In some embodiments, R 8 is an optionally substituted C 2-8 Aliphatic or C 2-8 In some embodiments, R 8 is an optionally substituted C 2-8 In some embodiments, R 8 is an optionally substituted C 2-6 In some embodiments, R 8 is an optionally substituted C 2-4 In some embodiments, R 8 is an optionally substituted C2 aliphatic. In some embodiments, R 8 is an optionally substituted C3 aliphatic. In some embodiments, R 8 is an optionally substituted C4 aliphatic. In some embodiments, R 8 is an optionally substituted C5 aliphatic. In some embodiments, R 8 is an optionally substituted C6 aliphatic. In some embodiments, R 8 is an optionally substituted C7 aliphatic. In some embodiments, R 8 is an optionally substituted C8 aliphatic.

[0173] In some embodiments, R 8 is an optionally substituted C 2-8 In some embodiments, R 8 is an optionally substituted C 2-6 In some embodiments, R 8 is an optionally substituted C 2-4 In some embodiments, R 8 is an optionally substituted C haloaliphatic. In some embodiments, R 8 is an optionally substituted C haloaliphatic. In some embodiments, R 8 is an optionally substituted C haloaliphatic. In some embodiments, R 8is an optionally substituted C haloaliphatic. In some embodiments, R 8 is an optionally substituted C haloaliphatic. In some embodiments, R 8 is an optionally substituted C7 haloaliphatic. In some embodiments, R 8 is an optionally substituted C8 haloaliphatic.

[0174] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0175] In some embodiments, -L 3 -R is [ka] is selected from the group consisting of:

[0176] As noted above, in some embodiments of Formula I′, R 1 is 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)2N(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)2R 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)2R 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 )2C(O)OR 2 ;-CR 2 (R 3 )2;-OP(O)(OR 2 )2, or -P(O)(OR 2 )2 or R 1 teeth, [ka] 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 R3 The group is optionally substituted with a substituted or unsubstituted aryl group.

[0177] In some embodiments of Formula I, R 1 represents 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)2R 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)2R 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 )R2 ;-C(O)N(R 2 ) OR 2 ;-C(R 2 )N(R 2 )2C(O)OR 2 ; [ka] ;-CR 2 (OR 2 )R 3 ; [ka] is.

[0178] In some embodiments, R 1 is 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)2N(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)2R 2 ;-NR 2 C(O)N(R 2 )2;-NR 2 C(S)N(R 2 )2;-NR2 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)2R 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 )2C(O)OR 2 ;-CR 2 (R 3 )2;-OP(O)(OR 2 )2, or -P(O)(OR 2 )2.

[0179] In some embodiments, R 1 teeth, [ka] 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 The group is optionally substituted with a substituted or unsubstituted aryl group.

[0180] In some embodiments, R 1 teeth, [ka] is.

[0181] In some embodiments, R 1 is hydrogen; optionally substituted phenyl; 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 ;-OC(O)R 2 ;-OC(O)OR 2 ;-CN;-N(R 2 )2;-C(O)N(R 2 )2;-S(O)2N(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)2R 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)2R 2 ;-N(OR 2 )C(O)OR 2 ;-N(OR 2 )C(O)N(R 2 )2;-N(OR 2 )C(S)N(R2 )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 )2C(O)OR 2 ;-CR 2 (R 3 )2;-OP(O)(OR 2 )2;-P(O)(OR 2 )2 [ka] is.

[0182] In some embodiments, R 1 is hydrogen.

[0183] In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is phenyl optionally substituted with one or more -OR°; -C(O)N(R°)2; or one or more -OH; 1-4 Alkyl; -OR ● 、 -C(O)NH2;-C(O)NHR ● or -C(O)NR ● 2. In some embodiments, R 1 is phenyl substituted with —C(O)N(R°)2, where one R° is further substituted with —C(O)NH2. 1 is C 1-4 It is phenyl substituted with alkyl.

[0184] In some embodiments, R1 is an optionally substituted 3- to 7-membered alicyclic. In some embodiments, R 1 is an optionally substituted 4- to 7-membered alicyclic. In some embodiments, R 1 is an optionally substituted 5-6 membered alicyclic. In some embodiments, R 1 is an optionally substituted 3-membered alicyclic. In some embodiments, R 1 is an optionally substituted 4-membered alicyclic. In some embodiments, R 1 is an optionally substituted 5-membered alicyclic. In some embodiments, R 1 is an optionally substituted 6-membered alicyclic. In some embodiments, R 1 is an optionally substituted 7-membered alicyclic. In some embodiments, R 1 is optionally substituted cyclopentyl. In some embodiments, R 1 is optionally substituted cyclohexyl. In some embodiments, R 1 is an optionally substituted cycloheptyl.

[0185] In some embodiments, R 1 is an optionally substituted 3-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 4-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-6 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1is a 5- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is selected from one or more of -OR°; ═O; -C(O)N(R°)2; or one or more of -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R is a 5-6 membered heterocyclyl substituted with alkyl. 1 is an optionally substituted 3-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 4-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 5-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is selected from one or more of -OR°; ═O; -C(O)N(R°)2; or one or more of -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R is a 5-membered heterocyclyl substituted with alkyl. 1 is an optionally substituted 5-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 1 is a 5-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur, and is selected from one or more of -OR°; ═O; -C(O)N(R°)2; or one or more of -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R is a 5-membered heterocyclyl substituted with alkyl. 1is an optionally substituted 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is selected from one or more of -OR°; ═O; -C(O)N(R°)2; or one or more of -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R is a 6-membered heterocyclyl substituted with alkyl. 1 is an optionally substituted 6-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 1 is a 6-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur, and is selected from one or more of -OR°; ═O; -C(O)N(R°)2; or one or more of -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R is a 6-membered heterocyclyl substituted with alkyl. 1 is an optionally substituted 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 7-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 7-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted group selected from morpholinyl, pyrrolidinyl, thiomorpholinyl, piperidinyl, piperazinyl, and imidazolidinyl. 1 is an optionally substituted morpholinyl. In some embodiments, R1 is an optionally substituted pyrrolidinyl. In some embodiments, R 1 is an optionally substituted thiomorpholinyl. In some embodiments, R 1 is optionally substituted piperidinyl. In some embodiments, R 1 is an optionally substituted piperazinyl. In some embodiments, R 1 is an optionally substituted imidazolidinyl.

[0186] In some embodiments, R 1 is an optionally substituted 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-membered monocyclic heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 6-membered monocyclic heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 1is an optionally substituted pyridinyl or triazolyl. In some embodiments, R 1 is an optionally substituted pyridinyl. In some embodiments, R 1 is an optionally substituted triazolyl.

[0187] In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-membered bicyclic heteroaryl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-membered bicyclic heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 9-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 9-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is selected from one or more of -OR°; -C(O)N(R°)2; or one or more of -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R is a 9-membered bicyclic heteroaryl substituted with alkyl. 1 is an optionally substituted 9-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1is an optionally substituted 9-membered bicyclic heteroaryl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 9-membered bicyclic heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is an optionally substituted 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 10-membered bicyclic heteroaryl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 10-membered bicyclic heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is an optionally substituted indazolyl.

[0188] In some embodiments, R 1 -OR 2 , -OC(O)OR 2 , -C(O)OR 2 , -C(O)SR 2 , -N(R 2 )2, -C(O)N(R 2 )2, -S(O)2N(R 2 )2, -NR 2 C(O)R 2 , -NR 2 S(O)2R 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, or -CR 2 (OR 2)R 3 In some embodiments, each R 1 are independently -C(O)OR 2 , -C(O)SR 2 , -N(R 2 )2, -C(O)N(R 2 )2, -S(O)2N(R 2 )2, -NR 2 C(O)R 2 , or -CR 2 (R 3 )2. In some embodiments, R 1 -CR 2 (R 3 )2, [ka] In some embodiments, R 1 is an optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; —OR 2 , or -CR 2 (R 3 )2. In some embodiments, R 1 -OR 2 ;-CR 2 (R 3 )2; or a 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl ring is 2 or R 3 The group is optionally substituted with a substituted or unsubstituted aryl group.

[0189] In some embodiments, R 1 -OR 2 , -CR 2 (R 3 )2, or [ka] In some embodiments, R 1 -OR 2 , -CR 2 (R 3 )2, [ka] In some embodiments, R 1 -OR 2 In some embodiments, R 1 is -OC(O)OR 2 In some embodiments, R 1 is -C(O)OR 2 In some embodiments, R 1 is -C(O)SR 2 In some embodiments, R 1 is -N(R 2 )2. In some embodiments, R 1 is -C(O)N(R 2 )2. In some embodiments, R 1 is -S(O)2N(R 2 )2. In some embodiments, R 1 is -NR 2 C(O)R 2 In some embodiments, R 1 is -NR 2 S(O)2R 2 In some embodiments, R 1 is -NR 2 C(O)N(R 2 )2. In some embodiments, R 1 is -NR 2 C(S)N(R 2 )2. In some embodiments, R 1 is -NR 2 C(NR 2 )N(R 2 )2. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 -CR 2 (R 3 )2. In some embodiments, R 1 -CR 2 (OR2 )R 3 In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0190] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0191] As noted above, in some embodiments of Formula I′, each R 2 are independently hydrogen; oxo; -CN; -NO2; -OR 4 ;-S(O)2R 4 ;-S(O)2N(R 4 )2;-(CH2) n -R 4 ; or C 1-6an 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 together with the atom to which it is attached, R 2 Two occurrences of form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

[0192] In some embodiments of Formula I, each R 2 are independently hydrogen; -CN; -NO2; -OR 4 ;-S(O)2R 4 ;-S(O)2N(R 4 )2;-(CH2) n -R 4 ; or C 1-6 an optionally substituted group selected from an aliphatic, a 3- to 7-membered alicyclic ring, and a 3- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or together with the atom to which it is attached, R 2 Two occurrences of form an optionally substituted 4-7 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

[0193] In some embodiments, each R 2 are independently hydrogen; oxo; -CN; -NO2; -OR 4 ;-S(O)2R 4 ;-S(O)2N(R 4 )2;-(CH2) n -R 4 or an optionally substituted group selected from phenyl, a 3- to 7-membered alicyclic, a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or which, together with the atom to which it is attached, is R 2Two occurrences of form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

[0194] In some embodiments, each R 2 are independently hydrogen; oxo; -(CH2) 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 together with the atom to which it is attached, R 2 Two occurrences of R form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. 2 are independently hydrogen; oxo; or C 1-6 an optionally substituted group selected from aliphatic, phenyl, and 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or together with the atom to which it is attached, R 2 Two occurrences of form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

[0195] In some embodiments, each R 2 are independently hydrogen, oxo, -(CH2) n -R 4 or optionally substituted C 1-6 In some embodiments, each R 2 are independently hydrogen, oxo, or -(CH2) n -R 4 is.

[0196] In some embodiments, each R 2 is hydrogen. In some embodiments, each R 2 is -CN.

[0197] In some embodiments, each R 2 are independently -(CH2) n -R 4 In some embodiments, each R 2 are independently -(CH2)-R 4 , -(CH2)2-R 4 , or -(CH2)3-R 4 In some embodiments, each R 2 are independently -(CH2)2-R 4 or -(CH2)3-R 4 In some embodiments, each R 2 are independently -(CH2)-R 4 In some embodiments, each R 2 are independently -(CH2)2-R 4 In some embodiments, each R 2 are independently -(CH2)3-R 4 In some embodiments, each R 2 are independently -(CH2)4-R 4 is.

[0198] In some embodiments, each R 2 independently represents an optionally substituted C 1-6 In some embodiments, each R 2 independently represents an optionally substituted C 1-4 In some embodiments, each R 2 is independently an optionally substituted C aliphatic. In some embodiments, each R 2 is independently an optionally substituted C2 aliphatic. In some embodiments, each R 2 is independently an optionally substituted C3 aliphatic. In some embodiments, each R 2 is independently an optionally substituted C4 aliphatic. In some embodiments, each R 2 is independently an optionally substituted C5 aliphatic. In some embodiments, each R 2 is independently an optionally substituted C6 aliphatic. In some embodiments, each R 2is methyl. In some embodiments, each R 2 is ethyl.

[0199] In some embodiments, each R 2 is independently an optionally substituted phenyl. In some embodiments, each R 2 are independently phenyl and are selected from one or more of -OR°, -C(O)N(R°)2, or one or more of -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R is phenyl substituted with alkyl. 2 is C 1-4 It is phenyl substituted with alkyl.

[0200] In some embodiments, each R 2 is independently an optionally substituted 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is independently an optionally substituted 5-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is independently an optionally substituted 5-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is independently an optionally substituted 5-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is independently an optionally substituted 5-membered monocyclic heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 2 is independently an optionally substituted 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2is independently an optionally substituted 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is independently an optionally substituted 6-membered monocyclic heteroaryl containing one heteroatom selected from nitrogen, oxygen, and sulfur. 2 is independently an optionally substituted pyridinyl.

[0201] In some embodiments, R together with the atom to which it is attached 2 Two occurrences of R form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atoms to which it is attached, 2 Two occurrences of R form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atoms to which it is attached, 2 Two occurrences of - represent a 5-6 membered heterocyclyl containing 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and including one or more -OR°; -C(O)N(R°)2; or one or more -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R 1 , taken together with the atom to which it is attached, forms a 5- to 6-membered heterocyclyl substituted with alkyl. 2 Two occurrences of R form an optionally substituted 4-membered heterocyclyl containing zero additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atoms to which it is attached, 2 Two occurrences of R form an optionally substituted 5-membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atom to which it is attached, 2Two occurrences of R form an optionally substituted 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atom to which it is attached, 2 Two occurrences of - represent a 6-membered heterocyclyl containing 0 to 1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and including one or more -OR°; -C(O)N(R°)2; or one or more -OH or -OR ● C optionally substituted with 1-4 In some embodiments, R , taken together with the atom to which it is attached, forms a 6-membered heterocyclyl substituted with alkyl. 2 Two occurrences of R form an optionally substituted 7-membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atom to which it is attached, 2 Two occurrences form an optionally substituted piperazinyl.

[0202] As noted above, in some embodiments of either of Formulas I′ and I, each R 3 are independently -(CH2) n -R 4 or together with the atom to which it is bonded, R 3 Two occurrences of form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

[0203] In some embodiments, each R 3 are independently -(CH2) n -R 4 In some embodiments, each 3 are independently 4 In some embodiments, each R 3 are independently -(CH2)-R 4 In some embodiments, each R 3 are independently -(CH2)2-R 4 In some embodiments, each R3 are independently -(CH2)3-R 4 In some embodiments, each R 3 are independently -(CH2)4-R 4 is.

[0204] In some embodiments, R together with the atom to which it is attached 3 Two occurrences of R form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atoms to which it is attached, 3 Two occurrences of R form an optionally substituted 5-membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atom to which it is attached, 3 Two occurrences of form an optionally substituted 6-membered heterocyclyl containing 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

[0205] As noted above, in some embodiments of either of Formulas I′ and I, 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)2R 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] In some embodiments, each R 4 are independently -OR 5 or -N(R 5 )2.

[0206] In some embodiments, each R 4 is hydrogen. In some embodiments, each 4 are independently -OR 5 In some embodiments, each 4 are independently -N(R 5 )2. In some embodiments, each R 4 are independently -C(O)N(R 5 )2. In some embodiments, each R 4 are independently -NR 5 C(O)R 5 In some embodiments, each R 4 are independently -NR 5 C(S)N(R 5 )2. In some embodiments, each R 4 is, independently, [ka] is.

[0207] As noted above, in some embodiments of either of Formulas I′ and I, each R 5 are independently hydrogen or optionally substituted C 1-6 Aliphatic or together with the atom to which it is attached, R 5 Two occurrences of form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

[0208] In some embodiments, each R 5 is hydrogen.

[0209] In some embodiments, each R 5independently represents an optionally substituted C 1-6 In some embodiments, each R 5 independently represents an optionally substituted C 1-4 In some embodiments, each R 5 is independently an optionally substituted C aliphatic. In some embodiments, each R 5 is independently an optionally substituted C2 aliphatic. In some embodiments, each R 5 is independently an optionally substituted C3 aliphatic. In some embodiments, each R 5 is independently an optionally substituted C4 aliphatic. In some embodiments, each R 5 is independently an optionally substituted C5 aliphatic. In some embodiments, each R 5 is independently an optionally substituted C6 aliphatic. In some embodiments, each R 5 is methyl. In some embodiments, each R 5 is ethyl.

[0210] In some embodiments, R together with the atom to which it is attached 5 Two occurrences of R form an optionally substituted 4-7 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atoms to which it is attached, 5 Two occurrences of R form an optionally substituted 5-6 membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atoms to which it is attached, 5 Two occurrences of R form an optionally substituted 4-membered heterocyclyl containing zero additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atoms to which it is attached, 5 Two occurrences of R form an optionally substituted 5-membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atom to which it is attached,5 Two occurrences of R form an optionally substituted 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R, taken together with the atom to which it is attached, 5 Two occurrences form an optionally substituted morpholinyl.

[0211] As noted above, in some embodiments of either of Formulas I′ and I, each R 6 independently, C 4-12 In some embodiments, each R 6 independently, C 4-8 In some embodiments, each R 6 independently, C 6-12 In some embodiments, each R 6 is independently a C4 aliphatic. 6 is independently a C5 aliphatic. 6 is independently a C6 aliphatic. 6 is independently a C7 aliphatic. 6 is independently a C aliphatic. 6 is independently a C9 aliphatic. 6 independently, C 10 In some embodiments, each R 6 independently, C 11 In some embodiments, each R 6 independently, C 12 It is aliphatic.

[0212] As noted above, in some embodiments of either of Formulas I' and I, each n is independently 0 to 4. In some embodiments, each n is independently 1 to 4. In some embodiments, each n is independently 1 to 3. In some embodiments, each n is independently 2 or 3. In some embodiments, each n is 0. In some embodiments, each n is 1. In some embodiments, each n is 2. In some embodiments, each n is 3. In some embodiments, each n is 4.

[0213] In some embodiments, the present disclosure provides a compound of formula Ia: [ka] or its N-oxide, or a salt thereof, wherein R, R', R 1 , L 1 , L 2 , L 3 and N-oxides thereof, or salts thereof, each of which is as defined above for any of formulae I' and I, and which, both alone and in combination, are as described above and in classes and subclasses herein.

[0214] In some embodiments, the present disclosure provides a compound of formula Ib: [ka] or its N-oxide, or a salt thereof, wherein R, R', R 1 , L 1 , L 2 , L 3 and N-oxides thereof, or salts thereof, each of which is as defined above for any of formulae I' and I, and which, both alone and in combination, are as described above and in classes and subclasses herein.

[0215] In some embodiments, the present disclosure provides a compound of formula Ic: [ka] or its N-oxide, or a salt thereof, wherein R, R', R 1 , L 1 , L 2 , L 3 and N-oxides thereof, or salts thereof, each of which is as defined above for any of formulae I' and I, and which, both alone and in combination, are as described above and in classes and subclasses herein.

[0216] In some embodiments, the present disclosure provides a compound of formula Id: [ka] or its N-oxide, or a salt thereof, wherein R′, R 1 , L 1 , L 2 , L 3 and N-oxides thereof, or salts thereof, each of which is as defined above for any of formulae I' and I, and which, both alone and in combination, are as described above and in classes and subclasses herein.

[0217] In some embodiments, the present disclosure provides a compound of formula Ie: [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, R', R 1 , L 1 , L 2 and X are each defined above for any of formulae I' and I, and are as described above and in classes and subclasses herein, both alone and in combination, or an N-oxide thereof, or a salt thereof.

[0218] In some embodiments, the present disclosure provides a compound of formula Iei: [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, R', R 1 , L 1 , and L 2 and N-oxides thereof, or salts thereof, each of which is as defined above for any of formulae I' and I, and which, both alone and in combination, are as described above and in classes and subclasses herein.

[0219] In some embodiments, the present disclosure provides a compound of formula Ie-ii: [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, R', R 1 , L 1 , and L 2 and N-oxides thereof, or salts thereof, each of which is as defined above for any of formulae I' and I, and which, both alone and in combination, are as described above and in classes and subclasses herein.

[0220] In some embodiments, the present disclosure provides a compound of formula Ie-iii: [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, R', R 1 , L 1 , and L 2 and N-oxides thereof, or salts thereof, each of which is as defined above for any of formulae I' and I, and which, both alone and in combination, are as described above and in classes and subclasses herein.

[0221] It will be understood that "[compound / formula] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof," as used herein, refers to i) the respective compound or formula, or ii) a pharmaceutically acceptable salt of an N-oxide of such compound or formula.

[0222] In some embodiments, the disclosure provides a compound selected from Table 1. [Table 1] TIFF2024503976000056.tif213170TIFF2024503976000057.tif233170TIFF2024503976000058.tif218169TIFF2024503976000059.tif122170 or a pharmaceutically acceptable salt thereof.

[0223] Unless otherwise specified or prohibited by a preceding definition of any of Formulas I', I, Ia, Ib, Ic, Id, Ie, Iei, Ie-ii, and Ie-iii, the variables L defined above and described in the classes and subclasses herein are 1 , L 2 , L 3 ,X,R',R,R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 It will be understood that the embodiments of, n, and p, both alone and in combination, apply to compounds of any of formulae I', I, Ia, Ib, Ic, Id, Ie, Iei, Ie-ii, and Ie-iii.

[0224] It will be understood that throughout this disclosure, unless otherwise indicated, references to compounds of formula I' are intended to include any of formulas I, I, Ia, Ib, Ic, Id, Ie, Iei, Ie-ii, and Ie-iii, as well as species of compounds of such formulas disclosed herein.

[0225] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to a salt thereof, unless otherwise indicated.

[0226] In some embodiments of any of Formulas I, Ia, Ib, Ic, and Id, the salt is a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the present disclosure encompasses the recognition that provided compounds exhibit certain desirable characteristics, e.g., compared to a reference compound or other known compounds. For example, in some embodiments, provided compounds exhibit more potent delivery to various cell types in one or more experiments described herein and / or have one or more other characteristics that make them more suitable for delivery of cargo, such as therapeutic or prophylactic agents, than other known compounds. Without wishing to be bound by any particular theory, the present disclosure encompasses the recognition that provided compounds characterized by including at least one acetal feature containing one or more unsaturated and / or halogenated (e.g., fluorinated) units exhibit certain more desirable characteristics (e.g., more potent delivery to various cell types in one or more experiments described herein) than corresponding compounds lacking the same acetal feature.

[0228] B. Preparation of the Provided Compounds The provided compounds can generally be made by the processes described in the schemes and examples that follow. In some embodiments, the provided compounds (e.g., compounds of either formula I' or I) are prepared according to the following scheme: [ka] In the formula, L 1 , L 2 , L 3 , X, R, R', and R1 are each defined above for any of Formulae I' and I, and are as described in classes and subclasses herein, both alone and in combination. Thus, in some embodiments, intermediate I-3 is prepared by a process comprising contacting compounds of formulae I-1 and I-2 in the presence of a coupling reagent (e.g., DCC). In some embodiments, intermediate I-5 is prepared by a process comprising contacting intermediate I-3 with a compound of formula I-4 under suitable conditions. In some embodiments, intermediate I-7 is prepared by a process comprising contacting a compound of formula I-6 with an oxidizing agent (e.g., PCC). In some embodiments, intermediate I-9 is prepared by a process comprising contacting intermediate I-7 with a compound of formula I-8 under suitable conditions. In some embodiments, a compound of either formula I' or I is prepared by a process comprising contacting intermediates I-5 and I-9 under suitable conditions.

[0229] C. Ionizable lipids Among other things, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials that include one or more ionizable lipids described herein.

[0230] In particular, it has been surprisingly discovered that different ratios of ionizable lipids affect one or more functional activities, such as the desired tropism, stabilization, and drug delivery efficacy, of the compositions, preparations, nanoparticles, and / or nanomaterials described herein. For example, the present disclosure demonstrates the surprising discovery that amounts of ionizable lipids different from those described in the art (see, e.g., U.S. Pat. No. 8,058,069 B2 or, e.g., U.S. Pat. No. 9,364,435, the entire contents of both of which are incorporated herein by reference) are important and / or affect one or more functional activities of the compositions, preparations, nanoparticles, and / or nanomaterials described herein. For example, in some embodiments, compositions, preparations, nanoparticles, and / or nanomaterials having an ionizable lipid content of about 50 mol percent or less, based on the total moles of the lipid nanoparticle components, have been found to be useful and / or important for the functional activities of the lipid nanoparticles, such as the desired tropism, stabilization, and drug delivery efficacy, described herein.

[0231] In some embodiments, the ionizable lipid may comprise an amine-containing group on the head group. In some embodiments, the ionizable lipid is or comprises a compound of any one of Formulae I', I, Ia, Ib, Ic, Id, Ie, Iei, Ie-ii, and Ie-iii. In some embodiments, the ionizable lipid is present in the lipid nanoparticle (LNP) preparation at about 30 mol percent to about 70 mol percent based on the total moles of the lipid nanoparticle components. In some embodiments, the ionizable lipid is present at about 33 mol percent to about 60 mol percent based on the total moles of the lipid nanoparticle components. In some embodiments, the ionizable lipid is present at about 34 mol percent to about 55 mol percent based on the total moles of the lipid nanoparticle components. In some embodiments, the ionizable lipid is present at about 33 mol percent to about 51 mol percent based on the total moles of the lipid nanoparticle components. In some embodiments, the ionizable lipid is present at about 34.7 mol percent based on the total moles of the lipid nanoparticle components. In some embodiments, the ionizable lipid is present at about 50 mole percent, based on the total moles of the constituent components of the lipid nanoparticle.

[0232] In particular, in some embodiments, the lipid nanoparticle composition comprises an ionizable lipid. In some embodiments, the lipid nanoparticle preparation comprises an ionizable lipid, a phospholipid, a conjugate-linker lipid, and cholesterol. In some embodiments, the ionizable lipid comprises a structure according to any one of Formulas I', I, Ia, Ib, Ic, Id, Ie, Iei, Ie-ii, and Ie-iii. In some embodiments, the ionizable lipid is present in the LNP preparation at about 30 mole percent to about 70 mole percent, based on the total moles of the lipid nanoparticle components.

[0233] D. Sterols Among other things, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials that include one or more sterols described herein.

[0234] In some embodiments, the sterol is cholesterol, or a variant or derivative thereof. In some embodiments, the cholesterol is modified. In some embodiments, the cholesterol is oxidized cholesterol. In some embodiments, the cholesterol is esterified cholesterol. Unmodified cholesterol may be enzymatically acted upon to form variants with oxidized side chains or rings. In some embodiments, cholesterol may be oxidized on the beta-ring structure or hydrocarbon tail structure. In some embodiments, the sterol is a phytosterol. Exemplary sterols contemplated for use in the lipid nanoparticles of the present disclosure include, but are not limited to, 25-hydroxycholesterol (25-OH), 20α-hydroxycholesterol (20α-OH), 27-hydroxycholesterol, 6-keto-5α-hydroxycholesterol, 7-ketocholesterol, 7β-hydroxycholesterol, 7α-hydroxycholesterol, 7β-25-dihydroxycholesterol, beta-sitosterol, stigmasterol, brassicasterol, campesterol, or combinations thereof. In some embodiments, side-chain oxidized cholesterol may enhance cargo delivery compared to other cholesterol variants. In some embodiments, the cholesterol is unmodified cholesterol.

[0235] In some embodiments, the LNP composition comprises about 20 mol percent to about 50 mol percent sterol. In some embodiments, the LNP composition comprises about 38 mol percent sterol. In some embodiments, the LNP composition comprises about 38.5 mol percent sterol. In some embodiments, the LNP composition comprises about 33.8 mol percent cholesterol.

[0236] E. Conjugate-Linker Lipid Among other things, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials that include one or more conjugate-linker lipids described herein.

[0237] In some embodiments, the conjugate-linker lipid is or includes a polyethylene glycol (PEG) lipid or a PEG-modified lipid. In some embodiments, PEG or a PEG-modified lipid may alternatively be referred to as a PEGylated lipid or a PEG lipid. The inclusion of a PEGylated lipid may be used to enhance lipid nanoparticle colloidal stability in vitro and circulation time in vivo. In some embodiments, the PEGylation is reversible, in that the PEG moiety is gradually released into the blood circulation. Exemplary PEG lipids include, but are not limited to, PEG conjugated to a saturated or unsaturated alkyl chain having a length of C6-C20. PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide (PEG-CER), PEG-modified dialkylamine, PEG-modified diacylglycerol (PEG-DAG), PEG-modified dialkylglycerol, and mixtures thereof. For example, in some embodiments, the PEG lipid may be a PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPE, PEG-DSG, or PEG-DSPE lipid.

[0238] In some embodiments, the conjugate-linker lipid comprises a polyethylene glycol lipid. In some embodiments, the conjugate-linker lipid comprises dimyristylglycerol (DMG), 1,2-dipalmitoyl-rac-glycerol, methoxypolyethylene glycol (DPG-PEG), or 1,2-distearoyl-rac-glycero-3-methylpolyoxyethylene (DSG-PEG). In some embodiments, the conjugate-linker lipid has an average molecular weight of about 500 Da to about 5000 Da. In some embodiments, the conjugate-linker lipid has an average molecular weight of about 2000 Da. In some embodiments, the LNP composition comprises about 0 mol percent to about 5 mol percent of the conjugate-linker lipid. In some embodiments, the LNP composition comprises about 1.5 mol percent of the conjugate-linker lipid. In some embodiments, the LNP composition comprises about 3 mol percent of the conjugate-linker lipid.

[0239] F. Phospholipids In particular, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials comprising one or more phospholipids described herein. In some embodiments, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials comprising one or more (poly)unsaturated lipids.

[0240] In some embodiments, one or more phospholipids may be assembled into one or more lipid bilayers. In some embodiments, one or more phospholipids may comprise a phospholipid moiety. In some embodiments, one or more phospholipids may comprise one or more fatty acid moieties. In some embodiments, one or more phospholipids may comprise a phospholipid moiety and one or more fatty acid moieties. In some embodiments, the phospholipid moiety includes, but is not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, 2-lysophosphatidylcholine, and sphingomyelin. In some embodiments, the fatty acid moiety includes, but is not limited to, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, erucic acid, phytanic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid. Also contemplated are unnatural species, including natural species with modifications and substitutions, including branching, oxidation, cyclization, and alkynes. For example, phospholipids can be functionalized or crosslinked with one or more alkynes (e.g., alkenyl groups in which one or more double bonds are replaced with triple bonds). Under appropriate reaction conditions, the alkyne group can undergo copper-catalyzed cycloaddition when exposed to azide. Such reactions can be useful for functionalizing the lipid bilayer of nanoparticle compositions to facilitate membrane permeation or cell recognition, or for conjugating nanoparticle compositions to useful components, such as targeting or imaging moieties (e.g., dyes).

[0241] Exemplary phospholipids include, but are not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycerophosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero -3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycerophosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl l-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME16.0PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE), distearoyl In some embodiments, the phospholipid may be DSPC, DMPC, 1-stearoyl-2-oleoyl-phosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-phosphatidylethanolamine (SOPE), 1-stearoyl-2-oleoylphosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoylphosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), or a combination thereof. In some embodiments, the phospholipid is DSPC. In some embodiments, the phospholipid is DMPC.

[0242] In some embodiments, the phospholipid comprises 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl) (succinyl PE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl) (succinyl-DPPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), or a combination thereof.

[0243] G.Diameter Among other things, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials having an average hydrodynamic diameter of about 30 to about 220 nm. In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials described herein 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, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, or any range having endpoints defined by any two of the foregoing values. For example, in some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials described herein have an average hydrodynamic diameter of between 50 nm and 200 nm.

[0244] In some embodiments, the lipid nanoparticles described herein may have an average hydrodynamic diameter of about 30 to about 220 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, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 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 between 50 nm and 200 nm.

[0245] H. Polydispersity In particular, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials having a polydispersity index (PDI) of about 0.01 to about 0.3. In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials described herein have a PDI of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, or any range having endpoints defined by any two of the foregoing values. For example, in some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials described herein have a PDI of about 0.05 to about 0.2, about 0.06 to about 0.1, or about 0.07 to about 0.09.

[0246] In some embodiments, the lipid nanoparticles described herein have a PDI of about 0.01 to about 0.3. In some embodiments, the lipid nanoparticles described herein have a PDI of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, or any range having endpoints defined by any two of the foregoing values. For example, in some embodiments, the lipid nanoparticles described herein have a PDI of about 0.05 to about 0.2, about 0.06 to about 0.1, or about 0.07 to about 0.09.

[0247] I. Encapsulation Efficiency Among other things, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials, wherein the encapsulation efficiency of the provided compositions, preparations, nanoparticles, and / or nanomaterials is about 80% to about 100%. In some embodiments, the encapsulation efficiency of the compositions, preparations, nanoparticles, and / or nanomaterials described herein is about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 100%, or any range having endpoints defined by any two of the foregoing values. For example, in some embodiments, the encapsulation efficiency of the compositions, preparations, nanoparticles, and / or nanomaterials described herein is about 90% to about 100%, about 95% to about 100%, about 95% to about 98%, or about 95.5% to about 97.5%. In some embodiments, the encapsulation efficiency of the compositions, preparations, nanoparticles, and / or nanomaterials described herein is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0248] In some embodiments, the encapsulation efficiency of the lipid nanoparticles described herein is about 80% to about 100%. In some embodiments, the encapsulation efficiency of the lipid nanoparticles described herein is about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 100%, or any range having endpoints defined by any two of the foregoing values. For example, in some embodiments, the encapsulation efficiency of the lipid nanoparticles described herein is about 90% to about 100%, about 95% to about 100%, about 95% to about 98%, or about 95.5% to about 97.5%. In some embodiments, the encapsulation efficiency of the lipid nanoparticles described herein is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0249] J.pKa Among other things, the present disclosure describes compositions, preparations, nanoparticles, and / or nanomaterials having a pKa of about 5 to about 9. In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials described herein have a pKa of about 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or any range having endpoints defined by any two of the foregoing values. In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials described herein have a pKa of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, or any range having endpoints defined by any two of the foregoing values.

[0250] In some embodiments, the lipid nanoparticles described herein have a pKa of about 5 to about 9. In some embodiments, the lipid nanoparticles described herein have a pKa of about 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or any range having endpoints defined by any two of the foregoing values. In some embodiments, the lipid nanoparticles described herein have a pKa of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, or any range having endpoints defined by any two of the foregoing values.

[0251] II. Exemplary LNP Preparations The present invention provides compositions, preparations, nanoparticles, and / or nanomaterials comprising lipid nanoparticles. In some embodiments, the lipid nanoparticle preparation comprises about 30 mole percent to about 70 mole percent ionizable lipid, about 5 mole percent to about 25 mole percent phospholipid, about 25 mole percent to about 45 mole percent cholesterol, and about 0 mole percent to about 5 mole percent conjugate-linker lipid.

[0252] In some embodiments, the lipid nanoparticle preparation comprises about 45 mole percent ionizable lipid, about 9 mole percent phospholipid, about 44 mole percent cholesterol, and about 2 mole percent conjugate-linker lipid. In some embodiments, the lipid nanoparticle preparation comprises about 50 mole percent ionizable lipid, about 9 mole percent phospholipid, about 38 mole percent cholesterol, and about 3 mole percent conjugate-linker lipid.

[0253] In some embodiments, the lipid nanoparticle preparation comprises about 40 mole percent to about 60 mole percent of an ionizable lipid of any one of formulas I', I, Ia, Ib, Ic, Id, Ie, Iei, Ie-ii, and Ie-iii, about 5 mole percent to about 15 mole percent of 1-2-distearoyl-sn-glycero-3-phosphocholine, about 1 mole percent to about 5 mole percent of C14PEG2000, and about 30 mole percent to about 47 mole percent of cholesterol, based on the total moles of these four components.

[0254] In some embodiments, the lipid nanoparticle (LNP) preparation comprises a mass ratio of (ionizable lipid, cholesterol, lipid-PEG, and phospholipid):mRNA of about 2:1 to 50:1. In some embodiments, the LNP preparation comprises a mass ratio of about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, about 25:1, about 26:1, about 27:1, about 28:1, about 29:1, about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about 40:1, about 41:1, about 42:1, about 43:1, about 44:1, about 45:1, about 46:1, about 47:1, about 48:1, about 49:1, about 50:1, about 51:1, about 52:1, about 53:1, about 54:1, about 55:1, about 56:1, about 57:1, about 58:1, about 59:1, about 60:1, about 61:1, about 62:1, about 63:1, about 64:1, about 65:1, about 66:1, ionizable lipids, cholesterol, lipid-PEG, and phospholipids:mRNA in a mass ratio of about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about 40:1, about 41:1, about 42:1, about 43:1, about 44:1, about 45:1, about 46:1, about 47:1, about 48:1, about 49:1, or about 50:1. In some embodiments, the lipid nanoparticle (LNP) preparation comprises a mass ratio of about 11.7:1 to 19:1 (ionizable lipids, cholesterol, lipid-PEG, and phospholipids):mRNA.

[0255] In some embodiments, the lipid nanoparticle preparation comprises a mass ratio of (ionizable lipid, cholesterol, lipid-PEG, and phospholipid): siRNA of about 2:1 to 50:1. In some embodiments, the LNP preparation comprises a mass ratio of about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, about 25:1, about 26:1, about 27:1, about 28:1, about 29:1, about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about 40:1, about 41:1, about 42:1, about 43:1, about 44:1, about 45:1, about 46:1, about 47:1, about 48:1, about 49:1, about 50:1, about 51:1, about 52:1, about 53:1, about 54:1, about 55:1, about 56:1, about 57:1, about 58:1, about 59:1, about 60:1, about 61:1, about 62:1, about 63:1, about 64:1, about 65:1, about 66:1, about 67 ionizable lipids, cholesterol, lipid-PEG, and phospholipids:mRNA in a mass ratio of about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about 40:1, about 41:1, about 42:1, about 43:1, about 44:1, about 45:1, about 46:1, about 47:1, about 48:1, about 49:1, or about 50:1. In some embodiments, the lipid nanoparticle (LNP) preparation comprises a mass ratio of about 11.7:1 to 19:1 (ionizable lipids, cholesterol, lipid-PEG, and phospholipids):mRNA.

[0256] III. Pharmaceutical Compositions The present invention provides compositions, preparations, nanoparticles, and / or nanomaterials, including pharmaceutical compositions. In particular, in some embodiments, the pharmaceutical compositions comprise the lipid nanoparticles and lipid nanoparticle preparations described herein. For example, in some embodiments, the lipid nanoparticles and lipid nanoparticle preparations described herein may be formulated in whole or in part as pharmaceutical compositions.

[0257] In some embodiments, a pharmaceutical composition may comprise one or more nanoparticle compositions described herein. For example, a pharmaceutical composition may comprise one or more nanoparticle compositions comprising one or more different therapeutic and / or prophylactic agents, including, but not limited to, different types of one or more nucleic acids, or may encode different agents. In some embodiments, a pharmaceutical composition comprises one or more pharmaceutically acceptable excipients or auxiliary ingredients, including, but not limited to, a pharmaceutically acceptable carrier.

[0258] The pharmaceutical composition can be administered to a subject. In some embodiments, the pharmaceutical composition is administered as described herein. In some in vivo approaches, the nanoparticle composition disclosed herein is administered to a subject in a therapeutically effective amount as described herein.

[0259] In some embodiments, those skilled in the art will be able to devise appropriate dosage levels and administration regimens using the pharmaceutical compositions described herein for the treatment of various conditions in various patients, taking into account the recipient's therapeutic background, age, and general health. For example, in some embodiments, the selected dosage will depend on the desired therapeutic effect, the route of administration, and the desired duration of treatment. In some embodiments, dosage levels of about 0.001 mg to about 5 mg of nucleic acid per kg of body weight are typically administered to mammals, with each dose administered. More specifically, in some embodiments, the preferred dosage of nucleic acid in the disclosed nanoparticles is about 0.1 mg / kg to about 1.0 mg / kg. The disclosed nanoparticles are typically administered to mammals at dosage levels of about 0.2 mg to about 100 mg of the four components (ionizable lipid, cholesterol, conjugate-linker conjugate, and phospholipid) per kg of body weight. More specifically, in some embodiments, the preferred dosage of the disclosed nanoparticles is about 0.5 mg / kg to about 5 mg / kg of the four components per kg of body weight.

[0260] In some embodiments, the pharmaceutical compositions described herein are administered locally, for example, by direct injection into the site to be treated. Typically, the injection causes a local increase in the concentration of the composition that is higher than that achieved by systemic administration. In some embodiments, the pharmaceutical compositions described herein can be combined with the matrices described herein to help create an increase in the local concentration of the polypeptide composition by reducing passive diffusion of the polypeptide from the site to be treated.

[0261] A. Preparations for Parenteral Administration In some embodiments, compositions, preparations, nanoparticles, and / or nanomaterials disclosed herein, including those containing lipid nanoparticles, are administered parenterally in aqueous solution. In some embodiments, the preparations may also be in the form of a suspension or emulsion. Generally, pharmaceutical compositions containing an effective amount of lipid nanoparticles are provided, optionally including pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, and / or carriers. Such compositions optionally include one or more additives, such as diluents, sterile water, buffered saline solutions (e.g., Tris-HCl, acetate, phosphate) of various buffer contents, pH, and ionic strength; detergents and solubilizers (e.g., TWEEN® 20 (polysorbate-20), TWEEN 80 (polysorbate-80)), antioxidants (e.g., ascorbic acid, sodium metabisulfite), and preservatives (e.g., Thimersol, benzyl alcohol), and bulking agents (e.g., lactose, mannitol). Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.The formulation can be lyophilized and redissolved / resuspended immediately before use.The formulation can be sterilized, for example, by filtering through a bacteria-retaining filter, by incorporating a sterilizing agent into the composition, by irradiating the composition, or by heating the composition.

[0262] B. Controlled Delivery Polymer Matrix In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials disclosed herein can also be administered in controlled-release formulations. In some embodiments, controlled-release polymeric devices can be fabricated for extended systemic release after implantation of a polymeric device (e.g., rod, cylinder, film, disk, etc.) or injection (e.g., microparticle). In some embodiments, the matrix can be in the form of microparticles, such as microspheres. In some embodiments, the drug is dispersed within a solid polymer matrix or microcapsules. In some embodiments, the core is of a different material than the polymer shell of any of the described compositions, preparations, nanoparticles, and / or nanomaterials. In some embodiments, the peptide is dispersed or suspended in the core, which can be liquid or solid in nature, of any of the described compositions, preparations, nanoparticles, and / or nanomaterials. Unless specifically defined otherwise herein, microparticles, microspheres, and microcapsules are used interchangeably. In some embodiments, the polymers can be cast as thin slabs or films ranging from nanometers to 4 centimeters, as powders produced by milling or other standard techniques, or even as gels, such as hydrogels.

[0263] In some embodiments, non-biodegradable matrices are used to deliver the described compositions, preparations, nanoparticles, and / or nanomaterials. In some embodiments, biodegradable matrices are used to deliver the described compositions, preparations, nanoparticles, and / or nanomaterials. In some embodiments, biodegradable matrices are preferred. In some embodiments, biodegradable matrices comprise natural or synthetic polymers. In some embodiments, synthetic polymers are preferred due to better characterization of degradation and release profiles. In some embodiments, the polymer is selected based on the desired period of release. In some embodiments, linear release may be most useful, while in other embodiments, pulsed or "bulk release" may provide more effective results. In some embodiments, the polymer may be in the form of a hydrogel (typically absorbing up to about 90% water by weight), optionally crosslinked with multivalent ions or polymers.

[0264] The matrix can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art. Bioerodible microspheres can be prepared using any of the methods developed to make microspheres for drug delivery, such as those described by Mathiowitz and Langer, J. Controlled Release, 5:13-22 (1987); Mathiowitz, et al., Reactive Polymers, 6:275-283 (1987); and Mathiowitz, et al., J. Appl. Polymer Sci., 35:755-774 (1988), the entire disclosures of which are incorporated herein by reference.

[0265] In some embodiments, the described compositions, preparations, nanoparticles, and / or nanomaterials can be formulated for local release to treat the area of ​​implantation or injection, and will typically deliver a much lower dose than for whole body treatment or systemic delivery. They may be implanted or injected subcutaneously, into muscle, fat, or swallowed.

[0266] C. Cargo Among other things, the present invention provides compositions, preparations, nanoparticles, and / or nanomaterials comprising the cargo described herein. In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials comprise a therapeutic or prophylactic agent for delivery to a subject. In some embodiments, the therapeutic or prophylactic agent is encapsulated by the lipid nanoparticles. In some embodiments, the lipid nanoparticles are loaded with one or more nucleic acids.

[0267] D. Therapeutic and / or Prophylactic Agents The cargo delivered via the LNP composition can be a biologically active agent. In some embodiments, the cargo can be an mRNA, a guide RNA (gRNA), a nucleic acid, an RNA-guided DNA binder, an expression vector, a template nucleic acid, an antibody (e.g., monoclonal, chimeric, humanized, nanobody, and fragments thereof), cholesterol, a hormone, a peptide, a protein, a chemotherapeutic agent and other types of antineoplastic agents, a small molecule drug, a vitamin, a cofactor, a nucleoside, a nucleotide, an oligonucleotide, an enzymatic nucleic acid, an antisense nucleic acid, a triplex-forming oligonucleotide, an antisense DNA or RNA composition, a chimeric DNA:RNA composition, an allozyme, an aptamer, a ribozyme, decoys and analogs thereof, a plasmid, and other types of vectors. The biologically active agent may be or include one or more biologically active agents, such as small nucleic acid molecules, RNAi agents, short interfering nucleic acids (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), microRNA (miRNA), short hairpin RNA (shRNA), "self-replicating RNA" molecules (which encode replicase enzyme activity and can induce its own replication or amplification in vivo), peptide nucleic acids (PNAs), locked nucleic acid ribonucleotides (LNAs), morpholino nucleotides, threose nucleic acids (TNAs), glycol nucleic acids (GNAs), sisiRNAs (small internal segmented interfering RNAs), and iRNAs (asymmetric interfering RNAs). The above list of biologically active agents is illustrative only and is not intended to be limiting. Such compounds may be purified or partially purified, naturally occurring or synthetic, and chemically modified.

[0268] The cargo delivered via the LNP composition can be RNA, such as an mRNA molecule encoding a protein of interest. For example, in some embodiments, mRNA for expressing a protein such as green fluorescent protein (GFP), an RNA-guided DNA binder, or a Cas nuclease is described herein. LNP compositions are provided that include a Cas nuclease mRNA, e.g., a Class 2 Cas nuclease mRNA, that enables intracellular expression of a Class 2 Cas nuclease, such as Cas9 or a Cpfl protein. Additionally, the cargo can contain one or more guide RNAs or nucleic acids encoding the guide RNAs. For example, a template nucleic acid for repair or recombination can also be included in the composition, or the template nucleic acid can be used in the methods described herein. In some embodiments, the cargo optionally includes an mRNA encoding Streptococcus pyogenes Cas9 and an S. pyogenes gRNA. In some embodiments, the cargo optionally includes an mRNA encoding Neisseria meningitidis Cas9 and an nme gRNA.

[0269] "mRNA" refers to a polynucleotide that contains an open reading frame that can be translated into a polypeptide (i.e., can serve as a substrate for translation by ribosomes and amino-acylated tRNAs). mRNA can contain a phosphate-sugar backbone that includes ribose residues or analogs thereof, e.g., 2'-methoxyribose residues. In some embodiments, the sugars of the mRNA phosphate sugar backbone consist essentially of ribose residues, 2'-methoxyribose residues, or combinations thereof. Generally, mRNA does not contain substantial amounts of thymidine residues (e.g., 0 residues or less than 30, 20, 10, 5, 4, 3, or 2 thymidine residues; or a thymidine content of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, or 0.1%). mRNA can contain modified uridines at some or all of its uridine positions.

[0270] E. CRISPR / Cas cargo In some embodiments, the disclosed compositions, preparations, nanoparticles, and / or nanomaterials comprise mRNA encoding an RNA-guided DNA binder, such as a Cas nuclease. In certain embodiments, the disclosed compositions, preparations, nanoparticles, and / or nanomaterials comprise mRNA encoding a Class 2 Cas nuclease, such as S. pyogenes Cas9.

[0271] As used herein, "RNA-guided DNA binding agent" refers to a polypeptide or polypeptide complex having RNA and DNA binding activity, or a DNA-binding subunit of such a complex, where the DNA-binding activity is sequence-specific and dependent on the sequence of the RNA. Exemplary RNA-guided DNA binding agents include Cas cleavase / nickases and their inactivated forms (dCas DNA binders). "Cas nuclease," as used herein, encompasses Cas cleavage enzymes, Cas nickases, and dCas DNA binders. Cas cleavage enzymes / nickases and dCas DNA binders include the Csm or Cmr complex of a type III CRISPR system, its Cas1O, Csml, or Cmr2 subunit, the Cascade complex of a type I CRISPR system, its Cas3 subunit, and class 2 Cas nucleases. As used herein, a "class 2 Cas nuclease" is a single-chain polypeptide having RNA-guided DNA binding activity. Class 2 Cas nucleases include Class 2 Cas cleavages / nickases that also have RNA-guided DNA cleavage or nickase activity (e.g., H840A, D10A, or N863A variants), and Class 2 dCas DNA binders in which the cleavage / nickase activity has been inactivated. Class 2 Cas nucleases include, for example, Cas9, Cpfl, C2cl, C2c2, C2c3, HF Cas9 (e.g., N497A, R661A, Q695A, Q926A variants), HypaCas9 (e.g., N692A, M694A, Q695A, H698A variants), eSPCas9(1.0) (e.g., K810A, K1003A, R1060A variants), and eSPCas9(1.1) (e.g., K848A, K1003A, R1060A variants) proteins and modifications thereof. The Cpfl protein, Zetsche et al., Cell, 163:1-13 (2015), is homologous to Cas9 and contains a RuvC-like nuclease domain. The Cpfl sequences of Zetsche are incorporated herein by reference in their entirety, see, e.g., Tables S1 and S3 of Zetsche.See, for example, Makarova et al., Nat Rev Microbiol, 13(11):722-36 (2015); Shmakov et al., Molecular Cell, 60:385-397 (2015), the contents of which are incorporated herein by reference in their entirety.

[0272] As used herein, "ribonucleoprotein" (RNP) or "RNP complex" refers to a guide RNA comprising an RNA-guided DNA-binding agent, e.g., a Cas nuclease, e.g., a Cas cleavase, a Cas nickase, or a dCas DNA-binding agent (e.g., Cas9). In some embodiments, the guide RNA guides the RNA-guided DNA-binding agent, such as Cas9, to a target sequence, the guide RNA hybridizes to the target sequence, and an agent binds to the target sequence, where the agent is a cleavase or nickase and can perform cleavage or nicking after binding.

[0273] In some embodiments, the cargo of the LNP composition comprises at least one guide RNA comprising a guide sequence that guides an RNA-guided DNA-binding agent, which may be a nuclease (e.g., a Cas nuclease such as Cas9), to a target DNA. The gRNA may guide the Cas nuclease or a Class 2 Cas nuclease to a target sequence on a target nucleic acid molecule. In some embodiments, the gRNA binds to a Class 2 Cas nuclease, thereby providing specificity for cleavage. In some embodiments, the gRNA and Cas nuclease may form a ribonucleoprotein (RNP), e.g., a CRISPR / Cas complex, such as a CRISPR / Cas9 complex. In some embodiments, the CRISPR / Cas complex may be a Type II CRISPR / Cas9 complex. In some embodiments, the CRISPR / Cas complex may be a Type V CRISPR / Cas complex, such as a Cpfl / guide RNA complex. The Cas nuclease and cognate gRNA may be paired. The gRNA scaffold structure that pairs with each Class 2 Cas nuclease varies depending on the specific CRISPR / Cas system.

[0274] "Guide RNA," "gRNA," and simply "guide" are used interchangeably herein to refer to either crRNA (also known as CRISPR RNA) or a combination of crRNA and trRNA (also known as tracrRNA). Guide RNA may include modified RNA as described herein. CrRNA and trRNA may associate as a single-stranded RNA molecule (single guide RNA, sgRNA) or in two separate RNA molecules (dual guide RNA, dgRNA). "Guide RNA" or "gRNA" refers to each type. The trRNA may be a naturally occurring sequence or a trRNA sequence with modifications or mutations compared to the naturally occurring sequence.

[0275] As used herein, a "guide sequence" refers to a sequence within a guide RNA that is complementary to a target sequence and functions to guide the guide RNA to the target sequence for binding or modification (e.g., cleavage) by an RNA-guided DNA-binding agent. A "guide sequence" may also be referred to as a "targeting sequence" or a "spacer sequence." A guide sequence may be 20 base pairs in length, for example, in the case of Streptococcus pyogenes (i.e., Spy Cas9) and related Cas9 homologs / orthologs. Shorter or longer sequences, e.g., 15, 16, 17, 18, 19, 21, 22, 23, 24, or 25 nucleotides in length, can also be used as a guide. In some embodiments, the target sequence is, for example, within a gene or on a chromosome, and is complementary to the guide sequence. In some embodiments, the degree of complementarity or identity between a guide sequence and its corresponding target sequence may be about or at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the guide sequence and target region may be 100% complementary or identical over a region of at least 15, 16, 17, 18, 19, or 20 contiguous nucleotides. In other embodiments, the guide sequence and target region may contain at least one mismatch. For example, the guide sequence and target sequence may contain one, two, three, or four mismatches, and the total length of the target sequence is at least 17, 18, 19, 20, or more base pairs. In some embodiments, the guide sequence and target region may contain one to four mismatches, and the guide sequence comprises at least 17, 18, 19, 20, or more nucleotides. In some embodiments, the guide sequence and the target region may contain 1, 2, 3, or 4 mismatches, and the guide sequence comprises 20 nucleotides.

[0276] The target sequence of an RNA-guided DNA-binding protein, such as a Cas protein, includes both the positive and negative strands of genomic DNA (i.e., the given sequence and the reverse complement of the sequence) because the nucleic acid substrate of the Cas protein is a double-stranded nucleic acid. Thus, when a guide sequence is said to be "complementary to a target sequence," it should be understood that the guide RNA can be directed to bind to the reverse complement of the target sequence. Thus, in some embodiments, when the guide sequence binds to the reverse complement of the target sequence, the guide sequence is identical to certain nucleotides of the target sequence (e.g., the target sequence without the PAM) except for the substitution of U for T in the guide sequence.

[0277] The length of the targeting sequence depends on the CRISPR / Cas system and components used. For example, different Class 2 Cas nucleases from different bacterial species have varying optimal targeting sequence lengths. Thus, the targeting sequence may comprise 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, or more than 50 nucleotides in length. In some embodiments, the targeting sequence length is 0, 1, 2, 3, 4, or 5 nucleotides longer or shorter than the guide sequence of a naturally occurring nucleotide sequence.

[0278] In certain embodiments of the CRISPR / Cas system, the Cas nuclease and gRNA scaffold will be derived from the same CRISPR / Cas system. In some embodiments, the targeting sequence may comprise or consist of 18-24 nucleotides. In some embodiments, the targeting sequence may comprise or consist of 19-21 nucleotides. In some embodiments, the targeting sequence may comprise or consist of 20 nucleotides.

[0279] In some embodiments, the sgRNA is a "Cas9 sgRNA" capable of mediating RNA-guided DNA cleavage by a Cas9 protein. In some embodiments, the sgRNA is a "Cpfl sgRNA" capable of mediating RNA-guided DNA cleavage by a Cpfl protein. In some embodiments, the gRNA comprises sufficient crRNA and tracrRNA to form an active complex with a Cas9 protein and mediate RNA-guided DNA cleavage. In some embodiments, the gRNA comprises sufficient crRNA to form an active complex with a Cpfl protein and mediate RNA-guided DNA cleavage. See Zetsche 2015.

[0280] Certain embodiments of the present invention also provide nucleic acids, e.g., expression cassettes, encoding the gRNAs described herein. "Guide RNA nucleic acid" is used herein to refer to guide RNAs (e.g., sgRNAs or dgRNAs) and guide RNA expression cassettes, which are nucleic acids that encode one or more guide RNAs.

[0281] Certain embodiments of the present disclosure also provide for delivery of adenine base editors ("ABEs") using the LNP compositions, preparations, nanoparticles, and / or nanomaterials described herein. ABEs and methods of using same are described, for example, in U.S. Patent No. 10,113,163 and U.S. Patent Publication No. 2021 / 0130805, the contents of each of which are incorporated herein by reference in their entirety.

[0282] Certain embodiments of the present disclosure also provide for delivery of cytosine base editors ("CBEs") using the LNP compositions, preparations, nanoparticles, and / or nanomaterials described herein. CBEs and methods of using same are described, for example, in U.S. Patent Nos. 10,167,457 and 9,840,699, the contents of each of which are incorporated herein by reference in their entirety.

[0283] The term "base editor (BE)" or "nucleic acid base editor (NBE)" refers to an agent comprising a polypeptide capable of making modifications to bases (e.g., A, T, C, G, or U) in a nucleic acid sequence (e.g., DNA or RNA). In some embodiments, the base editor is capable of deaminating a base in a nucleic acid. In some embodiments, the base editor is capable of deaminating a base in a DNA molecule. In some embodiments, the base editor is capable of deaminating adenine (A) in DNA. In some embodiments, the deaminase is a cytosine deaminase or a cytidine deaminase. In some embodiments, the base editor is a fusion protein comprising a nucleic acid programmable DNA binding protein (napDNAbp) fused to an adenosine deaminase. In some embodiments, the base editor is a Cas9 protein fused to an adenosine deaminase. In some embodiments, the base editor is a Cas9 nickase (nCas9) fused to an adenosine deaminase. In some embodiments, the base editor is a nuclease-inactive Cas9 (dCas9) fused to an adenosine deaminase. In some embodiments, the base editor is fused to an inhibitor of base excision repair (e.g., a UGI domain or a dISN domain). In some embodiments, the fusion protein comprises a Cas9 nickase fused to a deaminase and an inhibitor of base excision repair (e.g., a UGI domain or a dISN domain). The term "nucleic acid-programmed DNA-binding protein" or "napDNAbp" refers to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nucleic acid, that guides the napDNAbp to a specific nucleic acid sequence. For example, a Cas9 protein can associate with a guide RNA that guides the Cas9 protein to a specific DNA sequence that has complementarity to the guide RNA. In some embodiments, the napDNAbp is a Class 2 microbial CRISPR-Cas effector. In some embodiments, the napDNAbp is a Cas9 domain, e.g., a nuclease-active Cas9, a Cas9 nickase (nCas9), or a nuclease-inactive Cas9 (dCas9).Examples of nucleic acid-programmed DNA-binding proteins include, but are not limited to, Cas9 (e.g., dCas9 and nCas9), CasX, CasY, Cpf1, C2c1, C2c2, C2C3, and Argonaute. However, it should be understood that nucleic acid-programmed DNA-binding proteins can also include nucleic acid-programmed proteins that bind to RNA. For example, napDNAbp can associate with a nucleic acid that guides the napDNAbp to RNA. Other nucleic acid-programmed DNA-binding proteins are also within the scope of this disclosure, although they may not be specifically listed in this disclosure.

[0284] F. Modified RNA In certain embodiments, the disclosed compositions, preparations, nanoparticles, and / or nanomaterials comprise modified nucleic acids, including modified RNA.

[0285] Modified nucleosides or nucleotides can be present in an RNA, such as a gRNA or mRNA. For example, a gRNA or mRNA that includes one or more modified nucleosides or nucleotides is referred to as a "modified" RNA, accounting for the presence of one or more non-natural and / or naturally occurring components or arrangements used in place of or in addition to the standard A, G, C, and U residues. In some embodiments, the modified RNA is synthesized with non-standard nucleosides or nucleotides and is referred to herein as "modified."

[0286] Modified nucleosides and nucleotides can include one or more of: (i) alteration, e.g., replacement, of one or both of one or more of the unlinked and / or linked phosphate oxygens in the phosphodiester backbone linkages (exemplary backbone modifications); (ii) alteration, e.g., replacement, of a component of the ribose sugar, e.g., the 2' hydroxyl on the ribose sugar (exemplary sugar modifications); (iii) wholesale replacement of a phosphate moiety with a "dephospho" linker (exemplary backbone modifications); (iv) modification or replacement of a naturally occurring nucleobase, including a non-canonical nucleobase (exemplary base modifications); (v) replacement or modification of the ribose-phosphate backbone (exemplary backbone modifications); (vi) modification of the 3' or 5' end of the oligonucleotide, e.g., removal, modification, or replacement of a terminal phosphate group or conjugation of a moiety, cap, or linker (such 3' or 5' cap modifications can include sugar and / or backbone modifications); and (vii) modification or replacement of a sugar (exemplary sugar modifications). Certain embodiments include 5'-end modifications to the mRNA, gRNA, or nucleic acid. Certain embodiments include 3'-end modifications to the mRNA, gRNA, or nucleic acid. The modified RNA may contain 5'-end and 3'-end modifications. The modified RNA may contain one or more modified residues at non-terminal positions. In certain embodiments, the gRNA includes at least one modified residue. In certain embodiments, the mRNA includes at least one modified residue.

[0287] Unmodified nucleic acids may be susceptible to degradation, for example, by intracellular nucleases or those found in serum. For example, nucleases can hydrolyze phosphodiester bonds of nucleic acids. Thus, in one aspect, RNAs (e.g., mRNAs, gRNAs) described herein may contain one or more modified nucleosides or nucleotides, for example, to introduce stability against intracellular or serum-based nucleases. In some embodiments, modified gRNA molecules described herein may exhibit a reduced innate immune response when introduced into a cell population, both in vivo and ex vivo. The term "innate immune response" includes cellular responses to exogenous nucleic acids, including single-stranded nucleic acids, including induction of cytokine (particularly interferon) expression and release and cell death.

[0288] Thus, in some embodiments, the RNA or nucleic acid in the compositions, preparations, nanoparticles, and / or nanomaterials of the present disclosure comprises at least one modification that confers increased or enhanced stability to the nucleic acid, including, for example, improved resistance to nuclease digestion in vivo. As used herein, the terms "modification" and "modified," when such terms relate to the nucleic acids provided herein, preferably include at least one alteration that enhances stability and makes the RNA or nucleic acid more stable (e.g., resistant to nuclease digestion) than a wild-type or naturally occurring version of the RNA or nucleic acid. As used herein, the terms "stable" and "stability," when such terms relate to the nucleic acids of the present invention, particularly with respect to RNA, refer to, for example, increased or enhanced resistance to degradation by nucleases (i.e., endonucleases or exonucleases) that would normally degrade such RNA. Increased stability can include, for example, reduced susceptibility to hydrolysis or other destruction by endogenous enzymes (e.g., endonucleases or exonucleases) or conditions within target cells or tissues, thereby increasing or enhancing the presence of such RNA in the target cells, tissues, subjects, and / or cytoplasm. The stabilized RNA molecules provided herein exhibit a longer half-life compared to their naturally occurring, unmodified counterparts (e.g., wild-type versions of mRNA). Also contemplated by the terms "modification" and "modified," when such terms relate to the mRNA of the LNP compositions disclosed herein, are modifications that improve or enhance translation of the mRNA nucleic acid, including, for example, the inclusion of a sequence that functions in the initiation of protein translation (e.g., a Kozac consensus sequence). (Kozak, M., Nucleic Acids Res 15(20):8125-48 (1987)), the entire contents of which are incorporated herein by reference.)

[0289] In some embodiments, the RNA or nucleic acid of the compositions, preparations, nanoparticles, and / or nanomaterials disclosed herein is chemically or biologically modified to make it more stable. Exemplary modifications to RNA include base depletion (e.g., by deletion or by substituting one nucleotide for another) or base modification, e.g., chemical modification of the base. As used herein, the phrase "chemical modification" includes modifications that introduce chemical properties different from those found in naturally occurring RNA, e.g., covalent modifications such as the introduction of modified nucleotides (e.g., nucleotide analogs or pendant groups not naturally found in such RNA molecules).

[0290] In some backbone modifications, the phosphate group of the modified residue may be modified by replacing one or more oxygens with different substituents. Furthermore, modified residues, such as those present in modified nucleic acids, may include extensive replacement of unmodified phosphate moieties with modified phosphate groups, as described herein. In some embodiments, backbone modifications of the phosphate backbone may include modifications that result in either uncharged linkers or charged linkers with asymmetric charge distribution. Examples of modified phosphate groups include phosphorothioates, phosphoroselenates, boranophosphates, boranophosphate esters, hydrogen phosphonates, phosphoramidates, alkyl or aryl phosphonates, and phosphotriesters. The phosphate atom in an unmodified phosphate group is achiral. However, replacing one of the non-bridging oxygens with one of the atoms or groups of atoms described above can make the phosphorus atom chiral. The stereogenic phosphorus atom may have either the "R" configuration (referred to herein as Rp) or the "S" configuration (referred to herein as Sp). The backbone can also be modified by replacing bridging oxygens (i.e., oxygens linking the phosphate to the nucleoside) with nitrogen (bridging phosphoramidates), sulfur (bridging phosphorothioates), and carbon (bridging methylene phosphonates). Replacement can occur at either bridging oxygen or both bridging oxygens. The phosphate group can be replaced by a non-phosphorus-containing linking group in some backbone modifications. In some embodiments, the charged phosphate group can be replaced by a neutral moiety. Examples of moieties that can replace the phosphate group can include, but are not limited to, for example, methylphosphonate, hydroxylamino, siloxane, carbonate, carboxymethyl, carbamate, amide, thioether, ethylene oxide linker, sulfonate, sulfonamide, thioformacetal, formacetal, oxime, methyleneimino, methylenemethylimino, methylenehydrazo, methylenedimethylhydrazo, methyleneoxymethylimino.

[0291] G. mRNA In some embodiments, the compositions, preparations, nanoparticles, and / or nanomaterials of the present disclosure comprise an mRNA comprising an open reading frame (ORF) encoding an RNA-guided DNA-binding agent, such as a Cas nuclease or Class 2 Cas nuclease, described herein. In some embodiments, an mRNA comprising an ORF encoding an RNA-guided DNA-binding agent, such as a Cas nuclease or Class 2 Cas nuclease, is provided, used, or administered. The mRNA may comprise one or more of a 5' cap, a 5' untranslated region (UTR), a 3' UTR, and a polyadenine tail. The mRNA may comprise an open reading frame modified, for example, to encode a nuclear localization sequence or to use alternative codons to encode a protein.

[0292] The mRNA in the disclosed compositions, preparations, nanoparticles, and / or nanomaterials can encode, for example, a normally secreted hormone, enzyme, receptor, polypeptide, peptide, or other protein of interest. In one embodiment of the present invention, the mRNA can optionally have chemical or biological modifications that, for example, improve the stability and / or half-life of such mRNA or improve or enhance protein production.

[0293] Additionally, suitable modifications include alterations in one or more nucleotides of a codon such that the codon encodes the same amino acid but is more stable than the codon found in the wild-type version of the mRNA. For example, an inverse relationship between RNA stability and a higher number of cytidine (C) and / or uridine (U) residues has been demonstrated, with RNA lacking C and U residues being found to be stable against most RNases (Heidenreich, et al. J Biol Chem 269, 2131-8 (1994), the entire disclosure of which is incorporated herein by reference). In some embodiments, the number of C and / or U residues in an mRNA sequence is reduced. In other embodiments, the number of C and / or U residues is reduced by substituting one codon encoding a particular amino acid with another codon encoding the same or a related amino acid. Contemplated modifications of the mRNA nucleic acids of the present invention also include the incorporation of pseudouridine. The incorporation of pseudouridine into the mRNA nucleic acids of the present invention can enhance stability and translation ability, as well as reduce immunogenicity in vivo. See, for example, Kariko, K., et al., Molecular Therapy 16(11):1833-1840 (2008), the entire contents of which are incorporated herein by reference. Substitutions and modifications to the mRNA of the present invention can be made by methods readily known to those skilled in the art.

[0294] Constraints on reducing the number of C and U residues in a sequence will likely be greater in the coding region of an mRNA compared to untranslated regions (i.e., it will likely not be possible to eliminate all of the C and U residues present in a message while still retaining the capacity of the message to enc...

Claims

1. Compound of formula I': 【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 ３ is absent or optionally substituted C １－１０ Alkylenyl, or optionally substituted C ２－１０ heteroalkylenyl, X is absent, —OC(O)—, —C(O)O—, or —OC(O)O—; Each R' is independently C ４－１２ 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 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 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 -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 Together with the atom it bonds to, ２ two occurrences 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 Together with the atom it bonds to, ３ two occurrences 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 Together with the atom it bonds to, ５ two occurrences 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. The compound is a compound of formula I-a, I-b, I-c, I-e, I-ei, I-e-ii, or I-e-iii: 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, according to claim 1:

3. L １ But, C １－５ alkylenyl, in particular L 1 is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —; and / or each L 2 is independently C 5-10 alkylenyl or C 5-10 heteroalkylenyl, particularly each L 2 is independently C 5-10 alkylenyl, particularly 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 -, or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -; and / or L 3 is absent, L 3 is C 2-4 alkylenyl, or -L 3 -R is 【Chemistry 15】 Selected from the group consisting of:

3. A compound according to claim 1 or 2.

4. Each R' is independently an optionally substituted C ４－１２ Alkyl, optionally substituted C ４－１２ alkenyl, or optionally substituted C ４－１２ alkynyl, and each R′ is independently an optionally substituted C ４－１２ When alkyl, X is -OC(O)O-; Specifically, each R' is independently C 4-12 alkenyl, C 4-12 alkynyl, or C 4-12 haloaliphatic; In particular, each R′ is 【Chemistry 12】 3. The compound of claim 1 or 2, independently selected from the group consisting of:

5. each 【Chemistry 13】 but, 【Chemistry 14】 3. The compound of claim 1 or 2, independently selected from the group consisting of:

6. R is hydrogen; or C ６－２０ 3. The compound of claim 1 or 2, wherein R is an optionally substituted group selected from aliphatic, 3-7 membered alicyclic, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl, in particular, R is an optionally substituted group selected from C 6-20 aliphatic and 1-adamantyl.

7. R １ is an optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ２ , or -CR ２ (R ３ ) ２ or R 1 is -OR 2 ; -CR 2 (R 3 ) 2 ; or 3-7 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heterocyclyl ring being optionally substituted with 1 to 4 R 2 or R 3 groups, especially R 1 is -OR 2 , CR 2 (R 3 ) 2 , 【Chemistry 16】 or R 1 is 【Chemistry 17】 Selected from the group consisting of:

3. A compound according to claim 1 or 2.

8. Each R ２ are independently hydrogen, oxo, or -(CH ２ ) ｎ -R ４ and In particular, each R 4 is independently —OR 5 ; In particular, a compound according to claim 1 or 2, wherein each R 5 is hydrogen.

9. The compound is 【Chemistry 18】 【change】 【change】 【change】 【change】 2. The compound of claim 1, selected from:

10. A lipid nanoparticle (LNP) preparation comprising a compound according to any one of claims 1, 2 and 9.

11. A phospholipid, Cholesterol and The LNP preparation of claim 10, further comprising a conjugate-linker lipid (e.g., a polyethylene glycol lipid).

12. further comprising 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 are or comprise RNA or DNA, In particular, the LNP preparation is formulated to deliver the therapeutic and / or prophylactic agent to target cells; In particular, 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 heart cell, or a cell in the central nervous system, In particular, the target cells are or comprise hematopoietic stem cells (HSCs), The LNP preparation of claim 10.

13. A pharmaceutical composition comprising the LNP preparation of claim 10 and a pharma- ceutically acceptable excipient.

14. The pharmaceutical composition of claim 13 for use in a method, the method comprising: 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 13, in particular a method for treating a disease or disorder in a subject in need thereof, or a method for slowing and / or halting the progression of a disease or disorder in a subject in need thereof, wherein said therapeutic and / or prophylactic agent is effective in treating said disease, or A method of producing a polypeptide of interest in a mammalian cell, comprising contacting said cell with the pharmaceutical composition of claim 13, 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, comprising contacting said cell with the pharmaceutical composition of claim 13, 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 A method for specifically delivering a therapeutic and / or prophylactic agent to a mammalian organ, comprising contacting said mammalian organ with the pharmaceutical composition of claim 13, whereby said therapeutic and / or prophylactic agent is delivered to said organ, in particular comprising administering to said subject the pharmaceutical composition of claim 13; or A method of vaccination by administering a pharmaceutical composition according to claim 13, or 1. A method for inducing an adaptive immune response in a subject, comprising administering to the subject an effective amount of said composition comprising at least one RNA.

23. The pharmaceutical composition according to claim 22,

15. A method for delivering a therapeutic and / or prophylactic agent to a mammalian cell derived from a subject, comprising contacting the cell of the subject that has been administered the LNP preparation of claim 10 or the pharmaceutical composition of claim 13.

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