Ionizable lipids and lipid nanoparticle compositions for delivery of nucleic acids

Abstract

Disclosed herein are novel lipids that can be used in combination with other lipid components to form lipid nanoparticles for delivery of nucleic acid cargo. Also provided herein are pharmaceutical compositions comprising the novel lipid, or lipid nanoparticles comprising said novel lipids.

Description

[0001] Attorney Docket No.41543-59274 (002WO) IONIZABLE LIPIDS AND LIPID NANOPARTICLE COMPOSITIONS FOR DELIVERY OF NUCLEIC ACIDS BACKGROUND [1] The effective targeted delivery of nucleic acids represents a continuing medical challenge. In particular, the delivery of nucleic acids to cells is made difficult by their relative instability and low cell permeability. [2] Lipid-containing nanoparticles (lipid nanoparticles or LNPs), liposomes, and lipoplexes have proven effective as transport vehicles into cells and / or intracellular compartments for nucleic acids. LNPs typically contain four or more components, e.g., ionizable lipid(s), cationic lipid(s), helper lipid(s), structural lipid(s), and conjugated lipid(s) (also known as PEGylated lipids), among which the ionizable lipid plays a major role in protecting RNAs and facilitating their cytosolic transport. Ionizable lipids are positively charged at acidic pH to condense RNAs into LNPs but are neutral at physiological pH to minimize toxicity. They can be protonated in the acidic endosome after cellular uptake and interact with anionic endosomal phospholipids to form cone-shaped ion pairs that are not compatible with a bilayer. These cationic-anionic lipid pairs drive the transition from the bilayer structure to the inverted hexagonal HIIphase, which facilitates membrane fusion / disruption, endosomal escape and cargo release into the cytosol. [3] Though a variety of such LNPs have been demonstrated, improvements in safety, efficacy, and specificity are still lacking. There remains a need in the art for improved therapeutic nucleic acid compositions that are suitable for general therapeutic use. Preferably, these compositions would encapsulate nucleic acids with high efficiency, have high drug:lipid ratios, protect the encapsulated nucleic acid from degradation and clearance in serum, be suitable for systemic delivery, and provide intracellular delivery of the encapsulated nucleic acid. In addition, these LNPs should be well- tolerated and provide an adequate therapeutic index, such that patient treatment at an effective dose of the nucleic acid is not associated with significant toxicity and / or risk to the patient. The present disclosure provides such compositions and methods of using the compositions to introduce nucleic acids into cells, including for the treatment of diseases. SUMMARY [4] The present disclosure provides ionizable lipids and related LNPs, compositions, and methods. The LNPs can be used to encapsulate therapeutic nucleic acid cargo. Pharmaceutical compositions comprising such LNPs are also provided. [5] In one aspect, ionizable lipids are provided herein, wherein the ionizable lipid is a compound of formula (I): Attorney Docket No.41543-59274 (002WO) (I) wherein: X is selected from -CH2-, -C(O)-, Y is selected from C1-C6alkylene and C1-C6heteroalkylene; R1is selected from -(CH2)nOC(O)Z1and -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl or C6-C20alkenyl, and n is an integer from 1-10; R2is selected from -(CH2)mOC(O)Z2, -(CH2)mC(O)OZ2, and C10-C20alkyl, wherein Z2is C6-C20alkyl or C6-C20alkenyl, and m is an integer from 0-10; R3is selected from H and C1-C6alkyl; R4is selected from H and OH; R5is C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -OR’, -SH, -SR’, -SCOR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, NR’COR’, -CO2H, -CO2R’, -COR’, -CONH2, - CONHR’, -CON(R’)2, -COSH, -COSR’, wherein R’ is C1-6alkyl or C3-10cycloalkyl; R6is C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -OR’, -SH, -SR’, -SCOR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, NR’COR’, -CO2H, -CO2R’, -COR’, -CONH2, - CONHR’, -CON(R’)2, -COSH, -COSR’, wherein R’ is C1-6alkyl or C3-10cycloalkyl; or R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl; or is a pharmaceutically acceptable salt thereof. [6] In another aspect, the present disclosure provides a LNP comprising one or more compounds of formula I and, optionally, one or more additional ionizable lipid, one or more cationic lipid, one or more structural lipid, one or more conjugated lipid, and one or more helper lipid. The LNP encapsulates nucleic acid cargo (i.e., polynucleotides). Nucleic acid compositions of any structure may be included in the LNPs, e.g., a mRNA, a siRNA, a shRNA, a guide RNA (gRNA), a microRNA (miRNA), or a circular RNA (circRNA). [7] In another aspect, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising one or more compounds of formula I and one or more pharmaceutically acceptable excipients. [8] In another aspect, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a plurality of LNPs and one or more pharmaceutically acceptable excipients, wherein each LNP comprises one or more compounds of formula I. In some embodiments, the pharmaceutical composition is administered parenterally (e.g., subcutaneous, intravenous, intraarterial, Attorney Docket No.41543-59274 (002WO) intramuscular, intradermal, intraperitoneal, intrathecal, or intraocular). In some embodiments, the pharmaceutical composition is administered by inhalation (e.g., intranasal, by nebulization or aerosolization). DETAILED DESCRIPTION 1. DEFINITIONS [9] When describing the embodiments of the present disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated

[0010] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further Attorney Docket No.41543-59274 (002WO) understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0011] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0012] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub- ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0013] As used herein, the term “alkyl” refers to both straight and branched chain C1-C30hydrocarbons and includes both saturated and unsaturated hydrocarbons. The use of designations such as, for example, “C1-C20” is intended to refer to an alkyl (e.g., straight or branched chain and inclusive of alkenes and alkyls) having the recited range carbon atoms. In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–C10alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–C9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–C8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–C7alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–C6alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–C5alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–C4alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1– C3alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1–6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Attorney Docket No.41543-59274 (002WO)

[0014] As used herein, the term “alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2–C20alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–C10alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–C9alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–C8alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–C7alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–C6alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–C5alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–C4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–C3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon–carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1– butenyl). Examples of C2–4alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0015] As used herein, the terms “alkylene” and “alkenylene” refer to a divalent radical of an alkyl or alkenyl group, respectively. When a range or number of carbons is provided for a particular “alkylene” or “alkenylene”, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene” and “alkenylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.

[0016] As used herein, the terms “effective amount,” “pharmaceutically effective amount,” or “therapeutically effective amount” as used herein mean a sufficient amount of the composition to provide the desired utility when administered to a subject having a particular condition. The term “therapeutically effective amount” therefore refers to an amount of therapeutic cells or a composition having therapeutic cells that is sufficient to promote a particular effect when administered to a subject in need of treatment. An effective amount would also include an amount sufficient to prevent or delay the development of a symptom of the disease, alter the course of a symptom of the disease (for example but not limited to, slow the progression of a symptom of the disease), or reverse a symptom of the disease. It is understood that for any given case, an appropriate “effective amount” can be determined by one of ordinary skill in the art using routine experimentation.

[0017] As used herein, the term “heteroalkyl” refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be Attorney Docket No.41543-59274 (002WO) oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, - CH2-CH2, -S(O)2, -S(O)-CH3, -S(O)2-CH2,-CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2- CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as –CH2O, –NRBRC, or the like, it will be understood that the terms heteroalkyl and –CH2O or –NRBRCare not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH2O, –NRBRC, or the like.

[0018] As used herein, the term “heteroalkylene” refers to a divalent radical of a heteroalkyl group.

[0019] As used herein, the term “heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” may be used interchangeably. Heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperizynyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0020] As used herein, the phrase “ionizable lipid” refers to any of a number of lipid species that carry a net positive charge at a selected pH level, such as pH 4, and a neutral charge at other pH levels, such as pH 7. Attorney Docket No.41543-59274 (002WO)

[0021] As used herein, the term “loaded” or “encapsulated” with respect to a polynucleotide in a LNP refers to the polynucleotide’s incorporation into the LNP. The process of LNP incorporation is known and described in, e.g., Lasic, et al., FEBS Lett., 312: 255-258, 1992). The polynucleotide may be completely or partially located in the interior space of the LNP, within a bilayer membrane of the LNP, or associated with the exterior surface of the LNP.

[0022] As used herein, the term “lipid nanoparticle” refers to a transfer vehicle comprising one or more lipids (e.g., in certain embodiments, ionizable lipid, cationic lipids, helper lipids, structural lipids, and conjugated lipids).

[0023] As used herein, the term “nucleic acid” and “polynucleotide” are used interchangeably herein to describe a polymer of any length, e.g., greater than 2 bases, greater than 10 bases, greater than 100 bases, greater than 500 bases, greater than 1000 bases, or up to 10,000 or more bases, composed of nucleotides, e.g., deoxyribonucleotides or ribonucleotides, and may be produced enzymatically or synthetically (e.g., as described in U.S. Pat. No.5,948,902 and the references cited therein), which can hybridize with naturally occurring nucleic acids in a sequence specific manner analogous to that of two naturally occurring nucleic acids, e.g., can participate in Watson-Crick base pairing interactions. Naturally occurring nucleic acids are comprised of nucleotides including guanine, cytosine, adenine, thymine, and uracil (G, C, A, T, and U respectively).

[0024] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p– toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived Attorney Docket No.41543-59274 (002WO) from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, as mean a polymer composed of deoxyribonucleotides.

[0026] As used herein, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a hydrogen attached to a carbon or nitrogen atom of a group) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0027] Compounds described herein may also comprise one or more isotopic substitutions. For ; C the range. For example, “C1–C6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–C6, C1–C5, C1–C4, C1–C3, C1–C2, C2–C6, C2–C5, C2–C4, C2–C3, C3–C6, C3–C5, C3–C4, C4–C6, C4–C5, and C5–C6alkyl.

[0029] In typical embodiments, the present disclosure is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In certain embodiments, the present disclosure includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a solvate (e.g., hydrate) of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein.

[0030] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in Attorney Docket No.41543-59274 (002WO) one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. 2. IONIZABLE LIPIDS

[0031] In one aspect, the present disclosure provides compounds that are ionizable lipids. The lipid compounds are typically employed in the LNP to encapsulate nucleic acid cargo, e.g., mRNA.

[0032] The present disclosure provides a compound, wherein the compound is of formula I: (I) wherein: X is selected from -CH2-, -C(O)-, - ; Y is selected from C1-C6alkylene and C1-C6heteroalkylene; R1is selected from -(CH2)nOC(O)Z1and -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl or C6-C20alkenyl, and n is an integer from 1-10; R2is selected from -(CH2)mOC(O)Z2, -(CH2)mC(O)OZ2, and C10-C20alkyl, wherein Z2is C6-C20alkyl or C6-C20alkenyl, and m is an integer from 0-10; R3is selected from H and C1-C6alkyl; R4is selected from H and OH; R5is C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -OR’, -SH, -SR’, -SCOR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, NR’COR’, -CO2H, -CO2R’, -COR’, -CONH2, - CONHR’, -CON(R’)2, -COSH, -COSR’, wherein R’ is C1-6alkyl or C3-10cycloalkyl; R6is C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -OR’, -SH, -SR’, -SCOR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, NR’COR’, -CO2H, -CO2R’, -COR’, -CONH2, - CONHR’, -CON(R’)2, -COSH, -COSR’, wherein R’ is C1-6alkyl or C3-10cycloalkyl; or R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl; or is a pharmaceutically acceptable salt thereof. Attorney Docket No.41543-59274 (002WO)

[0033] In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl.

[0034] In certain embodiments of formula I, R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl.

[0035] In certain embodiments of formula I, R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkyl.

[0036] In certain embodiments of formula I, R2is C10-C20 alkyl.

[0037] In certain embodiments of formula I, R4is OH.

[0038] In certain embodiments of formula I, R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20 alkenyl.

[0039] In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl.

[0040] In certain embodiments of formula I, R2is C10-C20 alkyl and R4is H.

[0041] In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1.

[0042] In certain embodiments of formula I, R2is -(CH2)mC(O)OZ2.

[0043] In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; and R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl. In certain embodiments of formula I, R1is - (CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is H; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is H; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is C1-C6alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is C1-C6alkyl; and R4is OH.

[0044] In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; and R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkyl. In certain embodiments of formula I, R1is - (CH2)nOC(O)Z1, wherein Z1is C6-C20 alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20 alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkyl; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkyl; R3is H; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkyl; R3is H; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20 alkyl; R3is C1-C6 alkyl; and R4is H. In certain embodiments of formula I, R1is - Attorney Docket No.41543-59274 (002WO) (CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkyl; R3is C1-C6alkyl; and R4is OH.

[0045] In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; and R2is C10-C20alkyl. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6- C20alkenyl; R2is C10-C20alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is C10-C20alkyl; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is C10-C20alkyl; R3is H; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is C10-C20alkyl; R3is H; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is C10-C20alkyl; R3is C1-C6alkyl; and R4is H. In certain embodiments of formula I, R1is - (CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is C10-C20alkyl; R3is C1-C6alkyl; and R4is OH.

[0046] In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; and R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl. In certain embodiments of formula I, R1is - (CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl; R3is H; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl; R3is H; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl; R3is C1-C6alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl; R3is C1-C6alkyl; and R4is OH.

[0047] In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20 alkyl; and R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl. In certain embodiments of formula I, R1is - (CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is H; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20 alkenyl; R3is H; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is C1-C6alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is C1-C6alkyl; and R4is OH. Attorney Docket No.41543-59274 (002WO)

[0048] In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; and R2is C10-C20alkyl. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is C10-C20alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is C10-C20alkyl; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is C10-C20alkyl; R3is H; and R4is H. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is C10-C20alkyl; R3is H; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is C10-C20alkyl; R3is C1-C6alkyl; and R4is H. In certain embodiments of formula I, R1is - (CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl; R2is C10-C20alkyl; R3is C1-C6alkyl; and R4is OH.

[0049] In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkenyl; and R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl. In certain embodiments of formula I, R1is - (CH2)nC(O)OZ1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is H; and R4is H. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is H; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is C1-C6alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkenyl; R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; R3is C1-C6alkyl; and R4is OH.

[0050] In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl; and R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkyl. In certain embodiments of formula I, R1is - (CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl; R2is - (CH2)mC(O)OZ2, wherein Z2is C6-C20alkyl; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkyl; R3is H; and R4is H. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkyl; R3is H; and R4is OH. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6- C20alkyl; R3is C1-C6alkyl; and R4is H. In certain embodiments of formula I, R1is -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl; R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkyl; R3is C1-C6alkyl; and R4is OH.

[0051] In certain embodiments of formula I, R5is C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -OR’, -SH, -SR’, -NH2, -NHR’, and -N(R’)2, wherein R’ is C1-6alkyl Attorney Docket No.41543-59274 (002WO) or C3-10cycloalkyl. In certain embodiments of formula I, R5is C1-C6alkyl, optionally substituted with -OH.

[0052] In certain embodiments of formula I, R6is C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -OR’, -SH, -SR’, -NH2, -NHR’, and -N(R’)2, wherein R’ is C1-6alkyl or C3-10cycloalkyl. In certain embodiments of formula I, R6is C1-C6alkyl, optionally substituted with -OH.

[0053] In certain embodiments of formula I, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH. In certain embodiments of formula I, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with optionally substituted C1-C6alkyl. In certain embodiments of formula I, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with optionally substituted C1-C6heteroalkyl. In certain embodiments of formula I, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0054] In certain embodiments of formula I, X is -C(O)-, and Y is C1-C6alkylene. In certain embodiments of formula I, X is -C(O)-, and Y is C1-C3alkylene. In certain embodiments of formula I, X is -C(O)-, and Y is C1-C2alkylene.

[0055] In certain embodiments of formula I, -NH-X-Y-NR5R6, thereby providing a compound of formula I-1: 1) wherein o is an integer from 1

[0056] In certain embodiments of formula I-1, o is an integer from 1 to 4. In certain embodiments of formula I-1, o is an integer from 1 to 3. In certain embodiments of formula I-1, o is an integer selected from 1 and 2. In certain embodiments of formula I-1, o is 1. In certain embodiments of formula I-1, o is 2. In certain embodiments of formula I-1, o is 3. In certain embodiments, of formula I-1 o is 4. In certain embodiments of formula I-1, o is 5.

[0057] In certain embodiments of formula I-1, R5and R6are each C1-C6alkyl. In certain embodiments of formula I-1, R5and R6are methyl. In certain embodiments of formula I-1, R5is C1-C6 Attorney Docket No.41543-59274 (002WO) alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula I-1, R5is methyl and R6is -CH2CH2OH.

[0058] In certain embodiments of formula I-1, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula I-1, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0059] In certain embodiments of , thereby providing a compound of formula I-2: 2) wherein o is an integer from 1 S, and NR9, wherein R9is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0060] In certain embodiments of formula I-2, o is an integer from 1 to 4. In certain embodiments of formula I-2, o is an integer from 1 to 3. In certain embodiments of formula I-2, o is an integer selected from 1 and 2. In certain embodiments of formula I-2, o is 1. In certain embodiments of formula I-2, o is 2. In certain embodiments of formula I-2, o is 3. In certain embodiments of formula I-2, o is 4. In certain embodiments of formula I-2, o is 5.

[0061] In certain embodiments of formula I-2, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula I-2, A is CHR9, wherein R9is OH. In certain embodiments of formula I-2, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula I-2, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula I-2, A is CHR9, wherein R9is -CH2CH2OH.

[0062] In certain embodiments of formula I-2, A is S.

[0063] In certain embodiments of formula I-2, A is O.

[0064] In certain embodiments of formula I-2, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and Attorney Docket No.41543-59274 (002WO) certain embodiments of formula I-2, A is NR9, wherein R9is C1-C6alkyl (e.g., of formula I-2, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain I-2, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula I-2, A is NR9, wherein R9. In certain embodiments of formula I-2, A is NR9, .

[0065] In certain embodiments of , thereby providing a compound of formula I- 3) wherein o is an integer from selected from H, OH, and hydroxy-C1-C6alkyl.

[0066] In certain embodiments of formula I-3, o is an integer from 1 to 4. In certain embodiments of formula I-3, o is an integer from 1 to 3. In certain embodiments of formula I-3, o is an integer selected from 1 and 2. In certain embodiments of formula I-3, o is 1. In certain embodiments of formula I-3, o is 2. In certain embodiments of formula I-3, o is 3. In certain embodiments of formula I-3, o is 4. In certain embodiments of formula I-3, o is 5.

[0067] In certain embodiments of formula I-3, R10and R11are each H. In certain embodiments of formula I-3, R10and R11are each OH. In certain embodiments of formula I-3, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula I-3, R10and R11are each -CH2OH. In certain embodiments of formula I-3, R10is H and R11is OH.

[0068] In certain embodiments of formula I, X is -C(O)-, and Y is C1-C6heteroalkylene. In certain embodiments of formula I, X is -C(O)-, and Y is C1-C3heteroalkylene. In certain embodiments of Attorney Docket No.41543-59274 (002WO) formula I, X is -C(O)-, and Y is C1-C2heteroalkylene. In certain embodiments, X is -C(O)- and Y is - CH2-S-(CH2)q-, wherein q is an integer from 1 to 4.

[0069] In certain embodiments of formula I, -NH-X-Y-NR5R6, thereby providing a compound of formula I-4: 4) wherein Q is selected from S

[0070] In certain embodiments of formula I-4, o is an integer from 1 to 3. In certain embodiments of formula I-4, o is an integer selected from 1 and 2. In certain embodiments of formula I-4, o is 1. In certain embodiments of formula I-4, o is 2. In certain embodiments of formula I-4, o is 3. In certain embodiments of formula I-4, o is 4.

[0071] In certain embodiments of formula I-4, Q is S and R5and R6are each C1-C6alkyl. In certain embodiments of formula I-4, Q is S and R5and R6are methyl. In certain embodiments of formula I-4, Q is S, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula I-4, Q is S, R5is methyl, and R6is -CH2CH2OH.

[0072] In certain embodiments of formula I-4, Q is O and R5and R6are each C1-C6alkyl. In certain embodiments of formula I-4, Q is O and R5and R6are methyl. In certain embodiments of formula I-4, Q is O, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula I-4, Q is O, R5is methyl, and R6is -CH2CH2OH.

[0073] In certain embodiments of formula I-4, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula I-4, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0074] In certain embodiments of formula I, -NH-X-Y-NR5R6, thereby providing a compound of formula I-5: Attorney Docket No.41543-59274 (002WO) 5) wherein o is an integer from is selected from CHR9, O, S, and NR9, wherein R9is selected alkyl, optionally substituted C1- C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0075] In certain embodiments of formula I-5, o is an integer from 1 to 3. In certain embodiments of formula I-5, o is an integer selected from 1 and 2. In certain embodiments of formula I-5, o is 1. In certain embodiments of formula I-5, o is 2. In certain embodiments of formula I-5, o is 3. In certain embodiments of formula I-5, o is 4.

[0076] In certain embodiments of formula I-5, Q is S and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula I-5, Q is S and A is CHR9, wherein R9is OH. In certain embodiments of formula I-5, Q is S and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula I-5, Q is S and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula I-5, Q is S and A is CHR9, wherein R9is - CH2CH2OH.

[0077] In certain embodiments of formula I-5, Q is S and A is S.

[0078] In certain embodiments of formula I-5, Q is S and A is O.

[0079] In certain embodiments of formula I-5, Q is S and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula I-5, Q is S and A is NR9, wherein R9is C1- In certain embodiments of formula I-5, Q is S and A is NR9, wherein R9is certain embodiments of formula I-5, Q is S and A is NR9, wherein R9is - In certain embodiments of formula I-5, Q is S and A is NR9, wherein R9is embodiments of formula I-5, Q is S and A is NR9, wherein R9is Attorney Docket No.41543-59274 (002WO)

[0080] In certain embodiments of formula I-5, Q is O and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula I-5, Q is O and A is CHR9, wherein R9is OH. In certain embodiments of formula I-5, Q is O and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula I-5, Q is O and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula I-5, Q is O and A is CHR9, wherein R9is - CH2CH2OH.

[0081] In certain embodiments of formula I-5, Q is O and A is S.

[0082] In certain embodiments of formula I-5, Q is O and A is O.

[0083] In certain embodiments of formula I-5, Q is O and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula I-5, Q is O and A is NR9, wherein R9is C1- In certain embodiments of formula I-5, Q is O and A is NR9, wherein R9is In certain embodiments of formula I-5, Q is O and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula I-5, Q is O and A is NR9, wherein R9is certain embodiments of formula I-5, Q is O and A is NR9, wherein R9is .

[0084] In certain embodiments of , thereby providing a compound of formula I- Attorney Docket No.41543-59274 (002WO) 6) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0085] In certain embodiments of formula I-6, o is an integer from 1 to 3. In certain embodiments of formula I-6, o is an integer selected from 1 and 2. In certain embodiments of formula I-6, o is 1. In certain embodiments of formula I-6, o is 2. In certain embodiments of formula I-6, o is 3. In certain embodiments of formula I-6, o is 4.

[0086] In certain embodiments of formula I-6, Q is S and R10and R11are each H. In certain embodiments of formula I-6, Q is S and R10and R11are each OH. In certain embodiments of formula I-6, Q is S and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula I-6, Q is S and R10and R11are each -CH2OH. In certain embodiments of formula I-6, Q is S, R10is H, and R11is OH.

[0087] In certain embodiments of formula I-6, Q is O and R10and R11are each H. In certain embodiments of formula I-6, Q is O and R10and R11are each OH. In certain embodiments of formula I-6, Q is O and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula I-6, Q is O and R10and R11are each -CH2OH. In certain embodiments of formula I-6, Q is O, R10is H, and R11is OH.

[0088] In certain embodiments of formula I, X is -C(O)S- and Y is C1-C6alkylene. In certain embodiments of formula I, X is -C(O)S- and Y is C1-C3alkylene. In certain embodiments of formula I, X is -C(O)S- and Y is C1-C2alkylene.

[0089] In certain embodiments of formula I, -NH-X-Y-NR5R6, thereby providing a compound of formula I-7: 7) wherein o is an integer from 1

[0090] In certain embodiments of formula I-7, o is an integer from 1 to 4. In certain embodiments of formula I-7, o is an integer from 1 to 3. In certain embodiments of formula I-7, o is an integer selected Attorney Docket No.41543-59274 (002WO) from 1 and 2. In certain embodiments of formula I-7, o is 1. In certain embodiments of formula I-7, o is 2. In certain embodiments of formula I-7, o is 3. In certain embodiments of formula I-7, o is 4. In certain embodiments of formula I-7, o is 5.

[0091] In certain embodiments of formula I-7, R5and R6are each C1-C6alkyl. In certain embodiments of formula I-7, R5and R6are methyl. In certain embodiments of formula I-7, R5is C1-C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula I-7, R5is methyl and R6is -CH2CH2OH.

[0092] In certain embodiments of formula I-7, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula I-7, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0093] In certain embodiments of , thereby providing a compound of formula I-8: 8) wherein o is an integer from 19 9 and NR , wherein R is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0094] In certain embodiments of formula I-8, o is an integer from 1 to 5. In certain embodiments of formula I-8, o is an integer from 1 to 3. In certain embodiments of formula I-8, o is an integer selected from 1 and 2. In certain embodiments of formula I-8, o is 1. In certain embodiments of formula I-8, o is 2. In certain embodiments of formula I-8, o is 3. In certain embodiments of formula I-8, o is 4. In certain embodiments of formula I-8, o is 5. In certain embodiments of formula I-8, o is 6.

[0095] In certain embodiments of formula I-8, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula I-8, A is CHR9, wherein R9is OH. In certain embodiments of formula I-8, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula I-8, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula I-8, A is CHR9, wherein R9is -CH2CH2OH.

[0096] In certain embodiments of formula I-8, A is S. Attorney Docket No.41543-59274 (002WO)

[0097] In certain embodiments of formula I-8, A is O.

[0098] In certain embodiments of formula I-8, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula I-8, A is NR9, wherein R9is C1-C6alkyl (e.g., of formula I-8, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain I-8, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula I-8, A is NR9, wherein R9. In certain embodiments of formula I-8, A is NR9, .

[0099] In certain embodiments of , thereby providing a compound of formula I- 9) wherein o is an integer from selected from H, OH, and hydroxy-C1-C6alkyl.

[0100] In certain embodiments of formula I-9, o is an integer from 1 to 5. In certain embodiments of formula I-9, o is an integer from 1 to 3. In certain embodiments of formula I-9, o is an integer selected from 1 and 2. In certain embodiments of formula I-9, o is 1. In certain embodiments of formula I-9, o is 2. In certain embodiments of formula I-9, o is 3. In certain embodiments of formula I-9, o is 4. In certain embodiments of formula I-9, o is 5. In certain embodiments of formula I-9, o is 6.

[0101] In certain embodiments of formula I-9, R10and R11are each H. In certain embodiments of formula I-9, R10and R11are each OH. In certain embodiments of formula I-9, R10and R11are each Attorney Docket No.41543-59274 (002WO) hydroxy-C1-C6alkyl. In certain embodiments of formula I-9, R10and R11are each -CH2OH. In certain embodiments of formula I-9, R10is H, and R11is OH.

[0102] In certain embodiments of formula I, X is -CH2- and Y is C1-C6alkylene. In certain embodiments of formula I, X is -CH2- and Y is C1-C3alkylene. In certain embodiments of formula I, X is -CH2- and Y is C1-C2alkylene.

[0103] In certain embodiments of formula I, -NH-X-Y-NR5R6is , thereby providing a compound of formula I-10: wherein o is an integer from 1

[0104] In certain embodiments of formula I-10, o is an integer from 1 to 4. In certain embodiments of formula I-10, o is an integer from 1 to 3. In certain embodiments of formula I-10, o is an integer selected from 1 and 2. In certain embodiments of formula I-10, o is 1. In certain embodiments of formula I-10, o is 2. In certain embodiments of formula I-10, o is 3. In certain embodiments of formula I-10, o is 4. In certain embodiments of formula I-10, o is 5.

[0105] In certain embodiments of formula I-10, R5and R6are each C1-C6alkyl. In certain embodiments of formula I-10, R5and R6are methyl. In certain embodiments of formula I-10, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula I-10, R5is methyl, and R6is -CH2CH2OH.

[0106] In certain embodiments of formula I-10, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula I-10, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0107] In certain embodiments of formula I, -NH-X-Y-NR5R6, thereby providing a compound of formula I-11: Attorney Docket No.41543-59274 (002WO) wherein o is an integer from 1 S, and NR9, wherein R9is selected from H, OH, optionally C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0108] In certain embodiments of formula I-11, o is an integer from 1 to 4. In certain embodiments of formula I-11, o is an integer from 1 to 3. In certain embodiments of formula I-11, o is an integer selected from 1 and 2. In certain embodiments of formula I-11, o is 1. In certain embodiments of formula I-11, o is 2. In certain embodiments of formula I-11, o is 3. In certain embodiments of formula I-11, o is 4. In certain embodiments of formula I-11, o is 5.

[0109] In certain embodiments of formula I-11, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula I-11, A is CHR9, wherein R9is OH. In certain embodiments of formula I-11, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula I-11, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula I-11, A is CHR9, wherein R9is -CH2CH2OH.

[0110] In certain embodiments of formula I-11, A is S.

[0111] In certain embodiments of formula I-11, A is O.

[0112] In certain embodiments of formula I-11, A is NR9, wherein R9is selected from C1-C6alkyl , and certain embodiments of formula I-11, A is NR9, wherein R9is C1-C6alkyl embodiments of formula I-11, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula I-11, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula I-11, A is NR9, wherein R9. In certain embodiments of formula I-11, A is NR9, . Attorney Docket No.41543-59274 (002WO)

[0113] In certain embodiments of , thereby providing a compound of formula I- R1R3R2N wherein o is an integer I, and R10and R11are each independently selected from H,

[0114] In certain embodiments of formula I-12, o is an integer from 1 to 4. In certain embodiments of formula I-12, o is an integer from 1 to 3. In certain embodiments of formula I-12, o is an integer selected from 1 and 2. In certain embodiments of formula I-12, o is 1. In certain embodiments of formula I-12, o is 2. In certain embodiments of formula I-12, o is 3. In certain embodiments of formula I-12, o is 4. In certain embodiments of formula I-12, o is 5.

[0115] In certain embodiments of formula I-12, R10and R11are each H. In certain embodiments of formula I-12, R10and R11are each OH. In certain embodiments of formula I-12, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula I-12, R10and R11are each -CH2OH. In certain embodiments of formula I-12, R10is H, and R11is OH.

[0116] In certain embodiments of formula I, R1is –(CH2)nOC(O)Z1, R2is -(CH2)mOC(O)Z2, R3is H, and R4is H, thereby providing a compound of formula Ia: or a pharmaceutically Z1and Z2are each C6-C20 alkenyl; n is an integer from 1 to 10; and m is an integer from 1 to 10.

[0117] In certain embodiments of formula Ia, Z1and Z2are the same. In certain embodiments of formula Ia, Z1and Z2are different. Attorney Docket No.41543-59274 (002WO)

[0118] In certain embodiments of formula Ia, Z1has at least two double bonds, such as, for example, three double bonds, four double bonds, or five double bonds. In certain embodiments of formula Ia, Z1has two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ia, the double bonds of Z1are cis.

[0119] In certain embodiments of formula Ia, Z2has at least two double bonds, such as, for example, three double bonds, four double bonds, or five double bonds. In certain embodiments of formula Ia, Z2has two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ia, the double bonds of Z2are cis.

[0120] In certain embodiments of formula Ia, Z1and Z2have at least two double bonds. In certain embodiments of formula Ia, Z1and Z2have two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ia, the double bonds of Z1and Z2are cis.

[0121] In certain embodiments of formula Ia, Z1is C10-C20alkenyl. In certain embodiments of formula Ia, Z1is C15-C20alkenyl. In certain embodiments of formula Ia, Z1is C17alkenyl. In certain embodiments of formula Ia, Z1is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0122] In certain embodiments of formula Ia, Z2is C10-C20alkenyl. In certain embodiments of formula Ia, Z2is C15-C20alkenyl. In certain embodiments of formula Ia, Z2is C17alkenyl. In certain embodiments of formula Ia, Z2is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0123] In certain embodiments of formula Ia, Z1and Z2are C10-C20alkenyl. In certain embodiments of formula Ia, Z1and Z2are C15-C20alkenyl. In certain embodiments of formula Ia, Z1and Z2are C17alkenyl. In certain embodiments of formula Ia, Z1and Z2are -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0124] In certain embodiments of formula Ia, n is an integer from 1 to 5. In certain embodiments of formula Ia, n is an integer from 1 to 3. In certain embodiments of formula Ia, n is an integer selected from 1 and 2. In certain embodiments of formula Ia, n is 1. In certain embodiments of formula Ia, n is 2. In certain embodiments of formula Ia, n is 3. In certain embodiments of formula Ia, n is 4. In certain embodiments of formula Ia, n is 5.

[0125] In certain embodiments of formula Ia, m is an integer from 1 to 5. In certain embodiments of formula Ia, m is an integer from 1 to 3. In certain embodiments of formula Ia, m is an integer selected from 1 and 2. In certain embodiments of formula Ia, m is 1. In certain embodiments of formula Ia, m is 2. In certain embodiments of formula Ia, m is 3. In certain embodiments of formula Ia, m is 4. In certain embodiments of formula Ia, m is 5.

[0126] In certain embodiments of formula Ia, Z1is C10-C20alkenyl, Z2is C10-C20alkenyl, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of formula Ia, Z1is C10-C20alkenyl, Z2is C10-C20alkenyl, n is an integer from 1 to 3, and m is an integer from 1 to 3. In certain embodiments of formula Ia, Z1is C10-C20alkenyl, Z2is C10-C20alkenyl, n is 2, and m is 1. Attorney Docket No.41543-59274 (002WO)

[0127] In certain embodiments of formula Ia, Z1is C15-C20alkenyl, Z2is C15-C20alkenyl, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of formula Ia, Z1is C15-C20alkenyl, Z2is C15-C20alkenyl, n is an integer from 1 to 3, and m is an integer from 1 to 3. In certain embodiments of formula Ia, Z1is C15-C20alkenyl, Z2is C15-C20alkenyl, n is 2, and m is 1.

[0128] In certain embodiments of formula Ia, X is -C(O)-, and Y is C1-C6alkylene. In certain embodiments of formula I, X is -C(O)-, and Y is C1-C3alkylene. In certain embodiments of formula I, X is -C(O)-, and Y is C1-C2alkylene.

[0129] In certain embodiments of formula Ia, -NH-X-Y-NR5R6, thereby providing a compound of formula Ia-1: 1) wherein o is an integer I.

[0130] In certain embodiments of formula Ia-1, o is an integer from 1 to 4. In certain embodiments of formula Ia-1, o is an integer from 1 to 3. In certain embodiments of formula Ia-1, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-1, o is 1. In certain embodiments of formula Ia-1, o is 2. In certain embodiments of formula Ia-1, o is 3. In certain embodiments, of formula Ia-1 o is 4. In certain embodiments of formula Ia-1, o is 5.

[0131] In certain embodiments of formula Ia-1, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ia-1, R5and R6are methyl. In certain embodiments of formula Ia-1, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ia-1, R5is methyl and R6is -CH2CH2OH.

[0132] In certain embodiments of formula Ia-1, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ia-1, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle. Attorney Docket No.41543-59274 (002WO)

[0133] In certain embodiments of formula , thereby providing a compound of formula Ia-2: 2) wherein o is an integer NR9, wherein R9is selected from H, OH, C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0134] In certain embodiments of formula Ia-2, o is an integer from 1 to 4. In certain embodiments of formula Ia-2, o is an integer from 1 to 3. In certain embodiments of formula Ia-2, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-2, o is 1. In certain embodiments of formula Ia-2, o is 2. In certain embodiments of formula Ia-2, o is 3. In certain embodiments of formula Ia-2, o is 4. In certain embodiments of formula Ia-2, o is 5.

[0135] In certain embodiments of formula Ia-2, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ia-2, A is CHR9, wherein R9is OH. In certain embodiments of formula Ia-2, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ia-2, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ia-2, A is CHR9, wherein R9is -CH2CH2OH.

[0136] In certain embodiments of formula Ia-2, A is S.

[0137] In certain embodiments of formula Ia-2, A is O.

[0138] In certain embodiments of formula Ia-2, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and certain embodiments of formula Ia-2, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ia-2, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-2, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Ia-2, A is NR9, wherein R9. In certain embodiments of formula Ia-2, A is NR9, .

[0139] In certain embodiments of formula , thereby providing a compound of formula Ia-3: 3) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0140] In certain embodiments of formula Ia-3, o is an integer from 1 to 4. In certain embodiments of formula Ia-3, o is an integer from 1 to 3. In certain embodiments of formula Ia-3, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-3, o is 1. In certain embodiments of formula Ia-3, o is 2. In certain embodiments of formula Ia-3, o is 3. In certain embodiments of formula Ia-3, o is 4. In certain embodiments of formula Ia-3, o is 5.

[0141] In certain embodiments of formula Ia-3, R10and R11are each H. In certain embodiments of formula Ia-3, R10and R11are each OH. In certain embodiments of formula Ia-3, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-3, R10and R11are each -CH2OH. In certain embodiments of formula Ia-3, R10is H, and R11is OH.

[0142] In certain embodiments of formula Ia, X is -C(O)-, and Y is C1-C6heteroalkylene. In certain embodiments of formula Ia, X is -C(O)-, and Y is C1-C3heteroalkylene. In certain embodiments of formula Ia, X is -C(O)-, and Y is C1-C2heteroalkylene. In certain embodiments, X is -C(O)- and Y is - CH2-S-(CH2)q-, wherein q is an integer from 1 to 4. Attorney Docket No.41543-59274 (002WO)

[0143] In certain embodiments of formula Ia, -NH-X-Y- , thereby providing a compound of formula Ia-4: 4) wherein o is an integer R6are as defined for formula I.

[0144] In certain embodiments of formula Ia-4, o is an integer from 1 to 3. In certain embodiments of formula Ia-4, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-4, o is 1. In certain embodiments of formula Ia-4, o is 2. In certain embodiments of formula Ia-4, o is 3. In certain embodiments of formula Ia-4, o is 4.

[0145] In certain embodiments of formula Ia-4, Q is S and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ia-4, Q is S and R5and R6are methyl. In certain embodiments of formula Ia- 4, Q is S, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ia-4, Q is S, R5is methyl, and R6is -CH2CH2OH.

[0146] In certain embodiments of formula Ia-4, Q is O and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ia-4, Q is O and R5and R6are methyl. In certain embodiments of formula Ia- 4, Q is O, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ia-4, Q is O, R5is methyl, and R6is -CH2CH2OH.

[0147] In certain embodiments of formula Ia-4, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ia-4, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0148] In certain embodiments of formula Ia, -NH-X-Y-NR5R6, thereby providing a compound of formula Ia-5: Attorney Docket No.41543-59274 (002WO) 5) wherein o is an integer from CHR9, O, S, 99 and NR , wherein R is alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0149] In certain embodiments of formula Ia-5, o is an integer from 1 to 3. In certain embodiments of formula Ia-5, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-5, o is 1. In certain embodiments of formula Ia-5, o is 2. In certain embodiments of formula Ia-5, o is 3. In certain embodiments of formula Ia-5, o is 4.

[0150] In certain embodiments of formula Ia-5, Q is S and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ia-5, Q is S and A is CHR9, wherein R9is OH. In certain embodiments of formula Ia-5, Q is S and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ia-5, Q is S and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ia-5, Q is S and A is CHR9, wherein R9is - CH2CH2OH.

[0151] In certain embodiments of formula Ia-5, Q is S and A is S.

[0152] In certain embodiments of formula Ia-5, Q is S and A is O.

[0153] In certain embodiments of formula Ia-5, Q is S and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ia-5, Q is S and A is NR9, wherein R9is C1- In certain embodiments of formula Ia-5, Q is S an9 9 d A is NR , wherein R is hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-5, Q is S and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ia-5, Q is S and A is NR9, wherein R9is Attorney Docket No.41543-59274 (002WO) certain embodiments of formula Ia-5, Q is S and A is NR9, wherein R9is . of formula Ia-5, Q is O and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ia-5, Q is O and A is CHR9, wherein R9is OH. In certain embodiments of formula Ia-5, Q is O and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ia-5, Q is O and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ia-5, Q is O and A is CHR9, wherein R9is - CH2CH2OH.

[0155] In certain embodiments of formula Ia-5, Q is O and A is S.

[0156] In certain embodiments of formula Ia-5, Q is O and A is O.

[0157] In certain embodiments of formula Ia-5, Q is O and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ia-5, Q is O and A is NR9, wherein R9is C1- In certain embodiments of formula Ia-59 9 , Q is O and A is NR , wherein R is hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-5, Q is O and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ia-5, Q is O and A is NR9, wherein R9is certain embodiments of formula Ia-5, Q is O and A is NR9, wherein R9is .

[0158] In certain embodiments of formula , thereby providing a compound of formula Ia-6: Attorney Docket No.41543-59274 (002WO) 6) wherein o is an are each independently

[0159] In certain embodiments of formula Ia-6, o is an integer from 1 to 3. In certain embodiments of formula Ia-6, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-6, o is 1. In certain embodiments of formula Ia-6, o is 2. In certain embodiments of formula Ia-6, o is 3. In certain embodiments of formula Ia-6, o is 4.

[0160] In certain embodiments of formula Ia-6, Q is S and R10and R11are each H. In certain embodiments of formula Ia-6, Q is S and R10and R11are each OH. In certain embodiments of formula Ia-6, Q is S and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-6, Q is S and R10and R11are each -CH2OH. In certain embodiments of formula Ia-6, Q is S, R10is H, and R11is OH.

[0161] In certain embodiments of formula Ia-6, Q is O and R10and R11are each H. In certain embodiments of formula Ia-6, Q is O and R10and R11are each OH. In certain embodiments of formula Ia-6, Q is O and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-6, Q is O and R10and R11are each -CH2OH. In certain embodiments of formula Ia-6, Q is O, R10is H, and R11is OH.

[0162] In certain embodiments of formula Ia, X is -C(O)S- and Y is C1-C6 alkylene. In certain embodiments of formula Ia, X is -C(O)S- and Y is C1-C3alkylene. In certain embodiments of formula Ia, X is -C(O)S- and Y is C1-C2alkylene.

[0163] In certain embodiments of formula Ia, -NH-X-Y-NR5R6, thereby providing a compound of formula Ia-7: 7) wherein o is an integer I. Attorney Docket No.41543-59274 (002WO)

[0164] In certain embodiments of formula Ia-7, o is an integer from 1 to 5. In certain embodiments of formula Ia-7, o is an integer from 1 to 3. In certain embodiments of formula Ia-7, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-7, o is 1. In certain embodiments of formula Ia-7, o is 2. In certain embodiments of formula Ia-7, o is 3. In certain embodiments of formula Ia-7, o is 4. In certain embodiments of formula Ia-7, o is 5. In certain embodiments of formula Ia-7, o is 6.

[0165] In certain embodiments of formula Ia-7, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ia-7, R5and R6are methyl. In certain embodiments of formula Ia-7, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ia-7, R5is methyl and R6is -CH2CH2OH.

[0166] In certain embodiments of formula Ia-7, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ia-7, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0167] In certain embodiments of formula , thereby providing a compound of formula Ia-8: 8) wherein o is an integer9 9 NR , wherein R is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0168] In certain embodiments of formula Ia-8, o is an integer from 1 to 5. In certain embodiments of formula Ia-8, o is an integer from 1 to 3. In certain embodiments of formula Ia-8, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-8, o is 1. In certain embodiments of formula Ia-8, o is 2. In certain embodiments of formula Ia-8, o is 3. In certain embodiments of formula Ia-8, o is 4. In certain embodiments of formula Ia-8, o is 5. In certain embodiments of formula Ia-8, o is 6.

[0169] In certain embodiments of formula Ia-8, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ia-8, A is CHR9, wherein R9is OH. In certain embodiments of formula Ia-8, A is CHR9, wherein R9is C1-C6alkyl (e.g., Attorney Docket No.41543-59274 (002WO) methyl). In certain embodiments of formula Ia-8, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ia-8, A is CHR9, wherein R9is -CH2CH2OH.

[0170] In certain embodiments of formula Ia-8, A is S.

[0171] In certain embodiments of formula Ia-8, A is O.

[0172] In certain embodiments of formula Ia-8, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ia-8, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ia-8, A is NR9, wherein R9is hydroxy-C1-C6alkyl. of formula Ia-8, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ia-8, A is NR9, wherein R9. In certain embodiments of formula Ia-8, A is NR9, .

[0173] In certain embodiments of formula , thereby providing a compound of formula Ia-9: 9) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0174] In certain embodiments of formula Ia-9, o is an integer from 1 to 5. In certain embodiments of formula Ia-9, o is an integer from 1 to 3. In certain embodiments of formula Ia-9, o is an integer Attorney Docket No.41543-59274 (002WO) selected from 1 and 2. In certain embodiments of formula Ia-9, o is 1. In certain embodiments of formula Ia-9, o is 2. In certain embodiments of formula Ia-9, o is 3. In certain embodiments of formula Ia-9, o is 4. In certain embodiments of formula Ia-9, o is 5. In certain embodiments of formula Ia-9, o is 6.

[0175] In certain embodiments of formula Ia-9, R10and R11are each H. In certain embodiments of formula Ia-9, R10and R11are each OH. In certain embodiments of formula Ia-9, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-9, R10and R11are each -CH2OH. In certain embodiments of formula Ia-9, R10is H, and R11is OH.

[0176] In certain embodiments of formula Ia, X is -CH2- and Y is C1-C6alkylene. In certain embodiments of formula Ia, X is -CH2- and Y is C1-C3alkylene. In certain embodiments of formula Ia, X is -CH2- and Y is C1-C2alkylene.

[0177] In certain embodiments of formula Ia, -NH-X-Y-NR5R6, thereby providing a compound of formula Ia-10: wherein o is an integer I.

[0178] In certain embodiments of formula Ia-10, o is an integer from 1 to 4. In certain embodiments of formula Ia-10, o is an integer from 1 to 3. In certain embodiments of formula Ia-10, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-10, o is 1. In certain embodiments of formula Ia-10, o is 2. In certain embodiments of formula Ia-10, o is 3. In certain embodiments of formula Ia-10, o is 4. In certain embodiments of formula Ia-10, o is 5.

[0179] In certain embodiments of formula Ia-10, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ia-10, R5and R6are methyl. In certain embodiments of formula Ia-10, R5is C1-C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ia-10, R5is methyl and R6is -CH2CH2OH.

[0180] In certain embodiments of formula Ia-10, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ia-10, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle. Attorney Docket No.41543-59274 (002WO)

[0181] In certain embodiments of formula Ia, -NH-X-Y-NR5R6, thereby providing a compound of formula Ia-11: wherein o is an integer wherein R9is selected from H, OH, C1-C6heteroalkyl, and optionally substituted

[0182] In certain embodiments of formula Ia-11, o is an integer from 1 to 4. In certain embodiments of formula Ia-11, o is an integer from 1 to 3. In certain embodiments of formula Ia-11, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-11, o is 1. In certain embodiments of formula Ia-11, o is 2. In certain embodiments of formula Ia-11, o is 3. In certain embodiments of formula Ia-11, o is 4. In certain embodiments of formula Ia-11, o is 5.

[0183] In certain embodiments of formula Ia-11, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ia-11, A is CHR9, wherein R9is OH. In certain embodiments of formula Ia-11, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ia-11, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ia-11, A is CHR9, wherein R9is -CH2CH2OH.

[0184] In certain embodiments of formula Ia-11, A is S.

[0185] In certain embodiments of formula Ia-11, A is O.

[0186] In certain embodiments of formula Ia-11, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and certain embodiments of formula Ia-11, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ia-11, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-11, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Ia-11, A is NR9, wherein R9. In certain embodiments of formula Ia-11, A is NR9, .

[0187] In certain embodiments of formula , thereby providing a compound of formula Ia-12: wherein o is an integer from H, OH, and hydroxy-C1-C6alkyl.

[0188] In certain embodiments of formula Ia-12, o is an integer from 1 to 4. In certain embodiments of formula Ia-12, o is an integer from 1 to 3. In certain embodiments of formula Ia-12, o is an integer selected from 1 and 2. In certain embodiments of formula Ia-12, o is 1. In certain embodiments of formula Ia-12, o is 2. In certain embodiments of formula Ia-12, o is 3. In certain embodiments of formula Ia-12, o is 4. In certain embodiments of formula Ia-12, o is 5.

[0189] In certain embodiments of formula Ia-12, R10and R11are each H. In certain embodiments of formula Ia-12, R10and R11are each OH. In certain embodiments of formula Ia-12, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ia-12, R10and R11are each -CH2OH. In certain embodiments of formula Ia-12, R10is H, and R11is OH.

[0190] In certain embodiments, the present disclosure provides a compound of formula I, wherein R1is -(CH2)nOC(O)Z1, R2is C6-C20alkenyl, R3is H, and R4is OH, thereby forming a compound of formula Ib: Attorney Docket No.41543-59274 (002WO) or a pharmaceutically acceptable Z1is C6-C20alkenyl; n is an integer from 1 to 10; and R2is C10-C20alkyl.

[0191] In certain embodiments of formula Ib, Z1has at least two double bonds, such as, for example, three double bonds, four double bonds, or five double bonds. In certain embodiments of formula Ib, Z1has two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ib, the double bonds of Z1are cis.

[0192] In certain embodiments of formula Ib, Z1is C10-C20alkenyl. In certain embodiments of formula Ib, Z1is C15-C20alkenyl. In certain embodiments of formula Ib, Z1is C17alkenyl. In certain embodiments of formula Ib, Z1is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0193] In certain embodiments of formula Ib, n is an integer from 1 to 5. In certain embodiments of formula Ib, n is an integer from 1 to 3. In certain embodiments of formula Ib, n is an integer selected from 1 and 2. In certain embodiments of formula Ib, n is 1. In certain embodiments of formula Ib, n is 2. In certain embodiments of formula Ib, n is 3. In certain embodiments of formula Ib, n is 4. In certain embodiments of formula Ib, n is 5.

[0194] In certain embodiments of formula Ib, R2is C13-C20alkyl. In certain embodiments of formula Ib, R2is C15-C20alkyl. In certain embodiments of formula Ib, R2is C15H31.

[0195] In certain embodiments of formula Ib, Z1is C10-C20alkenyl, n is an integer from 1 to 5, and R2is C10-C20alkyl. In certain embodiments of formula Ib, Z1is C10-C20alkenyl, n is an integer from 1 to 3, and R2is C10-C20alkyl. In certain embodiments of formula Ib, Z1is C10-C20alkenyl, n is 2, and R2is C10-C20alkyl.

[0196] In certain embodiments of formula Ib, Z1is C15-C20alkenyl, n is an integer from 1 to 5, and R2is C15-C20 alkyl. In certain embodiments of formula Ib, Z1is C15-C20 alkenyl, n is an integer from 1 to 3, and R2is C15-C20alkyl. In certain embodiments of formula Ib, Z1is C15-C20alkenyl, n is 2, and R2is C15-C20alkyl.

[0197] In certain embodiments of formula Ib, X is -C(O)-, and Y is C1-C6alkylene. In certain embodiments of formula Ib, X is -C(O)-, and Y is C1-C3alkylene. In certain embodiments of formula Ib, X is -C(O)-, and Y is C1-C2alkylene. Attorney Docket No.41543-59274 (002WO)

[0198] In certain embodiments of formula Ib, -NH-X-Y-NR5R6is , thereby providing a compound of formula Ib-1: 1) wherein o is an integer from 1 formula I.

[0199] In certain embodiments of formula Ib-1, o is an integer from 1 to 4. In certain embodiments of formula Ib-1, o is an integer from 1 to 3. In certain embodiments of formula Ib-1, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-1, o is 1. In certain embodiments of formula Ib-1, o is 2. In certain embodiments of formula Ib-1, o is 3. In certain embodiments, of formula Ib-1 o is 4. In certain embodiments of formula Ib-1, o is 5.

[0200] In certain embodiments of formula Ib-1, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ib-1, R5and R6are methyl. In certain embodiments of formula Ib-1, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ib-1, R5is methyl and R6is -CH2CH2OH.

[0201] In certain embodiments of formula Ib-1, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ib-1, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0202] In certain embodiments of formula , thereby providing a compound of formula Ib-2: Attorney Docket No.41543-59274 (002WO) 2) wherein o is an integer from 1 S, and NR9, wherein R9is selected from H, OH, optionally C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0203] In certain embodiments of formula Ib-2, o is an integer from 1 to 4. In certain embodiments of formula Ib-2, o is an integer from 1 to 3. In certain embodiments of formula Ib-2, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-2, o is 1. In certain embodiments of formula Ib-2, o is 2. In certain embodiments of formula Ib-2, o is 3. In certain embodiments of formula Ib-2, o is 4. In certain embodiments of formula Ib-2, o is 5.

[0204] In certain embodiments of formula Ib-2, A is CHR9, wherein R9is selected from OH, C1-C6 alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ib-2, A is CHR9, wherein R9is OH. In certain embodiments of formula Ib-2, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ib-2, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ib-2, A is CHR9, wherein R9is -CH2CH2OH.

[0205] In certain embodiments of formula Ib-2, A is S.

[0206] In certain embodiments of formula Ib-2, A is O.

[0207] In certain embodiments of formula Ib-2, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ib-2, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ib-2, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-2, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Ib-2, A is NR9, wherein R9. In certain embodiments of formula Ib-2, A is NR9, .

[0208] In certain embodiments of formula , thereby providing a compound of formula Ib-3: 3) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0209] In certain embodiments of formula Ib-3, o is an integer from 1 to 4. In certain embodiments of formula Ib-3, o is an integer from 1 to 3. In certain embodiments of formula Ib-3, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-3, o is 1. In certain embodiments of formula Ib-3, o is 2. In certain embodiments of formula Ib-3, o is 3. In certain embodiments of formula Ib-3, o is 4. In certain embodiments of formula Ib-3, o is 5.

[0210] In certain embodiments of formula Ib-3, R10and R11are each H. In certain embodiments of formula Ib-3, R10and R11are each OH. In certain embodiments of formula Ib-3, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-3, R10and R11are each -CH2OH. In certain embodiments of formula Ib-3, R10is H, and R11is OH.

[0211] In certain embodiments of formula Ib, X is -C(O)-, and Y is C1-C6heteroalkylene. In certain embodiments of formula Ib, X is -C(O)-, and Y is C1-C3heteroalkylene. In certain embodiments of formula Ib, X is -C(O)-, and Y is C1-C2heteroalkylene. In certain embodiments, X is -C(O)- and Y is - CH2-S-(CH2)q-, wherein q is an integer from 1 to 4. Attorney Docket No.41543-59274 (002WO)

[0212] In certain embodiments of formula Ib, -NH-X-Y- , thereby providing a compound of formula Ib-4: 4) wherein Q is selected from S and R6are as defined for formula I.

[0213] In certain embodiments of formula Ib-4, o is an integer from 1 to 3. In certain embodiments of formula Ib-4, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-4, o is 1. In certain embodiments of formula Ib-4, o is 2. In certain embodiments of formula Ib-4, o is 3. In certain embodiments of formula Ib-4, o is 4.

[0214] In certain embodiments of formula Ib-4, Q is S and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ib-4, Q is S and R5and R6are methyl. In certain embodiments of formula Ib- 4, Q is S, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ib-4, Q is S, R5is methyl, and R6is -CH2CH2OH.

[0215] In certain embodiments of formula Ib-4, Q is O and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ib-4, Q is O and R5and R6are methyl. In certain embodiments of formula Ib- 4, Q is O, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ib-4, Q is O, R5is methyl, and R6is -CH2CH2OH.

[0216] In certain embodiments of formula Ib-4, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ib-4, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0217] In certain embodiments of formula Ib, -NH-X-Y-NR5R6, thereby providing a compound of formula Ib-5: Attorney Docket No.41543-59274 (002WO) 5) wherein Q is selected from O is selected from CHR9, O, S, and NR9, wherein R9is selected alkyl, optionally substituted C1- C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0218] In certain embodiments of formula Ib-5, o is an integer from 1 to 3. In certain embodiments of formula Ib-5, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-5, o is 1. In certain embodiments of formula Ib-5, o is 2. In certain embodiments of formula Ib-5, o is 3. In certain embodiments of formula Ib-5, o is 4.

[0219] In certain embodiments of formula Ib-5, Q is S and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ib-5, Q is S and A is CHR9, wherein R9is OH. In certain embodiments of formula Ib-5, Q is S and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ib-5, Q is S and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ib-5, Q is S and A is CHR9, wherein R9is - CH2CH2OH.

[0220] In certain embodiments of formula Ib-5, Q is S and A is S.

[0221] In certain embodiments of formula Ib-5, Q is S and A is O.

[0222] In certain embodiments of formula Ib-5, Q is S and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ib-5, Q is S and A is NR9, wherein R9is C1- In certain embodiments of formula Ib-5, Q is9 9 S and A is NR , wherein R is hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-5, Q is S and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ib-5, Q is S and A is NR9, wherein R9is Attorney Docket No.41543-59274 (002WO) certain embodiments of formula Ib-5, Q is S and A is NR9, wherein R9is . of formula Ib-5, Q is O and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ib-5, Q is O and A is CHR9, wherein R9is OH. In certain embodiments of formula Ib-5, Q is O and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ib-5, Q is O and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ib-5, Q is O and A is CHR9, wherein R9is -CH2CH2OH.

[0224] In certain embodiments of formula Ib-5, Q is O and A is S.

[0225] In certain embodiments of formula Ib-5, Q is O and A is O.

[0226] In certain embodiments of formula Ib-5, Q is O and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ib-5, Q is O and A is NR9, wherein R9is C1- In certain embodiments of formula Ib-59 9 , Q is O and A is NR , wherein R is hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-5, Q is O and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ib-5, Q is O and A is NR9, wherein R9is certain embodiments of formula Ib-5, Q is O and A is NR9, wherein R9is .

[0227] In certain embodiments of formula , thereby providing a compound of formula Ib-6: Attorney Docket No.41543-59274 (002WO) 6) wherein Q is selected R11are each independently selected from H, OH, and

[0228] In certain embodiments of formula Ib-6, o is an integer from 1 to 3. In certain embodiments of formula Ib-6, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-6, o is 1. In certain embodiments of formula Ib-6, o is 2. In certain embodiments of formula Ib-6, o is 3. In certain embodiments of formula Ib-6, o is 4.

[0229] In certain embodiments of formula Ib-6, Q is S and R10and R11are each H. In certain embodiments of formula Ib-6, Q is S and R10and R11are each OH. In certain embodiments of formula Ib-6, Q is S and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-6, Q is S and R10and R11are each -CH2OH. In certain embodiments of formula Ib-6, Q is S, R10is H, and R11is OH.

[0230] In certain embodiments of formula Ib-6, Q is O and R10and R11are each H. In certain embodiments of formula Ib-6, Q is O and R10and R11are each OH. In certain embodiments of formula Ib-6, Q is O and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-6, Q is O and R10and R11are each -CH2OH. In certain embodiments of formula Ib-6, Q is O, R10is H, and R11is OH.

[0231] In certain embodiments of formula Ib, X is -C(O)S- and Y is C1-C6alkylene. In certain embodiments of formula Ib, X is -C(O)S- and Y is C1-C3 alkylene. In certain embodiments of formula Ib, X is -C(O)S- and Y is C1-C2alkylene.

[0232] In certain embodiments of formula Ib, -NH-X-Y-NR5R6is , thereby providing a compound of formula Ib-7: 7) wherein o is an integer from 1 formula I. Attorney Docket No.41543-59274 (002WO)

[0233] In certain embodiments of formula Ib-7, o is an integer from 1 to 5. In certain embodiments of formula Ib-7, o is an integer from 1 to 3. In certain embodiments of formula Ib-7, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-7, o is 1. In certain embodiments of formula Ib-7, o is 2. In certain embodiments of formula Ib-7, o is 3. In certain embodiments of formula Ib-7, o is 4. In certain embodiments of formula Ib-7, o is 5. In certain embodiments of formula Ib-7, o is 6.

[0234] In certain embodiments of formula Ib-7, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ib-7, R5and R6are methyl. In certain embodiments of formula Ib-7, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ib-7, R5is methyl and R6is -CH2CH2OH.

[0235] In certain embodiments of formula Ib-7, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ib-7, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0236] In certain embodiments of formula , thereby providing a compound of formula Ib-8: 8) wherein o is an integer from 1 S, and NR9, wherein R9is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0237] In certain embodiments of formula Ib-8, o is an integer from 1 to 5. In certain embodiments of formula Ib-8, o is an integer from 1 to 3. In certain embodiments of formula Ib-8, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-8, o is 1. In certain embodiments of formula Ib-8, o is 2. In certain embodiments of formula Ib-8, o is 3. In certain embodiments of formula Ib-8, o is 4. In certain embodiments of formula Ib-8, o is 5. In certain embodiments of formula Ib-8, o is 6.

[0238] In certain embodiments of formula Ib-8, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ib-8, A is CHR9, Attorney Docket No.41543-59274 (002WO) wherein R9is OH. In certain embodiments of formula Ib-8, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ib-8, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ib-8, A is CHR9, wherein R9is -CH2CH2OH.

[0239] In certain embodiments of formula Ib-8, A is S.

[0240] In certain embodiments of formula Ib-8, A is O.

[0241] In certain embodiments of formula Ib-8, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ib-8, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ib-8, A is NR9, wherein R9is hydroxy-C1-C6alkyl. of formula Ib-8, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ib-8, A is NR9, wherein R9. In certain embodiments of formula Ib-8, A is NR9, .

[0242] In certain embodiments of formula , thereby providing a compound of formula Ib-9: 9) wherein o is an integer from selected from H, OH, and hydroxy-C1-C6alkyl. Attorney Docket No.41543-59274 (002WO)

[0243] In certain embodiments of formula Ib-9, o is an integer from 1 to 5. In certain embodiments of formula Ib-9, o is an integer from 1 to 3. In certain embodiments of formula Ib-9, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-9, o is 1. In certain embodiments of formula Ib-9, o is 2. In certain embodiments of formula Ib-9, o is 3. In certain embodiments of formula Ib-9, o is 4. In certain embodiments of formula Ib-9, o is 5. In certain embodiments of formula Ib-9, o is 6.

[0244] In certain embodiments of formula Ib-9, R10and R11are each H. In certain embodiments of formula Ib-9, R10and R11are each OH. In certain embodiments of formula Ib-9, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-9, R10and R11are each -CH2OH. In certain embodiments of formula Ib-9, R10is H, and R11is OH.

[0245] In certain embodiments of formula Ib, X is -CH2- and Y is C1-C6alkylene. In certain embodiments of formula Ib, X is -CH2- and Y is C1-C3alkylene. In certain embodiments of formula Ib, X is -CH2- and Y is C1-C2alkylene.

[0246] In certain embodiments of formula , thereby providing a compound of formula Ib-10: wherein o is an integer from 1 formula I.

[0247] In certain embodiments of formula Ib-10, o is an integer from 1 to 4. In certain embodiments of formula Ib-10, o is an integer from 1 to 3. In certain embodiments of formula Ib-10, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-10, o is 1. In certain embodiments of formula Ib-10, o is 2. In certain embodiments of formula Ib-10, o is 3. In certain embodiments of formula Ib-10, o is 4. In certain embodiments of formula Ib-10, o is 5.

[0248] In certain embodiments of formula Ib-10, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ib-10, R5and R6are methyl. In certain embodiments of formula Ib-10, R5is C1-C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ib-10, R5is methyl and R6is -CH2CH2OH.

[0249] In certain embodiments of formula Ib-10, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally Attorney Docket No.41543-59274 (002WO) substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ib-10, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0250] In certain embodiments of formula Ib, -NH-X-Y-NR5R6, thereby providing a compound of formula Ib-11: wherein o is an integer from 1 and NR9, wherein R9is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0251] In certain embodiments of formula Ib-11, o is an integer from 1 to 4. In certain embodiments of formula Ib-11, o is an integer from 1 to 3. In certain embodiments of formula Ib-11, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-11, o is 1. In certain embodiments of formula Ib-11, o is 2. In certain embodiments of formula Ib-11, o is 3. In certain embodiments of formula Ib-11, o is 4. In certain embodiments of formula Ib-11, o is 5.

[0252] In certain embodiments of formula Ib-11, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ib-11, A is CHR9, wherein R9is OH. In certain embodiments of formula Ib-11, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ib-11, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ib-11, A is CHR9, wherein R9is -CH2CH2OH.

[0253] In certain embodiments of formula Ib-11, A is S.

[0254] In certain embodiments of formula Ib-11, A is O.

[0255] In certain embodiments of formula Ib-11, A is NR9, wherein R9is selected from C1-C6alkyl certain embodiments of formula Ib-11, A is NR9, wherein R9is C1-C6alkyl Attorney Docket No.41543-59274 (002WO) (e.g., methyl). In certain embodiments of formula Ib-11, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-11, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ib-11, A is NR9, wherein R9. In certain embodiments of formula Ib-11, A is NR9, .

[0256] In certain embodiments of formula , thereby providing a compound of formula Ib-12: wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0257] In certain embodiments of formula Ib-12, o is an integer from 1 to 4. In certain embodiments of formula Ib-12, o is an integer from 1 to 3. In certain embodiments of formula Ib-12, o is an integer selected from 1 and 2. In certain embodiments of formula Ib-12, o is 1. In certain embodiments of formula Ib-12, o is 2. In certain embodiments of formula Ib-12, o is 3. In certain embodiments of formula Ib-12, o is 4. In certain embodiments of formula Ib-12, o is 5.

[0258] In certain embodiments of formula Ib-12, R10and R11are each H. In certain embodiments of formula Ib-12, R10and R11are each OH. In certain embodiments of formula Ib-12, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ib-12, R10and R11are each -CH2OH. In certain embodiments of formula Ib-12, R10is H, and R11is OH.

[0259] In certain embodiments, the present disclosure provides a compound of formula I, wherein R1is -(CH2)nOC(O)Z1, R2is selected from -(CH2)mOC(O)Z2, R3is H, and R4is H, thereby forming a compound of formula Ic: Attorney Docket No.41543-59274 (002WO) or a pharmaceutically Z1is C6-C20alkenyl; n is an integer from 1 to 10; m is an integer from 1 to 10; and R7and R8are each C4-C20alkyl.

[0260] In certain embodiments of formula Ic, Z1has at least two double bonds, such as, for example, three double bonds, four double bonds, or five double bonds. In certain embodiments of formula Ic, Z1has two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ic, the double bonds of Z1are cis.

[0261] In certain embodiments of formula Ic, Z1is C10-C20alkenyl. In certain embodiments of formula Ic, Z1is C15-C20alkenyl. In certain embodiments of formula Ic, Z1is C17alkenyl. In certain embodiments of formula Ic, Z1is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0262] In certain embodiments of formula Ic, n is an integer from 1 to 5. In certain embodiments of formula Ic, n is an integer from 1 to 3. In certain embodiments of formula Ic, n is an integer selected from 1 and 2. In certain embodiments of formula Ic, n is 1. In certain embodiments of formula Ic, n is 2. In certain embodiments of formula Ic, n is 3. In certain embodiments of formula Ic, n is 4. In certain embodiments of formula Ic, n is 5.

[0263] In certain embodiments of formula Ic, m is an integer from 3 to 8. In certain embodiments of formula Ic, m is an integer selected from 5, 6, or 7. In certain embodiments of formula Ic, m is 5. In certain embodiments of formula Ic, m is 6. In certain embodiments of formula Ic, m is 7.

[0264] In certain embodiments of formula Ic, R7is C4-C20alkyl. In certain embodiments of formula Ic, R7is C4-C15alkyl. In certain embodiments of formula Ic, R7is C4-C10alkyl.

[0265] In certain embodiments of formula Ic, R8is C4-C20alkyl. In certain embodiments of formula Ic, R8is C4-C15alkyl. In certain embodiments of formula Ic, R8is C4-C10alkyl.

[0266] In certain embodiments of formula Ic, R7and R8are the same. In certain embodiments of formula Ic, R7and R8are different.

[0267] In certain embodiments of formula Ic, Z1is C10-C20alkenyl, n is an integer from 1 to 5, m is an integer from 3 to 8, R7is C4-C20alkyl, and R8is C4-C20alkyl. In certain embodiments of formula Ic, Z1is C10-C20alkenyl, n is an integer from 1 to 3, m is an integer from 4 to 6, R7is C4-C20alkyl, and R8 Attorney Docket No.41543-59274 (002WO) is C4-C20alkyl. In certain embodiments of formula Ic, Z1is C10-C20alkenyl, n is 2, m is 5, R7is C4-C20alkyl, and R8is C4-C20alkyl.

[0268] In certain embodiments of formula Ic, Z1is C15-C20alkenyl, n is an integer from 1 to 5, m is an integer from 3 to 8, R7is C4-C15alkyl, and R8is C4-C15alkyl. In certain embodiments of formula Ic, Z1is C15-C20alkenyl, n is an integer from 1 to 3, m is an integer from 4 to 6, R7is C4-C15alkyl, and R8is C4-C15alkyl. In certain embodiments of formula Ic, Z1is C15-C20alkenyl, n is 2, m is 5, R7is C4-C15alkyl, and R8is C4-C15alkyl.

[0269] In certain embodiments of formula Ic, Z1is C15-C20alkenyl, n is an integer from 1 to 5, m is an integer from 3 to 8, R7is C4-C10alkyl, and R8is C4-C10alkyl. In certain embodiments of formula Ic, Z1is C15-C20alkenyl, n is an integer from 1 to 3, m is an integer from 4 to 6, R7is C4-C10alkyl, and R8is C4-C10alkyl. In certain embodiments of formula Ic, Z1is C15-C20alkenyl, n is 2, m is 5, R7is C4-C10alkyl, and R8is C4-C10alkyl.

[0270] In certain embodiments of formula Ic, X is -C(O)-, and Y is C1-C6alkylene. In certain embodiments of formula Ic, X is -C(O)-, and Y is C1-C3alkylene. In certain embodiments of formula Ic, X is -C(O)-, and Y is C1-C2alkylene.

[0271] In certain embodiments of formula Ic, -NH-X-Y-NR5R6, thereby providing a compound of formula Ic-1: 1) wherein o is an integer I.

[0272] In certain embodiments of formula Ic-1, o is an integer from 1 to 4. In certain embodiments of formula Ic-1, o is an integer from 1 to 3. In certain embodiments of formula Ic-1, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-1, o is 1. In certain embodiments of formula Ic-1, o is 2. In certain embodiments of formula Ic-1, o is 3. In certain embodiments, of formula Ic-1 o is 4. In certain embodiments of formula Ic-1, o is 5.

[0273] In certain embodiments of formula Ic-1, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ic-1, R5and R6are methyl. In certain embodiments of formula Ic-1, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ic-1, R5is methyl and R6is -CH2CH2OH. Attorney Docket No.41543-59274 (002WO)

[0274] In certain embodiments of formula Ic-1, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ic-1, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0275] In certain embodiments of , thereby providing a compound of formula Ic-2: Z1O 2)wherein o is an integer9 9 NR , wherein R is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0276] In certain embodiments of formula Ic-2, o is an integer from 1 to 4. In certain embodiments of formula Ic-2, o is an integer from 1 to 3. In certain embodiments of formula Ic-2, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-2, o is 1. In certain embodiments of formula Ic-2, o is 2. In certain embodiments of formula Ic-2, o is 3. In certain embodiments of formula Ic-2, o is 4. In certain embodiments of formula Ic-2, o is 5.

[0277] In certain embodiments of formula Ic-2, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ic-2, A is CHR9, wherein R9is OH. In certain embodiments of formula Ic-2, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ic-2, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ic-2, A is CHR9, wherein R9is -CH2CH2OH.

[0278] In certain embodiments of formula Ic-2, A is S.

[0279] In certain embodiments of formula Ic-2, A is O.

[0280] In certain embodiments of formula Ic-2, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and Attorney Docket No.41543-59274 (002WO) certain embodiments of formula Ic-2, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ic-2, A is NR9, wherein R9is hydroxy-C1-C6alkyl. of formula Ic-2, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ic-2, A is NR9, wherein R9. In certain embodiments of formula Ic-2, A is NR9, .

[0281] In certain embodiments of , thereby providing a compound of formula 3) wherein o is an from H, OH, and hydroxy-C1-C6alkyl.

[0282] In certain embodiments of formula Ic-3, o is an integer from 1 to 4. In certain embodiments of formula Ic-3, o is an integer from 1 to 3. In certain embodiments of formula Ic-3, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-3, o is 1. In certain embodiments of formula Ic-3, o is 2. In certain embodiments of formula Ic-3, o is 3. In certain embodiments of formula Ic-3, o is 4. In certain embodiments of formula Ic-3, o is 5.

[0283] In certain embodiments of formula Ic-3, R10and R11are each H. In certain embodiments of formula Ic-3, R10and R11are each OH. In certain embodiments of formula Ic-3, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ic-3, R10and R11are each -CH2OH. In certain embodiments of formula Ic-3, R10is H, and R11is OH. Attorney Docket No.41543-59274 (002WO)

[0284] In certain embodiments of formula Ic, X is -C(O)-, and Y is C1-C6heteroalkylene. In certain embodiments of formula Ic, X is -C(O)-, and Y is C1-C3heteroalkylene. In certain embodiments of formula Ic, X is -C(O)-, and Y is C1-C2heteroalkylene. In certain embodiments, X is -C(O)- and Y is - CH2-S-(CH2)q-, wherein q is an integer from 1 to 4.

[0285] In certain embodiments of formula Ic, -NH-X-Y- , thereby providing a compound of formula Ic-4: 4) wherein o is an integer are as defined for formula I.

[0286] In certain embodiments of formula Ic-4, o is an integer from 1 to 3. In certain embodiments of formula Ic-4, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-4, o is 1. In certain embodiments of formula Ic-4, o is 2. In certain embodiments of formula Ic-4, o is 3. In certain embodiments of formula Ic-4, o is 4.

[0287] In certain embodiments of formula Ic-4, Q is S and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ic-4, Q is S and R5and R6are methyl. In certain embodiments of formula Ic- 4, Q is S, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ic-4, Q is S, R5is methyl, and R6is -CH2CH2OH.

[0288] In certain embodiments of formula Ic-4, Q is O and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ic-4, Q is O and R5and R6are methyl. In certain embodiments of formula Ic- 4, Q is O, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ic-4, Q is O, R5is methyl, and R6is -CH2CH2OH.

[0289] In certain embodiments of formula Ic-4, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ic-4, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle. Attorney Docket No.41543-59274 (002WO)

[0290] In certain embodiments of formula Ic, -NH-X-Y-NR5R6, thereby providing a compound of formula Ic-5: 5) wherein o is an integer from CHR9, O, S, 99 and NR , wherein R is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0291] In certain embodiments of formula Ic-5, o is an integer from 1 to 3. In certain embodiments of formula Ic-5, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-5, o is 1. In certain embodiments of formula Ic-5, o is 2. In certain embodiments of formula Ic-5, o is 3. In certain embodiments of formula Ic-5, o is 4.

[0292] In certain embodiments of formula Ic-5, Q is S and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ic-5, Q is S and A is CHR9, wherein R9is OH. In certain embodiments of formula Ic-5, Q is S and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ic-5, Q is S and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ic-5, Q is S and A is CHR9, wherein R9is - CH2CH2OH.

[0293] In certain embodiments of formula Ic-5, Q is S and A is S.

[0294] In certain embodiments of formula Ic-5, Q is S and A is O.

[0295] In certain embodiments of formula Ic-5, Q is S and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ic-5, Q is S and A is NR9, wherein R9is C1- In certain embodiments of formula Ic-5, Q is S and A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ic-5, Q is S and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ic-5, Q is S and A is NR9, wherein R9is Attorney Docket No.41543-59274 (002WO) certain embodiments of formula Ic-5, Q is S and A is NR9, wherein R9is . of formula Ic-5, Q is O and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ic-5, Q is O and A is CHR9, wherein R9is OH. In certain embodiments of formula Ic-5, Q is O and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ic-5, Q is O and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ic-5, Q is O and A is CHR9, wherein R9is - CH2CH2OH.

[0297] In certain embodiments of formula Ic-5, Q is O and A is S.

[0298] In certain embodiments of formula Ic-5, Q is O and A is O.

[0299] In certain embodiments of formula Ic-5, Q is O and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ic-5, Q is O and A is NR9, wherein R9is C1- In certain embodiments of fo9 9 rmula Ic-5, Q is O and A is NR , wherein R is hydroxy-C1-C6alkyl. In certain embodiments of formula Ic-5, Q is O and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ic-5, Q is O and A is NR9, wherein R9is certain embodiments of formula Ic-5, Q is O and A is NR9, wherein R9is .

[0300] In certain embodiments of , thereby providing a compound of formula Attorney Docket No.41543-59274 (002WO) 1 10 6) wherein o is an from H, OH, and hydroxy-C1-C6

[0301] In certain embodiments of formula Ic-6, o is an integer from 1 to 3. In certain embodiments of formula Ic-6, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-6, o is 1. In certain embodiments of formula Ic-6, o is 2. In certain embodiments of formula Ic-6, o is 3. In certain embodiments of formula Ic-6, o is 4.

[0302] In certain embodiments of formula Ic-6, Q is S and R10and R11are each H. In certain embodiments of formula Ic-6, Q is S and R10and R11are each OH. In certain embodiments of formula Ic-6, Q is S and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ic-6, Q is S and R10and R11are each -CH2OH. In certain embodiments of formula Ic-6, Q is S, R10is H, and R11is OH.

[0303] In certain embodiments of formula Ic-6, Q is O and R10and R11are each H. In certain embodiments of formula Ic-6, Q is O and R10and R11are each OH. In certain embodiments of formula Ic-6, Q is O and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ic-6, Q is O and R10and R11are each -CH2OH. In certain embodiments of formula Ic-6, Q is O, R10is H, and R11is OH.

[0304] In certain embodiments of formula Ic, X is -C(O)S- and Y is C1-C6alkylene. In certain embodiments of formula Ic, X is -C(O)S- and Y is C1-C3alkylene. In certain embodiments of formula Ic, X is -C(O)S- and Y is C1-C2alkylene.

[0305] In certain embodiments of formula Ic, -NH-X-Y-NR5R6, thereby providing a compound of formula Ic-7: Z1O 7)wherein o is an integer I. Attorney Docket No.41543-59274 (002WO)

[0306] In certain embodiments of formula Ic-7, o is an integer from 1 to 5. In certain embodiments of formula Ic-7, o is an integer from 1 to 3. In certain embodiments of formula Ic-7, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-7, o is 1. In certain embodiments of formula Ic-7, o is 2. In certain embodiments of formula Ic-7, o is 3. In certain embodiments of formula Ic-7, o is 4. In certain embodiments of formula Ic-7, o is 5. In certain embodiments of formula Ic-7, o is 6.

[0307] In certain embodiments of formula Ic-7, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ic-7, R5and R6are methyl. In certain embodiments of formula Ic-7, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ic-7, R5is methyl and R6is -CH2CH2OH.

[0308] In certain embodiments of formula Ic-7, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ic-7, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0309] In certain embodiments of , thereby providing a compound of formula Ic-8: wherein o is an integer wherein R9is selected from H, OH, C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0310] In certain embodiments of formula Ic-8, o is an integer from 1 to 5. In certain embodiments of formula Ic-8, o is an integer from 1 to 3. In certain embodiments of formula Ic-8, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-8, o is 1. In certain embodiments of formula Ic-8, o is 2. In certain embodiments of formula Ic-8, o is 3. In certain embodiments of formula Ic-8, o is 4. In certain embodiments of formula Ic-8, o is 5. In certain embodiments of formula Ic-8, o is 6.

[0311] In certain embodiments of formula Ic-8, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ic-8, A is CHR9, wherein R9is OH. In certain embodiments of formula Ic-8, A is CHR9, wherein R9is C1-C6alkyl (e.g., Attorney Docket No.41543-59274 (002WO) methyl). In certain embodiments of formula Ic-8, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ic-8, A is CHR9, wherein R9is -CH2CH2OH.

[0312] In certain embodiments of formula Ic-8, A is S.

[0313] In certain embodiments of formula Ic-8, A is O.

[0314] In certain embodiments of formula Ic-8, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ic-8, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ic-8, A is NR9, wherein R9is hydroxy-C1-C6alkyl. of formula Ic-8, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ic-8, A is NR9, wherein R9. In certain embodiments of formula Ic-8, A is NR9, .

[0315] In certain embodiments of , thereby providing a compound of formula 9) wherein o is an from H, OH, and hydroxy-C1-C6alkyl.

[0316] In certain embodiments of formula Ic-9, o is an integer from 1 to 5. In certain embodiments of formula Ic-9, o is an integer from 1 to 3. In certain embodiments of formula Ic-9, o is an integer Attorney Docket No.41543-59274 (002WO) selected from 1 and 2. In certain embodiments of formula Ic-9, o is 1. In certain embodiments of formula Ic-9, o is 2. In certain embodiments of formula Ic-9, o is 3. In certain embodiments of formula Ic-9, o is 4. In certain embodiments of formula Ic-9, o is 5. In certain embodiments of formula Ic-9, o is 6.

[0317] In certain embodiments of formula Ic-9, R10and R11are each H. In certain embodiments of formula Ic-9, R10and R11are each OH. In certain embodiments of formula Ic-9, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ic-9, R10and R11are each -CH2OH. In certain embodiments of formula Ic-9, R10is H, and R11is OH.

[0318] In certain embodiments of formula Ic, X is -CH2- and Y is C1-C6alkylene. In certain embodiments of formula Ic, X is -CH2- and Y is C1-C3alkylene. In certain embodiments of formula Ic, X is -CH2- and Y is C1-C2alkylene.

[0319] In certain embodiments of formula Ic, -NH-X-Y-NR5R6, thereby providing a compound of formula Ic-10: wherein o is an integer I.

[0320] In certain embodiments of formula Ic-10, o is an integer from 1 to 4. In certain embodiments of formula Ic-10, o is an integer from 1 to 3. In certain embodiments of formula Ic-10, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-10, o is 1. In certain embodiments of formula Ic-10, o is 2. In certain embodiments of formula Ic-10, o is 3. In certain embodiments of formula Ic-10, o is 4. In certain embodiments of formula Ic-10, o is 5.

[0321] In certain embodiments of formula Ic-10, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ic-10, R5and R6are methyl. In certain embodiments of formula Ic-10, R5is C1-C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ic-10, R5is methyl and R6is -CH2CH2OH.

[0322] In certain embodiments of formula Ic-10, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ic-10, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle. Attorney Docket No.41543-59274 (002WO)

[0323] In certain embodiments of formula Ic, -NH-X-Y-NR5R6, thereby providing a compound of formula Ic-11: Z1O wherein o is an integer wherein R9is selected from H, OH, C1-C6heteroalkyl, and optionally substituted

[0324] In certain embodiments of formula Ic-11, o is an integer from 1 to 4. In certain embodiments of formula Ic-11, o is an integer from 1 to 3. In certain embodiments of formula Ic-11, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-11, o is 1. In certain embodiments of formula Ic-11, o is 2. In certain embodiments of formula Ic-11, o is 3. In certain embodiments of formula Ic-11, o is 4. In certain embodiments of formula Ic-11, o is 5.

[0325] In certain embodiments of formula Ic-11, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ic-11, A is CHR9, wherein R9is OH. In certain embodiments of formula Ic-11, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ic-11, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ic-11, A is CHR9, wherein R9is -CH2CH2OH.

[0326] In certain embodiments of formula Ic-11, A is S.

[0327] In certain embodiments of formula Ic-11, A is O.

[0328] In certain embodiments of formula Ic-11, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and certain embodiments of formula Ic-11, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ic-11, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ic-11, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Ic-11, A is NR9, wherein R9. In certain embodiments of formula Ic-11, A is NR9, .

[0329] In certain embodiments of , thereby providing a compound of formula Z1O wherein o is an from H, OH, and hydroxy-C1-C6alkyl.

[0330] In certain embodiments of formula Ic-12, o is an integer from 1 to 4. In certain embodiments of formula Ic-12, o is an integer from 1 to 3. In certain embodiments of formula Ic-12, o is an integer selected from 1 and 2. In certain embodiments of formula Ic-12, o is 1. In certain embodiments of formula Ic-12, o is 2. In certain embodiments of formula Ic-12, o is 3. In certain embodiments of formula Ic-12, o is 4. In certain embodiments of formula Ic-12, o is 5.

[0331] In certain embodiments of formula Ic-12, R10and R11are each H. In certain embodiments of formula Ic-12, R10and R11are each OH. In certain embodiments of formula Ic-12, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ic-12, R10and R11are each -CH2OH. In certain embodiments of formula Ic-12, R10is H, and R11is OH.

[0332] In certain embodiments, the present disclosure provides a compound of formula I, wherein R1is –(CH2)nOC(O)Z1, R2is C10-C20alkyl, R3is H, and R4is OH, thereby forming a compound of formula Id: Attorney Docket No.41543-59274 (002WO) or a pharmaceutically n is an integer from 1 to 10; R2is C10-C20alkyl; and R7and R8are each C4-C20alkyl.

[0333] In certain embodiments of formula Id, n is an integer from 3 to 8. In certain embodiments of formula Id, n is an integer from 4 to 7. In certain embodiments of formula Id, n is an integer selected from 4, 5, and 6. In certain embodiments of formula Id, n is 4. In certain embodiments of formula Id, n is 5. In certain embodiments of formula Id, n is 6.

[0334] In certain embodiments of formula Id, R2is C13-C20alkyl. In certain embodiments of formula Id, R2is C15-C20alkyl. In certain embodiments of formula Id, R2is C15H31.

[0335] In certain embodiments of formula Id, R7is C4-C20alkyl. In certain embodiments of formula Id, R7is C4-C15alkyl. In certain embodiments of formula Id, R7is C4-C10alkyl.

[0336] In certain embodiments of formula Id, R8is C4-C20alkyl. In certain embodiments of formula Id, R8is C4-C15alkyl. In certain embodiments of formula Id, R8is C4-C10alkyl.

[0337] In certain embodiments of formula Id, R7and R8are the same. In certain embodiments of formula Id, R7and R8are different.

[0338] In certain embodiments of formula Id, n is an integer from 3 to 8, R2is C10-C20alkyl, R7is C4-C20alkyl, and R8is C4-C20alkyl. In certain embodiments of formula Id, n is an integer from 5 to 7, R2is C10-C20alkyl, R7is C4-C20alkyl, and R8is C4-C20alkyl. In certain embodiments of formula Id, n is 6, R2is C10-C20alkyl, R7is C4-C20alkyl, and R8is C4-C20alkyl.

[0339] In certain embodiments of formula Id, n is an integer from 3 to 8, R2is C15-C20alkyl, R7is C4-C15alkyl, and R8is C4-C15alkyl. In certain embodiments of formula Id, n is an integer from 5 to 7, R2is C15-C20alkyl, R7is C4-C15alkyl, and R8is C4-C15alkyl. In certain embodiments of formula Id, n is 6, R2is C15-C20alkyl, R7is C4-C20alkyl, and R8is C4-C20alkyl.

[0340] In certain embodiments of formula Id, n is an integer from 3 to 8, R2is C15-C20alkyl, R7is C4-C10alkyl, and R8is C4-C10alkyl. In certain embodiments of formula Id, n is an integer from 5 to 7, R2is C15-C20alkyl, R7is C4-C10alkyl, and R8is C4-C10alkyl. In certain embodiments of formula Id, n is 6, R2is C15-C20alkyl, R7is C4-C10alkyl, and R8is C4-C10alkyl. Attorney Docket No.41543-59274 (002WO)

[0341] In certain embodiments of formula Id, X is -C(O)-, and Y is C1-C6alkylene. In certain embodiments of formula Id, X is -C(O)-, and Y is C1-C3alkylene. In certain embodiments of formula Id, X is -C(O)-, and Y is C1-C2alkylene.

[0342] In certain embodiments of formula Id, -NH-X-Y-NR5R6, thereby providing a compound of formula Id-1: 1) wherein o is an integer from I.

[0343] In certain embodiments of formula Id-1, o is an integer from 1 to 4. In certain embodiments of formula Id-1, o is an integer from 1 to 3. In certain embodiments of formula Id-1, o is an integer selected from 1 and 2. In certain embodiments of formula Id-1, o is 1. In certain embodiments of formula Id-1, o is 2. In certain embodiments of formula Id-1, o is 3. In certain embodiments, of formula Id-1 o is 4. In certain embodiments of formula Id-1, o is 5.

[0344] In certain embodiments of formula Id-1, R5and R6are each C1-C6alkyl. In certain embodiments of formula Id-1, R5and R6are methyl. In certain embodiments of formula Id-1, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Id-1, R5is methyl and R6is -CH2CH2OH.

[0345] In certain embodiments of formula Id-1, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Id-1, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0346] In certain embodiments of , thereby providing a compound of formula Id-2: Attorney Docket No.41543-59274 (002WO) 2) wherein o is an integer from and NR9, wherein R9is selected from H, OH, C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0347] In certain embodiments of formula Id-2, o is an integer from 1 to 4. In certain embodiments of formula Id-2, o is an integer from 1 to 3. In certain embodiments of formula Id-2, o is an integer selected from 1 and 2. In certain embodiments of formula Id-2, o is 1. In certain embodiments of formula Id-2, o is 2. In certain embodiments of formula Id-2, o is 3. In certain embodiments of formula Id-2, o is 4. In certain embodiments of formula Id-2, o is 5.

[0348] In certain embodiments of formula Id-2, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Id-2, A is CHR9, wherein R9is OH. In certain embodiments of formula Id-2, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Id-2, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Id-2, A is CHR9, wherein R9is -CH2CH2OH.

[0349] In certain embodiments of formula Id-2, A is S.

[0350] In certain embodiments of formula Id-2, A is O.

[0351] In certain embodiments of formula Id-2, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and certain embodiments of formula Id-2, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Id-2, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Id-2, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Id-2, A is NR9, wherein R9. In certain embodiments of formula Id-2, A is NR9, .

[0352] In certain embodiments of , thereby providing a compound of formula 3) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0353] In certain embodiments of formula Id-3, o is an integer from 1 to 4. In certain embodiments of formula Id-3, o is an integer from 1 to 3. In certain embodiments of formula Id-3, o is an integer selected from 1 and 2. In certain embodiments of formula Id-3, o is 1. In certain embodiments of formula Id-3, o is 2. In certain embodiments of formula Id-3, o is 3. In certain embodiments of formula Id-3, o is 4. In certain embodiments of formula Id-3, o is 5.

[0354] In certain embodiments of formula Id-3, R10and R11are each H. In certain embodiments of formula Id-3, R10and R11are each OH. In certain embodiments of formula Id-3, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Id-3, R10and R11are each -CH2OH. In certain embodiments of formula Id-3, R10is H, and R11is OH.

[0355] In certain embodiments of formula Id, X is -C(O)-, and Y is C1-C6heteroalkylene. In certain embodiments of formula Id, X is -C(O)-, and Y is C1-C3heteroalkylene. In certain embodiments of formula Id, X is -C(O)-, and Y is C1-C2heteroalkylene. In certain embodiments, X is -C(O)- and Y is - CH2-S-(CH2)q-, wherein q is an integer from 1 to 4. Attorney Docket No.41543-59274 (002WO)

[0356] In certain embodiments of formula Id, -NH-X-Y- , thereby providing a compound of formula Id-4: 4) wherein o is an integer from and R6are as defined for formula I.

[0357] In certain embodiments of formula Id-4, o is an integer from 1 to 3. In certain embodiments of formula Id-4, o is an integer selected from 1 and 2. In certain embodiments of formula Id-4, o is 1. In certain embodiments of formula Id-4, o is 2. In certain embodiments of formula Id-4, o is 3. In certain embodiments of formula Id-4, o is 4.

[0358] In certain embodiments of formula Id-4, Q is S and R5and R6are each C1-C6alkyl. In certain embodiments of formula Id-4, Q is S and R5and R6are methyl. In certain embodiments of formula Id- 4, Q is S, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Id-4, Q is S, R5is methyl, and R6is -CH2CH2OH.

[0359] In certain embodiments of formula Id-4, Q is O and R5and R6are each C1-C6alkyl. In certain embodiments of formula Id-4, Q is O and R5and R6are methyl. In certain embodiments of formula Id- 4, Q is O, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Id-4, Q is O, R5is methyl, and R6is -CH2CH2OH.

[0360] In certain embodiments of formula Id-4, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Id-4, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0361] In certain embodiments of formula Id, -NH-X-Y-NR5R6, thereby providing a compound of formula Id-5: Attorney Docket No.41543-59274 (002WO) 5) Wherein o is an integer selected from CHR9, O, S, 99 and NR , wherein R is C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0362] In certain embodiments of formula Id-5, o is an integer from 1 to 3. In certain embodiments of formula Id-5, o is an integer selected from 1 and 2. In certain embodiments of formula Id-5, o is 1. In certain embodiments of formula Id-5, o is 2. In certain embodiments of formula Id-5, o is 3. In certain embodiments of formula Id-5, o is 4.

[0363] In certain embodiments of formula Id-5, Q is S and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Id-5, Q is S and A is CHR9, wherein R9is OH. In certain embodiments of formula Id-5, Q is S and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Id-5, Q is S and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Id-5, Q is S and A is CHR9, wherein R9is - CH2CH2OH.

[0364] In certain embodiments of formula Id-5, Q is S and A is S.

[0365] In certain embodiments of formula Id-5, Q is S and A is O.

[0366] In certain embodiments of formula Id-5, Q is S and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Id-5, Q is S and A is NR9, wherein R9is C1- In certain embodiments of formula Id-5, Q is S and A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Id-5, Q is S and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Id-5, Q is S and A is NR9, wherein R9is Attorney Docket No.41543-59274 (002WO) certain embodiments of formula Id-5, Q is S and A is NR9, wherein R9is . of formula Id-5, Q is O and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Id-5, Q is O and A is CHR9, wherein R9is OH. In certain embodiments of formula Id-5, Q is O and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Id-5, Q is O and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Id-5, Q is O and A is CHR9, wherein R9is -CH2CH2OH.

[0368] In certain embodiments of formula Id-5, Q is O and A is S.

[0369] In certain embodiments of formula Id-5, Q is O and A is O.

[0370] In certain embodiments of formula Id-5, Q is O and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Id-5, Q is O and A is NR9, wherein R9is C1- In certain embodiments of fo9 9 rmula Id-5, Q is O and A is NR , wherein R is hydroxy-C1-C6alkyl. In certain embodiments of formula Id-5, Q is O and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Id-5, Q is O and A is NR9, wherein R9is certain embodiments of formula Id-5, Q is O and A is NR9, wherein R9is .

[0371] In certain embodiments of , thereby providing a compound of formula Attorney Docket No.41543-59274 (002WO) 6) wherein o is an integer R11are each independently selected

[0372] In certain embodiments of formula Id-6, o is an integer from 1 to 3. In certain embodiments of formula Id-6, o is an integer selected from 1 and 2. In certain embodiments of formula Id-6, o is 1. In certain embodiments of formula Id-6, o is 2. In certain embodiments of formula Id-6, o is 3. In certain embodiments of formula Id-6, o is 4.

[0373] In certain embodiments of formula Id-6, Q is S and R10and R11are each H. In certain embodiments of formula Id-6, Q is S and R10and R11are each OH. In certain embodiments of formula Id-6, Q is S and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Id-6, Q is S and R10and R11are each -CH2OH. In certain embodiments of formula Id-6, Q is S, R10is H, and R11is OH.

[0374] In certain embodiments of formula Id-6, Q is O and R10and R11are each H. In certain embodiments of formula Id-6, Q is O and R10and R11are each OH. In certain embodiments of formula Id-6, Q is O and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Id-6, Q is O and R10and R11are each -CH2OH. In certain embodiments of formula Id-6, Q is O, R10is H, and R11is OH.

[0375] In certain embodiments of formula Id, X is -C(O)S- and Y is C1-C6alkylene. In certain embodiments of formula Id, X is -C(O)S- and Y is C1-C3alkylene. In certain embodiments of formula Id, X is -C(O)S- and Y is C1-C2alkylene.

[0376] In certain embodiments of formula Id, -NH-X-Y- , thereby providing a compound of formula Id-7: Attorney Docket No.41543-59274 (002WO) 7) wherein o is an integer from I.

[0377] In certain embodiments of formula Id-7, o is an integer from 1 to 5. In certain embodiments of formula Id-7, o is an integer from 1 to 3. In certain embodiments of formula Id-7, o is an integer selected from 1 and 2. In certain embodiments of formula Id-7, o is 1. In certain embodiments of formula Id-7, o is 2. In certain embodiments of formula Id-7, o is 3. In certain embodiments of formula Id-7, o is 4. In certain embodiments of formula Id-7, o is 5. In certain embodiments of formula Id-7, o is 6.

[0378] In certain embodiments of formula Id-7, R5and R6are each C1-C6alkyl. In certain embodiments of formula Id-7, R5and R6are methyl. In certain embodiments of formula Id-7, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Id-7, R5is methyl and R6is -CH2CH2OH.

[0379] In certain embodiments of formula Id-7, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Id-7, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0380] In certain embodiments of , thereby providing a compound of formula Id-

[0002] Attorney Docket No.41543-59274 (002WO) 8) wherein o is an integer from and NR9, wherein R9is selected from H, OH, C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0381] In certain embodiments of formula Id-8, o is an integer from 1 to 5. In certain embodiments of formula Id-8, o is an integer from 1 to 3. In certain embodiments of formula Id-8, o is an integer selected from 1 and 2. In certain embodiments of formula Id-8, o is 1. In certain embodiments of formula Id-8, o is 2. In certain embodiments of formula Id-8, o is 3. In certain embodiments of formula Id-8, o is 4. In certain embodiments of formula Id-8, o is 5. In certain embodiments of formula Id-8, o is 6.

[0382] In certain embodiments of formula Id-8, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Id-8, A is CHR9, wherein R9is OH. In certain embodiments of formula Id-8, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Id-8, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Id-8, A is CHR9, wherein R9is -CH2CH2OH.

[0383] In certain embodiments of formula Id-8, A is S.

[0384] In certain embodiments of formula Id-8, A is O.

[0385] In certain embodiments of formula Id-8, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and certain embodiments of formula Id-8, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Id-8, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Id-8, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Id-8, A is NR9, wherein R9. In certain embodiments of formula Id-8, A is NR9, .

[0386] In certain embodiments of , thereby providing a compound of formula 9) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0387] In certain embodiments of formula Id-9, o is an integer from 1 to 5. In certain embodiments of formula Id-9, o is an integer from 1 to 3. In certain embodiments of formula Id-9, o is an integer selected from 1 and 2. In certain embodiments of formula Id-9, o is 1. In certain embodiments of formula Id-9, o is 2. In certain embodiments of formula Id-9, o is 3. In certain embodiments of formula Id-9, o is 4. In certain embodiments of formula Id-9, o is 5. In certain embodiments of formula Id-9, o is 6.

[0388] In certain embodiments of formula Id-9, R10and R11are each H. In certain embodiments of formula Id-9, R10and R11are each OH. In certain embodiments of formula Id-9, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Id-9, R10and R11are each -CH2OH. In certain embodiments of formula Id-9, R10is H, and R11is OH.

[0389] In certain embodiments of formula Id, X is -CH2- and Y is C1-C6alkylene. In certain embodiments of formula Id, X is -CH2- and Y is C1-C3alkylene. In certain embodiments of formula Id, X is -CH2- and Y is C1-C2alkylene. Attorney Docket No.41543-59274 (002WO)

[0390] In certain embodiments of formula Id, -NH-X-Y-NR5R6is , thereby providing a compound of formula Id-10: wherein o is an integer from I.

[0391] In certain embodiments of formula Id-10, o is an integer from 1 to 4. In certain embodiments of formula Id-10, o is an integer from 1 to 3. In certain embodiments of formula Id-10, o is an integer selected from 1 and 2. In certain embodiments of formula Id-10, o is 1. In certain embodiments of formula Id-10, o is 2. In certain embodiments of formula Id-10, o is 3. In certain embodiments of formula Id-10, o is 4. In certain embodiments of formula Id-10, o is 5.

[0392] In certain embodiments of formula Id-10, R5and R6are each C1-C6alkyl. In certain embodiments of formula Id-10, R5and R6are methyl. In certain embodiments of formula Id-10, R5is C1-C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Id-10, R5is methyl and R6is -CH2CH2OH.

[0393] In certain embodiments of formula Id-10, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Id-10, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0394] In certain embodiments of formula Id, -NH-X-Y-NR5R6, thereby providing a compound of formula Id-11:

[0003] Attorney Docket No.41543-59274 (002WO) wherein o is an integer from and NR9, wherein R9is selected from H, OH, C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0395] In certain embodiments of formula Id-11, o is an integer from 1 to 4. In certain embodiments of formula Id-11, o is an integer from 1 to 3. In certain embodiments of formula Id-11, o is an integer selected from 1 and 2. In certain embodiments of formula Id-11, o is 1. In certain embodiments of formula Id-11, o is 2. In certain embodiments of formula Id-11, o is 3. In certain embodiments of formula Id-11, o is 4. In certain embodiments of formula Id-11, o is 5.

[0396] In certain embodiments of formula Id-11, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Id-11, A is CHR9, wherein R9is OH. In certain embodiments of formula Id-11, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Id-11, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Id-11, A is CHR9, wherein R9is -CH2CH2OH.

[0397] In certain embodiments of formula Id-11, A is S.

[0398] In certain embodiments of formula Id-11, A is O.

[0399] In certain embodiments of formula Id-11, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and certain embodiments of formula Id-11, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Id-11, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Id-11, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Id-11, A is NR9, wherein R9. In certain embodiments of formula Id-11, A is NR9, .

[0400] In certain embodiments of , thereby providing a compound of formula wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0401] In certain embodiments of formula Id-12, o is an integer from 1 to 4. In certain embodiments of formula Id-12, o is an integer from 1 to 3. In certain embodiments of formula Id-12, o is an integer selected from 1 and 2. In certain embodiments of formula Id-12, o is 1. In certain embodiments of formula Id-12, o is 2. In certain embodiments of formula Id-12, o is 3. In certain embodiments of formula Id-12, o is 4. In certain embodiments of formula Id-12, o is 5.

[0402] In certain embodiments of formula Id-12, R10and R11are each H. In certain embodiments of formula Id-12, R10and R11are each OH. In certain embodiments of formula Id-12, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Id-12, R10and R11are each -CH2OH. In certain embodiments of formula Id-12, R10is H, and R11is OH.

[0403] In certain embodiments, the present disclosure provides a compound of formula I, wherein R1is -(CH2)nOC(O)Z1, R2is -(CH2)mC(O)OZ2, R3is H, and R4is H, thereby forming a compound of formula Ig: Attorney Docket No.41543-59274 (002WO) or a pharmaceutically Z1is C6-C20alkenyl; n is an integer from 1 to 10; m is an integer from 1 to 10; and R7is C4-C20alkyl.

[0404] In certain embodiments of formula Ig, Z1has at least two double bonds, such as, for example, three double bonds, four double bonds, or five double bonds. In certain embodiments of formula Ig, Z1has two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ig, the double bonds of Z1are cis.

[0405] In certain embodiments of formula Ig, Z1is C10-C20alkenyl. In certain embodiments of formula Ig, Z1is C15-C20alkenyl. In certain embodiments of formula Ig, Z1is C17alkenyl. In certain embodiments of formula Ig, Z1is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0406] In certain embodiments of formula Ig, n is an integer from 1 to 5. In certain embodiments of formula Ig, n is an integer from 1 to 3. In certain embodiments of formula Ig, n is an integer selected from 1 and 2. In certain embodiments of formula Ig, n is 1. In certain embodiments of formula Ig, n is 2. In certain embodiments of formula Ig, n is 3. In certain embodiments of formula Ig, n is 4. In certain embodiments of formula Ig, n is 5.

[0407] In certain embodiments of formula Ig, m is an integer from 3 to 8. In certain embodiments of formula Ig, m is an integer selected from 5, 6, or 7. In certain embodiments of formula Ig, m is 5. In certain embodiments of formula Ig, m is 6. In certain embodiments of formula Ig, m is 7.

[0408] In certain embodiments of formula Ig, R7is C4-C20alkyl. In certain embodiments of formula Ig, R7is C4-C15alkyl. In certain embodiments of formula Ig, R7is C4-C10alkyl.

[0409] In certain embodiments of formula Ig, Z1is C10-C20alkenyl, n is an integer from 1 to 5, m is an integer from 3 to 8, and R7is C4-C20alkyl. In certain embodiments of formula Ig, Z1is C10-C20alkenyl, n is an integer from 1 to 3, m is an integer from 4 to 6, and R7is C4-C20alkyl. In certain embodiments of formula Ig, Z1is C10-C20alkenyl, n is 3, m is 5, and R7is C4-C20alkyl.

[0410] In certain embodiments of formula Ig, Z1is C15-C20alkenyl, n is an integer from 1 to 5, m is an integer from 3 to 8, and R7is C4-C15alkyl. In certain embodiments of formula Ig, Z1is C15-C20 Attorney Docket No.41543-59274 (002WO) alkenyl, n is an integer from 1 to 3, m is an integer from 4 to 6, and R7is C4-C15alkyl. In certain embodiments of formula Ig, Z1is C15-C20alkenyl, n is 3, m is 5, and R7is C4-C15alkyl.

[0411] In certain embodiments of formula Ig, Z1is C15-C20alkenyl, n is an integer from 1 to 5, m is an integer from 3 to 8, and R7is C4-C10alkyl. In certain embodiments of formula Ig, Z1is C15-C20alkenyl, n is an integer from 1 to 3, m is an integer from 4 to 6, and R7is C4-C10alkyl. In certain embodiments of formula Ig, Z1is C15-C20alkenyl, n is 2, m is 5, and R7is C4-C10alkyl.

[0412] In certain embodiments of formula Ig, X is -C(O)-, and Y is C1-C6alkylene. In certain embodiments of formula Ig, X is -C(O)-, and Y is C1-C3alkylene. In certain embodiments of formula Ig, X is -C(O)-, and Y is C1-C2alkylene.

[0413] In certain embodiments of formula Ig, -NH-X-Y-NR5R6, thereby providing a compound of formula Ig-1: 1) wherein o is an

[0414] In certain embodiments of formula Ig-1, o is an integer from 1 to 4. In certain embodiments of formula Ig-1, o is an integer from 1 to 3. In certain embodiments of formula Ig-1, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-1, o is 1. In certain embodiments of formula Ig-1, o is 2. In certain embodiments of formula Ig-1, o is 3. In certain embodiments, of formula Ig-1 o is 4. In certain embodiments of formula Ig-1, o is 5.

[0415] In certain embodiments of formula Ig-1, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ig-1, R5and R6are methyl. In certain embodiments of formula Ig-1, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ig-1, R5is methyl and R6is -CH2CH2OH.

[0416] In certain embodiments of formula Ig-1, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ig-1, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle. Attorney Docket No.41543-59274 (002WO)

[0417] In certain embodiments of , thereby providing a compound of formula Ig-2: 2) wherein o is an wherein R9is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0418] In certain embodiments of formula Ig-2, o is an integer from 1 to 4. In certain embodiments of formula Ig-2, o is an integer from 1 to 3. In certain embodiments of formula Ig-2, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-2, o is 1. In certain embodiments of formula Ig-2, o is 2. In certain embodiments of formula Ig-2, o is 3. In certain embodiments of formula Ig-2, o is 4. In certain embodiments of formula Ig-2, o is 5.

[0419] In certain embodiments of formula Ig-2, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ig-2, A is CHR9, wherein R9is OH. In certain embodiments of formula Ig-2, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ig-2, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ig-2, A is CHR9, wherein R9is -CH2CH2OH.

[0420] In certain embodiments of formula Ig-2, A is S.

[0421] In certain embodiments of formula Ig-2, A is O.

[0422] In certain embodiments of formula Ig-2, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and certain embodiments of formula Ig-2, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ig-2, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-2, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Ig-2, A is NR9, wherein R9. In certain embodiments of formula Ig-2, A is NR9, .

[0423] In certain embodiments of , thereby providing a compound of formula 3) wherein o is an from H, OH, and hydroxy-C1-C6alkyl.

[0424] In certain embodiments of formula Ig-3, o is an integer from 1 to 4. In certain embodiments of formula Ig-3, o is an integer from 1 to 3. In certain embodiments of formula Ig-3, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-3, o is 1. In certain embodiments of formula Ig-3, o is 2. In certain embodiments of formula Ig-3, o is 3. In certain embodiments of formula Ig-3, o is 4. In certain embodiments of formula Ig-3, o is 5.

[0425] In certain embodiments of formula Ig-3, R10and R11are each H. In certain embodiments of formula Ig-3, R10and R11are each OH. In certain embodiments of formula Ig-3, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-3, R10and R11are each -CH2OH. In certain embodiments of formula Ig-3, R10is H, and R11is OH.

[0426] In certain embodiments of formula Ig, X is -C(O)-, and Y is C1-C6heteroalkylene. In certain embodiments of formula Ig, X is -C(O)-, and Y is C1-C3heteroalkylene. In certain embodiments of formula Ig, X is -C(O)-, and Y is C1-C2heteroalkylene. In certain embodiments, X is -C(O)- and Y is - CH2-S-(CH2)q-, wherein q is an integer from 1 to 4. Attorney Docket No.41543-59274 (002WO)

[0427] In certain embodiments of formula Ig, -NH-X-Y- , thereby providing a compound of formula Ig-4: 1 Z O 4) wherein o is an as defined for formula I.

[0428] In certain embodiments of formula Ig-4, o is an integer from 1 to 3. In certain embodiments of formula Ig-4, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-4, o is 1. In certain embodiments of formula Ig-4, o is 2. In certain embodiments of formula Ig-4, o is 3. In certain embodiments of formula Ig-4, o is 4.

[0429] In certain embodiments of formula Ig-4, Q is S and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ig-4, Q is S and R5and R6are methyl. In certain embodiments of formula Ig- 4, Q is S, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ig-4, Q is S, R5is methyl, and R6is -CH2CH2OH.

[0430] In certain embodiments of formula Ig-4, Q is O and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ig-4, Q is O and R5and R6are methyl. In certain embodiments of formula Ig- 4, Q is O, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ig-4, Q is O, R5is methyl, and R6is -CH2CH2OH.

[0431] In certain embodiments of formula Ig-4, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ig-4, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0432] In certain embodiments of formula Ig, -NH-X-Y-NR5R6, thereby providing a compound of formula Ig-5: Attorney Docket No.41543-59274 (002WO) 5) wherein o is an from CHR9, O, S, and NR9, wherein optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0433] In certain embodiments of formula Ig-5, o is an integer from 1 to 3. In certain embodiments of formula Ig-5, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-5, o is 1. In certain embodiments of formula Ig-5, o is 2. In certain embodiments of formula Ig-5, o is 3. In certain embodiments of formula Ig-5, o is 4.

[0434] In certain embodiments of formula Ig-5, Q is S and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ig-5, Q is S and A is CHR9, wherein R9is OH. In certain embodiments of formula Ig-5, Q is S and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ig-5, Q is S and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ig-5, Q is S and A is CHR9, wherein R9is - CH2CH2OH.

[0435] In certain embodiments of formula Ig-5, Q is S and A is S.

[0436] In certain embodiments of formula Ig-5, Q is S and A is O.

[0437] In certain embodiments of formula Ig-5, Q is S and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ig-5, Q is S and A is NR9, wherein R9is C1- In certain embodiments of formula Ig-5, Q is S and A9 9 is NR , wherein R is hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-5, Q is S and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ig-5, Q is S and A is NR9, wherein R9is Attorney Docket No.41543-59274 (002WO) certain embodiments of formula Ig-5, Q is S and A is NR9, wherein R9is . of formula Ig-5, Q is O and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ig-5, Q is O and A is CHR9, wherein R9is OH. In certain embodiments of formula Ig-5, Q is O and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ig-5, Q is O and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ig-5, Q is O and A is CHR9, wherein R9is -CH2CH2OH.

[0439] In certain embodiments of formula Ig-5, Q is O and A is S.

[0440] In certain embodiments of formula Ig-5, Q is O and A is O.

[0441] In certain embodiments of formula Ig-5, Q is O and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ig-5, Q is O and A is NR9, wherein R9is C1- In certain embodiments of fo9 9 rmula Ig-5, Q is O and A is NR , wherein R is hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-5, Q is O and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ig-5, Q is O and A is NR9, wherein R9is certain embodiments of formula Ig-5, Q is O and A is NR9, wherein R9is .

[0442] In certain embodiments of , thereby providing a compound of formula Attorney Docket No.41543-59274 (002WO) 6) wherein o is an from H, OH, and hydroxy-C1-C6

[0443] In certain embodiments of formula Ig-6, o is an integer from 1 to 3. In certain embodiments of formula Ig-6, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-6, o is 1. In certain embodiments of formula Ig-6, o is 2. In certain embodiments of formula Ig-6, o is 3. In certain embodiments of formula Ig-6, o is 4.

[0444] In certain embodiments of formula Ig-6, Q is S and R10and R11are each H. In certain embodiments of formula Ig-6, Q is S and R10and R11are each OH. In certain embodiments of formula Ig-6, Q is S and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-6, Q is S and R10and R11are each -CH2OH. In certain embodiments of formula Ig-6, Q is S, R10is H, and R11is OH.

[0445] In certain embodiments of formula Ig-6, Q is O and R10and R11are each H. In certain embodiments of formula Ig-6, Q is O and R10and R11are each OH. In certain embodiments of formula Ig-6, Q is O and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-6, Q is O and R10and R11are each -CH2OH. In certain embodiments of formula Ig-6, Q is O, R10is H, and R11is OH.

[0446] In certain embodiments of formula Ig, X is -C(O)S- and Y is C1-C6alkylene. In certain embodiments of formula Ig, X is -C(O)S- and Y is C1-C3alkylene. In certain embodiments of formula Ig, X is -C(O)S- and Y is C1-C2alkylene.

[0447] In certain embodiments of formula Ig, -NH-X-Y-NR5R6, thereby providing a compound of formula Ig-7: 7) wherein o is an I. Attorney Docket No.41543-59274 (002WO)

[0448] In certain embodiments of formula Ig-7, o is an integer from 1 to 5. In certain embodiments of formula Ig-7, o is an integer from 1 to 3. In certain embodiments of formula Ig-7, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-7, o is 1. In certain embodiments of formula Ig-7, o is 2. In certain embodiments of formula Ig-7, o is 3. In certain embodiments of formula Ig-7, o is 4. In certain embodiments of formula Ig-7, o is 5. In certain embodiments of formula Ig-7, o is 6.

[0449] In certain embodiments of formula Ig-7, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ig-7, R5and R6are methyl. In certain embodiments of formula Ig-7, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ig-7, R5is methyl and R6is -CH2CH2OH.

[0450] In certain embodiments of formula Ig-7, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ig-7, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0451] In certain embodiments of , thereby providing a compound of formula Ig- 8) wherein o is an wherein R9is selected from H, C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0452] In certain embodiments of formula Ig-8, o is an integer from 1 to 5. In certain embodiments of formula Ig-8, o is an integer from 1 to 3. In certain embodiments of formula Ig-8, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-8, o is 1. In certain embodiments of formula Ig-8, o is 2. In certain embodiments of formula Ig-8, o is 3. In certain embodiments of formula Ig-8, o is 4. In certain embodiments of formula Ig-8, o is 5. In certain embodiments of formula Ig-8, o is 6.

[0453] In certain embodiments of formula Ig-8, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ig-8, A is CHR9, wherein R9is OH. In certain embodiments of formula Ig-8, A is CHR9, wherein R9is C1-C6alkyl (e.g., Attorney Docket No.41543-59274 (002WO) methyl). In certain embodiments of formula Ig-8, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ig-8, A is CHR9, wherein R9is -CH2CH2OH.

[0454] In certain embodiments of formula Ig-8, A is S.

[0455] In certain embodiments of formula Ig-8, A is O.

[0456] In certain embodiments of formula Ig-8, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ig-8, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ig-8, A is NR9, wherein R9is hydroxy-C1-C6alkyl. of formula Ig-8, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ig-8, A is NR9, wherein R9. In certain embodiments of formula Ig-8, A is NR9, .

[0457] In certain embodiments of , thereby providing a compound of formula 9) wherein o is an from H, OH, and hydroxy-C1-C6alkyl.

[0458] In certain embodiments of formula Ig-9, o is an integer from 1 to 5. In certain embodiments of formula Ig-9, o is an integer from 1 to 3. In certain embodiments of formula Ig-9, o is an integer Attorney Docket No.41543-59274 (002WO) selected from 1 and 2. In certain embodiments of formula Ig-9, o is 1. In certain embodiments of formula Ig-9, o is 2. In certain embodiments of formula Ig-9, o is 3. In certain embodiments of formula Ig-9, o is 4. In certain embodiments of formula Ig-9, o is 5. In certain embodiments of formula Ig-9, o is 6.

[0459] In certain embodiments of formula Ig-9, R10and R11are each H. In certain embodiments of formula Ig-9, R10and R11are each OH. In certain embodiments of formula Ig-9, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-9, R10and R11are each -CH2OH. In certain embodiments of formula Ig-9, R10is H, and R11is OH.

[0460] In certain embodiments of formula Ig, X is -CH2- and Y is C1-C6alkylene. In certain embodiments of formula Ig, X is -CH2- and Y is C1-C3alkylene. In certain embodiments of formula Ig, X is -CH2- and Y is C1-C2alkylene.

[0461] In certain embodiments of formula Ig, -NH-X-Y-NR5R6, thereby providing a compound of formula Ig-10: wherein o is an

[0462] In certain embodiments of formula Ig-10, o is an integer from 1 to 4. In certain embodiments of formula Ig-10, o is an integer from 1 to 3. In certain embodiments of formula Ig-10, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-10, o is 1. In certain embodiments of formula Ig-10, o is 2. In certain embodiments of formula Ig-10, o is 3. In certain embodiments of formula Ig-10, o is 4. In certain embodiments of formula Ig-10, o is 5.

[0463] In certain embodiments of formula Ig-10, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ig-10, R5and R6are methyl. In certain embodiments of formula Ig-10, R5is C1-C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ig-10, R5is methyl and R6is -CH2CH2OH.

[0464] In certain embodiments of formula Ig-10, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ig-10, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle. Attorney Docket No.41543-59274 (002WO)

[0465] In certain embodiments of formula Ig, -NH-X-Y-NR5R6, thereby providing a compound of formula Ig-11: wherein o is an wherein R9is selected from H, C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0466] In certain embodiments of formula Ig-11, o is an integer from 1 to 4. In certain embodiments of formula Ig-11, o is an integer from 1 to 3. In certain embodiments of formula Ig-11, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-11, o is 1. In certain embodiments of formula Ig-11, o is 2. In certain embodiments of formula Ig-11, o is 3. In certain embodiments of formula Ig-11, o is 4. In certain embodiments of formula Ig-11, o is 5.

[0467] In certain embodiments of formula Ig-11, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ig-11, A is CHR9, wherein R9is OH. In certain embodiments of formula Ig-11, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ig-11, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ig-11, A is CHR9, wherein R9is -CH2CH2OH.

[0468] In certain embodiments of formula Ig-11, A is S.

[0469] In certain embodiments of formula Ig-11, A is O.

[0470] In certain embodiments of formula Ig-11, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ig-11, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ig-11, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-11, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Ig-11, A is NR9, wherein R9. In certain embodiments of formula Ig-11, A is NR9, .

[0471] In certain embodiments of , thereby providing a compound of formula Ig- wherein o is an from H, OH, and hydroxy-C1-C6

[0472] In certain embodiments of formula Ig-12, o is an integer from 1 to 4. In certain embodiments of formula Ig-12, o is an integer from 1 to 3. In certain embodiments of formula Ig-12, o is an integer selected from 1 and 2. In certain embodiments of formula Ig-12, o is 1. In certain embodiments of formula Ig-12, o is 2. In certain embodiments of formula Ig-12, o is 3. In certain embodiments of formula Ig-12, o is 4. In certain embodiments of formula Ig-12, o is 5.

[0473] In certain embodiments of formula Ig-12, R10and R11are each H. In certain embodiments of formula Ig-12, R10and R11are each OH. In certain embodiments of formula Ig-12, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ig-12, R10and R11are each -CH2OH. In certain embodiments of formula Ig-12, R10is H, and R11is OH.

[0474] In certain embodiments, the present disclosure provides a compound of formula I, wherein R1is -(CH2)nOC(O)Z1, R2is -(CH2)nOC(O)Z2, R3is C1-C6alkyl, and R4is H, thereby forming a compound of formula Ih: Attorney Docket No.41543-59274 (002WO) or a pharmaceutically Z1and Z2are each C6-C20 n is an integer from 1 to 10; m is an integer from 0 to 10; and R3is C1-C6alkyl.

[0475] In certain embodiments of formula Ih, Z1and Z2are the same. In certain embodiments of formula Ih, Z1and Z2are different.

[0476] In certain embodiments of formula Ih, Z1has at least two double bonds, such as, for example, three double bonds, four double bonds, or five double bonds. In certain embodiments of formula Ih, Z1has two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ih, the double bonds of Z1are cis.

[0477] In certain embodiments of formula Ih, Z2has at least two double bonds, such as, for example, three double bonds, four double bonds, or five double bonds. In certain embodiments of formula Ih, Z2has two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ih, the double bonds of Z2are cis.

[0478] In certain embodiments of formula Ih, Z1and Z2have at least two double bonds. In certain embodiments of formula Ih, Z1and Z2have two double bonds. In each instance, the double bond can be cis or trans. In certain embodiments of formula Ih, the double bonds of Z1and Z2are cis.

[0479] In certain embodiments of formula Ih, Z1is C10-C20alkenyl. In certain embodiments of formula Ih, Z1is C15-C20alkenyl. In certain embodiments of formula Ih, Z1is C17alkenyl. In certain embodiments of formula Ih, Z1is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0480] In certain embodiments of formula Ih, Z2is C10-C20alkenyl. In certain embodiments of formula Ih, Z2is C15-C20alkenyl. In certain embodiments of formula Ih, Z2is C17alkenyl. In certain embodiments of formula Ih, Z2is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0481] In certain embodiments of formula Ih, Z1and Z2are C10-C20alkenyl. In certain embodiments of formula Ih, Z1and Z2are C15-C20alkenyl. In certain embodiments of formula Ih, Z1and Z2are C17alkenyl. In certain embodiments of formula Ih, Z1and Z2are -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0482] In certain embodiments of formula Ih, n is an integer from 1 to 5. In certain embodiments of formula Ih, n is an integer from 1 to 3. In certain embodiments of formula Ih, n is an integer selected Attorney Docket No.41543-59274 (002WO) from 1 and 2. In certain embodiments of formula Ih, n is 1. In certain embodiments of formula Ih, n is 2. In certain embodiments of formula Ih, n is 3. In certain embodiments of formula Ih, n is 4. In certain embodiments of formula Ih, n is 5.

[0483] In certain embodiments of formula Ih, m is an integer from 0 to 5. In certain embodiments of formula Ih, m is an integer from 0 to 3. In certain embodiments of formula Ih, m is an integer selected from 0, 1 and 2. In certain embodiments of formula Ih, m is 0. In certain embodiments of formula Ih, m is 1. In certain embodiments of formula Ih, m is 2. In certain embodiments of formula Ih, m is 3. In certain embodiments of formula Ih, m is 4. In certain embodiments of formula Ih, m is 5.

[0484] In certain embodiments of formula Ih, R3is C1-C3alkyl. In certain embodiments of formula Ih, R3is methyl, ethyl or propyl. In certain embodiments of formula Ih, R3is methyl.

[0485] In certain embodiments of formula Ih, Z1is C10-C20alkenyl, Z2is C10-C20alkenyl, n is an integer from 1 to 5, m is an integer from 0 to 5, and R3is C1-C3alkyl. In certain embodiments of formula Ih, Z1is C10-C20alkenyl, Z2is C10-C20alkenyl, n is an integer from 1 to 3, m is an integer from 0 to 3, and R3is C1-C3alkyl. In certain embodiments of formula Ih, Z1is C10-C20alkenyl, Z2is C10-C20alkenyl, n is 1, m is 0, and R3is methyl.

[0486] In certain embodiments of formula Ih, Z1is C15-C20alkenyl, Z2is C15-C20alkenyl, n is an integer from 1 to 5, m is an integer from 0 to 5, and R3is C1-C3alkyl. In certain embodiments of formula Ih, Z1is C15-C20alkenyl, Z2is C15-C20alkenyl, n is an integer from 1 to 3, m is an integer from 0 to 3, and R3is C1-C3alkyl. In certain embodiments of formula Ih, Z1is C15-C20alkenyl, Z2is C15-C20alkenyl, n is 1, m is 0, and R3is methyl.

[0487] In certain embodiments of formula Ih, X is -C(O)-, and Y is C1-C6alkylene. In certain embodiments of formula Ih, X is -C(O)-, and Y is C1-C3alkylene. In certain embodiments of formula Ih, X is -C(O)-, and Y is C1-C2alkylene.

[0488] In certain embodiments of formula Ih, -NH-X-Y-NR5R6, thereby providing a compound of formula Ih-1: 1) wherein o is an integer I. Attorney Docket No.41543-59274 (002WO)

[0489] In certain embodiments of formula Ih-1, o is an integer from 1 to 4. In certain embodiments of formula Ih-1, o is an integer from 1 to 3. In certain embodiments of formula Ih-1, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-1, o is 1. In certain embodiments of formula Ih-1, o is 2. In certain embodiments of formula Ih-1, o is 3. In certain embodiments, of formula Ih-1 o is 4. In certain embodiments of formula Ih-1, o is 5.

[0490] In certain embodiments of formula Ih-1, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ih-1, R5and R6are methyl. In certain embodiments of formula Ih-1, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ih-1, R5is methyl and R6is -CH2CH2OH.

[0491] In certain embodiments of formula Ih-1, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ih-1, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0492] In certain embodiments of , thereby providing a compound of formula Ih-2: 2) wherein o is an integer NR9, wherein R9is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0493] In certain embodiments of formula Ih-2, o is an integer from 1 to 4. In certain embodiments of formula Ih-2, o is an integer from 1 to 3. In certain embodiments of formula Ih-2, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-2, o is 1. In certain embodiments of formula Ih-2, o is 2. In certain embodiments of formula Ih-2, o is 3. In certain embodiments of formula Ih-2, o is 4. In certain embodiments of formula Ih-2, o is 5.

[0494] In certain embodiments of formula Ih-2, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ih-2, A is CHR9, Attorney Docket No.41543-59274 (002WO) wherein R9is OH. In certain embodiments of formula Ih-2, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ih-2, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ih-2, A is CHR9, wherein R9is -CH2CH2OH.

[0495] In certain embodiments of formula Ih-2, A is S.

[0496] In certain embodiments of formula Ih-2, A is O.

[0497] In certain embodiments of formula Ih-2, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ih-2, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ih-2, A is NR9, wherein R9is hydroxy-C1-C6alkyl. of formula Ih-2, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ih-2, A is NR9, wherein R9. In certain embodiments of formula Ih-2, A is NR9, .

[0498] In certain embodiments of , thereby providing a compound of formula Ih- 3) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl. Attorney Docket No.41543-59274 (002WO)

[0499] In certain embodiments of formula Ih-3, o is an integer from 1 to 4. In certain embodiments of formula Ih-3, o is an integer from 1 to 3. In certain embodiments of formula Ih-3, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-3, o is 1. In certain embodiments of formula Ih-3, o is 2. In certain embodiments of formula Ih-3, o is 3. In certain embodiments of formula Ih-3, o is 4. In certain embodiments of formula Ih-3, o is 5.

[0500] In certain embodiments of formula Ih-3, R10and R11are each H. In certain embodiments of formula Ih-3, R10and R11are each OH. In certain embodiments of formula Ih-3, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ih-3, R10and R11are each -CH2OH. In certain embodiments of formula Ih-3, R10is H, and R11is OH.

[0501] In certain embodiments of formula Ih, X is -C(O)-, and Y is C1-C6heteroalkylene. In certain embodiments of formula Ih, X is -C(O)-, and Y is C1-C3heteroalkylene. In certain embodiments of formula Ih, X is -C(O)-, and Y is C1-C2heteroalkylene. In certain embodiments, X is -C(O)- and Y is - CH2-S-(CH2)q-, wherein q is an integer from 1 to 4.

[0502] In certain embodiments of formula Ih, -NH-X-Y-NR5R6is , thereby providing a compound of formula Ih-4: 4) wherein o is an integer R6are as defined for formula I.

[0503] In certain embodiments of formula Ih-4, o is an integer from 1 to 3. In certain embodiments of formula Ih-4, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-4, o is 1. In certain embodiments of formula Ih-4, o is 2. In certain embodiments of formula Ih-4, o is 3. In certain embodiments of formula Ih-4, o is 4.

[0504] In certain embodiments of formula Ih-4, Q is S and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ih-4, Q is S and R5and R6are methyl. In certain embodiments of formula Ih- 4, Q is S, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ih-4, Q is S, R5is methyl, and R6is -CH2CH2OH.

[0505] In certain embodiments of formula Ih-4, Q is O and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ih-4, Q is O and R5and R6are methyl. In certain embodiments of formula Ih- Attorney Docket No.41543-59274 (002WO) 4, Q is O, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ih-4, Q is O, R5is methyl, and R6is -CH2CH2OH.

[0506] In certain embodiments of formula Ih-4, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ih-4, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0507] In certain embodiments of formula Ih, -NH-X-Y-NR5R6, thereby providing a compound of formula Ih-5: 5) wherein o is an integer9 from CHR , O, S, and NR9, wherein R9is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0508] In certain embodiments of formula Ih-5, o is an integer from 1 to 3. In certain embodiments of formula Ih-5, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-5, o is 1. In certain embodiments of formula Ih-5, o is 2. In certain embodiments of formula Ih-5, o is 3. In certain embodiments of formula Ih-5, o is 4.

[0509] In certain embodiments of formula Ih-5, Q is S and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ih-5, Q is S and A is CHR9, wherein R9is OH. In certain embodiments of formula Ih-5, Q is S and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ih-5, Q is S and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ih-5, Q is S and A is CHR9, wherein R9is - CH2CH2OH.

[0510] In certain embodiments of formula Ih-5, Q is S and A is S.

[0511] In certain embodiments of formula Ih-5, Q is S and A is O. Attorney Docket No.41543-59274 (002WO)

[0512] In certain embodiments of formula Ih-5, Q is S and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ih-5, Q is S and A is NR9, wherein R9is C1- In certain embodiments of formula Ih-5, Q is S and A is NR9, wherein R9is certain embodiments of formula Ih-5, Q is S and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ih-5, Q is S and A is NR9, wherein R9is certain embodiments of formula Ih-5, Q is S and A is NR9, wherein R9is . of formula Ih-5, Q is O and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ih-5, Q is O and A is CHR9, wherein R9is OH. In certain embodiments of formula Ih-5, Q is O and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ih-5, Q is O and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ih-5, Q is O and A is CHR9, wherein R9is -CH2CH2OH.

[0514] In certain embodiments of formula Ih-5, Q is O and A is S.

[0515] In certain embodiments of formula Ih-5, Q is O and A is O.

[0516] In certain embodiments of formula Ih-5, Q is O and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ih-5, Q is O and A is NR9, wherein R9is C1- In certain embodiments of formula Ih-5, Q is O and A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ih-5, Q is O and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ih-5, Q is O and A is NR9, wherein R9is Attorney Docket No.41543-59274 (002WO) is

[0517] In certain embodiments of , thereby providing a compound of formula Ih- 6) wherein o is an are each independently

[0518] In certain embodiments of formula Ih-6, o is an integer from 1 to 3. In certain embodiments of formula Ih-6, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-6, o is 1. In certain embodiments of formula Ih-6, o is 2. In certain embodiments of formula Ih-6, o is 3. In certain embodiments of formula Ih-6, o is 4.

[0519] In certain embodiments of formula Ih-6, Q is S and R10and R11are each H. In certain embodiments of formula Ih-6, Q is S and R10and R11are each OH. In certain embodiments of formula Ih-6, Q is S and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ih-6, Q is S and R10and R11are each -CH2OH. In certain embodiments of formula Ih-6, Q is S, R10is H, and R11is OH.

[0520] In certain embodiments of formula Ih-6, Q is O and R10and R11are each H. In certain embodiments of formula Ih-6, Q is O and R10and R11are each OH. In certain embodiments of formula Ih-6, Q is O and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ih-6, Q is O and R10and R11are each -CH2OH. In certain embodiments of formula Ih-6, Q is O, R10is H, and R11is OH.

[0521] In certain embodiments of formula Ih, X is -C(O)S- and Y is C1-C6alkylene. In certain embodiments of formula Ih, X is -C(O)S- and Y is C1-C3 alkylene. In certain embodiments of formula Ih, X is -C(O)S- and Y is C1-C2alkylene. Attorney Docket No.41543-59274 (002WO)

[0522] In certain embodiments of formula Ih, -NH-X-Y-NR5R6, thereby providing a compound of formula Ih-7: 7) wherein o is an integer I.

[0523] In certain embodiments of formula Ih-7, o is an integer from 1 to 5. In certain embodiments of formula Ih-7, o is an integer from 1 to 3. In certain embodiments of formula Ih-7, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-7, o is 1. In certain embodiments of formula Ih-7, o is 2. In certain embodiments of formula Ih-7, o is 3. In certain embodiments of formula Ih-7, o is 4. In certain embodiments of formula Ih-7, o is 5. In certain embodiments of formula Ih-7, o is 6.

[0524] In certain embodiments of formula Ih-7, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ih-7, R5and R6are methyl. In certain embodiments of formula Ih-7, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ih-7, R5is methyl and R6is -CH2CH2OH.

[0525] In certain embodiments of formula Ih-7, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ih-7, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0526] In certain embodiments of , thereby providing a compound of formula Ih-

[0004] Attorney Docket No.41543-59274 (002WO) 8) wherein o is an integer NR9, wherein R9is selected from H, OH, C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0527] In certain embodiments of formula Ih-8, o is an integer from 1 to 5. In certain embodiments of formula Ih-8, o is an integer from 1 to 3. In certain embodiments of formula Ih-8, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-8, o is 1. In certain embodiments of formula Ih-8, o is 2. In certain embodiments of formula Ih-8, o is 3. In certain embodiments of formula Ih-8, o is 4. In certain embodiments of formula Ih-8, o is 5. In certain embodiments of formula Ih-8, o is 6.

[0528] In certain embodiments of formula Ih-8, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ih-8, A is CHR9, wherein R9is OH. In certain embodiments of formula Ih-8, A is CHR9, wherein R9is C1-C6 alkyl (e.g., methyl). In certain embodiments of formula Ih-8, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ih-8, A is CHR9, wherein R9is -CH2CH2OH.

[0529] In certain embodiments of formula Ih-8, A is S.

[0530] In certain embodiments of formula Ih-8, A is O.

[0531] In certain embodiments of formula Ih-8, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, , and certain embodiments of formula Ih-8, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ih-8, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ih-8, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Ih-8, A is NR9, wherein R9. In certain embodiments of formula Ih-8, A is NR9, .

[0532] In certain embodiments of , thereby providing a compound of formula Ih- 9) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0533] In certain embodiments of formula Ih-9, o is an integer from 1 to 5. In certain embodiments of formula Ih-9, o is an integer from 1 to 3. In certain embodiments of formula Ih-9, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-9, o is 1. In certain embodiments of formula Ih-9, o is 2. In certain embodiments of formula Ih-9, o is 3. In certain embodiments of formula Ih-9, o is 4. In certain embodiments of formula Ih-9, o is 5. In certain embodiments of formula Ih-9, o is 6.

[0534] In certain embodiments of formula Ih-9, R10and R11are each H. In certain embodiments of formula Ih-9, R10and R11are each OH. In certain embodiments of formula Ih-9, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ih-9, R10and R11are each -CH2OH. In certain embodiments of formula Ih-9, R10is H, and R11is OH.

[0535] In certain embodiments of formula Ih, X is -CH2- and Y is C1-C6alkylene. In certain embodiments of formula Ih, X is -CH2- and Y is C1-C3alkylene. In certain embodiments of formula Ih, X is -CH2- and Y is C1-C2alkylene.

[0536] In certain embodiments of formula Ih, -NH-X-Y-NR5R6, thereby providing a compound of formula Ih-10: Attorney Docket No.41543-59274 (002WO) wherein o is an integer I.

[0537] In certain o an to 4. In certain embodiments of formula Ih-10, o is an integer from 1 to 3. In certain embodiments of formula Ih-10, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-10, o is 1. In certain embodiments of formula Ih-10, o is 2. In certain embodiments of formula Ih-10, o is 3. In certain embodiments of formula Ih-10, o is 4. In certain embodiments of formula Ih-10, o is 5.

[0538] In certain embodiments of formula Ih-10, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ih-10, R5and R6are methyl. In certain embodiments of formula Ih-10, R5is C1-C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ih-10, R5is methyl and R6is -CH2CH2OH.

[0539] In certain embodiments of formula Ih-10, R5and R6together form a C2-C9 heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ih-10, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0540] In certain embodiments of formula Ih, -NH-X-Y-NR5R6, thereby providing a compound of formula Ih-11: wherein o is an integer9 9 NR , wherein R is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0541] In certain embodiments of formula Ih-11, o is an integer from 1 to 4. In certain embodiments of formula Ih-11, o is an integer from 1 to 3. In certain embodiments of formula Ih-11, o is an integer Attorney Docket No.41543-59274 (002WO) selected from 1 and 2. In certain embodiments of formula Ih-11, o is 1. In certain embodiments of formula Ih-11, o is 2. In certain embodiments of formula Ih-11, o is 3. In certain embodiments of formula Ih-11, o is 4. In certain embodiments of formula Ih-11, o is 5.

[0542] In certain embodiments of formula Ih-11, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ih-11, A is CHR9, wherein R9is OH. In certain embodiments of formula Ih-11, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ih-11, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ih-11, A is CHR9, wherein R9is -CH2CH2OH.

[0543] In certain embodiments of formula Ih-11, A is S.

[0544] In certain embodiments of formula Ih-11, A is O.

[0545] In certain embodiments of formula Ih-11, A is NR9, wherein R9is selected from C1-C6alkyl , and certain embodiments of formula Ih-11, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ih-11, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ih-11, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ih-11, A is NR9, wherein R9. In certain embodiments of formula Ih-11, A is NR9, .

[0546] In certain embodiments of , thereby providing a compound of formula Attorney Docket No.41543-59274 (002WO) wherein o is an selected from H, OH, and hydroxy-C1-C6alkyl.

[0547] In certain embodiments of formula Ih-12, o is an integer from 1 to 4. In certain embodiments of formula Ih-12, o is an integer from 1 to 3. In certain embodiments of formula Ih-12, o is an integer selected from 1 and 2. In certain embodiments of formula Ih-12, o is 1. In certain embodiments of formula Ih-12, o is 2. In certain embodiments of formula Ih-12, o is 3. In certain embodiments of formula Ih-12, o is 4. In certain embodiments of formula Ih-12, o is 5.

[0548] In certain embodiments of formula Ih-12, R10and R11are each H. In certain embodiments of formula Ih-12, R10and R11are each OH. In certain embodiments of formula Ih-12, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ih-12, R10and R11are each -CH2OH. In certain embodiments of formula Ih-12, R10is H, and R11is OH.

[0549] In certain embodiments, the present disclosure provides a compound of formula I, wherein R1is -(CH2)nC(O)OZ1, R2is -(CH2)mC(O)OZ2, R3is H, and R4is H, thereby forming a compound of formula Ij: or a pharmaceutically Z1and Z2are each branched C6-C20alkyl; n is an integer from 1 to 10; and m is an integer from 0 to 10.

[0550] In certain embodiments of formula Ij, Z1is branched C15-C20alkyl. In certain embodiments of formula Ij, Z1is branched C15alkyl. Attorney Docket No.41543-59274 (002WO)

[0551] In certain embodiments of formula Ij, Z1is , wherein p is an integer from 3-8. In certain embodiments, p is selected from 4, 5, 6, and 7. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7.

[0552] In certain embodiments of formula Ij, Z2is branched C15-C20alkyl. In certain embodiments of formula Ij, Z2is branched C15alkyl.

[0553] In certain embodiments of , wherein p is an integer from 3-8. In certain embodiments, p is selected from embodiments, p is 5. In certain embodiments, p is 6. In certain

[0554] In certain embodiments of formula Ij, Z1and Z2are the same. In certain embodiments, both Z1and Z2are , wherein p is an integer from 3-8. In certain embodiments, p is selected from 4, 5, 6, and embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7.

[0555] In certain embodiments of formula Ij, Z1and Z2are different. In certain embodiments, both Z1and Z2are , wherein p is an integer from 3-8 and p is different for Z1and Z2. In certain embodiments of formula Ij, Z1and Z2are different branched C15-C20alkyl groups.

[0556] In certain embodiments of formula Ij, n is an integer from 1 to 5. In certain embodiments of formula Ij, n is an integer from 1 to 3. In certain embodiments of formula Ij, n is 1. In certain embodiments of formula Ij, n is 2. In certain embodiments of formula Ij, n is 3. In certain embodiments of formula Ij, n is 4. In certain embodiments of formula Ij, n is 5.

[0557] In certain embodiments of formula Ij, m is an integer from 0 to 5. In certain embodiments of formula Ij, m is an integer from 0 to 3. In certain embodiments of formula Ij, m is 0. In certain embodiments of formula Ij, m is 1. In certain embodiments of formula Ij, m is 2. In certain embodiments of formula Ij, m is 3. In certain embodiments of formula Ij, m is 4. In certain embodiments of formula Ij, m is 5. Attorney Docket No.41543-59274 (002WO)

[0558] In certain embodiments of formula Ij, Z1and Z2are each branched C6-C20alkyl, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of formula Ij, Z1and Z2are each branched C6-C20alkyl, n is an integer from 1 to 3, and m is an integer from 1 to 3. In certain embodiments of formula Ij, Z1and Z2are each branched C6-C20alkyl, n is 3, and m is 2.

[0559] In certain embodiments of formula Ij, Z1and Z2are branched C15-C20alkyl, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of formula Ij, Z1and Z2are branched C15-C20alkyl, n is an integer from 1 to 3, and m is an integer from 1 to 3. In certain embodiments of formula Ij, Z1and Z2are branched C15-C20alkyl, n is 3, and m is 2.

[0560] In certain embodiments of formula Ij, Z1and Z2, wherein p is an integer from 3-8, n is an integer from 1 to 5, and m is an integer from 1 embodiments of formula Ij, Z1and Z2are , wherein p is an integer from 3-8, n is an integer from 1 to 3, and m is an integer from 1 to 3. In certain embodiments of formula Ij, Z1and Z2are , wherein p is an integer from 3-8, n is 3, and m is 2.

[0561] In certain embodiments of formula Ij, X is -C(O)-, and Y is C1-C6alkylene. In certain embodiments of formula Ij, X is -C(O)-, and Y is C1-C3 alkylene. In certain embodiments of formula Ij, X is -C(O)-, and Y is C1-C2alkylene.

[0562] In certain embodiments of formula Ij, -NH-X-Y-NR5R6, thereby providing a compound of formula Ij-1: 1) wherein o is an integer I.

[0563] In certain embodiments of formula Ij-1, o is an integer from 1 to 4. In certain embodiments of formula Ij-1, o is an integer from 1 to 3. In certain embodiments of formula Ij-1, o is an integer Attorney Docket No.41543-59274 (002WO) selected from 1 and 2. In certain embodiments of formula Ij-1, o is 1. In certain embodiments of formula Ij-1, o is 2. In certain embodiments of formula Ij-1, o is 3. In certain embodiments, of formula Ij-1 o is 4. In certain embodiments of formula Ij-1, o is 5.

[0564] In certain embodiments of formula Ij-1, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ij-1, R5and R6are methyl. In certain embodiments of formula Ij-1, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ij-1, R5is methyl and R6is -CH2CH2OH.

[0565] In certain embodiments of formula Ij-1, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ij-1, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0566] In certain embodiments of providing a compound of formula Ij-2: 2) wherein o is an integer NR9, wherein R9is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0567] In certain embodiments of formula Ij-2, o is an integer from 1 to 4. In certain embodiments of formula Ij-2, o is an integer from 1 to 3. In certain embodiments of formula Ij-2, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-2, o is 1. In certain embodiments of formula Ij-2, o is 2. In certain embodiments of formula Ij-2, o is 3. In certain embodiments of formula Ij-2, o is 4. In certain embodiments of formula Ij-2, o is 5.

[0568] In certain embodiments of formula Ij-2, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ij-2, A is CHR9, wherein R9is OH. In certain embodiments of formula Ij-2, A is CHR9, wherein R9is C1-C6alkyl (e.g., Attorney Docket No.41543-59274 (002WO) methyl). In certain embodiments of formula Ij-2, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ij-2, A is CHR9, wherein R9is -CH2CH2OH.

[0569] In certain embodiments of formula Ij-2, A is S.

[0570] In certain embodiments of formula Ij-2, A is O.

[0571] In certain embodiments of formula Ij-2, A is NR9, wherein R9is selected from C1-C6alkyl certain embodiments of formula Ij-2, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ij-2, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In formula Ij-2, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ij-2, A is NR9, wherein R9. In certain embodiments of formula Ij-2, A is NR9, .

[0572] In certain embodiments of , thereby providing a compound of formula Ij- 3) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl. Attorney Docket No.41543-59274 (002WO)

[0573] In certain embodiments of formula Ij-3, o is an integer from 1 to 4. In certain embodiments of formula Ij-3, o is an integer from 1 to 3. In certain embodiments of formula Ij-3, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-3, o is 1. In certain embodiments of formula Ij-3, o is 2. In certain embodiments of formula Ij-3, o is 3. In certain embodiments of formula Ij-3, o is 4. In certain embodiments of formula Ij-3, o is 5.

[0574] In certain embodiments of formula Ij-3, R10and R11are each H. In certain embodiments of formula Ij-3, R10and R11are each OH. In certain embodiments of formula Ij-3, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ij-3, R10and R11are each -CH2OH. In certain embodiments of formula Ij-3, R10is H and R11is OH.

[0575] In certain embodiments of formula Ij, X is -C(O)-, and Y is C1-C6heteroalkylene. In certain embodiments of formula Ij, X is -C(O)-, and Y is C1-C3heteroalkylene. In certain embodiments of formula Ij, X is -C(O)-, and Y is C1-C2heteroalkylene. In certain embodiments, X is -C(O)- and Y is - CH2-S-(CH2)q-, wherein q is an integer from 1 to 4.

[0576] In certain embodiments of formula Ij, -NH-X-Y- , thereby providing a compound of formula Ij-4: 4) wherein o is an integer R6are as defined for formula I.

[0577] In certain embodiments of formula Ij-4, o is an integer from 1 to 3. In certain embodiments of formula Ij-4, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-4, o is 1. In certain embodiments of formula Ij-4, o is 2. In certain embodiments of formula Ij-4, o is 3. In certain embodiments of formula Ij-4, o is 4.

[0578] In certain embodiments of formula Ij-4, Q is S and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ij-4, Q is S and R5and R6are methyl. In certain embodiments of formula Ij-4, Q is S, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ij-4, Q is S, R5is methyl, and R6is -CH2CH2OH.

[0579] In certain embodiments of formula Ij-4, Q is O and R5and R6are each C1-C6alkyl. In certain embodiments of formula Ij-4, Q is O and R5and R6are methyl. In certain embodiments of formula Ij- Attorney Docket No.41543-59274 (002WO) 4, Q is O, R5is C1-C6alkyl, and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ij-4, Q is O, R5is methyl, and R6is -CH2CH2OH.

[0580] In certain embodiments of formula Ij-4, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ij-4, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0581] In certain embodiments of formula Ij, -NH-X-Y-NR5R6, thereby providing a compound of formula Ij-5: 5) wherein o is an integer9 from CHR , O, S, and NR9, wherein R9is selected from H, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0582] In certain embodiments of formula Ij-5, o is an integer from 1 to 3. In certain embodiments of formula Ij-5, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-5, o is 1. In certain embodiments of formula Ij-5, o is 2. In certain embodiments of formula Ij-5, o is 3. In certain embodiments of formula Ij-5, o is 4.

[0583] In certain embodiments of formula Ij-5, Q is S and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ij-5, Q is S and A is CHR9, wherein R9is OH. In certain embodiments of formula Ij-5, Q is S and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ij-5, Q is S and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ij-5, Q is S and A is CHR9, wherein R9is - CH2CH2OH.

[0584] In certain embodiments of formula Ij-5, Q is S and A is S.

[0585] In certain embodiments of formula Ij-5, Q is S and A is O. Attorney Docket No.41543-59274 (002WO)

[0586] In certain embodiments of formula Ij-5, Q is S and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ij-5, Q is S and A is NR9, wherein R9is C1- In certain embodiments of formula Ij-5, Q is S and A is NR9, wherein R9is certain embodiments of formula Ij-5, Q is S and A is NR9, wherein R9is - In certain embodiments of formula Ij-5, Q is S and A is NR9, wherein R9is embodiments of formula Ij-5, Q is S and A is NR9, wherein R9is of formula Ij-5, Q is O and A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ij-5, Q is O and A is CHR9, wherein R9is OH. In certain embodiments of formula Ij-5, Q is O and A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ij-5, Q is O and A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ij-5, Q is O and A is CHR9, wherein R9is - CH2CH2OH.

[0588] In certain embodiments of formula Ij-5, Q is O and A is S.

[0589] In certain embodiments of formula Ij-5, Q is O and A is O.

[0590] In certain embodiments of formula Ij-5, Q is O and A is NR9, wherein R9is selected from C1- C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, - , and certain embodiments of formula Ij-5, Q is O and A is NR9, wherein R9is C1- In certain embodiments of formula Ij-5, Q is O and A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ij-5, Q is O and A is NR9, wherein R9is - CH2CH2OCH2CH2OH. In certain embodiments of formula Ij-5, Q is O and A is NR9, wherein R9is Attorney Docket No.41543-59274 (002WO) is

[0591] In certain embodiments of , thereby providing a compound of formula Ij- 6) wherein o is an are each independently selected from H, OH, and hydroxy-C1-C6alkyl.

[0592] In certain embodiments of formula Ij-6, o is an integer from 1 to 3. In certain embodiments of formula Ij-6, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-6, o is 1. In certain embodiments of formula Ij-6, o is 2. In certain embodiments of formula Ij-6, o is 3. In certain embodiments of formula Ij-6, o is 4.

[0593] In certain embodiments of formula Ij-6, Q is S and R10and R11are each H. In certain embodiments of formula Ij-6, Q is S and R10and R11are each OH. In certain embodiments of formula Ij-6, Q is S and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ij-6, Q is S and R10and R11are each -CH2OH. In certain embodiments of formula Ij-6, Q is S, R10is H, and R11is OH.

[0594] In certain embodiments of formula Ij-6, Q is O and R10and R11are each H. In certain embodiments of formula Ij-6, Q is O and R10and R11are each OH. In certain embodiments of formula Ij-6, Q is O and R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ij-6, Q is O and R10and R11are each -CH2OH. In certain embodiments of formula Ij-6, Q is O, R10is H, and R11is OH. Attorney Docket No.41543-59274 (002WO)

[0595] In certain embodiments of formula Ij, X is -C(O)S- and Y is C1-C6alkylene. In certain embodiments of formula Ij, X is -C(O)S- and Y is C1-C3alkylene. In certain embodiments of formula Ij, X is -C(O)S- and Y is C1-C2alkylene.

[0596] In certain embodiments of formula Ij, -NH-X-Y-NR5R6, thereby providing a compound of formula Ij-7: 7) wherein o is an integer I.

[0597] In certain embodiments of formula Ij-7, o is an integer from 1 to 5. In certain embodiments of formula Ij-7, o is an integer from 1 to 3. In certain embodiments of formula Ij-7, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-7, o is 1. In certain embodiments of formula Ij-7, o is 2. In certain embodiments of formula Ij-7, o is 3. In certain embodiments of formula Ij-7, o is 4. In certain embodiments of formula Ij-7, o is 5. In certain embodiments of formula Ij-7, o is 6.

[0598] In certain embodiments of formula Ij-7, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ij-7, R5and R6are methyl. In certain embodiments of formula Ij-7, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ij-7, R5is methyl and R6is -CH2CH2OH.

[0599] In certain embodiments of formula Ij-7, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ij-7, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0600] In certain embodiments of , thereby providing a compound of formula Ij-8: Attorney Docket No.41543-59274 (002WO) 8) wherein o is an integer NR9, wherein R9is selected from H, OH, optionally C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0601] In certain embodiments of formula Ij-8, o is an integer from 1 to 5. In certain embodiments of formula Ij-8, o is an integer from 1 to 3. In certain embodiments of formula Ij-8, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-8, o is 1. In certain embodiments of formula Ij-8, o is 2. In certain embodiments of formula Ij-8, o is 3. In certain embodiments of formula Ij-8, o is 4. In certain embodiments of formula Ij-8, o is 5. In certain embodiments of formula Ij-8, o is 6.

[0602] In certain embodiments of formula Ij-8, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ij-8, A is CHR9, wherein R9is OH. In certain embodiments of formula Ij-8, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ij-8, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ij-8, A is CHR9, wherein R9is -CH2CH2OH.

[0603] In certain embodiments of formula Ij-8, A is S.

[0604] In certain embodiments of formula Ij-8, A is O.

[0605] In certain embodiments of formula Ij-8, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ij-8, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ij-8, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ij-8, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain Attorney Docket No.41543-59274 (002WO) embodiments of formula Ij-8, A is NR9, wherein R9. In certain embodiments of formula Ij-8, A is NR9, .

[0606] In certain embodiments of , thereby providing a compound of formula Ij- 9) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0607] In certain embodiments of formula Ij-9, o is an integer from 1 to 5. In certain embodiments of formula Ij-9, o is an integer from 1 to 3. In certain embodiments of formula Ij-9, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-9, o is 1. In certain embodiments of formula Ij-9, o is 2. In certain embodiments of formula Ij-9, o is 3. In certain embodiments of formula Ij-9, o is 4. In certain embodiments of formula Ij-9, o is 5. In certain embodiments of formula Ij-9, o is 6.

[0608] In certain embodiments of formula Ij-9, R10and R11are each H. In certain embodiments of formula Ij-9, R10and R11are each OH. In certain embodiments of formula Ij-9, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ij-9, R10and R11are each -CH2OH. In certain embodiments of formula Ij-9, R10is H, and R11is OH.

[0609] In certain embodiments of formula Ij, X is -CH2- and Y is C1-C6alkylene. In certain embodiments of formula Ij, X is -CH2- and Y is C1-C3alkylene. In certain embodiments of formula Ij, X is -CH2- and Y is C1-C2alkylene.

[0610] In certain embodiments of formula , thereby providing a compound of formula Ij-10: Attorney Docket No.41543-59274 (002WO) wherein o is an integer I.

[0611] In certain o an to 4. In certain embodiments of formula Ij-10, o is an integer from 1 to 3. In certain embodiments of formula Ij-10, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-10, o is 1. In certain embodiments of formula Ij-10, o is 2. In certain embodiments of formula Ij-10, o is 3. In certain embodiments of formula Ij-10, o is 4. In certain embodiments of formula Ij-10, o is 5.

[0612] In certain embodiments of formula Ij-10, R5and R6are each C1-C6alkyl. In certain embodiments of formula Ij-10, R5and R6are methyl. In certain embodiments of formula Ij-10, R5is C1- C6alkyl and R6is C1-C6alkyl substituted with -OH. In certain embodiments of formula Ij-10, R5is methyl and R6is -CH2CH2OH.

[0613] In certain embodiments of formula Ij-10, R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl. In certain embodiments of formula Ij-10, the C2-C9heterocycle is selected from a 5-membered heterocycle and a 6-membered heterocycle.

[0614] In certain embodiments of formula Ij, -NH-X-Y-NR5R6providing a compound of formula Ij-11: wherein o is an integer9 9 NR , wherein R is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

[0615] In certain embodiments of formula Ij-11, o is an integer from 1 to 4. In certain embodiments of formula Ij-11, o is an integer from 1 to 3. In certain embodiments of formula Ij-11, o is an integer Attorney Docket No.41543-59274 (002WO) selected from 1 and 2. In certain embodiments of formula Ij-11, o is 1. In certain embodiments of formula Ij-11, o is 2. In certain embodiments of formula Ij-11, o is 3. In certain embodiments of formula Ij-11, o is 4. In certain embodiments of formula Ij-11, o is 5.

[0616] In certain embodiments of formula Ij-11, A is CHR9, wherein R9is selected from OH, C1-C6alkyl (e.g., methyl), -CH2OH, and -CH2CH2OH. In certain embodiments of formula Ij-11, A is CHR9, wherein R9is OH. In certain embodiments of formula Ij-11, A is CHR9, wherein R9is C1-C6alkyl (e.g., methyl). In certain embodiments of formula Ij-11, A is CHR9, wherein R9is -CH2OH. In certain embodiments of formula Ij-11, A is CHR9, wherein R9is -CH2CH2OH.

[0617] In certain embodiments of formula Ij-11, A is S.

[0618] In certain embodiments of formula Ij-11, A is O.

[0619] In certain embodiments of formula Ij-11, A is NR9, wherein R9is selected from C1-C6alkyl (e.g., methyl), hydroxy-C1-C6alkyl, -CH2CH2OCH2CH2OH, certain embodiments of formula Ij-11, A is NR9, wherein R9is C1-C6alkyl embodiments of formula Ij-11, A is NR9, wherein R9is hydroxy-C1-C6alkyl. In certain embodiments of formula Ij-11, A is NR9, wherein R9is -CH2CH2OCH2CH2OH. In certain embodiments of formula Ij-11, A is NR9, wherein R9. In certain embodiments of formula Ij-11, A is NR9, .

[0620] In certain embodiments of , thereby providing a compound of formula Ij- Attorney Docket No.41543-59274 (002WO) wherein o is an integer selected from H, OH, and hydroxy-C1-C6alkyl.

[0621] In certain embodiments of formula Ij-12, o is an integer from 1 to 4. In certain embodiments of formula Ij-12, o is an integer from 1 to 3. In certain embodiments of formula Ij-12, o is an integer selected from 1 and 2. In certain embodiments of formula Ij-12, o is 1. In certain embodiments of formula Ij-12, o is 2. In certain embodiments of formula Ij-12, o is 3. In certain embodiments of formula Ij-12, o is 4. In certain embodiments of formula Ij-12, o is 5.

[0622] In certain embodiments of formula Ij-12, R10and R11are each H. In certain embodiments of formula Ij-12, R10and R11are each OH. In certain embodiments of formula Ij-12, R10and R11are each hydroxy-C1-C6alkyl. In certain embodiments of formula Ij-12, R10and R11are each -CH2OH. In certain embodiments of formula Ij-12, R10is H, and R11is OH.

[0623] In certain embodiments, a compound of the present disclosure is selected from Table 1, below or is a pharmaceutically acceptable salt thereof. Table 1

[0005] Attorney Docket No.41543-59274 (002WO) Compound Structure 3 O Attorney Docket No.41543-59274 (002WO) Compound Structure 11 Attorney Docket No.41543-59274 (002WO) Compound Structure 3. LIPID NANOPARTICLE (LNP) FORMULATIONS

[0624] In certain embodiments, the present disclosure provides a plurality of LPNs, each LNP comprising one or more of the following: one or more ionizable lipids, one or more cationic lipids, one or more structural lipids, one or more conjugated lipids, and one or more helper lipids. Each LNP encapsulates nucleic acid cargo. A. IONIZABLE LIPID

[0625] In certain embodiments, the ionizable lipid is a compound of formula I, described hereinabove. Attorney Docket No.41543-59274 (002WO)

[0626] In certain embodiments, the ionizable lipid is a cationic lipid. Cationic lipids and related analogs, which are useful in the lipid nanoparticles of the present disclosure, include but are not limited to, those lipids described in U.S. Patent Publication Nos.2006-0083780 and 2006-0240554; U.S. Pat. Nos.5,208,036; 5,264,618; 5,279,833; 5,283,185; 5,753,613; and 5,785,992; and PCT Publication No. WO 96 / 10390, the disclosures of which are herein incorporated by reference in their entirety for all purposes. Additional cationic lipids of interest include, but are not limited to, 1,2-distearyloxy-N,N- dimethyl-3-aminopropane (DSDMA), 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N-dimethyl-3-aminopropane (DLenDMA), 1,2-dioleyloxy-N,N-dimethyl-3- aminopropane (DODMA), and heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (DLin-MC3-DMA). B. STRUCTURAL LIPIDS

[0627] In certain embodiments, the LNP comprises one or more structural lipids. Structural lipids help mitigate aggregation of other lipids in the particle. Structural lipids can include, but are not limited to, cholesterol, fecosterol, ergosterol, bassicasterol, tomatidine, tomatine, ursolic, alpha-tocopherol, and mixtures thereof. In certain embodiments, the structural lipid is cholesterol. In certain embodiments, the structural lipid includes cholesterol and a corticosteroid (such as, for example, prednisolone, dexamethasone, prednisone, and hydrocortisone, or a combination thereof).

[0628] In certain embodiments, a structural lipid is described in international patent application PCT / US2019 / 015913.

[0629] In certain embodiments, the structural lipid is a sterol (e.g., phytosterols or zoosterols). Exemplary sterols can include, but are not limited to, cholesterol, β-sitosterol, fecosterol, ergosterol, sitosterol, campesterol, stigmasterol, brassicasterol, ergosterol, tomatidine, tomatine, ursolic acid, and alpha-tocopherol. C. CONJUGATED LIPIDS

[0630] In certain embodiments, the LNP comprises one or more conjugated lipids (sometimes called coat lipids) capable of reducing aggregation. In certain embodiments, conjugated lipids have a hydrocarbon tail or chain linked to a hydrophilic group which is capable of being configured at the surface of the LNP and provide for reduced LNP aggregation.

[0631] Exemplary conjugated lipids include, but are not limited to, polyethyleneglycol (PEG)-lipid conjugates. Other exemplary conjugated lipids include polyoxazoline (POZ)-lipid conjugates, polyamide (ATTA)-lipid conjugates, cationic-polymer-lipid conjugates (CPLs), or mixtures thereof.

[0632] In certain embodiments, the conjugated lipid is a PEG-modified lipid as described in International Pat. Appl. No. PCT / US2019 / 015913 or PCT / US2020 / 046407, which are incorporated Attorney Docket No.41543-59274 (002WO) herein by reference in their entirety. In an embodiment, a LNP comprises one or more PEG-modified lipids (also referred to as “PEGylated lipid” or “PEG-lipid”).

[0633] Non-limiting examples of PEG-modified lipids include PEG-modified phosphatidylethanolamines and phosphatidic acids, PEG-ceramide conjugates (e.g., PEG-CerC14 or PEG-CerC20), PEG-modified dialkylamines and PEG-modified 1,2-diacyloxypropan-3-amines. In certain further embodiments, a PEG-modified lipid may be, e,g,, PEG-c-DOMG, PEG-DMG, PEG- DLPE, PEG-DMPE, PEG-DPPC, or a PEG-DSPE.

[0634] In certain embodiments, the PEG-modified lipid is selected from 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino(polyethylene glycol)] (PEG-DSPE), PEG-disteryl glycerol (PEG-DSG), PEG-dipalmetoleyl, PEG-dioleyl, PEG-distearyl, PEG-diacylglycamide (PEG-DAG), PEG-dipalmitoyl phosphatidylethanolamine (PEG-DPPE), and PEG-l,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA).

[0635] In certain embodiments, the PEG-modified lipid is selected from DSPE-PEG, DMG-PEG, PEG-DAG, PEG-S-DAG, PEG-PE, PEG-S-DMG, PEG-cer, PEG-dialkoxypropylcarbamate, PEG-OR, PEG-OH, PEG-c-DOMG, or PEG-1. In certain embodiments, the PEG-modified lipid is DSPE- PEG(2000).

[0636] In certain embodiments, the PEG-modified lipid comprises a PEG moiety comprising 10-70 (e.g., 30-60) oxyethylene (−O−CH2−CH2−) units or portions thereof. In certain embodiments, the PEG- modified lipid comprises (OCH2CH2)v–ORw, and v is an integer between 0 and 70 (inclusive) (e.g., an integer between 30 and 60), w is hydrogen or alkyl.

[0637] In certain embodiments, the PEG-lipid is selected from the group consisting of a PEG- modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof.

[0638] In certain embodiments, the lipid moiety of the PEG-lipids includes those having lengths of from C14to C22, such as from C14to C16. In certain embodiments, a PEG moiety, for example a mPEG- NH2, has a size of 1000, 2000, 5000, 10,000, 15,000 or 20,000 daltons. In one embodiment, the PEG- lipid is PEG2k-DMG.

[0639] The conjugated lipids (e.g., PEG-lipids) can comprise from 0.1% to 20% (mol) of the total lipid present in the lipid nanoparticle, such as, for example, from 0.1% to 10% (mol), from 0.1% to 5% (mol), from 1% to 20% (mol) from 1% to 10% (mol), from 1% to 5% (mol), from 5% to 20% (mol), from 5% to 10% (mol), or from 10% to 20% (mol). Attorney Docket No.41543-59274 (002WO) D. HELPER LIPIDS

[0640] In certain embodiments, LNPs of the present disclosure comprises one or more helper lipids. Helper lipids are typically neutrally charged and sometimes called “neutral lipids.”

[0641] In certain embodiments, the helper lipid is a phospholipid. In certain embodiments, the helper lipid is a phospholipid substitute or replacement. In certain embodiments, the phospholipid or phospholipid substitute can be, for example, one or more saturated or (poly)unsaturated phospholipids, or phospholipid substitutes, or a combination thereof. In general, phospholipids comprise a phospholipid moiety and one or more fatty acid moieties.

[0642] A phospholipid moiety can be selected, for example, from the non-limiting group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl serine, phosphatidic acid, 2-lysophosphatidyl choline, and a sphingomyelin.

[0643] A fatty acid moiety can be selected, for example, from the non-limiting group consisting of lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, erucic acid, phytanoic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid.

[0644] Phospholipids include, but are not limited to, glycerophospholipids such as phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols, phosphatidy glycerols, and phosphatidic acids. Phospholipids also include phosphosphingolipid, such as sphingomyelin.

[0645] In certain embodiments, the helper lipid is a 1,2-distearoyl-177-glycero-3-phosphocholine (DSPC) analog, a DSPC substitute, oleic acid, or an oleic acid analog.

[0646] In certain embodiments, a helper lipid is a non-phosphatidyl choline (PC) zwitterionic lipid, a DSPC analog, oleic acid, an oleic acid analog, or a DSPC substitute.

[0647] Helper lipids suitable for use in a lipid composition of the disclosure include, for example, a variety of neutral, uncharged or zwitterionic lipids. Such helper lipids are preferably used in combination with one or more of the compounds and lipids disclosed herein. Examples of helper lipids include, but are not limited to, 5-heptadecylbenzene-1,3-diol (resorcinol), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), phosphatidylcholine (PLPC), 1,2-distearoylsn-glycero-3-phosphocholine (DAPC), phosphatidylethanolamine (PE), egg phosphatidylcholine (EPC), dilauryloylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), 1-myristoyl-2-palmitoyl phosphatidylcholine (MPPC), 1-paimitoyl-2-myristoyl phosphatidylcholine (PMPC), 1-palmitoyl-2-stearoyl phosphatidylcholine (PSPC), 1,2-diarachidoyl- sn-glycero-3-phosphocholine (DBPC), 1-stearoyl-2-palmitoyl phosphatidylcholine (SPPC), 1,2- Attorney Docket No.41543-59274 (002WO) dieicosenoyl-sn-glycero-3-phosphocholine (DEPC), paimitoyioieoyl phosphatidylcholine (POPC), lysophosphatidyl choline, dioleoyl phosphatidylethanol amine (DOPE) dilinoleoylphosphatidylcholine distearoylphosphatidylethanolamine (DSPE), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), palmitoyloleoyl phosphatidylethanolamine (POPE), lysophosphatidylethanolamine and combinations thereof.

[0648] In one embodiment, the helper lipid may be distearoylphosphatidylcholine (DSPC) or dimyristoyl phosphatidyl ethanolamine (DMPE). In another embodiment, the helper lipid may be distearoylphosphatidylcholine (DSPC).

[0649] Helper lipids function to stabilize and improve processing of the LNPs. Such helper lipids are preferably used in combination with other excipients, for example, one or more of the ionizable lipids disclosed herein. In certain embodiments, the helper lipid comprises a molar ratio of 1% to 40% (mol) of the total lipid present in the LNP, such as, for example, from 1% to 30% (mol), from 1% to 20% (mol), from 1% to 10% (mol), from 5% to 10% (mol), from 5% to 20% (mol), from 5% to 30% (mol), or from 5% to 40% (mol). E. OTHER COMPONENTS

[0650] LNPs of this disclosure can further comprise one or more additional components. In certain embodiments, the LNPs can include one or more anionic helper lipids. Example anionic helper lipids include, but are not limited to, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (sodium salt), 1,2-dioleoyl- sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt), 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt), bis(monooleoylglycero)phosphate (S,R Icertainr) (ammonium salt), 1,2-distearoyl-sn-glycero-3- phospho-(1'-rac-glycerol) (sodium salt), 1,2-distearoyl-sn-glycero-3-phosphoinositol (ammonium salt), and 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol-3',5'-bisphosphate) (ammonium salt).

[0651] In certain embodiments, the LNPs can include one or more targeting ligands. Suitable targeting ligands are selected such that the unique characteristics of a target cell are exploited, thus allowing the composition to discriminate between target and non-target cells. Examples of suitable targeting ligands include one or more peptides, proteins, aptamers, vitamins, and oligonucleotides. F. LIPID NANOPARTICLE PROPERTIES

[0652] In certain embodiments, a LNP has a mean diameter between 1 and 1000 nm. In certain embodiments, a LNP has a diameter that is less than 300 nm. In certain embodiments, a LNP has a diameter between 10 and 300 nm. In certain embodiments, a LNP has a diameter that is less than 200 nm. In certain embodiments, a LNP has a diameter between 25 and 200 nm. In certain embodiments, a LNP has a diameter between 50 and 150 nm. In certain embodiments, a LNP has a diameter between 70 and 120 nm.

[0653] The polydispersity index may be used to indicate the homogeneity of a LNP composition, e.g., the particle size distribution of the LNP composition. A small (e.g., less than 0.3) polydispersity Attorney Docket No.41543-59274 (002WO) index generally indicates a narrow particle size distribution. In certain embodiments, a LNP composition has a polydispersity index from 0 to 0.25, such as, for example, from 0.01 to 0.15, from 0.05 to 0.15, or from 0.08 to 0.15.

[0654] The zeta potential of a nanoparticle composition may be used to indicate the electrokinetic potential of the composition. LNPs with relatively low charges, positive or negative, are generally desirable, as more highly charged species may interact undesirably with cells, tissues, and other elements in the body. In certain embodiments, the zeta potential of a LNP may be from -20 mV to +20 mV, from -20 mV to +15 mV, from -20 mV to +10 mV, from -20 mV to +5 mV, from -20 mV to 0 mV, from -20 mV to -5 mV, from -20 mV to -10 mV, from -20 mV to -15 mV from -20 mV to +20 mV, from -20 mV to +15 mV, from -20 mV to +10 mV, from -20 mV to +5 mV, from -20 mV to 0 mV, from 0 mV to +20 mV, from 0 mV to +15 mV, from 0 mV to +10 mV, from 0 mV to +5 mV, from +5 mV to +20 mV, from +5 mV to +15 mV, or from +5 mV to +10 mV.

[0655] The efficiency of encapsulation of a nucleic acid / polynucleotide describes the amount of nucleic acid / polynucleotide encapsulated or otherwise associated with a LNP after preparation, relative to the initial amount provided. The encapsulation efficiency is desirably high (e.g., close to 100%). In certain embodiments, the encapsulation efficiency of a nucleic acid / polynucleotide is at least 50%, such as, for example, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 97%. In certain embodiments, the encapsulation efficiencies is 98%, 99%, or 100%. G. NUCLEIC ACID CARGO

[0656] LNPs of the present disclosure may include a cargo or payload, to be delivered to cells. In certain embodiments, the cargo comprises a polynucleotide. In certain embodiments, the polynucleotide is a RNA. RNA nucleic acid compositions of any structure may be included in the LNPs of the present disclosure. For example, the RNA may be linear, or it may be circular. It may be a mRNA, a siRNA, a shRNA, a guide RNA (gRNA), a microRNA (miRNA), or a circular RNA (circRNA). In certain embodiments, the RNA is chemically modified (e.g., RNA with chemically modified bases or sugars, or RNA with a chemically modified backbone). 3. PHARMACEUTICAL COMPOSITIONS

[0657] In another aspect, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising one or more of the lipids (i.e., compounds of formula I) described hereinabove and one or more pharmaceutically acceptable excipients. In another aspect, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a plurality of LNPs described hereinabove and one or more pharmaceutically acceptable excipients.

[0658] Pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical art. The excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. In accordance with another aspect of the Attorney Docket No.41543-59274 (002WO) disclosure there is also provided a process for the preparation of a pharmaceutical composition including a provided compound or pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients. The pharmaceutical composition can be for use in the treatment and / or prophylaxis of any of the conditions described herein.

[0659] Generally, a provided pharmaceutical composition is administered in a pharmaceutically effective amount. The amount administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the pharmaceutical composition administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0660] Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

[0661] Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may therefore be administered once or more than once a day. Such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

[0662] Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

[0663] In certain embodiments, the pharmaceutical composition comprises a preservative. In certain embodiments, suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride.

[0664] In certain embodiments, the pharmaceutical composition comprises a buffering agent. In certain embodiments, suitable buffering agents may include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts.

[0665] In certain embodiments, the concentration of LNPs in the pharmaceutical composition can vary, e.g., less than 1%, or at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% 10%, 15%, 20%, 25%, 30%, 35%, Attorney Docket No.41543-59274 (002WO) 40%, 45%, or 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.

[0666] In certain embodiments, the pharmaceutical composition is administered parenterally (e.g., subcutaneous, intravenous, intraarterial, intramuscular, intradermal, intraperitoneal, intrathecal, or intraocular). In certain embodiments, the pharmaceutical composition is administered by inhalation, such as, for example, intranasally, using nebulization, or aerosolization.

[0667] Pharmaceutical compositions can aqueous isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In certain embodiments, the LNPs provided herein can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids including water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol or hexadecyl alcohol, a glycol such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol, ketals such as 2,2-dimethyl-1,3- dioxolane-4-methanol, ethers, poly(ethyleneglycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0668] The parenteral pharmaceutical compositions can be presented in unit-dose or multi-dose sealed containers, such as ampoules or vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid excipient, for example, water for injections, immediately prior to use.

[0669] In certain embodiments, injectable pharmaceutical compositions are provided herein. The requirements for effective pharmaceutical carriers for injectable compositions are well-known to those of ordinary skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed, pages 622-630 (1986)).

[0670] In certain embodiments, the pharmaceutical compositions of the present disclosure are administered to a subject twice a day, daily, or every other day. In certain embodiments, the compositions of the present disclosure are administered to a subject twice a week, once a week, every ten days, every two weeks, every three weeks, every four weeks, once a month, every six weeks, every eight weeks, every three months, every four months, every six months, every eight months, every nine months or annually. Attorney Docket No.41543-59274 (002WO) EXAMPLES

[0671] The Examples in this section are offered by way of illustration, and not by way of limitation. The examples can represent only some embodiments, and it should be understood that the following examples are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein. EXAMPLE 1: Scaffold X Scaffold X Synthetic Scheme

[0672] Into a 3L four-neck round bottom flask, a solution of CAS# 86864-60-0 (100g, 1.0eq) and CAS# 109-83-1 (126g, 4.0eq) in acetonitrile (1L, 10V) was placed at room temperature under inert atmosphere. K2CO3(115.9g, 2.0eq) and NaI (31.5g, 0.5eq) were added to the above reaction mixture and allowed to stir at 55°C for 16h. The reaction was quenched with EtOAc (1L, 10V) and water (1L, 10V) and allowed to stir for 15min, collected the organic fractions. EtOAc (1L, 10V) was added to the aqueous fraction and allowed to stir for 15min, collected the organic fractions. The resulting fractions were combined and dried over sodium sulphate and concentrated under reduced pressure to afford a colorless liquid. The crude material was purified by flash column chromatography using neutral alumina. The product was eluted at 6-14% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford a pale yellow liquid.100 g of L1_X1, confirmed by1H NMR, ELSD: 98%, Mass (ES+, m / z): 234.3(M+1)+, Yield: Quantitative. Example 1.2-Synthesis of Scaffold X

[0673] Into a 500mL three neck round bottom flask, a solution of L1_X1 (25g, 1.0eq) in dichloromethane (250mL, 10V) was placed at room temperature under inert atmosphere. TEA (45mL, 3.0eq) and methane sulfonyl chloride (27mL, 2.0eq) were added dropwise to the above reaction mixture at 00C and the reaction mixture was allowed to stir 25+5oC for 2h. The reaction mixture was diluted with water (1L, 40V) and added with heptane (1L, 40V) and allowed to stir for 15min, collected the organic fractions. The organic fraction was added with solution of methanol and water (containing 10.0 wt.% citric acid) having a volume ratio of 8:2 (1L, 40V) and allowed to stir for 20min, collected the organic fraction. The organic fraction was washed with saturated brine solution (500mL, 20V), Attorney Docket No.41543-59274 (002WO) collected the organic fraction. The organic fraction was dried over sodium sulphate and concentrated under reduced pressure to afford pale yellow liquid. 12.7 g of Scaffold-X, confirmed by1H NMR, ELSD: 80%, Mass (ES+, m / z): 252.3(M+1)+, Yield: 47%. EXAMPLE 2: Scaffold R Scaffold R Synthetic Scheme

[0674] Into a 1L three neck round bottom flask, a solution of CAS# 623-51-8 (9.56 g, 1.0eq) in acetone (400mL, 20V) and potassium carbonate (32.75g, 3.0eq) was added at room temperature under inert atmosphere. Scaffold-X (20 g, 1.0eq) was added to the above reaction mixture followed by the addition of sodium iodide (11.77 g, 1.0eq) and allowed to stir at 70oC for 12h. The reaction mixture was filtered, and filtrate was concentrated under reduced pressure to afford colourless oil. The crude material was purified by flash column chromatography using 60-120 mesh silica gel. The product was eluted at 50% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford brown liquid.18.0 g of SR_A1, confirmed by 1H NMR, ELSD: 100%, MASS (ES, m / z): 336.2 [M+1]+,Yield: 67%. Example 2.2-Synthesis of Scaffold R

[0675] Into a 1L three neck round bottom flask, a solution of SR_A1 (18g, 1.0eq) in tetrahydrofuran (360mL, 20V) and DM water (360mL, 20V) were placed at room temperature. Lithium hydroxide (2.25g, 1.0eq) was added to the above reaction mixture and allowed to stir at 25+5oC for 12h. The reaction was quenched with ethyl acetate (360mL, 20V) and allowed to stir for 5min, collected the aqueous fraction. The resulting aqueous fraction was concentrated under reduced pressure to afford off white viscous material. 15.0 g of Scaffold-R, confirmed by1H NMR, ELSD: 63%, MASS (ES, m / z): 308.3 [M+1]+, Yield: Quantitative.

[0006] Attorney Docket No.41543-59274 (002WO) EXAMPLE 3: Scaffold Y Scaffold Y Synthetic Scheme Example 3.1-Synthesis of L9_A1:

[0676] To a solution of CAS# 3395-91-3 (50.0g, 1.0eq) and CAS# 109-83-1 (45.18g, 2.0eq) in MeCN (500mL, 10V), NaI (22.43g, 0.5eq) and K2CO3(62.34g, 1.5eq) were added at room temperature under inert atmosphere and the resulting mixture was allowed to stir at 80oC for 16h. The reaction mixture was concentrated under reduce pressure. The reaction was quenched with EtOAc (2X500mL, 10V) and water (500mL, 10V) and allowed to stir for 15min, collected the organic fractions. The resulting fractions were combined and dried over sodium sulphate and concentrated under reduced pressure to afford colourless liquid.45.0 g of L9_A1, confirmed by1H NMR, ELSD: 99%, Mass (ES+, m / z): 162.2 (M+1)+, Yield: 93% Example 3.2-Synthesis of Scaffold Y

[0677] To a solution of L9_A1 (40.0g, 1.0eq) in THF (200mL, 5V) at room temperature, lithium hydroxide (10.43g, 1.0eq) in water (200mL, 5V) was added at 25+5 °C and allowed the reaction mixture to stir for 16h. The reaction mixture was concentrated under reduced pressure. Reaction mixture was adjusted to pH using 5N HCl (30mL) and concentrated under vacuum to afford colourless liquid. 30.0 g of Scaffold-Y, confirmed by1H NMR, ELSD: 100%, Mass (ES+, m / z): 148.2 (M+1)+, Yield: 82% EXAMPLE 4: Scaffold A and related lipids Scaffold A Synthetic Scheme

[0678] Into a 5L four-neck round bottom flask, a solution of dimethyl 3-oxopentanedioate (150 g, Attorney Docket No.41543-59274 (002WO) 1.0 eq) in MeOH (600 mL, 4V) was placed at room temperature under inert atmosphere. Ammonium bicarbonate (136.2 g, 2.0 eq) was added to the reaction mixture and the resulting mixture was stirred at 25+5oC for 20 h. The reaction mixture was filtered through celite powder and washed with MeOH (750 mL, 5V). The fractions were combined and concentrated under reduced pressure to afford colourless oil (173 g of L1_A1, 87% yield). Confirmed by1H NMR, ELSD: 100%, Mass (ES+, m / z): 174.2 (M+1)+. Example 4.2 – Synthesis of L1_A2

[0679] Into a 2L three neck round bottom flask, to a solution of isopropyl alcohol (589 mL, 3.4V) was dropwise added H2SO4(107 mL, 2.0 eq) at 0ºC for 1h. The resulting solution was dropwise added to the t-BuNH2·BH3(80g, 1.0eq) in THF at -5 ºC and stirred for 10min. L1_A1 (173 g, 1.0 eq) was added to above reaction mixture at 0ºC and stirred at 25ºC + 5ºC for 17h. The reaction mixture was quenched with water (2L, 12V) at 0ºC and pH was adjusted to 9 using 5N sodium hydroxide solution and stirred for 10 min. DCM (2X6L, 40V) was added to the aqueous solution and stirred for 15min. The organic fractions were collected. The resulting fractions were combined and dried over sodium sulphate and concentrated under reduced pressure to afford colorless oil (110 g of L1_A2, 63% yield). Confirmed by1H NMR, ELSD: 90%, Mass (ES, m / z): 176.2 (M+1)+. Example 4.3 – Synthesis of L1_A3

[0680] Into a 3L four-neck round bottom flask, a solution of L1_A2 (110g, 1.0eq) in DCM (1.1L, 10V) was placed at room temperature under inert atmosphere. TEA (220mL, 2.5eq) and Boc anhydride (200mL, 2.2eq) were added at 0 ºC and the reaction mixture was allowed to stir at 25±5 ºC for 16h. EtOAc (2X2L, 20V) and water (2L, 20V) were added to above reaction mixture and allowed to stir for 15 min. The organic fraction was collected. The organic fraction was collected. The organic fractions were combined and dried over sodium sulphate and concentrated under reduced pressure to afford yellow oil. The crude material was purified by flash column chromatography (silica gel 60-120 mesh, solvent: ethyl acetate and hexane). The product was eluted at 20-25% EtOAc in hexane. The fractions were combined and concentrated under reduced pressure to afford off-white solid (44.0 g of L1_A3, 25% yield). Confirmed by1H NMR, ELSD: 92%, Mass (ES, m / z): 276.3 (M+1)+. Example 4.4 – Synthesis of L1_A4

[0681] Into a 1L three-neck round bottom flask, a solution of L1_A3 (44g, 1.0eq) in ethanol (450mL, 10V) was placed at room temperature under inert atmosphere. Sodium borohydride (24.3g, 1.0eq) was portion wise added to the above mixture at 0 ºC and allowed to stir at 25±5 ºC for 5h. The reaction mixture was concentrated under reduced pressure to afford orange residue. EtOAc (880mL, 20V) and water (440mL, 10V) were added to the orange residue and allowed to stir for 15 min. The organic fraction was collected. EtOAc (880mL, 20V) was added to the aqueous fraction and allowed to stir for 15 min. The organic fraction was collected. The resulting organic fractions were combined and dried Attorney Docket No.41543-59274 (002WO) over sodium sulphate and concentrated under reduced pressure to afford colourless oil. The crude material was purified by flash column chromatography (silica gel: 100-200 mesh; solvent: EtOAc and hexane). The product was eluted at 90-95% EtOAc in hexane. The fractions were combined and concentrated under reduced pressure to afford colourless oil (23.0 g of L1_A4, 66% yield). Confirmed by1H NMR, ELSD: 99%, Mass (ES, m / z): 220.3 (M+1)+. Example 4.5 – Synthesis of L1_A5

[0682] Into a 1L three-neck round bottom flask, a solution of L1_A4 (23g, 1.0eq) and Linoleic acid (“Lin”) (58.8g, 2.0eq) in acetonitrile (230mL, 10V) placed at room temperature under inert atmosphere. DMAP (12.8g, 1.0eq) and EDC.HCl (44.13g, 2.2eq) were added to the above reaction mixture at 0ºC and allowed to stir at 25±5 ºC for 16h. The reaction mixture was concentrated under reduced pressure to afford orange residue. EtOAc (2X300mL, 13V) and water (500mL, 22V) were added to the orange residue and allowed to stir for 15 min. The organic fractions were collected. The organic fraction was collected. The resulting organic fractions were dried over sodium sulphate and concentrated under reduced pressure to afford transparent oil. The crude material was purified by flash column chromatography (silica gel 60-120 mesh; solvent: EtOAc and hexane). The product was eluted at 4- 10% EtOAc in hexane. The fractions were combined and concentrated under reduced pressure to afford colourless oil (35.0 g of L1_A5, 45% yield). Confirmed by1H NMR, ELSD: 100%, Mass (ES, m / z): 643.4 (M-100)+. Example 4.6 – Synthesis of Scaffold A

[0683] Into a 250mL three-neck round bottom flask, a solution of L1_A5 (5g, 1.0eq) in DCM (50mL, 10V) was placed at room temperature under inert atmosphere. TFA (10mL, 2V) was dropwise added to the above reaction mixture at 0ºC, and the reaction mixture was allowed to stir at 25±5ºC for 3h. The resulting mixture was concentrated under reduced pressure to afford dark brown oil (5.0 g of Scaffold A, quantitative yield). Confirmed by1H NMR, ELSD: 98%, Mass (ES, m / z): 646.9 (M+1)+. Example 4.7 – Synthesis of Lipid 1

[0684] Step 1: To a solution of Scaffold-A (4.5 g, 1.0 eq) in Acetonitrile (45 mL, 10V) under inert atmosphere were added KI (0.23 g, 0.2 eq), K2CO3 (1.45 g, 1.5 eq) followed by Scaffold-X (2.10 g, 1.2 eq) and the resulting mixture was stirred at 70°C for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (90 mL, 20 V) and water (90 mL, 20 V). After 10 min stirring, two layers were separated, and the aqueous layer was extracted with EtOAc (90 mL, 20V). The organic fractions were combined, dried over Na2SO4, concentrated under vacuum and the crude residue was Attorney Docket No.41543-59274 (002WO) purified by flash column chromatography on neutral alumina (eluent: 0 to 10% Methanol in CH2Cl2) to afford L1_A1 (1.5 g, 22%) as brown coloured viscous liquid. Confirmed by1H NMR, ELSD: 76%, Mass (ES+, m / z): 860.3 (M+1)+.

[0685] Step 2: A 50 mL flask was charged with a solution L1_A1 (1.3 g, 1.0 eq) in 1,4-dioxane (13 mL, 10V) and cooled to 0°C under inert atmosphere. 4.0 M HCl in dioxane (1.3 mL, 1V) was added dropwise to the reaction mixture at 0°C and stirred at the same temperature for 30min. The reaction mixture was concentrated directly under reduced pressure and the crude material was purified by flash column chromatography on neutral alumina (eluent: 0 to 10% Methanol in CH2Cl2) to provide lipid 1 (0.17 g, 15%).1H NMR (400 MHz, CDCl3)δ 5.46– 5.25 (m, 8H), 4.28 (dt, J = 12.8, 6.7 Hz, 2H), 4.17 (dt, J = 11.9, 6.4 Hz, 2H), 3.76 – 3.68 (m, 2H), 2.96 – 2.86 (m, 3H), 2.79 (t, J = 6.4 Hz, 8H), 2.73 – 2.63 (m, 3H), 2.43 (s, 3H), 2.32 (t, J = 7.6 Hz, 4H), 2.11 – 2.01 (m, 8H), 1.97 – 1.86 (m, 3H), 1.91 – 1.06 (m, 4H), 1.42– 1.23 (m, 28H), 0.91 (t, J = 6.8 Hz, 6H); LC-MS (ES, m / z): 745.9 [M+H]+; ELSD: 99%. Example 4.8 – Synthesis of Lipid 9

[0686] To a solution of Scaffold-A (5.0 g, 1.0 eq) and Scaffold-Y (3.65 g, 3.2 eq) in anhydrous DMF (50 mL, 10V) was added DIPEA (4.0 mL, 3.0 eq) in dropwise at 00C. After 10 min, HOBt (1.04 g, 1.0eq) and EDC.HCl (2.23 g, 1.5 eq) were added sequentially to the reaction mixture at 00C, and the mixture was allowed to warm to room temperature and stirred for 16h. The reaction was diluted with EtOAc (50 mL, 10V) and water (100 mL, 20V). After 30 min stirring, the organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL, 10V). The organic layers were combined, dried over Na2SO4, concentrated and the crude material was purified by flash silica gel column chromatography (eluent: 0 to 10% methanol in EtOAc) to give lipid-9 (0.89 g, 15% yield) as pale- yellow liquid.1H NMR (400 MHz, CDCl3)δ 5.47– 5.29 (m, 8H), 4.26– 4.03 (m, 5H), 3.77 (t, J = 5.1 Hz, 2H), 3.20 – 2.90 (m, 3H), 2.85 – 2.76 (m, 5H), 2.67 (t, J = 5.1 Hz, 2H), 2.46 (t, J = 6.1 Hz, 2H), 2.38 (s, 3H), 2.31 (t, J = 7.6 Hz, 4H), 2.11 – 2.01 (m, 8H), 1.91 – 1.77 (m, 3H), 1.69 – 1.57 (m, 4H), 1.43 – 1.23 (m, 28H), 0.91 (t, J = 6.7 Hz, 6H); LC-MS (ES+, m / z): 774.5 (M+H)+; ELSD: 99.21%. Attorney Docket No.41543-59274 (002WO) Example 4.9 – Synthesis of Lipid 17 a g, g, DMF (20 mL, 8V) were added HATU (2.21 g, 1.5eq) and DIPEA (1.5 g, 3.0eq) at 0oC under inert atmosphere. The reaction mixture was stirred at room temperature for 3h, quenched with water (100 mL, 40V), and diluted with EtOAc (50mL, 20V). The aqueous layer was extracted with EtOAc (50mL, 10V). The combined organic layers were washed with 10% aq. citric acid (50 mL, 20V), 10% aq. NaHCO3(50mL, 20V), brine (50 mL), dried over Na2SO4and concentrated to give crude product as pale-yellow liquid. The crude material was purified by flash silica gel column chromatography (eluent: 0 to 100% EtOAc in hexanes) to give L17_A1 (1.7 g, 46% yield) as yellow oil. Confirmed by 1H NMR, ELSD: 90.17%, Mass (ES+, m / z): 934.3 (M+H)+.

[0688] Step 2: 4.0 M HCl in dioxane (4.0 mL, 2.6V) was added to a solution of L17_A1 (1.5 g, 1.0 eq) in CH2Cl2(15 mL, 10V) at 0oC under inert atmosphere and stirred at room temperature for 3h. The reaction mixture was concentrated under vacuum and the resulting crude material was purified by silica gel column chromatography (0 to 10% methanol in CH2Cl2) to afford lipid 17 (0.71 g, 61% yield) as a light brown liquid.1H NMR (400 MHz, MeOD) δ 5.47 – 5.26 (m, 8H), 4.24 – 4.04 (m, 4H), 3.98 – 3.88 (m, 2H), 3.60 – 3.48 (m, 1H), 3.48– 3.38 (m, 2H), 3.31 (s, 2H), 3.28– 3.21 (m, 1H), 3.11 – 2.99 (m, 2H), 2.99 (s, 3H), 2.80 (t, J = 6.3 Hz, 3H), 2.35 (t, J = 7.5 Hz, 4H), 2.13 – 2.03 (m, 8H), 1.99 – 1.86 (m, 2H), 1.84 – 1.71 (m, 2H), 1.70 – 1.57 (m, 4H), 1.47 – 1.26 (m, 32H), 0.99 – 0.88 (m, 6H); LC-MS (ES+, m / z): 820.1 (M+H)+; ELSD: 94.08%.

[0007] Attorney Docket No.41543-59274 (002WO) EXAMPLE 5: Scaffold B and related lipids Scaffold B Synthetic Scheme

[0689] Into a 5L four-neck round bottom flask, a solution of CAS# 112-72-1 (200g, 1.0eq) in Dichloromethane (2000mL, 10V) was placed under inert atmosphere at room temperature. Dess– Martin periodinate (400g, 1.0eq) was added portion wise to the reaction mixture at 0ºC and the resulting mixture was allowed to stir at 25±5ºC for 3h.10% NaHCO3solution (3500mL, 17.5V) was added to the reaction mixture and allowed to stir for 15min, filtered through celite powder. The filtrate was collected. The filtrate was washed with water (3L, 15V). The organic fraction was collected. The resulting fraction was dried over sodium sulphate and concentrated under reduced pressure to afford a white solid. The crude material was purified by glass column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 3-5% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford a white solid (140 g of L2_X1, 71% yield). Confirmed by1H NMR. Attorney Docket No.41543-59274 (002WO) Example 5.2 – Synthesis of L2_A1

[0690] Into a 10L four-neck round bottom flask, a solution of CAS# 14358-33-9 (300g, 1.0eq) in DCM (3L, 10V) was placed under inert atmosphere at room temperature. Triethylamine (425mL, 2.0eq) and Di-tert-butyl dicarbonate (331g, 1.0eq) were added to the reaction mixture at 0oC and the resulting mixture was allowed to stir at 25±5oC for 18h. Water (5L, 16.6V) and DCM (5L, 16.6V) were added to the above reaction mixture and allowed to stir for 10min. The organic fraction was collected. DCM (5L, 16.5V) was added to the aqueous fraction and allowed to stir for 10min. The organic fraction was collected. The organic fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford a brown oil (450 g crude of L2_A1, quantitative yield). Confirmed by1H NMR. Example 5.3 – Synthesis of L2_A2

[0691] Into a 10L four-neck round bottom flask, a solution of L2_A1 (270g, 1.0eq) in Acetonitrile (4.05L, 15V) was placed under inert atmosphere at room temperature.4-Dimethylaminopyridine (126g, 1.0eq) and Di-tert-butyldicarbonate (338g, 1.5eq) were added to the above reaction mixture at 0oC and the resulting mixture was allowed to stir at 25±5oC for 18h. Water (4L, 14.8V) and ethyl acetate (2.5L, 9.2V) were added to the above reaction mixture and allowed to stir for 10min. The organic fraction was collected. EtOAc (2.5L, 9.2V) was added to the aqueous fraction and allowed to stir for 10min. The organic fraction was collected. The resulting fractions were combined and dried over sodium sulphate and concentrated under reduced pressure to afford a brown oil. The crude material was purified by glass column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 15-20% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford a light brown oil (250 g of L2_A2, 67% yield). Confirmed by1H NMR. Example 5.4 – Synthesis of L2_A4

[0692] Into a 5L four-neck round bottom flask, a solution of L2_A2 (236g, 1.0eq) in di-ethyl ether (2.36L, 10V) was placed under inert atmosphere at room temperature. Diisobutylaluminum hydride (784mL, 1.2eq) was dropwise added to the above reaction mixture at -78oC and the resulting mixture was allowed to stir at -78oC for 1h. NH4Cl solution (1.89L, 8V) and ethyl acetate (1.89L, 8V) were added to the reaction mixture at -78oC and allowed to stir for 30min. The resulting mixture was filtered through celite powder. The filtrate was separated, and the organic fraction was collected. The organic fraction was dried by sodium sulphate and concentrated under reduced pressure to afford a yellow oil (218 g of L2_A3, quantitative). Confirmed by Mass. The crude material was used directly in the next step.

[0693] Into a 2L four-neck round bottom flask, a solution of L2_A3 (Crude) (150g, 1.0eq) in methanol (1.5L, 10V) was placed under inert atmosphere at room temperature. Sodium borohydride (784g, 1.2eq) was added portion-wise for 3-4h to the reaction mixture at 0oC and the resulting mixture was allowed to stir 0oC for 1h. Ethyl acetate (1L, 6.6V) and NaHCO3 solution (500mL, 3.3V) were Attorney Docket No.41543-59274 (002WO) added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected. EtOAc (1L, 6.6V) was added to the aqueous fraction and allowed to stir for 10min. The organic fraction was collected. The resulting organic fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to a afford white oil. The crude material was purified by glass column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 30-35% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford a colourless oil (98.0 g of L2_A4, 45% yield). Confirmed by1H NMR, ELSD: 100%, MASS: (ES, m / z): 334.5 [M+1]+. Example 5.5 – Synthesis of L2_A5

[0694] Into a 3L four-neck round bottom flask, a solution of L2_A4 (95g, 1.0eq) in DMF (950mL, 10V) was placed under inert atmosphere at room temperature. Triethylamine (119mL, 3.0eq) and 4- dimethylaminopyridine (17.4g, 0.5eq) were added to the reaction mixture at 0oC and allowed to stir at 0oC for 30min. Tert-butylchlorodiphenylsilane (117.6g, 1.5eq) was added to the above reaction mixture at 0oC and allowed to stir at 25±5oC for 2h. EtOAc (2X600mL, 6.3V) and water (500mL, 5.2V) were added to the reaction mixture and allowed to stir for 15min. The organic fraction was collected. The resulting organic fractions were combined and washed with brine (1L, 10.5V). The organic fractions were collected, dried over sodium sulphate, and concentrated under reduced pressure to afford yellow oil. The crude material was purified by glass column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 7-10% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford yellow oil (140 g of L2_A5, 86% yield). Confirmed by1H NMR, ELSD: 100%, MASS: (ES, m / z): 472.7 [M-100] - . Example 5.6 – Synthesis of L2_A6

[0695] Into a 20L four-neck round bottom flask, a solution of L2_A5 (240g, 1.0eq) in Acetonitrile (7.2L, 30V) was placed under inert atmosphere at room temperature. Lithium bromide (291g, 8.0eq) was added to the reaction mixture at room temperature and the resulting mixture was allowed to stir 80- 85°C for 7-8h. The reaction mixture was concentrated under reduced pressure. DCM (2.4L, 10V) and water (2.4L, 10V) were added to the above crude and allowed to stir for 15min. The organic fraction was collected. DCM (2.4L, 10V) was added to the aqueous fraction and allowed to stir for 15min. The organic fraction was collected. The resulting organic fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford a pale yellow oil (196 g of L2_A6, quantitative yield). Confirmed by ELSD: 100%, MASS (ES, m / z): 372.2 [M-100]-. Quantitative. Example 5.7 – Synthesis of L2_A7

[0696] Into a 10L four-neck round bottom flask, a solution of Dimethyl methyl phosphonate (98.4g, 2.5eq) in tetrahydrofuran (750mL, 5V) was placed under inert atmosphere at -78°C. n-Butyl lithium (784mL, 2.5eq) was dropwise added to the reaction mixture, and the resulting mixture was allowed to stir -78oC for 1h. L2_A6 (150g, 1.0eq) was dropwise added to the above reaction mixture at -78oC and Attorney Docket No.41543-59274 (002WO) allowed to stir at 25±5oC for 3-4h. NH4Cl solution (750mL, 5V) and ethyl acetate (750mL, 5V) were added dropwise to the reaction mixture and allowed to stir for 10min. The organic fraction was collected. EtOAc (750mL, 5V) was added to the aqueous fraction and allowed to stir for 10min. The organic fraction was collected. The organic fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford a pale-yellow oil. The crude material was purified by glass column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 70-75% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford a pale-yellow oil (89.0 g of L2_A7, 50% yield). Confirmed by1H NMR, ELSD: 100%, MASS (ES, m / z): 564.5 [M+1]+. Example 5.8 – Synthesis of L2_A8

[0697] Into a 5L four-neck round bottom flask, a mixture of L2_A7 (116g, 1.0eq), lithium chloride (34.8g, 4.0eq) and N, N-Diisopropylethylamine (46mL, 4.0eq) in tetrahydrofuran (2.55L, 22V) were placed under inert atmosphere at 25±5oC for 1h. L2_X1 (43.6gm, 1.0eq), was added to the reaction mixture, and the resulting mixture was allowed to stir at 25±5oC for 48h. EtOAc (1.2L, 10V) and water (1200mL, 10V) were added to the above mixture and allowed to stir. The organic fraction was collected. The aqueous layer was again extracted with ethyl acetate (600mL, 5V) and the organic fraction was collected. The organic fractions were combined, dried over Na2SO4, and concentrated under reduced pressure to afford a pale-yellow crude oil (140 g of L2_A5, quantitative yield). Confirmed by ELSD purity: 89%, MASS; (ES, m / z): 550.5 [M-100]-. Example 5.9 – Synthesis of L2_A9

[0698] Into a 5L four-neck round bottom flask, a solution of L2_A8 (128g, 1.0eq) in Toluene (1.28L, 10V) was placed under inert atmosphere at -78°C. Diisobutylaluminum hydride (352mL, 1.8eq) was dropwise added to the reaction mixture and allowed to stir at -78oC for 1h. NH4Cl solution (500mL, 3.9V) and ethyl acetate (1L, 7.8V) were added to the reaction mixture at -78°C and allowed to stir for 30min. The resulting mixture was filtered through celite powder and washed with EtOAc (1L, 7.8V). The organic fraction was collected, dried with sodium sulphate, and concentrated under reduced pressure to afford a yellow oil. The crude material was purified by glass column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 9-15% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford yellow oil (85.0 g of L2_A9, 66% yield). Confirmed by1H NMR, ELSD: 92%, MASS: (ES, m / z): 652.9 [M+1]+. Example 5.10 – Synthesis of L2_A10

[0699] Into a 3L three neck round bottom flask, a solution L2_A9 (80g, 1.0eq) in ethanol (800mL, 10V) was placed under inert atmosphere at room temperature.10% Pd / C (16g, 20% w / w) was added to the reaction mixture and allowed to stir at 25±5oC for 3-4h under H2. The resulting mixture was filtered through celite powder and washed with 400mL methanol. The filtrate was concentrated under reduced Attorney Docket No.41543-59274 (002WO) pressure to afford a light brown oil (75.0 g of L2_A10, quantitative yield). Confirmed by1H NMR, ELSD: 90%, MASS: (ES, m / z): 654.9 [M+1]+. Example 5.11 – Synthesis of L2_A11

[0700] Into a 1L four-neck round bottom flask, a solution of L2_A10 (240g, 1.0eq) in tetrahydrofuran (400mL, 10V) was placed under inert atmosphere at 0oC. Tetra-n-butyl ammonium fluoride (91mL, 1.5eq) was added to the reaction mixture at 0oC and allowed to stir at 25±5oC for 1h. EtOAc (200mL, 5V) and water (200mL, 5V) were added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected. EtOAc (200mL, 5V) was added to the aqueous fraction and allowed to stir for 10min. The organic fraction was collected. The organic fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford a pale white solid. The crude material was purified by glass column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 20-25% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford a pale white solid (20.0 g of L2_A11, 79% yield). Confirmed by1H NMR, ELSD: 80%, MASS: (ES, m / z): 416.5 [M+1]+. Example 5.12 – Synthesis of L2_A12

[0701] Into a 1L four-neck round bottom flask, a solution of L2_A11 (19g, 1.0eq) in DMF (378mL, 20V) was placed under inert atmosphere at room temperature. Linoleic acid (9g, 0.7eq) and 4- Dimethylaminopyridine (11.1g, 2.0eq) were added to the reaction mixture at room temperature. EDC·HCl (17.4g, 2.0eq) was added portion wise to the reaction mixture and allowed to stir at 25±5oC for 4h. Water (200mL, 10.5V) and EtOAc (200mL, 10.5V) were added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected. EtOAc (100mL, 5.2V) was added to the aqueous layer and allowed to stir for 10min. The organic fraction was collected. The organic fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford a pale- yellow oil. The crude material was purified by flash column chromatography (silica gel 100-200 mesh and solvent: ethyl acetate and hexane). The product was eluted at 7-15% ethyl acetate in hexane. Fractions were combined and concentrated under reduced pressure to afford a white semi-solid (10.6 of L2_A12, 32% yield). Confirmed by1H NMR, ELSD: 95%, MASS: (ES, m / z): 416.5 [M+1]+. Example 5.13 – Synthesis of Scaffold B

[0702] Into a 250mL three neck round bottom flask, a solution of L2_A12 (7g, 1.0eq) in dichloromethane (70mL, 10V) was placed under inert atmosphere at 0oC. TFA (17.5ml, 2.5V) was dropwise added to the reaction mixture at 0°C and allowed to stir at 25±5oC for 1h. 10% NaHCO3solution (100mL, 13V) and DCM (100mL, 13V) were added to the reaction and allowed to stir for 10min. The organic fraction was collected. DCM (100mL, 13V) was added to the aqueous fraction and allowed to stir for 10min. The organic fraction was collected. The organic fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford a brown oil (7.0 g crude of Scaffold B, quantitative yield). Confirmed by 1H NMR, ELSD: 99%, MASS: (ES, m / z): 578.7 Attorney Docket No.41543-59274 (002WO) [M+1]+. Example 5.14 – Synthesis of Lipid 2 (1.81 g, 1.0 eq), K2CO3(3.34 g, 2.0 eq) followed by Scaffold-X (4.55 g, 1.5 eq) under inert atmosphere and the resulting reaction mixture was stirred at 60°C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (70 mL, 10 V) and water (70 mL, 10 V). After 10 min, two layers were separated, and the aqueous layer was extracted with EtOAc (70 mL, 10V). The organic fractions were combined, dried over Na2SO4, concentrated under vacuum, and the crude residue was purified by flash column chromatography on neutral alumina (eluent: 0 to 20% EtOAc in hexane) to afford L2_X1 (1.4 g, 15%) as pale-yellow liquid. Confirmed by 1H NMR, Mass (ES+, m / z): 794.9 (M+H)+.

[0704] Step 2: To a 50 mL flask, a solution of L2_X1 (1.4 g, 1.0 eq) in CH2Cl2(14 mL, 10V) was added and cooled to 0°C under inert atmosphere.4.0 M HCl in dioxane (2.8 mL, 2V) was added to the reaction mixture at 0 °C in dropwise and stirred at the same temperature for 2h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash silica gel column chromatography (eluent: 0 to 10% 7M methanolic ammonia in CH2Cl2) to provide lipid 2 (0.35 g, 29%). 1H NMR (400 MHz, CDCl3) δ 5.44 – 5.27 (m, 4H), 4.45– 4.30 (m, 1H), 4.28 – 4.15 (m, 1H), 4.09 – 3.98 (m, 1H), 3.83– 3.67 (m, 4H), 3.31– 3.19 (m, 1H), 3.15– 3.07 (m, 1H), 3.05– 2.96 (m, 1H), 2.96 – 2.89 (m, 1H), 2.90 – 2.82 (m, 1H), 2.81– 2.76 (m, 2H), 2.76 – 2.71 (m, 2H), 2.48 (s, 3H), 2.33 (t, J = 7.6 Hz, 2H), 2.14 – 1.99 (m, 5H), 1.70 – 1.48 (m, 4H), 1.49 – 1.02 (m, 40H), 0.98 – 0.81 (m, 6H); LC-MS (ES+, m / z): 679.9 (M+H)+. Example 5.15 – Synthesis of Lipid 10 , (10 mL, 6.6V) was added DIPEA (1.0 g, 3.0 eq) and HATU (1.47g, 1.5eq) at 00C. The reaction was warmed to room temperature and stirred for 3 h. Then, the reaction was diluted with EtOAc (50 mL, Attorney Docket No.41543-59274 (002WO) 33V) and water (50 mL, 33V) and stirred for 30 min. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL, 33V). The combined organic layers were washed with 10% aq. Citric acid (50 mL), 10% aq. NaHCO3(50 mL), brine (50 mL), dried over Na2SO4, and concentrated. The crude material was purified by flash silica gel column chromatography (eluent: 0 to 12% methanol in CH2Cl2) to give lipid 10 (0.75 g, 38% yield) as brown viscous liquid.1H NMR (400 MHz, MeOD) δ 5.48 – 5.22 (m, 4H), 4.22 – 4.08 (m, 2H), 3.97 – 3.89 (m, 1H), 3.81 – 3.74 (m, 2H), 3.60 – 3.50 (m, 1H), 3.15 – 3.06 (m, 2H), 2.97 – 2.86 (m, 2H), 2.80 (t, J = 6.3 Hz, 2H), 2.66 – 2.54 (m, 4H), 2.39 – 2.29 (m, 2H), 2.17 – 2.03 (m, 5H), 1.75 – 1.58 (m, 3H), 1.54 – 1.20 (m, 44H), 0.98 – 0.88 (m, 6H); LC-MS (ES+, m / z): 707.2 (M+H)+; ELSD: 98.33%. Example 5.16 – Synthesis of Lipid 18 DMF (20 mL, 8V) were added HATU (2.46 g, 1.5eq) and DIPEA (1.67 g, 3.0 eq) at 0oC under inert atmosphere. The reaction mixture was warmed to room temperature and stirred for 3h. Th reaction was quenched with water (100 mL, 40V), and diluted with EtOAc (100 mL, 20V). Two layers were separated, and the aqueous layer was extracted with EtOAc (50 mL, 10V). The combined organic layers were washed with 10% aq. citric acid (50 mL, 20V), 10% aq. NaHCO3(50 mL, 20V), brine (50 mL), dried over Na2SO4, and concentrated to give crude product as pale-yellow oil. The crude material was purified by flash silica gel column chromatography (eluent: 0 to 10% MeOH in CH2Cl2) to give L18_A1 (1.4 g, 37% yield) as yellow oil. Confirmed by 1H NMR, ELSD: 90.75%, Mass (ES+, m / z): 867.2 (M+1)+.

[0707] Step 2: 4.0 M HCl in dioxane (2.8 mL, 2V) was added to a solution of L18_A1 (1.4 g, 1.0 eq) in CH2Cl2(10 mL, 7.1V) at 0oC under inert atmosphere and stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the resulting crude material was purified by silica gel column chromatography (0 to 10% methanol in CH2Cl2) to afford lipid 18 (0.63 g, 57% yield) as Attorney Docket No.41543-59274 (002WO) light-yellow liquid.1H NMR (400 MHz, MeOD) δ 5.45 – 5.27 (m, 4H), 4.18 – 4.06 (m, 4H), 4.00 – 3.90 (m, 1H), 3.87 (t, J = 5.4 Hz, 2H), 3.59 – 3.52 (m, 1H), 3.41 – 3.36 (m, 1H), 3.30– 3.25 (m, 1H), 3.22 – 3.14 (m, 2H), 3.00 (t, J = 7.3 Hz, 2H), 2.84 (s, 3H), 2.80 (t, J = 6.3 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.14 – 2.04 (m, 5H), 1.76 – 1.22 (m, 46H), 1.00 – 0.88 (m, 6H); LC-MS (ES+, m / z): 753.0 (M+H)+; ELSD: 100%. EXAMPLE 6: Scaffold C and related lipids Scaffold C Synthetic Scheme

[0708] Into a 5L three neck round bottom flask, a solution of CAS# 155542-33-9 (300g, 1.0eq) and NMM (104g, 1.0eq) in THF (2500mL, 8.3V) was placed under inert atmosphere at room temperature. ClCO2Et (112g, 1.0eq) was added dropwise at -10°C and allowed stir at -10°C for 30min. The resulting mixture was filtered to remove the NMM-HCl salt. The organic fraction was collected. Freshly prepared NaBH4(88.20g, 2.25eq) soln. in H2O (1200mL, 4V) was added to the organic fraction at 0oC and allowed to stir 25±5oC for 2h.3M HCl solution (1L, 3.3V) and EtOAc (4mL, 13V) were added to the reaction mixture and allowed to stir for 15min. The organic fraction was collected. The organic fraction was washed with 10% NaCl (3L, 15V) solution. The resulting fraction was dried over sodium sulphate and concentrated under vacuum reduce pressure to afford a brown oil (210 g of L3_A1, 73% yield). Confirmed by1H- NMR, LCMS: 91%, MASS (ES+, m / z): 276.3 [M+1]+. Attorney Docket No.41543-59274 (002WO) Example 6.2 – Synthesis of L3_B1

[0709] Into a 10L four-neck round bottom flask, a solution of CO2Cl2(100mL, 1.7eq) in DCM (400mL, 3V) was cooled to -78oC. DMSO (178mL, 3.5eq) in DCM (300mL, 1.6V) was added dropwise at -78°C and allowed to stir at -78°C for 30min. L3_A1 (180g, 1.0eq) in DCM (400mL, 2.2V) and TEA (440mL, 5.2eq) in DCM (400mL, 4V) were added to the above reaction mixture at -78°C and allowed to stir at -78oC for 2h.1M NaHSO4H2O (2L, 11V) and diethyl ether (2L, 11V) were added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected. The organic fraction was washed with 10% NaHCO3solution (2.5L, 13.8V) and 10% NaCl solution (2.5L, 13.8V). The resulting organic fraction was dried over sodium sulphate and concentrated under reduced pressure to afford a colourless oil (176 g of L3-B1, 98% yield). Confirmed by1H NMR, ELSD: 98%. Example 6.3 – Synthesis of L3_A2

[0710] Into a 10L three-neck round bottom flask, a solution of CAS# 1779-49-3 (470 g, 2.0eq) in THF (1L, 2V) was added dropwise to 1M KHMDS in THF (1316.5mL, 2.0eq) at room temperature and allowed to stir at 25±5oC for 1h. L3_B1 (180.0g, 1.0eq) in THF (300mL, 2V) was added dropwise at - 78°C and allowed to stir at 25±5oC for 2h. Sat. NH4Cl solution (2L, 11.11V) and diethyl ether (3L, 16.6V) were added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected, washed with 1M HCl solution (2L, 11.11V), 10% NaHCO3solution (2L, 11.11V), and 10% NaCl (1L, 5.55V) solution. The resulting organic fraction was dried over sodium sulphate and concentrated under reduced pressure to afford a brown oil. The crude material was purified by flash column chromatography using silica gel 60-120 mesh and ethyl acetate and hexane. The product was eluted at 10-15% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford a pale colorless liquid (150 g of L3_A2, 84% yield). Confirmed by1H NMR, MASS (ES+, m / z): 272.2 [M+1]+. Example 6.4 – Synthesis of L3_D1

[0711] Into a 1L three-neck round bottom flaks, a solution of L3_A2 (125g, 1.0eq) in DCM (125mL, 1V) was placed under inert atmosphere at room temperature. Int.-Y (157.7g, 1.8eq) and CAS# 301224- 40-8 (28.9g, 0.1eq) were added to the reaction mixture and allowed to stir at 60oC for 16h. The reaction mixture was concentrated under reduced pressure to afford a brown oil. The crude material was purified flash column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane. The product was eluted at 5-10% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford brown oil (100 g of L3_D1, 50% yield). Confirmed by1H NMR, LCMS: 87%, MASS (ES+, m / z): 434.6 [M+1]+. Example 6.5 – Synthesis of L3_D2

[0712] Into a 1L three neck round bottom flask, a solution of L3_D1 (100g, 1.0eq) in THF (1L, 10V) was placed under inert atmosphere at room temperature.10% Pd / C (20.0g, 20% w / w) was added to the Attorney Docket No.41543-59274 (002WO) reaction mixture and allowed to stir at 25±5oC for 16h under H2condition. The reaction mixture was filtered through Celite powder and concentrated under reduced pressure to afford a brown oil. The crude material was purified by flash column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 15-20% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford a brown oil (40.0 g of L3_D2, 50% yield). Confirmed by1H NMR, ELSD:95%, MASS (ES+, m / z): 346.7 [M+1]+. Example 6.6 – Synthesis of L3_D3

[0713] Into a 500mL three-neck round bottom flask, a solution of CAS# 25354-91-6 (32.66g, 1.1eq), and L3_D2 (40g, 1.0eq) in MDC (200mL, 5V) were placed under inert atmosphere at room temperature. EDC-HCl (33.17g, 1.5eq) and DMAP (28.25g, 0.5eq) were added to the reaction mixture and allowed to stir at 25+5oC for 4h. EtOAc (100mL, 2.5V) and water (500mL, 12.5V) were added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected. EtOAc (100mL, 2.5V) was added to the aqueous fraction and allowed to stir for 10min. The organic fraction was collected. The organic fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford a colourless liquid. The crude material purified by flash column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 5-10% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford a colourless liquid (50.0 g of L3_D3, 74% yield). Confirmed by1H-NMR, MASS (ES+, m / z): 602.0 [M+18]+. Example 6.7 – Synthesis of L3_A7

[0714] Into a 1L four-neck round bottom flask, a solution of L3_D3 (40.0g, 1.0eq) in DCM (400mL, 10V) was placed under inert atmosphere at room temperature. TFA (100mL, 2.5V) was added dropwise at room temperature and allowed to stir at 25+5oC for 5h. The reaction mixture was concentrated under reduced pressure to afford a brown liquid. DCM (200mL, 5V) and DIPEA (61mL, 4.0eq) were added to the brown liquid and the resulting mixture was allowed to stir 0oC for 30min. (Boc)2O (40.84g, 2.0eq) was added dropwise to the reaction mixture at 0oC and allowed to stir at 25+5oC for 16h. The reaction mixture was concentrated under reduced pressure to afford a sticky solid. EtOAc (500mL, 12.5V) was added to the sticky solid and washed with sat. Brine solution (1L, 25V), collected the organic fractions. The resulting organic fraction was dried over sodium sulphate and concentrated under reduced pressure to afford a brown liquid (80.0 g crude of L3_A7, quantitative yield). Confirmed by1H-NMR, MASS (ES+, m / z): 546.0 [M+1]+. Example 6.8 – Synthesis of L3_A8

[0715] Into a 2L three neck round bottom flask, a solution of L3_A7 (80g, 1.0eq) and NMM (15.33g, 1.0eq) in THF (800mL, 10V) were placed under inert atmosphere at room temperature. ClCO2Et (16.43g, 1.0eq) was added dropwise to the reaction mixture at -10°C and allowed to stir at -10°C for 30min. The resulting mixture was filtered to remove NMM-HCl salt. The organic fraction was collected. Freshly prepared NaBH4 (12.92g, 2.25eq) solution in H2O (320mL, 4V) was added to the Attorney Docket No.41543-59274 (002WO) organic fraction at 0oC and allowed to stir at 25+5oC for 2h. 3M HCl solution (100mL, 1.25V) and EtOAc (2L, 25V) was added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected. The organic fraction was dried over sodium sulphate and concentrated under reduced pressure to afford a brown oil. The crude material was purified by flash column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 10-15% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford a colourless liquid (30.0 g of L3_A8, 39% yield). Confirmed by1H- NMR, ELSD: 100%, MASS (ES+, m / z): 514.9 [M+1]+. Example 6.9 – Synthesis of L3_A9

[0716] Into a 500mL three-neck round bottom flask, a solution of linoleic acid (19.62g, 1.2eq) and L3_A9 (30g, 1.0eq) in MDC (200mL, 6.66V) were placed under inert atmosphere at room temperature. EDC·HCl (16.75g, 1.5eq) and DMAP (3.56g, 0.5eq) were added to the reaction mixture and allowed to stir at 25±5oC for 16h. DCM (300mL, 10V) and water (1L, 33.3V) were added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected, dried over sodium sulphate, and concentrated under reduced pressure to afford a colourless liquid. The crude material was purified by flash column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 5-10% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford a colourless liquid (30.0 g of L3_A9, 66% yield). Confirmed by1H-NMR, ELSD: 98%, MASS (ES, m / z): 794.7 [M+18]+. Example 6.10 – Synthesis of Int.-Y

[0717] Into a 2L four-neck round bottom flask, a solution of NaH (26.79g, 1.9eq) in THF (900mL, 15V) was placed under inert atmosphere at 0oC. CAS# 821-41-0 (60g, 1.0eq) and benzyl bromide (123.12g, 1.2eq) were added to the reaction mixture at 0°C and allowed to stir at stir 25+5oC for 6h. NH4Cl solution (200mL, 3.3V) and diethyl ether (1.2L, 20V) were added to the reaction mixture and allowed to stir for 10min. The organic fraction was collected, dried over sodium sulphate, and concentrated under reduced pressure to afford a colourless liquid. The crude material was purified by flash column chromatography (silica gel 60-120 mesh; solvent: ethyl acetate and hexane). The product was eluted at 0-5% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford a colourless liquid (80.0 g of Int-Y, 70% yield). Confirmed by1H-NMR, ELSD: 78%, MASS (ES+, m / z): 208.3 [M+18]+. Example 6.11 – Synthesis of Scaffold C

[0718] Into a 250mL four-neck round bottom flask, a solution of L3_A9 (8.0g, 1.0eq) in DCM (80mL, 10V) was placed under inert atmosphere at room temperature. TFA (16mL, 2V) was added dropwise to the reaction mixture at 0°C and allowed to stir at 25±5oC for 2h. The reaction mixture was concentrated under reduced pressure to afford a crude brown liquid (10.0 g of Scaffold C, quantitative Attorney Docket No.41543-59274 (002WO) yield). Confirmed by1H-NMR, ELSD: 95%, MASS (ES+, m / z): 676.9 [M+1]+. Example 6.12 – Synthesis of Lipid 3 4V) was placed at room temperature under inert atmosphere. K2CO3(4.07g, 2.0eq) and NaI (2.21g, 1.0eq) were added to the above reaction mixture and the resulting mixture was allowed to stir under inert atmosphere. Scaffold-X in acetonitrile (40mL, 4V) and dimethylformamide (20mL, 2V) were added to the above reaction mixture and allowed to stir 60oC for 2h. The reaction was quenched with EtOAc (2X100mL, 10V) and chilled water (100mL, 10V) and allowed to stir for 5min, collected the organic fractions. The resulting fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford pale yellow oil. The crude material was purified by Biotage using neutral alumina. The product was eluted at 15-20% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford pale yellow liquid. 1.6 g of L3_X1, confirmed by 1H NMR, ELSD: 98.37%, Mass (ES+, m / z): 891.1 (M+1)+, Yield: 12%

[0720] Step 2: Into a 50 mL three neck round bottom flask, a solution of L3_X1 (1.5g, 1.0eq) in dichloromethane (15mL, 10V) was placed at room temperature under inert atmosphere. 4M HCl in dioxane (3.0mL, 2V) was added to the above reaction mixture at 0°C and allowed to stir at 25+5oC for 2h. The reaction mixture was concentrated under vacuum to afford brown oil. The crude material was purified by flash column Biotage using silica gel 60 - 120 mesh. The product was eluted at 8-10% 7M methanolic ammonia in DCM. Fractions were combined and concentrated under reduced pressure to afford light brown liquid.0.75 g of Lipid 3, confirmed by 1H NMR, ELSD: 97.54%, Mass (ES+, m / z): 778.1 (M+1)+, Yield: 59%.1H NMR (400 MHz, MeOD) δ 5.42 – 5.27 (m, 4H), 4.34 – 4.19 (m, 2H), 4.11 (t, J = 6.5 Hz, 2H), 3.76 – 3.70 (m, 2H), 3.31 – 3.21 (m, 2H), 2.80 (t, J = 6.0 Hz, 2H), 2.72 – 2.60 Attorney Docket No.41543-59274 (002WO) (m, 2H), 2.43 – 2.30 (m, 4H), 2.16 – 2.03 (m, 6H), 1.83 – 1.19 (m, 55H), 0.97 – 0.86 (m, 9H); LC-MS (ES+, m / z): 778.1 (M+H)+. Example 6.13 – Synthesis of Lipid 11 Scaffold-Y (0.18g, 1.2eq) in dimethylformamide (7mL, 10V) was placed at room temperature under inert atmosphere. HATU (0.58g, 1.5eq) and DIPEA (0.40g, 3.0eq) were added to the above reaction mixture and allowed to stir at 25+5°C for 3h. The reaction was quenched with EtOAc (2X30mL, 40V) and chilled water (50mL, 70V) and allowed to stir for 5min, collected the organic fractions. The resulting fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford pale yellow liquid. The crude material was purified by Biotage using silica gel 60 - 120 mesh. The product was eluted at 7-10% MeOH in DCM. Fractions were combined and concentrated under reduced pressure to afford pale yellow liquid.0.58 g of Lipid-11, confirmed by 1H NMR, ELSD: 100%, Mass (ES+, m / z): 806.4 (M+1)+, Yield: 84%.1H NMR (400 MHz, MeOD) δ 5.48 – 5.22 (m, 4H), 4.22 – 4.08 (m, 2H), 3.97 – 3.89 (m, 1H), 3.81 – 3.74 (m, 2H), 3.60 – 3.50 (m, 1H), 3.15 – 3.06 (m, 2H), 2.97 – 2.86 (m, 2H), 2.80 (t, J = 6.3 Hz, 2H), 2.66 – 2.54 (m, 4H), 2.39– 2.29 (m, 2H), 2.17 – 2.03 (m, 5H), 1.75 – 1.58 (m, 3H), 1.54 – 1.20 (m, 44H), 0.98 – 0.88 (m, 6H); LC-MS (ES+, m / z): 707.2 (M+H)+.

[0008] Attorney Docket No.41543-59274 (002WO) Example 6.14 – Synthesis of Lipid 19 1.0eq) and Scaffold-R (0.54g, 1.5eq) in dimethylformamide (3mL, 3.75V) was placed at room temperature under inert atmosphere. HATU (0.67g, 1.5eq) and DIPEA (0.45g, 3.0eq) were added to the above reaction mixture and allowed to stir at 25+5oC for 3h. The reaction mixture was quenched with EtOAc (2X50mL, 60V) and chilled water (100mL, 120V) and allowed to stir for 5min, collected the organic fractions The resulting fractions were combined and washed with 10% citric acid solution (50mL, 60V) and 10% NaHCO3solution (50mL, 60V). The resulting fraction was dried over sodium sulphate and concentrated under reduced pressure to afford pale yellow liquid. The crude material was purified by Biotage using silica gel 60-120 mesh. The product was eluted at 70-80% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford pale yellow liquid.1.0 g of L19_A1, confirmed by 1H NMR, ELSD: 99.70%, Mass (ES+, m / z): 966.5 (M+1)+, Yield: 46%.

[0723] Step 2: Into a 50mL three neck round bottom flask, a solution of L19_A1 (1.0g, 1.0eq) in dichloromethane (10mL, 10V) was placed at room temperature under inert atmosphere. 4M HCl in dioxane (3ml, 3V) was added at 0oC and the reaction mixture was allowed to stir at 25+5oC for 2h. The reaction mixture was concentrated under vacuum to afford brown liquid. The crude material was purified by Biotage using silica gel 60-120 mesh. The product was eluted at 10-12% methanol in DCM. Fractions were combined and concentrated under reduced pressure to afford yellow liquid. 0.73 g of Lipid-19, confirmed by 1H NMR, ELSD: 96.13%, Mass (ES+, m / z): 852.2 (M+1)+, Yield: 82%.1H NMR (400 MHz, CDCl3)δ 5.46– 5.31 (m, 4H), 4.17– 3.99 (m, 4H), 3.76– 3.64 (m, 2H), 3.31– 3.24 (m, 1H), 2.96 – 2.75 (m, 5H), 2.47 (s, 3H), 2.39 – 2.25 (m, 4H), 2.18 – 2.03 (m, 6H), 1.98 – 1.72 (m, 2H), 1.69– 1.16 (m, 52H), 0.95– 0.85 (m, 9H); LC-MS (ES+, m / z): 852.2 (M+H)+. Attorney Docket No.41543-59274 (002WO) EXAMPLE 7: Scaffold D and related lipids Scaffold D Synthetic Scheme

[0724] Into a 3L four neck round bottom flask, a solution of CAS# 98303-20-9 (300g, 1.0eq) in DMF (900mL, 3V) and potassium carbonate (181.0g, 1.0eq) were placed at room temperature under inert atmosphere. Methyl iodide (163mL, 2.0eq) was added dropwise to the reaction mixture at 0°C for 20min. The reaction mixture was stirred at 25±5oC for 2h. EtOAc (1500mL, 5V) and chilled water (3000mL, 10V) were added to the reaction mixture and allowed to stir for 20min. The organic fraction was collected. EtOAc (1500mL, 5V) was added to the aqueous fraction and allowed to stir for 20min. The organic fraction was collected. The organic fractions were combined, dried over sodium sulphate, Attorney Docket No.41543-59274 (002WO) and concentrated under reduced pressure to afford a yellow liquid (300 g of L4-A1, 94% yield). Confirmed by1H NMR, LCMS: 100%, Mass (ES+, m / z): 244.3 (M+1)+. Example 7.2 – Synthesis of L4_A2

[0725] Into 10L four neck RBF, a solution of L4-A1 (300g, 1.0eq) in MeCN (720mL, 2.4V) and water (3.6L, 12V) and NaIO4(765g, 2.9eq) was added at room temperature under inert atmosphere. Ruthenium oxide (16.42g, 0.1eq) was added to the above reaction mixture at 0°C for 15min. The reaction mixture was stirred at 25+5oC for 5h. The reaction mixture was concentrated under reduced pressure. EtOAc (2X600mL, 2V) was added to the reaction mixture and allowed reaction mixture to stir for 10min, collected the organic fractions. Activated charcoal was added to the resulting fractions and allowed to stir for 30min and filtered through celite powder and concentrated under reduced pressure to afford yellow liquid.260 g of L4-A2, confirmed by LCMS: 95%, Mass (ES+, m / z): 244.3 (M+1)+, Yield: 82% Example 7.3 – Synthesis of L4_A3

[0726] Into a 5L four neck round bottom flask, a solution of L4-A2 (130g, 1.0eq) in THF (1300mL, 10V) was placed at room temperature under inert atmosphere. DIDAL-H (1.01L, 2.0eq) was added dropwise to the reaction mixture at -78°C for 30min. The reaction mixture was stirred at -78oC for 15min. 2-propenol (520mL, 4V) was added dropwise at -78°C and stirred for 20min, then potassium tartrate salt (35g) in water (200mL) was added at -78°C and stirred for 20min. The reaction mixture was diluted with diethyl ether (700mL, 6V) and filtered through celite powder. The organic fraction was collected, dried over sodium sulphate, and concentrated under reduced pressure to afford a yellow liquid (150 g of L4-A3, quantitative yield). Confirmed by1H NMR, LCMS: 73%, Mass (ES-, m / z): 258.3 (M-1)-. Example 7.4 – Synthesis of L4_A4

[0727] Into 5L four neck round bottom flask, a solution of L4-A3 (145g, 1.0eq) in MeCN (2.03L, 14V) placed at room temperature under inert atmosphere. CAS# 15097-38-8 (275.0g, 1.2eq) was added to the above reaction mixture at rt then the reaction mixture was allowed to stir at 80°C for 16h. The reaction mixture was concentrated under vacuum to afford yellow liquid. The crude material was purified by flash column chromatography using silica gel 60 - 120 mesh. The product was eluted at 15- 20% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford sticky solid. 255 g of L4-A4, confirmed by 1H NMR, HPLC: 95%, Mass (ES+, m / z): 392.4 (M+1)+, Yield: 38% Example 7.5 – Synthesis of L4_B1

[0728] Into 3L four neck round bottom flask, a solution of L4_A4 (100g, 1.0eq) in methanol (1.0L, 10V) was added at room temperature under inert atmosphere. 10% Pd / C (15.0g, 15%w / w) was added to the above reaction mixture at 25+5 °C and allowed to stir for 16h under H2condition. The reaction Attorney Docket No.41543-59274 (002WO) mixture was filtered through celite powder and concentrated under reduced pressure to afford pale yellow liquid.80.0 g of L4_B1, confirmed by 1H NMR, ELSD: 99%, Mass (ES+, m / z): 304.4 (M+1)+, Yield: Quantitative. Example 7.6 – Synthesis of L4_B2

[0729] Into 3L four-neck round bottom flask, a solution of L4_B2 (55g, 1.0eq) in THF (550mL, 10V) was added at room temperature under inert atmosphere. 1M BH3in THF (326mL, 1.8eq) was added dropwise to the above reaction mixture at 0°C and allowed to stir at 0°C for 1h.10% Acetic acid in methanol solution (250mL) was added dropwise to the above reaction mixture at 0°C for 10min. The reaction mixture was quenched with EtOAc (2X300mL, 5.5V) and 0.5N HCl solution (400mL, 7V) and allowed the reaction mixture to stir for 20min, collected the organic fractions. The resulting fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford pale yellow liquid.46.0 g of L4_B2, confirmed by 1H NMR, ELSD: 77%, Mass (ES+, m / z): 290.4 (M+1)+, Yield: 87% Example 7.7 – Synthesis of L4_B3

[0730] Into a 3L four-neck round bottom flask, a solution of L4_B2 (83g, 1.0eq) in DCM (830mL, 10V) was added at room temperature under inert atmosphere. Triethylamine (120mL, 3.0eq) and TBDMS-Cl (95.22g, 2.2eq) were added dropwise to the above reaction mixture at 0°C and allowed to stir at 25+5 °C for 8h. The reaction mixture was quenched with DCM (400mL, 5V) and water (2X400mL, 5V) and allowed to stir for 10min, collected the organic fractions. The resulting fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford yellow liquid. The crude material was purified by flash column chromatography using silica gel 60 - 120 mesh. The product was eluted at 15-20% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford pale yellow liquid.66.0 g of L4_B3, confirmed by 1H NMR, ELSD: 100%, Mass (ES+, m / z): 404.7 (M+1)+, Yield: 57%. Example 7.8 – Synthesis of L4_B4

[0731] Into a 3L four-neck round bottom flask, a solution of diethyl phosphate (94g, 2.5eq) in THF (700mL, 7V) was added at -78°C under inert atmosphere. 2.5M n-BuLi (250mL, 2.5eq) was added dropwise to the above reaction mixture at -78°C and allowed to stir at -78°C for 1h. L4_B3 (100g, 1.0eq) in THF (300mL, 3V) was added dropwise to the above reaction mixture at -78°C and allowed to stir at -78°C for 4h. The reaction mixture was quenched with EtOAc (2X500mL, 5V) and ammonium chloride solution (1L, 10V) and allowed to stir for 15min, collected the organic fractions. The resulting fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford yellow liquid. The crude material was purified by flash column chromatography using silica gel 60-120 mesh. The product was eluted at 35-40% EtOAc in hexane. Fractions were combined and concentrated Attorney Docket No.41543-59274 (002WO) under reduced pressure to afford pale yellow liquid.60.0 g of L4_B4, confirmed by 1H NMR, ELSD: 96%, Mass (ES-, m / z): 522.8 (M-1) -, Yield: 46%. Example 7.9 – Synthesis of L4_B5

[0732] Into a 2L four-neck round bottom flask, a solution of L4_B4 (60g, 1.0eq) and L2_X1 (26.75g, 1.1eq) in THF (600mL, 10V) was added at room temperature under inert atmosphere. DIPEA (58.7mL, 3.0eq) and lithium chloride (12.15g, 2.5eq) were added to the above reaction mixture and allowed to stir at 25+5 °C for 16h. The reaction mixture was quenched with EtOAc (2X300mL, 5V) and ammonium chloride solution (600mL, 10V) and allowed to stir for 15min, collected the organic fractions. The resulting fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford crude yellow liquid.69.0 g of L4_B5, confirmed by 1H NMR, ELSD: 100%, Mass (ES+, m / z): 583(M+1)+, Yield: Quantitative. Example 7.10 – Synthesis of L4_B6

[0733] Into a 3L three neck round bottom flask, a solution of L4_B5 (60g, 1.0eq) in methanol (600mL, 10V) was added at room temperature under inert atmosphere. NaBH4(19.49g, 5.0eq) was added portion-wise to the above reaction mixture at 0°C for a period of 1.5h and allowed to stir at 0°C for 30min. The reaction mixture was concentrated under vacuum to afford white solid. EtOAc (2X300mL, 5V) and water (600mL, 10V) was added to the reaction mixture and allowed to stir for 15min, collected the organic fractions. The resulting fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford yellow liquid. 54.0g (crude) of L4_B6, confirmed by 1H NMR, ELSD: 75%, Mass (ES+, m / z): 584.7 (M+1)+, Yield: Quantitative. Example 7.11 – Synthesis of L4_C1

[0734] Into a 1L four-neck round bottom flask, a solution of L4_B6 (30g, 1.0eq) and TBAI (19g, 1.0eq) in DMF (300mL, 10V) was added at room temperature under inert atmosphere.60% NaH (6.0g, 2.5eq) was added to the above reaction mixture at 0oC for a period of 30min and allowed to stir 0°C for 30min. Benzyl bromide (17.56g, 2.0eq) was added dropwise to the above reaction mixture at 0°C and allowed to stir at 60°C for 1h. The reaction mixture was quenched with EtOAc (2X300mL, 5V) and chilled water (600mL, 10V) and allowed to stir for 15min, collected the organic fractions. The resulting fractions were combined, dried over sodium sulphate, and concentrated under reduced pressure to afford yellow liquid. The crude material was purified by flash column chromatography using silica gel 60 - 120 mesh. The product was eluted at 7-10% EtOAc in hexane. Fractions were combined and concentrated under reduced pressure to afford colourless liquid.14.0g of L4_C1, confirmed by 1H NMR, ELSD: 72%, Mass (ES+, m / z): 674.9 (M+1)+, Yield: 46%. Example 7.12 – Synthesis of L4_C2

[0735] Into a 500mL three-neck round bottom flask, a solution of L4_C1 (22...

Claims

Attorney Docket No.41543-59274 (002WO) WHAT IS CLAIMED IS 1. A compound, wherein the compound is of formula I: (I) wherein:X is selected from -CH2-, -C(O)-, and -C(O)S-; Y is selected from C1-C6alkylene and C1-C6heteroalkylene; R1is selected from -(CH2)nOC(O)Z1and -(CH2)nC(O)OZ1, wherein Z1is C6-C20alkyl or C6- C20alkenyl, and n is an integer from 1-10; R2is selected from -(CH2)mOC(O)Z2, -(CH2)mC(O)OZ2, and C10-C20alkyl, wherein Z2is C6- C20alkyl or C6-C20alkenyl, and m is an integer from 0-10; R3is selected from H and C1-C6alkyl; R4is selected from H and OH; R5is C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -OR’, - SH, -SR’, -SCOR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, NR’COR’, -CO2H, -CO2R’, -COR’, -CONH2, - CONHR’, -CON(R’)2, -COSH, -COSR’, wherein R’ is C1-6alkyl or C3-10cycloalkyl; R6is C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -OR’, - SH, -SR’, -SCOR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, NR’COR’, -CO2H, -CO2R’, -COR’, -CONH2, - CONHR’, -CON(R’)2, -COSH, -COSR’, wherein R’ is C1-6alkyl or C3-10cycloalkyl; or R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl; or is a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein one or more of the following is true: (a) R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl; (b) R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkenyl; (c) R2is -(CH2)mOC(O)Z2, wherein Z2is C6-C20alkyl;Attorney Docket No.41543-59274 (002WO) (d) R2is C10-C20alkyl; (e) R4is OH; (f) R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl; (g) R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20 alkyl; (h) R2is C10-C20alkyl and R4is H; (i) R1is -(CH2)nC(O)OZ1; or (j) R2is -(CH2)mC(O)OZ2.

3. The compound of claim 2, wherein R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkenyl.

4. The compound of claim 2, wherein R2is -(CH2)mOC(O)Z2.

5. The compound of claim 4, wherein Z2is C6-C20alkenyl.

6. The compound of claim 4, wherein Z2is C6-C20alkyl.

7. The compound of claim 2, wherein R2is C10-C20alkyl.

8. The compound of claim 2 or 7, wherein R4is OH.

9. The compound of claim 2, wherein R2is -(CH2)mC(O)OZ2, wherein Z2is C6-C20alkenyl.

10. The compound of claim 2, wherein R1is -(CH2)nOC(O)Z1, wherein Z1is C6-C20alkyl.

11. The compound of claim 10, wherein R2is C10-C20alkyl and R4is H.

12. The compound of claim 2, wherein R1is -(CH2)nC(O)OZ1.

13. The compound of claim 12, wherein R2is -(CH2)mC(O)OZ2.

14. The compound of any one of claims 1-13, wherein R3is H.

15. The compound of any one of claims 1-13, wherein R3is C1-C6alkyl.

16. The compound of claim 1, wherein the compound is of formula Ia:Attorney Docket No.41543-59274 (002WO) wherein: Z1and Z2are each C6-C20alkenyl; n is an integer from 1 to 10; and m is an integer from 1 to 10.

17. The compound of claim 16, wherein one or both of Z1and Z2have at least two double bonds.

18. The compound of claim 16 or 17, wherein Z1and Z2are the same.

19. The compound of any one of claims 16-18, wherein Z1and Z2are -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

20. The compound of any one of claims 16-19, wherein n is 2.

21. The compound of any one of claims 16-20, wherein m is 1.

22. The compound of any one of claims 16-21, wherein the compound is selected from: Compound Structure d . 23.,Attorney Docket No.41543-59274 (002WO) wherein: Z1is C6-C20alkenyl; n is an integer from 1 to 10; and R2is C10-C20alkyl.

24. The compound of claim 23, wherein Z1has at least two double bonds.

25. The compound of claim 23 or 24, wherein Z1is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

26. The compound of any one of claims 23-25, wherein n is 2.

27. The compound of any one of claims 23-26, wherein the compound is selected from: Compound Structure 2 d . 28.wherein:Z1is C6-C20 alkenyl;Attorney Docket No.41543-59274 (002WO) n is an integer from 1 to 10; m is an integer from 1 to 10; and R7and R8are each C4-C20alkyl.

29. The compound of claim 28, wherein Z1has at least two double bonds.

30. The compound of claim 28 or 29, wherein Z1is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

31. The compound of any one of claims 28-30, wherein n is 2. The compound of any one of claims 28-31, wherein R7and R8are each C4-C10alkyl.

33. The compound of any one of claims 28-32, wherein m is 5.

34. The compound of any one of claims 28-33, wherein the compound is selected from: Compound Structure 3 35.,Attorney Docket No.41543-59274 (002WO) wherein: n is an integer from 1 to 10; R2is C10-C20alkyl; and R7and R8are each C4-C20alkyl.

36. The compound of claim 35, wherein R7and R8are each C4-C10alkyl.

37. The compound of claim 35 or 36, wherein m is 6.

38. The compound of any one of claims 35-37, wherein the compound is selected from: Compound Structure 4 3wherein:Z1is C6-C20alkenyl; n is an integer from 1 to 10; m is an integer from 1 to 10; andAttorney Docket No.41543-59274 (002WO) R7is C4-C20alkyl.

40. The compound of claim 39, wherein Z1has at least two double bonds.

41. The compound of claim 39 or 40, wherein Z1is -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

42. The compound of any one of claims 39-41, wherein n is 3.

43. The compound of any one of claims 39-42, wherein R7is C4-C10alkyl.

44. The compound of any one of claims 39-43, wherein m is 5.

45. The compound of any one of claims 39-44, wherein the compound is selected from: Compound Structure 7 d .wherein:Z1and Z2are each C6-C20alkenyl; n is an integer from 1 to 10; m is an integer from 0 to 10; andAttorney Docket No.41543-59274 (002WO) R3is C1-C6alkyl.

47. The compound of claim 46, wherein one or both of Z1and Z2have at least two double bonds.

48. The compound of claim 46 or 47, wherein Z1and Z2are the same.

49. The compound of any one of claims 46-48, wherein Z1and Z2are -(CH2)7CH=CHCH2CH=CH(CH2)4CH3.

50. The compound of any one of claims 46-49, wherein n is 1.

51. The compound of any one of claims 46-50, wherein m is 0.

52. The compound of any one of claims 46-51, wherein R3is methyl.

53. The compound of any one of claims 46-52, wherein the compound is selected from: Compound Structure 8 . 5wherein:Z1and Z2are each branched C6-C20alkyl;Attorney Docket No.41543-59274 (002WO) n is an integer from 1 to 10; and m is an integer from 0 to 10.

55. The compound of claim 54, wherein Z1and Z2are the same.

56. The compound of claim 54 or 55, wherein Z1and Z2are each , wherein p is an integer from 3-8.

57. The compound of any one of claims 54-56, wherein n is 3.

58. The compound of any one of claims 54-57, wherein m is 2.

59. The compound of any one of claims 54-58, wherein the compound is: .

60. The compound of, C6alkylene. The compound of claim 60, wherein -NH-X-Y-NR5R6is the following: , wherein o is an integer from 1 to 5.

62. The compound of claim 60 or 61, wherein R5and R6are C1-C6alkyl.

63. The compound of claim 62, wherein R5and R6are methyl.

64. The compound of claim 60 or 61, wherein R5is C1-C6alkyl and R6is hydroxy-C1-C6alkyl.

65. The compound of claim 64, wherein R5is methyl and R6is -CH2CH2OH.Attorney Docket No.41543-59274 (002WO) 66. The compound of claim 60 or 61, wherein R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

67. The compound of claim 66, wherein -NH-X-Y-NR5R6is the following: , wherein A is selected from CHR9, O,selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

68. The compound of claim 67, wherein A is CHR9and R9is OH.

69. The compound of claim 67, wherein A is CHR9and R9is C1-C6alkyl.

70. The compound of claim 67, wherein A is CHR9and R9is methyl.

71. The compound of claim 67, wherein A is CHR9and R9is -CH2OH.

72. The compound of claim 67, wherein A is CHR9and R9is -CH2CH2OH.

73. The compound of claim 67, wherein A is S.

74. The compound of claim 67, wherein A is O.

75. The compound of claim 67, wherein A is NR9and R9is C1-C6alkyl.

76. The compound of claim 67, wherein A is NR9and R9is hydroxy-C1-C6alkyl.

77. The compound of claim 67, wherein A is NR9and R9is -CH2CH2OCH2CH2OH.

78. The compound of claim 67, wherein A is NR9and R9is .Attorney Docket No.41543-59274 (002WO) 79. The compound of claim 67, wherein A is NR9and R9is .

80. The compound of claim 66, wherein the following:, wherein R10and R11are eachand hydroxy-C1-C6alkyl.

81. The compound of claim 80, wherein R10and R11are each H.

82. The compound of claim 80, wherein R10and R11are each OH.

83. The compound of claim 80, wherein R10and R11are each hydroxy-C1-C6alkyl.

84. The compound of claim 80, wherein R10is H and R11is OH.

85. The compound of any one of claims 1-59, wherein X is -C(O)- and Y is C1-C6heteroalkylene.

86. The compound of claim 85, wherein -NH-X-Y-NR5R6has the following structure: , wherein:Q is selected from S and O; and o is an integer from 1 to 4.

87. The compound of claim 85 or 86, wherein R5and R6are C1-C6alkyl.

88. The compound of claim 87, wherein R5and R6are methyl.

89. The compound of claim 85 or 86, wherein R5is C1-C6alkyl and R6is hydroxy-C1-C6alkyl.

90. The compound of claim 89, wherein R5is methyl and R6is -CH2CH2OH.Attorney Docket No.41543-59274 (002WO) 91. The compound of claim 85 or 86, wherein R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

92. The compound of claim 91, wherein -NH-X-Y-NR5R6is the following: , wherein: A is selected fromselected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

93. The compound of clam 92, wherein A is CHR9and R9is OH.

94. The compound of clam 92, wherein A is CHR9and R9is C1-C6alkyl.

95. The compound of claim 92, wherein A is CHR9and R9is methyl.

96. The compound of claim 92, wherein A is CHR9and R9is -CH2CH2OH.

97. The compound of claim 92, wherein A is S.

98. The compound of claim 92, wherein A is O.

99. The compound of claim 92, wherein A is NR9and R9is C1-C6alkyl.

100. The compound of claim 92, wherein A is NR9and R9is hydroxy-C1-C6alkyl.

101. The compound of claim 92, wherein A is NR9and R9is -CH2CH2OCH2CH2OH.

102. The compound of claim 92, wherein A is NR9and R9is .Attorney Docket No.41543-59274 (002WO) 103. The compound of claim 91, wherein -NH-X-Y-NR5R6is the following: , wherein R10and R11are eachhydroxy-C1-C6alkyl.

104. The compound of claim 103, wherein R10and R11are each H.

105. The compound of claim 103, wherein R10and R11are each OH.

106. The compound of claim 103, wherein R10and R11are each hydroxy-C1-C6alkyl.

107. The compound of claim 103, wherein R10is H and R11is OH.

108. The compound of any one of claims 1-59, wherein X is -C(O)S- and Y is C1-C6alkylene.

109. The compound of claim 108, wherein -NH-X-Y-NR5R6is the following: , wherein o is an integer from 1 to 6.

110. The compound of claim 108 or 109, wherein R5and R6are C1-C6alkyl.

111. The compound of claim 108 or 109, wherein R5and R6are methyl.

112. The compound of claim 108 or 109, wherein R5is C1-C6alkyl and R6is hydroxy-C1-C6alkyl.

113. The compound of claim 108 or 109, wherein R5is methyl and R6is -CH2CH2OH.

114. The compound of claim 108 or 109, wherein R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.Attorney Docket No.41543-59274 (002WO) 115. The compound of claim 114, wherein -NH-X-Y-NR5R6is the following: , wherein A is selected from CHR9,is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

116. The compound of claim 115, wherein A is CHR9and R9is OH.

117. The compound of claim 115, wherein A is CHR9and R9is C1-C6alkyl.

118. The compound of claim 115, wherein A is CHR9and R9is methyl.

119. The compound of claim 115, wherein A is CHR9and R9is -CH2OH.

120. The compound of claim 115, wherein A is CHR9and R9is -CH2CH2OH.

121. The compound of claim 115, wherein A is S.

122. The compound of claim 115, wherein A is O.

123. The compound of claim 115, wherein A is NR9and R9is C1-C6alkyl.

124. The compound of claim 115, wherein A is NR9and R9is hydroxy-C1-C6alkyl.

125. The compound of claim 115, wherein A is NR9and R9is -CH2CH2OCH2CH2OH.

126. The compound of claim 115, wherein A is NR9and R9is .

127. The compound of claim 115,R9is .Attorney Docket No.41543-59274 (002WO) 128. The compound of claim 115, wherein -NH-X-Y-NR5R6is the following: , wherein R10and R11are eachand hydroxy-C1-C6alkyl.

129. The compound of claim 128, wherein R10and R11are each H.

130. The compound of claim 128, wherein R10and R11are each OH.

131. The compound of claim 128, wherein R10and R11are each hydroxy-C1-C6alkyl.

132. The compound of claim 128, wherein R10is H and R11is OH.

133. The compound of any one of claims 1-59, wherein X is -CH2- and Y is C1-C6alkylene.

134. The compound of claim 133, wherein -NH-X-Y-NR5R6has the following structure: , wherein o is an integer from 0 to 5.

135. The compound of claim 133 or 134, wherein R5and R6are C1-C6alkyl.

136. The compound of claim 133 or 134, wherein R5and R6are methyl.

137. The compound of claim 133 or 134, wherein R5is C1-C6alkyl and R6is hydroxy-C1-C6alkyl.

138. The compound of claim 133 or 134, wherein R5is methyl and R6is -CH2CH2OH.

139. The compound of claim 133 or 134, wherein R5and R6together form a C2-C9heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

140. The compound of claim 139, wherein -NH-X-Y-NR5R6is the following: ,Attorney Docket No.41543-59274 (002WO) wherein A is selected from CHR9, O, S, and NR9, wherein R9is selected from H, OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, and optionally substituted C1-C6heterocyclyl-C1-C4alkyl.

141. The compound of claim 140, wherein A is CHR9and R9is OH.

142. The compound of claim 140, wherein A is CHR9and R9is C1-C6alkyl.

143. The compound of claim 140, wherein A is CHR9and R9is methyl.

144. The compound of claim 140, wherein A is CHR9and R9is -CH2OH.

145. The compound of claim 140, wherein A is CHR9and R9is -CH2CH2OH.

146. The compound of claim 140, wherein A is S.

147. The compound of claim 140, wherein A is O.

148. The compound of claim 140, wherein A is NR9and R9is C1-C6alkyl.

149. The compound of claim 140, wherein A is NR9and R9is hydroxy-C1-C6alkyl.

150. The compound of claim 140, wherein A is NR9and R9is -CH2CH2OCH2CH2OH.

151. The compound of claim 140, wherein A is NR9and R9is .

152. The compound of claim 140,R9is .

153. The compound of claim 140,is the following: , 10 1wherein R and R1are each H, and hydroxy-C1-C6alkyl.Attorney Docket No.41543-59274 (002WO) 154. The compound of claim 153, wherein R10and R11are each H.

155. The compound of claim 153, wherein R10and R11are each hydroxy-C1-C6alkyl.

156. The compound of claim 153, wherein R10is H and R11is OH.

157. A pharmaceutical composition comprising a compound of any one of claims 1-156 and one or more pharmaceutically acceptable excipient.

158. The pharmaceutical composition of claim 157, wherein the compound is in a lipid nanoparticle.

159. The pharmaceutical composition of claim 158, wherein the lipid nanoparticle further comprises one or more lipids selected from one or more ionizable lipids, one or more cationic lipids, one or more structural lipids, one or more conjugated lipids, and one more helper lipids.

160. The pharmaceutical composition of claim 158 or 159, wherein the lipid nanoparticle comprises a nucleic acid.

161. The pharmaceutical composition of claim 160, wherein the lipid nanoparticle encapsulates the nucleic acid.

162. The pharmaceutical composition of claim 160 or 161, wherein the nucleic acid is RNA.

163. The pharmaceutical composition of claim 162, wherein the RNA is selected from siRNA, antisense RNA, single stranded RNA, microRNA, mRNA, noncoding RNA, multivalent RNA, and circular RNA.

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