Rapamycin derivatives and compositions and uses thereof

Abstract

Provided herein are compounds e.g., of Formula (I), wherein the variables R1, R2, R3, and Y are defined herein, as well as compositions and uses thereof. (I)

Description

RAPAMYCIN DERIVATIVES AND COMPOSITIONS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 698,718, filed September 25, 2024, the disclosure of which is hereby incorporated by reference in its entirely for all purposes.DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0002] The contents of the electronic sequence listing submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: TRAI_007_03WO_SeqList_ST26.xml; Size: 427,207 bytes; and Date of Creation: September 24, 2024).BACKGROUND

[0003] Current treatments for patients who suffer from diseases characterized by excessive inflammation, such as autoinflammation and autoimmune disorders, cardiovascular disease and allograft rejection are inadequate. For example, transplantation requires suppression of the immune system to prevent organ rejection. Patients undergoing organ transplantation usually receive an immunosuppressive drug mixture, such as corticosteroids, tacrolimus, cyclosporine and sirolimus (rapamycin). Rapamycin is one of the most widely used immunosuppressive drugs in transplantation. This drug blocks T and B lymphocyte activation via mTOR inhibition and efficiently inhibits T cell proliferation. However, use of this drug is associated with severe side effects, including increased infection susceptibility. Due to the detrimental effects of life-long continuous immunosuppression a pressing need exists to reduce toxicity and improve long-term allograft survival.

[0004] Despite efforts to use currently available immunosuppressive agents in less toxic ways, no alternative regimen has seriously challenged these drugs’ almost universal use. There is, consequently, an ongoing need to reduce toxicity derived from chronic immunosuppressive. Historically, transplant immunologists have attempted to develop novel tolerogenic protocols bytargeting adaptive immune response mechanisms. Such work has been based on the observation that T cells are both necessary and sufficient to induce graft rejection. Accordingly, several therapeutic agents have been developed against signal 1 (T cell receptor / CD3 complex), signal 2 (co-stimulatory receptors), and signal 3 (cytokine production), which are required to successfully activate the effector lymphocytes that mediate allograft rejection. While these methodologies have produced promising results, long-term graft survival rates are suboptimal which underlines the need for alternative tolerance-inducing approaches.

[0005] There is a need for novel therapeutics for the treatment of diseases characterized by excessive inflammation, such as autoimmune disorders, cardiovascular disease and allograft rejection.SUMMARY

[0006] Provided herein are compounds and compositions that inhibit cells of the innate immune sy stem (particularly myeloid cells and myeloid progenitor cells) and are useful for the treatment of diseases characterized by excessive inflammation, including autoinflammation disorders, cardiovascular disease and graft rejection.

[0007] In embodiments, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:Rlis -heterocyclyl-L;9R2is -C2-3 alkylene;R3is hydrogen, alkyl, aryl or alkenyl;Y is an -Ci -12 alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, -alkylene-N-(alkylene- C(:=B)“NR’J-alkylene“NR’>-C(=;0)--W)2, or ~alkylene-N-(alkylene-C(=0)-W)2.; andR5is independently hydrogen, or alkyl;W is alkyl, -O-alkylene-C(H)(ORo)-alkylene-OR / , or a sterol;R6and R7are each independently Rsor -C(=O)-R8; andRsis alkyl; wherein each aforementioned alkyl, alkylene, aryl, alkenyl and heterocyclyl is optionally substituted.

[0008] In embodiments, the present disclosure provides a compound of Formula (I- A):or a pharmaceutically acceptable salt thereof, wherein Ri, R2, and R? are defined herein.

[0009] In embodiments, the present disclosure provides compound is of Formula (I-B):or a pharmaceutically acceptable salt thereof wherein:Rz, Rs, Y and L are defined herein; andX!is -N- and X2is -C-; or X1is -C- and X2is -N-.

[0010] In embodiments, the present disclosure provides a compound of Formula (I-C):or a pharmaceutically acceptable salt thereof; wherein Rz, Rs, X5, X2, Y and L are defined herein.

[0011] In embodiments, the present disclosure provides a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:Ro is C2-6 alkylene;RJis hydrogen, alkyl, aryl or alkenyl;Y is an -C1-6 alkylene or absent;R1is -C(-0)-W or W; andW is Co-Cbo alkyl or a sterol; wherein each aforementioned alkyl, alkylene, aryl, and alkenyl is optionally substituted.

[0012] In embodiments, the present disclosure provides a compound of Formula (II-2):(II-2) or a pharmaceutically acceptable salt thereof, wherein:R2is -C2-6 alkylene;R’ is -hydrogen, -alkyl, -aryl or -alkenyl;Y is a -C1-6 alkylene or absent;R1is -C(==O)-W or -W; andW is -Co-Cao alkyl or a sterol; wherein each aforementioned alkyl, alkylene, aryl, and alkenyl is optionally substituted, and wherein the compound is not:

[0013] In embodiments, the present disclosure provides a compound of Fomiuia (II- A):(II-A) or a pharmaceutically acceptable salt thereof; wherein Ri, Rs, and ¥ are defined herein andwherein n is 2 or 3.

[0014] In embodiments, the present disclosure provides a compound of Formula (II-B):or a pharmaceutically acceptable salt thereof wherein Ri, Rs, Y, and n are defined herein.

[0015] In embodiments, the present disclosure provides a compound of Formula ( I I-C ):or a pharmaceutically acceptable salt thereof, wherein Ri and R2 are defined herein.

[0016] In embodiments, the present disclosure provides a compound of Formula (II-D):or a pharmaceutically acceptable salt thereof, wherein Ri and R2 are defined herein.

[0017] In embodiments, the present disclosure provides a compound of Formula (II-E):(II-E) or a pharmaceutically acceptable salt thereof. wherein Ri and Rs are defined herein.

[0018] In embodiments, the present disclosure provides a compound of Formula (II -F):(II -F) or a pharmaceutically acceptable salt thereof, wherein Ri and Rs are defined herein.

[0019] In embodiments, the present disclosure provides a compound of Formula (II-G):or a pharmaceutically acceptable salt thereof, wherein Rs and Rs are defined herein.

[0020] In embodiments, the present disclosure provides a compound of Formula (II-H):(II-H) or a pharmaceutically acceptable salt thereof,

[0021] wherein R2 and R3 are defined hereinln embodiments, provided herein is a compound of Formula (III):or a pharmaceutically acceptable salt thereof; wherein:RC1is H or -C( =O)-RC 3; andRC2and RC3are each independently an optionally substituted C4-3oalkyl or C4-3oalkenyl.

[0022] In embodiments, the present disclosure provides a compound of Formula (III-2):(HI-2) or a pharmaceutically acceptable salt thereof; wherein:RC!is H or -C(=O)-RC3; andRC2and RC5are each independently an optionally substituted -C4-30 alkyl or -C4-30 alkenyl, wherein the compound is not:

[0023] In embodiments, the present disclosure provides a compound of Formula (III- A):or a pharmaceutically acceptable salt thereof wherein RC1and Rv2are defined herein.

[0024] In embodiments, the present disclosure provides a compound of Formula (III-B):(II-B) or pharmaceutically acceptable salt thereof, wherein RC1is H or -C(=O)-RC3; and R’: ;is -C4-30 alkenyl.

[0025] In embodiments, the present disclosure provides a compound of Formula (III-C):(II-C) or pharmaceutically acceptable salt thereof, wherein R'2is -C4-30 alkenyl.

[0026] In embodiments, the present disclosure provides a compound of Formula (IV)or a pharmaceutically acceptable salt thereof, wherein:RDiis hydrogen, -C(-O)NRD4-alkyl or -C(-O)NRD4-alkenyl;RD2is hydrogen, alkyl, aryl or alkenyl,RDJIS -Ce-Cso alkyl;RD4IS hydrogen, alkyl, aryl or alkenyl; wherein each aforementioned alkyl, aryl, and alkenyl is optionally substituted.

[0027] In embodiments, the present disclosure provides a compound of Formula (IV-2):or a pharmaceutically acceptable salt thereof; wherein:RD-!IS -hydrogen, -C(=O)NRD4-alkyl or -C(=O)NRD4-alkenyi.RD2IS -hydrogen, -alkyl, -aryl or -alkenyl;RD3is -Cs-Cso alkyl;RD4is -hydrogen, -alkyl, -aryl or -alkenyl.

[0028] In embodiments, provided herein is a compound of Formula (IV- A):or a pharmaceutically acceptable salt thereof.

[0029] In embodiments, the present disclosure provides a compound of Formula (V):or a pharmaceutically acceptable salt thereof; wherein:RE1is hydrogen or -C(-O)ORE3;RE2is -Cs-Cso alkyl or -Cs-Cso alkenyl;REJis -Ce-Cso alkyl or -Ce-Cso alkenyl; wherein each aforementioned alkyl and alkenyl is optionally substituted.

[0030] In embodiments, the present disclosure provides a compound of Formula (V -2):(V-2) or a pharmaceutically acceptable salt thereof; wherein:RE1IS hydrogen or -C(=O)OREJ;RE2IS -C6-C30 alkyl;RE3is -Cs-Cso alkyl or -Cs-Cso alkenyl; wherein each aforementioned alkyl and alkenyl is optionally substituted

[0031] In embodiments, the present disclosure provides a compound of Formula (V-A)(V-A) or a pharmaceutically acceptable salt thereof, wherein REIand R''2are defined herein.

[0032] In embodiments, the present disclosure provides a compound of Formula ( VI):or a pharmaceutically acceptable salt thereof; wherein Rf lis an optionally substituted Csooalkyl or optionally substituted Ce-soalkenyl.

[0033] In embodiments, the present disclosure provides a compound of Formula (IV -2):or a pharmaceutically acceptable salt thereof; wherein RF!is an optionally substituted Ce-so alkyl, wherein RF 1is not -Cs, -Ca, -C9, -C17, and -Ci » alkyl.

[0034] In embodiments, provided herein is a compound of Formula (VI-A) the compound is of Formula (VI-A):or a pharmaceutically acceptable salt thereof, wherein RF1is defined herein.

[0035] In embodiments, the present disclosure provides a HDL-derived nanoparticle, comprising a high-density' lipoprotein (HDL)-derived nanoparticle, wherein the nanoparticle comprises a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (I- B-l), (I-B-2), (I-C), (I-C- A). (I-C-B), (II), (II-2), (II- A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G),(II-H), (III), (III-2), (III-A), (III-B), (III-C), (IV), (IV-2), (IV- A), (V), (V-2), (V-A), (VI), (VI-2), (VI-A), Table 2, or Table 1)).

[0036] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-2), (II- A), (II-B), (II-C), (II-D), (II -E), (II-F), (II- G), (II-H), (III), (III-2), (III-A), (III-B), (III-C), (IV), (IV-2), (IV-A), (V), (V-2), (V-A), (VI), (VI- 2), (VI-A), Table 2, or Table l))or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0037] In embodiments, the present disclosure provides a method for the prophylaxis of organ or tissue rejection in a patient in need thereof, comprising administering a compound of the present disclosure (e.g., a compound of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-2), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (III), (HI-2), (III-A), (III-B), (III-C), (IV), (IV-2), (IV-A), (V), (V-2), (V-A), (VI), (VI-2), (VI-A), Table 2, or Table1))or a pharmaceutically acceptable salt thereof, or a composition of the present disclosure.

[0038] In embodiments, the present disclosure provides a method for inducing transplant tolerance in a patient comprising administering a compound of the present disclosure (e.g., a compound of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), ( 11 -2), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (III), (III-2), (III-A), (III-B), (III-C), (IV), (IV-2), (IV-A), (V), (V-2), (V-A), (VI), (VI-2), (VI-A), Table 2, or Table l))or a pharmaceutically acceptable salt thereof, or a composition of the present disclosure.BRIEF DESCRIPTION OF DRAWINGS

[0039] FIG. 1 depicts an overview of the study described in Example 10.

[0040] FIG. 2 depicts percent injected dose of FDG per gram of tissue in the bone marrow in the study described in Example 10.

[0041] FIG. 3A depicts percent injected dose of FDG per gram of tissue in the left lung in the study described in Example 10.

[0042] FIG. 38 depicts percent injected dose of FDG per gram of tissue in the right lung in the study described in Example 10.

[0043] FIG. 3C depicts percent injected dose of FDG per gram of tissue in the average lung in the study described in Example 10.

[0044] FIG. 4 depicts an overview of the study described in Example 11.

[0045] FIG. 5 depicts percent injected dose of FDG per gram of tissue in the bone marrow in the study described in Example 11.

[0046] FIG. 6 depicts standard Uptake Value (measured by in vivo PET imaging) of FDG (radiolabeled sugar analogue) per gram tissue in the bone marrow in the study described in Example 11.

[0047] FIG. 7 depicts stability data for the compounds of the present disclosure in solution and shows the fraction of intact compound in solution after 16 days.

[0048] FIGs. SA -81? depict stability' data for the nanoparticle compositions of the present disclosure and show the fraction of intact compound in the nanoparticle composition after 14 days (FIG. 8A) and stability of each of the nanoparticle compositions at different timepoints (FIG. SB).

[0049] FIG. 9 depicts the ICso data calculated for the compounds of the present disclosure formulated in a nanobiologic composition.DETAILED DESCRIPTION

[0050] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.Definitions[00511 For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0052] The term “about” when immediately preceding a numerical value means a range e.g., plus or minus 10% of that value. For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55, ... ”, “about 50” means a range extending to less than half the mterval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view' of the definition of the term “about” provided herein.

[0053] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, wdthin the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0054] The term “conservative substitution,” as used herein, refers to the exchange of one amino acid for another among the following amino acid groups: (i) the aliphatic ammo acids (alanine, valine, leucine, and isoleucine); (ii) amino acids with hydroxyl groups (serine and threonine); (iii) acidic amino acids (glutamic acid and aspartic acid); (iv) amino acids with amide side chains (asparagine and glutamine); (v) basic ammo acids (lysine and argmine); (vii) amino acids with aromatic side chains (phenylalanine, tyrosine, and tryptophan).

[0055] “Salts” include those obtained by reacting a compound functioning as a base, with an inorganic or organic acid to form a salt, or those obtained by reacting a compound functioning as an acid, with an inorganic or organic base to form a salt. “Salts” include derivatives of an active agent, wherein the active agent is modified by making acid or base addition salts thereof.Preferably, the salts are pharmaceutically acceptable salts. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic acid, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates and the like. Base addition salts include but are not limited to, ethylenediamine, N- methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dim ethyl amine, trimethylamine, ethylamine, basic amino acids, e, g., lysine and argmine dicyclohexylamine and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methyl ammonium, dimethylammonium , trimethylammonium , ethy lammonium , hydroxy ethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Standard methods for the preparation of pharmaceutically acceptable salts and their formulations are well known in the art, and are disclosed in various references, including for example, "Remington: The Science and Practice of Pharmacy", A. Gennaro, ed., 20th edition, Lippincot, Williams & Wilkins, Philadelphia, PA.

[0056] The term “carrier” or “vehicle” as used interchangeably herein encompasses carriers, excipients, adjuvants, and diluents or a combination of any of the foregoing, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body. In addition to the adjuvants, excipients and diluents known to one skilled in the art, the carrier includes nanoparticles of organic and inorganic nature.

[0057] For example, in embodiments the present disclosure provides nanoparticles (e.g.,HDL-denved nanoparticles) as delivery vehicles for an active agent (e.g., a compound of Formula(I), (II), (III), (IV), (V), or (VI) or Table 1). In embodiments, the agent is encapsulated within theThe association of the agent and the nanoparticle carrier may be

[0058] The terms “pharmaceutical combination,” “therapeutic combination” or“combination” as used herein, refers to a single dosage form comprising at least two therapeutically active agents, or separate dosage forms comprising at least two therapeutically active agents together or separately for use in combination therapy. Administration of a combination therapy includes: administration in the same or different composition(s) and / or combinations, either sequentially, simultaneously, or continuously, through the same or different routes. For example, one therapeutically active agent may be formulated into one dosage form and the other therapeutically active agent may be formulated into a single or different dosage forms. For example, one therapeutically active agent may be formulated into a solid oral dosage form whereas the second therapeutically active agent may be formulated into a solution dosage form for parenteral administration. In embodiments, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and / or inert substances.

[0059] The terms “treat”, "treating" or "treatment" refers to administering a composition disclosed herein and to reduce symptoms of, and / or pathology of, a disease or condition. A candidate compound described herein may be in a therapeutically effective amount in a formulation or medicament, which is an amount leads to a biological effect, such as reducing or eliminating symptoms of a disease or condition. In other aspects, the compositions may be used in a prophylactic manner to prevent a disease or condition arising, or from re-occurring. Transplantation provides a useful illustration. Subjects who have transplanted cells or organs may receive the disclosed compositions to control innate immune responses, such as inflammation. Subjects who plan to receive transplanted cells or organs may be administered the compositions disclosed herein prior to transplant and may also continue after transplant. After-transplant administration may promote a reduced inflammatory environment and greater tolerance to the implant. Without being bound by theory, it is thought that the compositions disclosed herein reduce inflammatory responses regulated by myeloid cells and their progenitors. In particular, it is thought that the nanoparticles improve delivery of compounds to the bone marrow and that such delivery promotes reduced inflammation driven by cells of the innate immune system. Notably, targeting the cells and progenitors in the bone marrow trains the immune system to have the desired effects, meaning that the immune cells that depart the bone marrow' and enter circulation retain the desired activity levels.

[0060] The term “patient” or “subject” as used herein, includes all mammals. The methods described herein may be useful for both human therapy and veterinary applications. In embodiments, the subject is a human. The subject may be suffering from inflammation. The inflammation may be acute or chronic. The subject may be suffering from autoinflammation, which involves inflammation involving aspects of the innate immune system.

[0061] As used herein, “therapeutically effective amount” means the amount of a compound or a therapeutically active agent that, when administered to a subject for treating or preventing a disease or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease or condition. The therapeutically effective amount will vary depending on the type of the selected compound or a therapeutically active agent, the disease or condition and its severity, and the age, weight, etc. of the patient to be treated.

[0062] By “optional” or “optionally” it is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which is does not. For example, “optionally substituted aryl” encompasses both “aryl” and “substituted aryl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and / or inherently unstable.

[0063] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[0064] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-Cs alkyl” is intended to encompass Ci, Cz, Cs, CT, Cs, Cs, Cue, Ci -5, Ci-4, Ci -a, Ci-2, C?.-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, CM, and C5-6 alkyl.

[0065] The term “acyl” as used herein refers to R — C(O) — groups such as, but not limited to, (alkyl)-C(O) — , (alkenyl)-C(O) — , (alkynyl)-C(O) — , (aryl)-C(O) — , (cycloalkyl)-C(O) — , (heteroaryl)-C(O) — , and (heterocyciyl)-C(O) — , wherein the group is attached to the parent molecular structure through the carbonyl functionality. In embodiments, it is a Ci-ioacyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl. For example, a Cr-acyl has three other ring or chain atoms plus carbonyl.

[0066] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain. In embodiments, an alkyl group contains from one to thirty carbon atoms. In embodiments, an alkyl group has from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. For example, alkyls comprising any number of carbon atoms from 1 to 30, or from 1 to 12 are included. An alkyl comprising up to 30 carbon atoms is a C1-C30 alkyl, an alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and analkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, Cz alkyls and Ci alkyl (z'.e., methyl). A Ct-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Cs alkyls, but also includes Cb, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, w-propyl, z-propyl, sec-propyl, w-butyl, z-butyl, sec-butyl, Z-butyl, zz-pentyl, t-amyl, zr-hexyl, zz-heptyl, zi-octyl, zz-nonyl, zi-decyl, zr-undecyl, and rz- dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. In embodiments, “alkyl” is a straight-chain hydrocarbon. In embodiments, “alkyl” is a branched hydrocarbon.

[0067] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain. In embodiments, an alkylene groups has from one to twelve carbon atoms. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, zz-butylene, ethenylene, propenylene, w-butenylene and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0068] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain. In embodiments, an alkenyl group contains from one to thirty carbon atoms, or from two to twelve carbon atoms, and having one or more carbon-carbon double bonds, such as a straight or branched group of 2-8 carbon atoms, referred to herein as C2-C8 alkenyl. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 30 are included. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 30 carbon atoms is a C2-C30 alkenyl, an alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes Cs alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties describedabove for C2-C5 alkenyls but also includes Ce alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes Cb, Cs, Cb and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2- propenyl (allyl), iso-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1- heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1 -octenyl, 2-octenyl, 3- octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1 -decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5- decenyl, 6-decenyl, 7-decenyl, 8-decenyL 9-decenyl, 1 -undecenyl, 2-undecenyl, 3-undecenyl, 4- undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1- dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8- dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11 -dodecenyl. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted.

[0069] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain. In embodiments, an alkynyl group contains from one to thirty carbon atoms, or from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds such as a straight or branched group of 2-8 carbon atoms, referred to herein as Ci-Cx alkynyl. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 30 are included. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 30 carbon atoms is a Cc-Cso alkynyl, An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes Cs alkynyls, Q alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Cs alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, Cs, C9 and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl,pentynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.

[0070] “Aryl’1refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, which is atached to the rest molecule by a single bond. For purposes of this invention, the aryl can be a monocyclic, bicyclic, tricyclic, tetracyclic ring system or other multicyclic ring system, which can include fused or bridged ring systems. Aryls include, but are not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the aryl can be optionally substituted.

[0071] “Aralkyl” or “arylalkyl” refers to a group of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rcis one or more aryls as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.

[0072] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon, and which is attached to the rest of the molecule by a single bond. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0073] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting solely of carbon and hydrogen atoms, which can include fused, spirocyclic, or bridged ring systems, having from three to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0074] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, spirocy clic, or bridged ring sy stems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyls include, for example, bicyclo[2.2.1 ]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkeny l group can be optionally substituted.

[0075] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having from 3 to 20 carbon atoms and one or more carbon-carbon triple bonds, which can include fused, spirocyclic, or bridged ring systems, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyls include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0076] “Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered aromatic or non-aromatic ring which consists of 2 to 12 carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocycles can be aromatic (heteroaryls) or non-aromatic. Unless stated otherwise specifically in the specification, the heterocyclyl can be a monocyclic, bicyclic, tricyclic, tetracyclic ring system or other multi-cyclic ring system, which can include fused, spirocyclic, or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, biotinyl, dihydrofuranyl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, pyranyl, pyrazolinyl, thiopyranyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrrolidin-2-only, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydroisoquinolyl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0077] “Heteroaryl” refers to a 5- to 20-membered ring system comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this disclosure, the heteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; the heteroaryl may contain one or more non-aromatic rings (e.g., cycloalkyl or heterocyclyl) fused to the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acndinyl, benzimidazolyl, benzothiazolyl, benzmdolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, mdolinyl, isomdolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1 -oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted,

[0078] “Heteroarylalkyl” refers to a group of the formula -Rb-Rf where Rb is an alkylene chain as defined above and Rr is a heteroaryl as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.

[0079] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, N-heterocyclyl, heteroaryl, etc) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialky Isilyl groups, dialkylarylsilyl groups, aikyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triplebond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with NRgRh,SORg, SChRg, OSOzRg, SChORg, NSTSChRg, and SOzNRgRh. Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with C(=O)Rg, C(=O)ORg, C(=O)NRgRh, CHzSChRg, CHzSOzNRgRh. In the foregoing, Rgand RE are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In addition, “substituted” means any of the above groups in which two hydrogen atoms are each replaced by a bond to form a fused ring system containing the atoms to which the hydrogens were attached.

[0080] The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The presentdisclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0081] The compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the present disclosure, even though only one tautomeric structure is depicted.

[0082] The term "triglyceride" as used herein means an ester derived from glycerol and three fatty acids. The fatty acids may be the same or different. The notation used in this specification to describe a trigly ceride is the same as that used below to describe a fatty acid. Fattyacids can attach to the glycerol molecule in any order, e.g., any fatty acid can react with any of the hydroxyl groups of the glycerol molecule for forming an ester linkage. For example. In a nonlimiting example, a triglyceride can comprise glycerol with any combination of the following fatty acids: C18:l, C14: l, C16: 1, polyunsaturated, and saturated. A triglyceride of C18:l fatty acid simply means that the fatty acid components of the triglyceride are derived from or based upon a C18:l fatty acid. That is, a C18 / 1 triglyceride is an ester of glycerol and three fatty acids of 18 carbon atoms each with each fatty acid having one double bond. Similarly, a Cl 4: 1 triglyceride is an ester of glycerol and three fatty acids of 14 carbon atoms each with each fatty' acid having one double bond. Likewise, a Cl 6:1 triglyceride is an ester of glycerol and three fatty acids of 16 carbon atoms each with each fatty' acid having one double bond. Triglycerides of Cl 8: 1 fatty acids in combination with C14:l and / or C16: l fatty acids means that: (a) a C18:l triglyceride is mixed with a Cl 4: 1 triglyceride or a C16: 1 triglyceride or both; or (b) at least one of the fatty acid components of the triglyceride is derived from or based upon a C l 8:1 fatty acid, while the other two are derived from or based upon C14: 1 fatiy acid and / or Cl 6: 1 fatty acid.

[0083] The term "fatty acid" and like terms mean a carboxylic acid with a long aliphatic tail that is either saturated or unsaturated. The term “long aliphatic tail” and “faty acid chain” are used interchangeably herein. As used herein, the fatty acid chain length includes from C4 to C30(e.g., C6 to C30), saturated or unsaturated, cis or trans, Zusammen (Z) or entgegen (E), unsubstituted or substituted with CI -10 side chains.

[0084] Unsaturated fatty acids have one or more double bonds between carbon atoms. Saturated fatty acids do not contain any double bonds. In embodiments, a fatty acid may be described herein by the capital letter "C" for carbon atom, followed by a number describing the number of carbon atoms in the fatty acid, followed by a colon and another number for the number of double bonds in the fatty acid. For example, Cl 6: 1 denotes a fatty acid of 16 carbon atoms with one double bond, e.g., palmitoleic acid. The number after the colon in this notation neither designates the placement of the double bond(s) in the fatty acid nor whether the hydrogen atoms bonded to the carbon atoms of the double bond are cis to one another. Other examples of this notation include Cl 8:0 (stearic acid), Cl 8:1 (oleic acid), Cl 8:2 (linoleic acid). Cl 8:3 (a-linolenic acid) and C20:4 (arachidonic acid).

[0085] The term "sterols" as used herein refers to animal or plant steroids which contain at least one hydroxyl group. In embodiments, the sterols of the present disclosure have a single hydroxyl group at the C3-position. In general, sterols contain 27 to 30 carbon atoms and one double bond in the 5 / 6 position and occasionally in the 7 / 8, 8 / 9 or other positions. Non-limiting examples of sterols contemplated herein, include sigmasterol, campesterol, sitosterol, sitostanols, brassicasterols, stigmasterol, D5 avenasterol, 1)7 avenasterol, ergosterol, citrostadienol, cholesterol, lanosterols, spongosterols, fungisterols, stellasterols, zymosterols and mixtures thereof. In embodiments, the sterol is cholesterol.

[0086] The term “sterol ester” as used herein refers to an ester derived from a sterol as defined above and a carboxylic acid. In embodiments, the carboxylic acid is of the formula Rb- C(O)-OH wherein Ri, is an aliphatic group. In embodiments, the carboxylic acid is acetic acid, propionic acid, hexanoic acid, butyric acid, valeric acid, caproic acid, caprylic acid, 2-ethyl hexanoic acid, capric acid, cyclopentanepropionic acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselic acid, linoleic acid, conjugated linoleic acid (CLA), linolenic acid, elaeostenc acid, arachic acid, arachidonic acid, gadoleic acid, behenic acid and erucic acid.

[0087] The term "phospholipid" refers to an amphiphilic compound comprised of a glycerol molecule bound to two fatty acids “tails” and a phosphate “head” group. The phosphate group may be further bound to hydrogen, choline, serine, ethanolamine, or inositol, thus, diversifying into phosphatidic acid, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol phospholipids, respectively.

[0088] The term "lysophospho lipid," as used herein, refers to a derivative of a phospholipid (e.g., as defined above) in which one of the acyl fatty acid tails is missing and, thus, lysophospholipids have a free alcohol in either the sri-l or sn-2 position. In non-limiting embodiments, the lysophospholipid is l-myristoyl-2-hydroxy-5??-glycero-3-phosphochohne (MHPC), 1 -palmitoyl-2-hydroxy-5«-glycero-3-phosphocholine (PHPC) or l-stearoyl-2-hydroxy- sw-glycero-3- phosphocholine (SHPC).

[0089] The term "apolipoprotein A-I" or "apoA-I", and also "apolipoprotein Al" or "apoAl", refers to a protein that is encoded by the APO Al gene in humans.CompoundsCompounds of Formula (I)

[0090] In embodiments, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is -heterocyclyl-L;R2is C2-3 alkylene;R3is hydrogen, alkyl, aryl or alkenyl;Y is an -C1-12 alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, ---alkylene-N- (alkylene-C(=O)-NR:,-alkylene-NR5-C(:=O)-W)2, or ~alkylene-N-(alkylene-C(=:O)-W)2; andR5is independently hydrogen, or alkyl;W is alkyl, -O-alkylene-C(H)(OR6)-alkylene-OR7, or a sterol;R6and R' are each independently R8or -C(:=:O)-R8; andR8is alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyclyl is optionally substituted.

[0091] In embodiments, the compound of Formula (I) is a compound of Formula (I- A):(I-A) or a pharmaceutically acceptable salt thereof, wherein:R1is -heterocyclyl-L;R2is C2-3 alkylene;R’ is hydrogen, alkyl, aryl or alkenyl;Y is an -C1-12 alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, ---alkylene-N- (alkylene-C(=O)-NR3-alkylene-NR3’C(=O)-W)2, or -alkylene-N-(alkylene-C(=O)-W)2; andR5is independently hydrogen, or alkyl;W is alkyl, -O-alkylene-C(H)(OR6)-alkylene-OR7, or a sterol;R&and R7are each independently R8or -C(=O)-R8; andR8IS alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyclyl is optionally substituted.

[0092] In embodiments, of the compounds of Formula (I) or (I-A), or a pharmaceutically acceptable salt thereof, R5is -heteroaryl-L.

[0093] In embodiments, of the compounds of Formula (I) or (I-A), or a pharmaceutically acceptable salt thereof, R!is -triazolyl-L.

[0094] In embodiments, of the compounds of Formula (I) or (I-A), or a pharmaceutically acceptable salt thereof, each alkyl, alkylene, alkenyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more RAsubstituents; wherein RAis independently selected for each occurrence from the group consisting of hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, - N{ R '}( R;}. -C(())^(RC)(RD), -N(RC)C(O)RB, -OC(O)NRCRD, -NRCC(O)ORB, -OC(O)RB, - C(O)ORB, -C(O)RB, -CO2H, -NO2, -SH, S(O)XRB, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and RB;Rcand RDare independently selected for each occurrence from the group consisting of hydrogen, alkyl, haloalkyl -C(O)RB, and -C(O)ORb; or Rcand Rnare taken together with the nitrogen to which they are attached to form a heterocyclic ring optionally substituted with RA;RBIS alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro; and x is 0, 1 , or 2.

[0095] In embodiments of the compounds of Formula (I) or (I-A), or a pharmaceutically acceptable salt thereof, R5is:X!is -N- and X2is -C-; or X1is -C- and X2is -N-; andRA!IS independently selected for each occurrence from the group consisting of hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(RC)(RD), -C(O)N(Rc)(RD), -N(Rc)C(O)RB, - OC(O)NRCRD, -NRCC(O)ORB, -OC(O)RB, -C(O)ORB, -C(O)RB, -CO2H, -NO2, -SH, S(O)xRB(wherein x is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and RB;Rcand RDare independently selected for each occurrence from the group consisting of hydrogen, alkyl, haloalkyl -C(O)RB, and -C(O)ORB; or Rcand RDare taken together with the nitrogen to which they are attached to form a heterocyclic ring optionally substituted with RA; andR:?is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro.

[0096] In embodiments of the compounds of Formula (I) or (I- A), or a pharmaceutically acceptable salt thereof, R!is:wherein RA1is independently selected for each occurrence from the group consisting of hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(RC1)(RD1), -C(O)N(Rcl)(RD1), - N(Rc’!)C(O)RB1, -0C(0)NRC,RD1, -NRC1C(O)ORB!, -OC(O)RB1, -C(O)ORB1, -C(O)RB1, -CO2H, -NO2, -SH, S(O)xiRBl(wherein xi is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and Rm;RC1and RDiare independently selected for each occurrence from the group consisting of hydrogen, alkyl, haloalkyl -C(O)RB1, and -C(O)ORB!; or RC1and RD{are taken together with the nitrogen to which they are attached to form a heterocyclic ring optionally substituted with RA1; andRB1is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro.

[0097] In embodiments of the compounds of Formula (I) or (I -A), or a pharmaceutically acceptable salt thereof, R1is:wherein RA1is independently selected for each occurrence from the group consisting of hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(RC!)(RU!), -C(O)N(Rcl)(R1'”), - N(Rcl)C(O)RB1, -OC(O)NRclRD1, -NRCIC(O)ORB1, -OC(O)RB1, -C(O)ORB1, -C(O)RB1, -CO2H, -NO?., -SH, S(O)XIRB1(wherein xi is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and RB!;RC1and RD!are independently selected for each occurrence from the group consisting of hydrogen, alkyl, haloalkyl -C(O)Rm, and -C(O)ORB1; or RC!and RD’!are taken together with the nitrogen to which they are attached to form a heterocyclic ring optionally substituted with RA!; andRB1is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro.

[0098] In embodiments of the compounds of Formula (I) or (I-A), or a pharmaceutically acceptable salt thereof, RA1is hydrogen.

[0099] In embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-B):(I-B) or a pharmaceutically acceptable salt thereof wherein:X1is -N- and X2is -C-; or X1is -C- and X2is -N-.R2is C2-3 alkylene;R3is hydrogen, alkyl, aryl or alkenyl;Y is an -Ci -12 alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, -alkylene-N-(alkylene- C(=0)-NR,-alkylene-NR’-C(=0)-1%'r)2, or -alkylene-N-(alkylene-C(=0)-W)2; andR5is independently hydrogen, or alkyl;W is alkyl, -O-alkylene~C(H)(OR°)~alkylene-OR', or a sterol;R6and R7are each independently Rsor -C(=O)-R8; andRsis alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyclyl is optionally substituted.

[0100] In embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-B-l):(I-B-l ) or a pharmaceutically acceptable salt thereof wherein:R2is C2-3 alkylene;R3is hydrogen, alkyl, aryl or alkenyl;Y is an -Ci -12 alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, -alkylene-N-(alkylene- C(=0)-NR,-alkylene-NR’-C(=0)-1%'r)2, or ~alkylene-N-(alkylene-C(=0)-W)2.; andR5is independently hydrogen, or alkyl;W is alkyl, -O-alkylene-C(H)(ORo)-alkylene-OR / , or a sterol;R6and R7are each independentlyRsis alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyclyl is optionally substituted.

[0101] In embodiments, the compound of Formula (I) , or a pharmaceutically acceptable salt thereof is a compound of Formula (I-B-2):or a pharmaceutically acceptable salt thereof wherein:Rzis C2-3 alkylene;R3is hydrogen, alkyl, aryl or alkenyl,Y is an -Ci-12 alkylene;L is alkyl, alkenyl, -alkylene-C^C^-W, -aikylene-O-C(=O)-W, -alkylene-N-(alkylene- C(=O)-NR5-alkylene-NR5-C(=O)-W)2, or -alkylene-N-(alkylene-C(=O)-W)2; andR3is independently hydrogen, or alkyl;W is alkyl, -O-alkylene-C(H)(OR6)-alkylene-OR7, or a sterol;R6and R1' are each independently R8or ••('( ();■•• R8; andR8is alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyclyl is optionally substituted.

[0102] In embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-C):or a pharmaceutically acceptable salt thereof wherein:X1is -N- and X2is -C-; or X1is -C- and X2is -N-.R2is C2-3 alkylene;R3is hydrogen, alkyl, aryl or alkenyl;Y is an -Ci -12 alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, -alkylene-N-(alkylene- C(:=B)“NR3-alkylene“NR3-C(=;O)--W)2, or ~alkylene-N-(alkylene-C(=O)-W)2.; andR5is independently hydrogen, or alkyl;W is alkyl, -O-alkylene-C(H)(OR°)-alkylene-OR', or a sterol;R6and R1' are each independently R8or ••('( ();■•• R8; andR8is alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyciyl is optionally substituted.

[0103] In embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-C-A):(I-C-A) or a pharmaceutically acceptable salt thereof wherein:R2is C'2-3 alkylene;RJis hydrogen, alkyl, aryl or alkenyl;Y is an -Ci- 12 alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, -alkylene-N-(alkylene- C(=O)-NR5-alkylene-NR5~C(=O)-W)2, or -alkylene-N-(alkylene-C(=O)-W)2; andR5is independently hydrogen, or alkyl;W is alkyl, -O-alkylene-C(H)(OR6)-alkylene-OR7, or a sterol;R° and R7are each independently R* or -C(:::O)-R8; andR* is alkyl, wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyciyl is optionally substituted.

[0104] In embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula ( I-C-B):or a pharmaceutically acceptable salt thereof wherein:Rzis C2-3 alkylene;R3is hydrogen, alkyl, aryl or alkenyl;Y is an -Ci -is alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, -alkylene-N-(alkylene- C(=O)-NR5-alkylene~NR5-C(:=O)-W)2, or -alkylene-N-(alkylene-C(=O)-W)2; andR;is independently hydrogen, or alkyl;W is alkyl, -O-alkylene-C(H)(OR°)-alkylene-OR / , or a sterol;R6and R7are each independently R8or -C(::::O)-R8; andR8is alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyclyl is optionally substituted.

[0105] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R2is -Cbalkylene .

[0106] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R2is -CH2CH2-.

[0107] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R3is Ci-salkyl or hydrogen.

[0108] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R3is -CH?..

[0109] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R3is H.

[0110] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l ), (I-B-2), (I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, Y is -Ci-salkylene.

[0111] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, Y is -CH2- or -CH2CH2CH2-

[0112] In embodiments of the compounds of Formula (I), (I- A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, Y is -CH2-.

[0113] In embodiments of the compounds of Formula (I), (I- A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, Y is -CH2CH2CH2-.

[0114] In embodiments of the compounds of Formula (I-B) or (I-C), or a pharmaceutically acceptable salt thereof, X1is -N- and X2is -C-; or X1is -C- and X2is -N-.

[0115] In embodiments of the compounds of Formula (I-B), (I-C), or a pharmaceutically acceptable salt thereof, X1is -N- and X2is -C-.

[0116] In embodiments of the compounds of Formula (I-B), (I-C), or a pharmaceutically acceptable salt thereof, X1is -C- and X2is -N-.

[0117] In embodiments of the compounds of Formula (I), (I- A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(:=O)-W, -alkyiene-N-(aikylene-C(=O)-NR5-alkylene-NR5-C(=O)-W)?., or ~alkylene-N-(alkylene-C(=O)-W)2.

[0118] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is alkyl, -alkylene- C( ())-W. or -alkylene-O-C(===O)-W.

[0119] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is alkyl.

[0120] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -Ci3-3oalkyl.

[0121] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -Ci5-2oalkyl.

[0122] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -Cisalkyl.

[0123] In embodiments of the compound of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -alkylene-O-C(=O)-W.

[0124] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I~C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -Cialkylene-O-C(=O)- W.

[0125] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -CH2-O-C(:=O)-W.

[0126] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is ~Ci-6alkylene~C(=O)~W.

[0127] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -Cialkylene-C(=O)-W.

[0128] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -CH2-C(=O)-W.

[0129] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L comprises a cholesteryl moiety or at least one fatty acid chain comprising at least 13 carbons. In embodiments, L comprises a cholesteryl moiety. In embodiments, L comprises at least one fatty acid chain comprising at least 13 carbons.

[0130] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L comprises at least two fatty acid chains comprising at least 15 carbons. In embodiments, L comprises at least one Cis fatty acid chain. In embodiments, L comprises at least two Cis fatty acid chains. In embodiments, L comprises at least one faty acid chains independently selected from a Cis alkyl or a Cis alkenyl. In embodiments, L comprises at least two fatty acid chains independently selected from a Cis alkyl or a Cis alkenyl.

[0131] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L comprises at least one Cie fatty acid chain. In embodiments, L comprises at least two Cis fatty acid chains. In embodiments, L comprises at least one faty acid chains independently selected from a Cis alkyl or a Ci6 alkenyl. In embodiments, L comprises at least two fatty acid chains independently selected from a Ci6 alkyl or a Ci6 alkenyl.

[0132] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L comprises at least one Ci ? fatty acid chain. In embodiments, L comprises at least two Cn fatty acid chains. In embodiments, L comprises at least one fatty acid chains independently selected from a C17 alkyl or a Ci7 alkenyl. In embodiments, L comprises at least two fatty acid chains independently selected from a Ci 7 alkyl or a C17 alkenyl.

[0133] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L comprises at least oneCi 8 fatty acid chain. In embodiments, L comprises at least two Cis fatty acid chains. In embodiments, L comprises at least one fatty acid chains independently selected from a Cis alkyl or a Cis alkenyl. In embodiments, L comprises at least two fatty acid chains independently selected from a Cis alkyl or a Cis alkenyl.

[0134] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, the fatty acid chain is derived from stearic acid or oleic acid. In embodiments, the fatty acid chain is derived from stearic acid. In embodiments, the faty acid chain is derived from oleic fatty acid. In embodiments, L comprises two fatty acid chains derived from stearic acid.

[0135] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l ), (I-B-2), (I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -Cu-isalkyl.

[0136] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l ), (I-B-2), (I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -CH2(CH2CH?.)8-CH3.

[0137] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, L is -Ci-6alkylene-C(=O)- W.

[0138] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, W is alkyl, -O-alkylene- C(H)(OR6)-alkylene-OR7, or a sterol.

[0139] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, W is alkyl.

[0140] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, W is -Cis-soalkyl.

[0141] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, W is -Ci5-2oalkyl.

[0142] In embodiments of the compounds of Formula (I), (I- A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or ( I-C-B ), or a pharmaceutically acceptable salt thereof, W is a sterol.

[0143] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, the sterol is:

[0144] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C- A), or (I-C-B), or a pharmaceutically acceptable salt thereof, the sterol is:

[0145] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, W is -O-alkylene- C(H)(OR°)-alkylene~OR7. In embodiments, R6and R7are each independently R8or -C(=O)-R8. In embodiments, R° and R' are each independently R8. In embodiments, R6and R' are each independently -C(=O)-RS.

[0146] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, W is:wherein R8and R8is each independently -Cs-soalkyl.

[0147] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, W is:wherein R8and R8is each independently -Cs-3oalkyl.

[0148] in embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I~C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, Rxand R8is each independently a -C5-2oalkyl.

[0149] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R8and R8is each independently a -Cn-nalkyl.

[0150] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I~C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R8and R® is each independently a -Cnalkyl,

[0151] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), Il¬C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R8and R8is each independently a -Cnalkyl.

[0152] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I- C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, Rsand R8are both - (CHzCH 2)5-CH3.

[0153] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2),(I-C), (I-C-A), or (I-C-B), or a pharmaceutically acceptable salt thereof, R8and R8’ are both - (CH2CH2)S-CH3.

[0154] In embodiments, provided herein is a compound selected from the group consisting of:Compounds of Formula (II)

[0155] In embodiments provided herein is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R2is C2-6 alkylene;RJis hydrogen, alkyl, aryl or alkenyl;Y is an -C1-6 alkylene or absent;R1is -C(=0)-W or W; andW is Ce-Cso alkyl or a sterol; wherein each aforementioned alkyl, alkylene, aryl, and alkenyl is optionally substituted.

[0156] In embodiments, the compound of Formula (II) is a compound of Formula (II-2)(II-2) or a pharmaceutically acceptable salt thereof, wherein:R2is -C2-6 alkylene;R3is -hydrogen, alkyl, -aryl or -alkenyl;Y is an -C1-6 alkylene or absent;R1is -C(= ())-W or -W; andW is -Ce-Cso alkyl or a sterol; wherein each aforementioned alkyl, alkylene, aryl, and alkenyl is optionally substituted, and wherein the compound is not:

[0157] In embodiments of the compounds of Formula (II) or (II-2), Rzis C2-4 alkylene.

[0158] In embodiments of the compounds of Formula (II) or (II-2), R2is C?, alkylene. In embodiments of the compounds of Formula (II) or (II-2), R2is Cs alkylene. In embodiments of the compounds of Formula (II) or (II-2), R2is alkylene.In embodiments, the compound of Formula (II) or (II-2) is a compound of Formulaor a pharmaceutically acceptable salt thereof wherein n is 2 or 3;R3is hydrogen, alkyl, aryl or alkenyl,Y is an -Ci-6 alkylene or absent,R1is ■( ( O)-W or W; andW is Cs-Cso alkyl or a sterol; wherein each aforementioned alkyl, alkylene, aryl, and alkenyl is optionally substituted.

[0160] In embodiments, the compound of Formula (II) or (II-2) is a compound of Formula(II-B):(II-B) or a pharmaceutically acceptable salt thereof wherein n is 2 or 3;R3is hydrogen, alkyl, aryl or alkenyl;Y is an -Ci -s alkylene or absent;R1is -C(=O)-W or W; andW is C6-C30 alkyl or a sterol; wherein each aforementioned alkyl, alkylene, aryl, and alkenyl is optionally substituted.

[0161] In embodiments, the compound of Formula (II) or (II-2) is a compound of Formula(II-C):or a pharmaceutically acceptable salt thereof wherein Ri is -Cz-Ce alkylene;Rs is -C(=O)-W or -W; andW is -Cs-Cso alkyl or sterol.

[0162] In embodiments, the compound of Formula (II) or (II-2) is a compound of Formula(II-D):(n-D) or a pharmaceutically acceptable salt thereof wherein Ri is -C2-C6 alkylene; andR2 is -C( O)-W or -W, andW is -Ce-Cso alkyl or sterol.In embodiments, the compound of Formula (II) or (71-2) is a compound of Formulaor a pharmaceutically acceptable salt thereof wherein Ri is -C2-C6 alkylene; andR3 is -hydrogen, -alkyl, -aryl, or -alkenyl.

[0164] In embodiments, the compound of Formula (II) or (EE-2) is a compound of Formula(II I )(II-F) or a pharmaceutically acceptable salt thereof wherein Ri is -C2-C6 alkylene; and R3 is -hydrogen, -alkyl, -aryl, or -alkenyl.

[0165] In embodiments, the compound of Formula (II) or (II-2) is a compound of Formula(II-G):(II-G) or a pharmaceutically acceptable salt thereof wherein R2 is C( ()}-\V or -W;R3 is -hydrogen, -alkyl, -aryl, or -alkenyl; and W is -Cs-Cso alkyl or sterol.

[0166] In embodiments, the compound of Formula (II) or (II-2) is a compound of Formula(II-H):(n-H) or a pharmaceutically acceptable salt thereof wherein R2 is C(:::0)-W or -W,Ra is -hydrogen, -alkyl, -aryl, or -alkenyl, and W is -Ce-Cso alkyl or sterol.

[0167] In embodiments of the compounds of Formula (II), (II-2), (II- A), (II -B), (II-E), (II-F), (II-G), or (II-H), R3is hydrogen, alkyl, aryl or alkenyl.

[0168] In embodiments of the compounds of Formula (II), (II-2), (II- / X), (II -B), (II-E), (II-F), (II-G), or (II-H), R3is Cnsalkyl or hydrogen.

[0169] In embodiments of the compounds of Formula (II), (II-2), (II- / X), (II -B), (II-E), (II-F), (II-G), or (II-H), R3is H.

[0170] In embodiments of the compounds of Formula (II), (II-2), (II- / X), (II -B), (II-E), (II-F), (II-G), or (II-H), R3is -CHs.

[0171] In embodiments of the compounds of Formula (II), (II-2), (II- / X), (II -B), (II-E), (II-F), (II-G), or (II-H), R3is -(CH2CI FbCH.-CI h

[0172] In embodiments of the compounds of Formula (II), (II-2), (II- A), (II -B), (II-E), (II-F), (II-G), or (II-H), R1is W.

[0173] In embodiments of the compounds of Formula (II), (II-2), (II- A), (II-B), (II-C), (II-D), (II-E), or (II-F), R1is Cs-Cis alkyl.

[0174] In embodiments of the compounds of Formula (II), (II-2), (II- A), (II-B), (II-C), (II-D), (II-E), or (II-F), R1is -Cs alkyl.

[0175] In embodiments of the compounds of Formula (II), (II-2), (II- A), (II-B), (II-C), (II-D), (II-E), or (II-F), R1is -Cis alkyl.

[0176] In embodiments of the compounds of Formula (II), (II-2), (II- A), (II-B), (II-C), (II-D), (II-E), or (II-F), R1is (Q kCI bECH. CI b

[0177] In embodiments of the compounds of Formula (II), (II-2), (II- A), (II-B), (II-C),

[0179] In embodiments of the compounds of Formula (II), ( 11 -2), (II-A), (II-B), (II-C), (II-D), (II-G), or (II-H), W is a sterol. In embodiments, the sterol is:

[0180] In embodiments of the compounds of Formula (II), (11-2), (II-A), or (II-B), Y is absent.In embodiments of the compounds of Formula (II), (11-2), (II-A), or (II-B), Y is

[0182] In embodiments of the compounds of Formula (II), (II-A), or (II-B), the compoundCompounds of Formula (III)

[0184] In embodiments, provided herein is a compound of Formula (III):or a pharmaceutically acceptable salt thereof; wherein:RC1is H or -C(=O)-R°; andRC2and RC3are each independently an optionally substituted C4-3oalkyi or C4-3oalkenyl.

[0185] In embodiments, provided herein is a compound of Formula (III-2):or a pharmaceutically acceptable salt thereof; wherein:RC!is H or -C(=O)-RC3; andRC2and RC5are each independently an optionally substituted -C4-30 alkyl or -C4-30 alkenyl, wherein the compound is not:

[0186] In embodiments, the compound of Formula (III) or (III-2) is a compound of Formula (III-A):or a pharmaceutically acceptable salt thereof.

[0187] In embodiments, the compounds of Formula (III) or (III-2) is a compound of Formula (III-B)or pharmaceutically acceptable salt thereof, wherein RC1is H or -C(:::())-Rc3; and R’: ;is -C4-30 alkenyl.

[0188] In embodiments, the compounds of Formula (III) or (III-2) is a compound of Formula (III-C)or pharmaceutically acceptable salt thereof, wherein RC2is -C 1-30 alkenyl.

[0189] In embodiments of the compounds of Formula (III), ( 111 -2 ), or (III-A), RC2and RC3are each independently an optionally substituted Cs-soalkyl or Cs-soalkenyl. In embodiments, Rc2and RCjare each independently an optionally substituted Cs-soalkyl or Cs-soalkenyl. In embodiments, R'~2and RC3are each independently an optionally substituted C?-3oalkyl or C7- soalkenyl.In embodiments, RCzand RCjare each independently an optionally substituted Cs-soalkyl or Cs-3oalkenyl. In embodiments, R2 zand RCjare each independently an optionally substituted C9- soalkyl or Cs-soalkenyl. In embodiments, Rc2and RC3are each independently an optionally substituted Cio-soalkyl or Cio-3oalkenyl. In embodiments, Rv2and Rl■’ are each independently an optionally substituted Cu-3oalkyl or Cn-soalkenyl. In embodiments, RC2and Rc" are each independently an Cn-nalkyl.

[0190] In embodiments of the compounds of Formula (III), (III-2), (III-A), or (III-B), RC2and RCjare the same.

[0191] In embodiments of the compounds of Formula (III), (III-2), (III-A), or (III-B), RC2and RCJare the different.

[0192] In embodiments of the compounds of Formula (III), (III-2), (III- A), or (III-B) RC2and Roare both Cn alkyl.

[0193] In embodiments of the compounds of Formula (III), (III- 2), or (III- A), RC1is hydrogen and RC2is t-butyl,

[0194] In embodiments of the compounds of Formula (111), (III-2), (III- A), (III-B), or (III- C), RCzis -C15-30 alkenyl.

[0195] In embodiments of the compounds of Formula (III), (III-2), (III- A), (III-B), or (III- C), Rc2is -C15-20 alkenyl,

[0196] In embodiments of the compounds of Formula (III), (III-2), (III- A), (III-B), or (III- C), Rc2is Ci7 alkenyl.

[0197] In embodiments of the compounds of Formula (III), (III-2), (III- A), (III-B), or (III- C), RC2is Ci? alkenyl, wherein the C17 alkenyl has a double bond at between the 8toand 9thcarbon.

[0198] In embodiments of the compounds of Formula (III), (III-2), (III- A), (III-B), or (III- C), Rc2is oleate.

[0199] In embodiments, the compounds of Formula (III), (III-2), (IIIA), (III-B), or (III- C) the compound is:Ċ

[0200] In embodiments, the compounds of Formula (III), (III-2), or (TITA), the compoundCompounds of Formula (IV)

[0201] In embodiments provided herein is a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein:RDiis hydrogen, -C(-O)NRD4-alkyl or -C(-O)NRD4-alkenyl;RD2is hydrogen, alkyl, aryl or alkenyl,RD3IS -C6-C30 alkyl;RD4IS hydrogen, alkyl, aryl or alkenyl; wherein each aforementioned alkyl, aryl, and alkenyl is optionally substituted.

[0202] In embodiments provided herein is a compound of Formula (IV-2):or a pharmaceutically acceptable salt thereof; wherein:RD-!IS -hydrogen, -C(=O)NRD4-alkyl or -C(=O)NRD4-alkenyl;RD2IS -hydrogen, -alkyl, -aryl or -alkenyl;RD3is -Cs-Cso alkyl;RD4is -hydrogen, -alkyl, -aryl or -alkenyl.

[0203] In embodiments, the compounds of Formula (IV) or (IV-2) is a compound ofFormula (IV- A):or a pharmaceutically acceptable salt thereof

[0204] In embodiments of the compounds of Formula (IV), (IV-2) or (IV-A), RD1is hydrogen or -C(=O)NRD4-alkyl.

[0205] In embodiments of the compounds of Formula (IV), (IV-2), or (IV-A), RD1is hydrogen.

[0206] In embodiments of the compounds of Formula (IV), (IV-2), or (TV-A), RD1is -C(-O)NRD4-alkyl.

[0207] In embodiments of the compounds of Formula (IV), (IV-2), or (IV-A), RD1is -C(K))NH-Cs-3oalky1.

[0208] In embodiments of the compounds of Formula (TV), (IV-2), or (IV-A), RD1is:

[0209] In embodiments of the compounds of Formula (IV ), (I V-2), or (IV-A), RD3is -Cs-24alkyl.

[0210] In embodiments of the compounds of Formula (IV), (IV-2), or (IV-A), RD3is -Cisalkyl.

[0211] In embodiments of the compounds of Formula (IV ), (I V-2), or (IV-A), RD3is:

[0212] In embodiments of the compounds of Formula (IV), (IV-2), or (IV-A), the compound is :Compounds of Formula (V)

[0213] In embodiments, provided herein is a compound of Formula (V),or a pharmaceutically acceptable salt thereof; wherein:RL1is hydrogen or -C(=O)ORE3;RE2is -C6-C30 alkyl or -C6-C30 alkenyl;R1"' is -Ce-Cso alkyl or -Ce-Cso alkenyl; wherein each aforementioned alkyl and alkenyl is optionally substituted.

[0214] In embodiments, the compound of Formula (V) is a compound of Formula (V-2):or a pharmaceutically acceptable salt thereof; wherein:RE1is hydrogen or -C(-())ORE3;RE2is -Cs-Cso alkyl;REJIS -Ce-Cso alkyl or -Ce-Cso alkenyl; wherein each aforementioned alkyl and alkenyl is optionally substituted.

[0215] In embodiments, the compound of Formula (V) or (V -2) is a compound of Formula(V-A):or a pharmaceutically acceptable salt thereof

[0216] In embodiments of the compounds of Formula (V), (V-2), or (V-A), RE!is hydrogen.

[0217] In embodiments of the compounds of Formula (V), (V-2), or (V-A), RE’!is -C(=O)ORE3.

[0218] In embodiments of the compounds of Formula (V), (V-2), or (V-A), REJis -Cs-24alkyl.

[0219] In embodiments of the compounds of Formula (V), (V-2), or (V-A), REJis -Cisalkyl.

[0220] In embodiments of the compounds of Formula (V), (V-2), or (V-A), RE?is -Cs-24alkyl.

[0221] In embodiments of the compounds of Formula (V), (V-2), or (V-A), R: zis -Cisalkyl.

[0222] In embodiments of the compound of Formula (V), (V-2), or (V-A), the compoundCompounds of Formula (VI)

[0223] In embodiments provided herein is a compound of Formula (VI):or a pharmaceutically acceptable salt thereof;wherein RF!is an optionally substituted Ce-soalkyl or optionally substituted Cs-soalkenyl.

[0224] In embodiments, the compound of Formula (VI), is a compound of Formula ( VI-2):or a pharmaceutically acceptable salt thereof; wherein RF1is an optionally substituted Cs-ao alkyl, wherein Rh lis not -Cs, -Cs, -C9, -C17, and -Cis alkyl.

[0225] In embodiments, the compound of Formula (VI) or (Vi-2) is compound ofFormula (VI-A)(VI-A) or a pharmaceutically acceptable salt thereof.

[0226] In embodiments of the compounds of Formula (VI), (VI-2), or (VI-A), RF1is an optionally substituted Cisooalkyl or optionally substituted Cis-soalkenyl. In embodiments, RF1is an optionally substituted Cis-soalkyl. In embodiments, RF!is an optionally substituted C15- 3oalkenyl.

[0227] In embodiments of the compounds of Formula (VI), (VI-2), or (VI-A), R: ;is an optionally substituted Cis-zoalkyl or optionally substituted Ci5-2oalkenyl. In embodiments, R: ;is an optionally substituted Cis-zoalkyl. In embodiments, RF!is an optionally substituted Cis- 2oalkenyl.

[0228] In embodiments of the compounds of Formula (VI), (VI-2) or (VI-A), RMis an optionally substituted Cisalkyl or optionally substituted Cisalkenyl. In embodiments of the compounds of Formula (VI), (VI-2), and (VI-A), RF lis an optionally substituted Cisalkyl. In embodiments of the compounds of Formula (VI), (VI-2), and (VI-A), RP1is an optionally substituted Cisalkenyl.

[0229] In embodiments, the compound of Formula (VI) is:

[0230] In embodiments provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0231] In embodiments, the compounds are any stereoisomer of a compound of Formula (I), (I- A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-2), (II- A), (II-B), (II-C), (II-D),(H-E), (II-F), ( II-G ), (II-H), (III), ( 111-2 ), (III-A), (III-B), (III-C), (IV), (IV-2), (IV-A), (V), ( V-2).(V-A), (VI), (VI-2), (VI- A), Table 2, or Table 1 .

[0232] In embodiments, provided herein is one or more compounds selected from Table

[0233] In embodiments, provided herein is one or more pharmaceutically acceptable salts of a compound selected from Table 1 .

[0234] In embodiments, provided herein is one or more compounds of selected from Table 1, or a stereoisomer, or a pharmaceutically acceptable salt thereof.Table 1Table 2Compositions

[0235] Provided herein are nanobiologic compositions comprising a nanoparticle carrier and one or more compounds of the present disclosure (such as a compound of Formula (I), (I- A), (I-B), (1-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II- A), (II-B), (III), (III- A), (IV), (IV- A), (V), (V-A), (VI), or (VI- A), as disclosed herein or Table 1).

[0236] In embodiments, the nanobiologic compositions comprising one or more compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-2), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (D-H), (III), (III-2), (III- A ), (III-B), (III-C), (IV), (IV-2), (IV- A), (V), (V-2), (V-A), (VI), (VI-2), (VI- A), Table 2, or Table 1.

[0237] In embodiments, the nanobiologic compositions comprising one or more compounds of Formula (I), (I-A), (I-B), (1-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-A), (II-B), (III), (III-A), (IV), (IV-A), (V), (V-A), (VI). or (VI- A), as disclosed herein or Table 1.

[0238] In embodiments, the nanobiologic compositions comprising one or more compounds of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II-2), (II-A), (II- B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (III-2), (III-A), (III-B), (III-C), (IV-2), (IV-A), (V- 2), (V-A), (VI-2), (VI- A), or Table 2.

[0239] In embodiments, the compounds of the present disclosure can be formulated in a nanoparticle carrier, which can include, but is not limited to polyplexes, colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-basedsystems including oil-in-water emulsions, micelles, mixed micelles, liposomes, lipoplexes, lipid nanoparticles, lipid nanocapsules, lipidoids, rapidly eliminated lipid nanoparticles (reLNPs), micro- and nano-emulsions, and the like, HDL-derived nanoparticles, polymeric nanoparticles, including poly (lactic-co-glycolic acid) (PLGA) nanoparticles such as PLGA microspheres, poly(lactide) (PLA) nanoparticles, poly (s-caprolact one) (PCL) nanoparticles, poly(butyl cyanoacrylate) (PBCA) nanoparticles, dendrimers, hyperbranched polyglycerol (HPG) nanoparticles, PEG-polyaspartate micellar nanoparticles, cationic polymers including for example poly(L-lysine), polyethylenimine (PEI), DEAE-dextran, poly(amino esters) (PBAE) and chitosan, cyclodextrin nanoparticles, metallic nanoparticles, surfactant based emulsions, virus like particles (e.g., particles that are primarily made up of viral structural proteins but that are not infectious or have low infectivity’), peptide or protein-based particles such as albumin nanoparticies, nanowires, gold nanoparticies, magnetic nanoparticies, core-shell nanoparticies, carbon nanotubes, nanocrystals, hyaluronidase, and combinations thereof

[0240] In embodiments, the compounds of the present disclosure may’ be formulated in a nanoparticle carrier, such as those described in US5, 567,434, USS, 552, 157, US5,565,213, US5,738,868, USS, 795, 587, US10,485,884, US2019 / 0290593, US2020 / 0253884, US2020 / 0376146, and WO2018 / 071549 the contents of each of which are incorporated herein by reference.

[0241] In embodiments, the nanoparticie carrier is a high-density' lipoprotein (HDL)- derived nanoparticie. The high-density lipoprotein (HDL)-derived nanoparticies are envisioned as delivery vehicles that may, for example, improve the therapeutic index of small-molecule immunomodulatory compounds and / or confer enhance delivery to cells of the innate immune system. By enhanced delivery' to innate immune cells (particularly myeloid cells and their progenitor cells) in the bone marrow; the therapeutic agents incorporated in the HDL-derived nanoparticies may be delivered in a more effective fashion. In embodiments, the high-density lipoprotein (HDL)-derived nanoparticie comprises apoA-I or a peptide mimetic of apoA-I. In embodiments, the high-density’ lipoprotein (HDL)-derived nanoparticie comprises apoA-I.

[0242] HDL-derived nanoparticles may contain multiple components including lipids (e.g., phospholipids, sphingolipids, triglycerides, sterols, such as cholesterol) and apolipoprotein A (apoA-1), the mam protein constituent of high-density lipoprotein.

[0243] In embodiments, the HDL-derived nanoparticle comprises a compound of the present disclosure (e.g., a compound of Formula (I), (I-A), (I-B), (I-B-l), (LB-2), (LC), (I-C-A), (LC-B), (II), (II-2), (ILA), ( ILB), (II-C), (ILD), (ILE), (ILF), (II-G), (II-FI), (III), (IIL2), (IILA), (IILB), (IILC), (IV), (IV-2), (IV-A), (V), (V-2), (V-A), (VI), (VI-2), (VLA), Table 2, or Table 1).

[0244] In embodiments, the HDL-derived nanoparticle comprises a compound of the present disclosure (e.g., a compound of Formula (I), (LA), (LB), (I-B-l), (LB-2), (I-C), (I-C-A), (LC-B), (II), (ILA), (ILB), (III), (IILA), (IV), (IV-A), (V), (V-A), (VI), or (VLA) or Table 1).

[0245] In embodiments, the HDL-derived nanoparticle comprises a compound of the present disclosure (e.g., a compound of Formula (I), (LA), (I-B), (I-B-l), (I-B-2), (LC), (I-C-A), (LC-B), (II-2), (ILA), (ILB), (II-C), (ILD), (ILE), (ILF), (ILG), (II-FI), (IIL2), (IILA), (IILB), (IILC), (IV-2), (IV-A), (V-2), (V-A), (VI-2), (VLA), or Table 2).

[0246] In embodiments, the HDL-derived nanoparticle comprises a phospholipid.

[0247] In embodiments, the HDL-derived nanoparticle comprises i) apo.A-I or a peptide mimetic of apoA-I; ii) a phospholipid; hi) optionally a lysophospholipid, iv) optionally a hydrophobic matrix core (e.g., one or more triglycerides) and v) optionally cholesterol, and a compound of the present disclosure (e.g., a compound of Formula (I), (LA), (I-B), (I-B-l), (I-B- 2), (LC), ( LC-A). (LC-B), (II), (IL2), (ILA), (ILB), (II-C), (ILD), (ILE), (ILF), (ILG), (II-FI), (III), (III-2), (IILA), (IILB), (IILC), (IV), (IV-2), (IV-A), (V), (V-2), (V-A), (VI), (VI-2), (VLA), Table 2, or Table 1).

[0248] In embodiments, the HDL-derived nanoparticle comprises i) apoA-I or a peptide mimetic of apoA-I; ii) a phospholipid; iii) optionally a lysophospholipid, iv) optionally a hydrophobic matrix core (e.g., one or more triglycerides) and v) optionally cholesterol, and a compound of the present disclosure (e.g., a compound of Formula (I), (LA), (LB), (1-B-l), (LB-2), (I-C), (I-C-A), (I-C-B), (II), (II-A), (II-B), (III), (III-A), (IV), (IV-A), (V), (V-A), (VI), or (VI- A)or Table 1).

[0249] In embodiments, the HDL-derived nanoparticle comprises i) apoA-I or a peptide mimetic of apoA-I; li) a phospholipid; iii) optionally a lysophospholipid, iv) optionally a hydrophobic matrix core (e.g., one or more triglycerides) and v) optionally cholesterol, and a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (I-B-l), (I-B- 2), (I-C), (I-C-A), (I-C-B), (11-2). (II-A), (II-B), (II-C), (II -D), (II-E), (II-F), (II-G), (II-H), ( I II - 2 ), (III-A), (III-B), (III-C), (IV-2), (IV-A), (V-2), (V-A), (VI-2), (VI-A), or Table 2).

[0250] In embodiments, the HDL-derived nanoparticle comprises i) apoA-I or a peptide mimetic of apoA-I; li) a phospholipid; iii) a lysophospholipid, iv) a hydrophobic matrix core (e.g., one or more triglycerides) and a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-2), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (III), (III-2), (III-A), (III-B), (III-C), (IV), (IV-2), (IV-A), (V), (V-2), (V-A), (VI), (VI-2), (VI-A), Table 2, or Table 1).

[0251] In embodiments, the HDL-derived nanoparticle comprises i) apoA-I or a peptide mimetic of apoA-I; li) a phospholipid; iii) a lysophospholipid, iv) a hydrophobic matrix core (e.g., one or more triglycerides) and a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (1-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-A), (II-B), (III), (III-A), (IV), (IV-A), (V), (V-A), (VI), or (VI-A) or Table 1).

[0252] In embodiments, the HDL-derived nanoparticle comprises i) apoA-I or a peptide mimetic of apoA-I; ii) a phospholipid; iii) a lysophospholipid, iv) a hydrophobic matrix core (e.g., one or more triglycerides) and a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II-2), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (III-2), (III-A), (III-B), (III-C), (IV-2), (IV-A), (V-2), (V-A), (VI-2), (VI-A), or Table 2).

[0253] In embodiments, the HDL-derived nanoparticle comprises i) apoA-I or a peptide mimetic of apoA-I; ii) a phospholipid; iii) a lysophospholipid, iv) a hydrophobic matrix core (e.g., one or more triglycerides) and v) cholesterol, and a compound of the present disclosure (e.g., acompound of Formula (I), (I- A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (11-2), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (III), (III -2), (III-A), (III-B), (III-C), (IV), (IV- 2), (IV- A), (V), (V-2), (V-A), ( VI), (VI-2), (VI- A), Table 2, or Table 1).

[0254] In embodiments, the HDL-derived nanoparticle comprises i) apoA-I or a peptide mimetic of apoA-I; ii) a phospholipid; hi) a lysophospholipid, iv) a hydrophobic matrix core (e.g., one or more triglycerides) and v) cholesterol, and a compound of the present disclosure (e.g., a compound of Formula (I), (I-A), (I-B), (1-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-A), (II- B), (III), (III-A), (IV), (TV- A), (V), (V-A), (VI), or (VI- A) or Table 1).

[0255] In embodiments, the HDL-derived nanoparticle comprises i) apoA-I or a peptide mimetic of apoA-I; ii) a phospholipid; iii) a lysophospholipid, iv) a hydrophobic matrix core (e.g., one or more triglycerides) and v) cholesterol, and a compound of the present disclosure (e.g., a compound of Formula (1), (1-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (II-2), (II-A), (II- B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), ( II I - 2 ), (III-A), (III-B), (III-C), (IV-2), (1V-A), (V- 2), (V-A), (VI-2), (VI-A), or Table 2).

[0256] In embodiments, the HDL-derived nanoparticle comprises human apolipoprotein A-I (apoA-I); for example, the ApoA-I sequence may have the mature peptide sequence shown below, or it may include either or both of a signal peptide (e.g., SEQ ID NO:347) or a pro-peptide portion (e.g., SEQ ID NO:348). The peptide may be manufactured by expressing a nucleic acid encoding all three of the signal peptide, pro-peptide portion and the mature peptide. During protein synthesis and maturation the mature peptide is released and can be purified from the host cell for use in the compositions herein. In certain host cells, such as bacteria, the encoded peptide may not be cleaved into a mature peptide. An N-terminal methione (M) residue of the Apo-Al peptide used herein may be a formyl-methoionine (fM) residue. In embodiments, the ApoA-I used in compositions herein comprises or consists of the sequence of SEQ ID NO: 349 or a sequence having 1 , 2, 4, 5, 6, 7, 8, 9, 10, or up to 20 conservative substitutions thereto.

[0257] Human apoA-I can be isolated or prepared by any method known in the art. In embodiments, human apoA-I is isolated from human HDL. Another known method comprises the synthesis of apoA-I by recombinant protein expression, for example in E. coli organisms. Whenexpressed in bacteria the apoA-I may include an N-terminal methionine or a formyl-methionine. The presence of the methionine group can be assessed by mass spectroscopic (MS) methods that are known in the art. The position of the methionine in the protein sequence can be assessed after digestion of apoA-I with subsequent analysis of the peptide mixture with MS, as is also known in the art. In embodiments, purifications of apoA-I, including any of its variations, may comprise any method known in the art (e.g. use of hydrophobic interaction chromatography, ion exchange columns, precipitations, etc.). Production methods may or may not comprise the use of affinity tags that enable the purification of the proteins; such tags require removal after purification to restore the human apoA-I identity.Table 2A. ApoA-I peptides

[0258] In embodiments, the HDL-derived nanoparticle comprises a peptide mimetic of apolipoprotein A-I (apoA-I) e.g. an apoA-I mimetic polypeptide disclosed in US20I80078625A1, which is incorporated by reference herein. Suitable apoA-I mimetic polypeptides may have the sequence shown in Table 2B (SEQ ID NOS: 256 to 263, and 342 to 346) or in SEQ ID NOS: 1 to 341.Table 2B. ApoA-I mimetics

[0259] In embodiments, the apo.A-I mimetic is DWLKAFYDKVAEKLKEAF (SEQ IDNO. 256). In embodiments, the apoA-I mimetic is Ac-DWLKAFYDKVAEKLKEAF-NIfc (SEQ ID NO. 257). In embodiments, the apoA-I mimetic is AC-DWFKAFYDKVAEKFKEAF-NIL (SEQ ID NO. 260).

[0260] In embodiments, apoA-I mimetics are optionally acetylated on the N-terminus, or optionally amidated on the C -terminus. In embodiments, the apoA-I mimetics are acetylated on the N-terminus. In embodiments, the apo.A-I mimetics are amidated on the C-terminus. In embodiments, the apoA-I mimetics are acetylated on the N-terminus and amidated on the C- termmus.

[0261] In embodiments, the high-density lipoprotein (HDL)-derived nanoparticle comprises apoA-1 Milano.

[0262] In embodiments, the HDL-denved nanoparticles of the present disclosure comprise one or more phospholipids. Examples of suitable phospholipids include, without limitation, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositol, phosphatidylserines, as well as phospholipid-containing oils such as lecithin oils. Non-limiting examples of the phospholipids that may be used in the present composition includephosphatidylcholines (PC), phosphatidylglycerols (PG), phosphatidylserines (PS), phosphatidylethanolamines (PE), and phosphatidic acid / esters (PA).

[0263] In embodiments, the phospholipid is independently selected from the group consisting of a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylinositol, a phosphatidylserine, a phospholipid-containing oil, a phosphatidylglycerol, a phosphatidic acid, and combinations thereof.

[0264] In embodiments, the phospholipid is one or more of the following: DI) PC CAS- 3436-44-0 l,2-Didecanoyl-sn-glycero-3-phosphocholine, DEPA-NA CAS-80724-31-8 1,2- Dierucoy l-sn-glycero-3-phosphate (Sodium Salt), DEPC CAS-56649-39-9 1,2-Dierucoyl-sn- glycero-3-phosphocholine, DEPE CAS-988-07-2 l,2-Dierucoyl-sn-glycero-3- phosphoethanolamine, DEPG-NA 1 ,2-Dierucoyl-sn-glycero-3-phospho-rac-(l-glycerol) (Sodium Salt), DLOPC CAS-998-06-1, l,2-Dilinoleoyl-sn-glycero-3 -phosphocholine, DLPA-NA 1,2- Dilauroyl-sn-glycero-3-phosphate (Sodium Salt), DLPC CAS-18194-25-7 1,2-Dilauroyl-sn- glycero-3-phosphocholine, DLPE 1 ,2-Dilauroyl-sn-giycero-3-phosphoethanolamine, DLPG-NA 1,2-Dilauroyl-sn-glycero- 3-phospho-rac-(l-glycerol) (Sodium Salt) , DLPG-NH4 1,2-Dilauroyl- sn-glycero~3~phospho-rac-(l-glycerol) (Ammonium Salt), DLPS-NA l,2-Dilauroyl-sn~glycero-3- phosphoserine (Sodium Salt), DMPA-NA CAS-80724-3 l,2-Dimyristoyi-sn-glycero-3-phosphate (Sodium Salt), DMPC CAS-18194-24-6 l,2-Dimyristoyl-sn-giycero-3 -phosphocholine, DMPE: CAS-988-07-2 1 ,2-Dimyristoyl-sn-glycero- 3 -phosphoethanolamine, DMPG-NA CAS-67232-80- 8 l,2-Dimyristoyl-sn-glycero-3-phospho-rac-(l-glycerol) (Sodium Salt), DMPG-NH4 1,2- Dmiyristoyl-sn-glycero-3-phospho-rac-(l-glycerol) (Ammonium Salt), DMPG-NH4 / NA 1,2- Dimynstoyl-sn-glycero-3-phospho-rac-(l-glycerol) (Sodium / Ammonium Salt), DMPS-NA 1,2- Dimynstoyl-sn-glycero-3 -phosphoserine (Sodium Salt), DOPA-NA l,2-Dioleoyl-sn-glycero-3- phosphate (Sodium Salt), DOPC CAS-4235-95-4 l,2-Dioleoyl-sn-glycero-3-phosphocholine, DOPE CAS-4004-5-1 l,2-Dioleoyl-sn-glycero-3-phosphoethanolamine, DOPG-NA CAS-62700- 69-0 l,2-Dio1eoyl-sn-glyeero-3-phospho-rac-(1-glycerol)(Sodium Salt), DOPS-NA CAS-70614- 14-1, l,2-Dioleoyl~sn-glycero-3-phosphoserine (Sodium Salt), DPPA-NA CAS-71065-87-7, 1,2- Dipalmitoyl-sn-glycero-3-phosphate (Sodium Salt), DPPC CAS-63-89-8, 1,2-Dipalmitoyl-sn- glycero-3-phosphocholine, DPPE CAS-923-61-5 l,2-Dipa1mitoyl-sn-glycero-3-phosphoethanolamine, DPPG-NA CAS-67232-81-9 1 ,2-Dipalmitoyl-sn-glycero-3-phospho-rac- (1-glycerol) (Sodium Salt), DPPG-NH4 CAS-73548-70-6 l,2-Dipalmitoylsn-glycero-3-phospho- rac-(l-glycerol) (Ammonium Salt), DPPS-NA l,2-Dipalmitoyl-sn- glycero-3 -phosphoserine (Sodium Salt), DSPA-NA CAS- 108321 -18-2 l,2-Distearoyl-snglycero-3-phosphate (Sodium Salt), DSPC CAS-816-94-4 l,2-Distearoyl-sn-glycero-3-phosphocholine, DSPE CAS-1069-79-0 1 ,2-Distearoyl-sn-glycero-3-phosphoethanolamine, DSPG-NA CAS-67232-82-0 1 ,2-Distearoyl- sn-glycero-3-phospho-rac-(l-glycerol) (Sodium Salt), DSPG-NH4 CAS-108347-80-4 1,2- Distearoyl-sn-glycero-3-phospho-rac-(l- glycerol) (Ammonium Salt), DSPS-NA 1,2-Distearoyl- sn-glycero-3-phosphoserine (Sodium Salt), EPC Egg-PC, HEPC Hydrogenated Egg PC, HSPC Hydrogenated Soy PC, MPPC l-Myristoyl-2-palmitoyl-sn-glycero 3-phosphocholine, MSPC 1- Myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, PMPC l-Palmitoyl-2-myristoyl-sn-glycero-3- phosphocholine, POPC CAS-26853-31 -6 l-Palmitoyl-2-oleoyl-sn-glycero- 3 -phosphocholine, POPE l-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, POPG-NA CAS-81490-05-3 1- Palmitoyl-2-oleoyl-sn-glycero-3[Phospho-rac-(l-glycerol)] (Sodium Salt), PSPC 1 -Palmitoyl-2- stearoyl-sn-glycero-3 -phosphocholine, SMPC l-Stearoyl-2-myristoyl-sn-glycero-3- phosphocholine, SOPC l-Stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, SPPC1 -Stearoyl 1-2- palmitoyl l-sn-glycero-3 -phosphocholine.

[0265] In embodiments, the phospholipid is dimyristoylphosphatidylcholine (DMPC), soy lecithin, dipalmitoylphosphatidyl choline (DPPC), distearoylphosphatidylcholine (DSPC), di lauryl olyph osphatidy Icholme (DLPC), dioleoylphosphatidylcholine (DOPC), dilaurylolylphosphatidylglycerol (DLPG), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylglycerol (DOPG), dimyristoyl phosphatidic acid (DMPA), dimyristoyl phosphatidic acid (DMPA), dipalmitoyl phosphatidic acid (DPPA), dipalmitoyl phosphatidic acid (DPP A), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl phosphatidyl serine (DMPS), dipalmitoyl phosphatidylserine (DPPS), and mixtures thereof.

[0266] In embodiments of the HDL-derived nanoparticles provided herein, the phospholipid is selected from the group consisting of l,2-dimyristoyl-sra-glycero-3-phosphocholine (DMPC), l-palmitoyl-2-oleoyl-sn-glycero-3 -phosphocholine (POPC), 1,2- dioleoyl-OT-glycero-3-phosphocholine (DOPC) and mixtures thereof.

[0267] In embodiments of the HDL-derived nanoparticles provided herein, the phospholipid is l,2-dimyristoyl-OT-glycero-3-phosphocholine (DMPC) or l-palmitoyl-2-oleoyl- OT-glycero-3-phosphocholine (POPC).

[0268] In embodiments of the HDL-derived nanoparticles provided herein, the phospholipid is DMPC.

[0269] In embodiments, the HDL-derived nanoparticles comprise a phospholipid and a lysophospholipid.

[0270] In embodiments, the lysophospholipid is a lysophosphatidylcholine.

[0271] In embodiments, the lysophospholipid is LYSOPC MYRISTIC 1-Myristoyl-sn- glycero-3-phosphocholine, LYSOPC PALMITIC CAS-17364-16-8 l-Palmitoyl-sn-glycero-3- phosphocholine, or LYSOPC STEARIC CAS-19420-57-6 l-Stearoyl-sn-glycero-3- phosphocholine,

[0272] In embodiments of the HDL -derived nanoparticles provided herein, the lysophospholipid is selected from the group consisting of l-myristoyl-2-hydroxy-.sra-glycero-3- phosphocholine (MHPC), 1-pa1mitoyl-2-hydroxy-sn-glycero-3-phosphocho1ine (PHPC), 1- stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (SHPC), and mixtures thereof.

[0273] In embodiments of the HDL-derived nanoparticles provided herein, the phospholipid is l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the lysophospholipid is 1 -palmitoyl-2-hydroxy-.w?-g1ycero-3-phosphocholine (PHPC).

[0274] In embodiments, when the present composition comprises two types of phospholipid, the weight ratio of two types of phospholipids ranges from about 1 : 10 to about 10: 1 , including about 1:9, about 1:8, about 1 :7, about 1 :6, about 1:5, about 1:4, about 1 :3, about 1 :2, about 1:1, about 2: 1, about 3: 1 , about 4: 1 , about 5:1, about 6: 1, about 7:1, about 8: 1 , about 9: 1 , to about 10: 1 , including all values and ranges therebetween.

[0275] In embodiments, when the present composition comprises a phospholipid and a lysophospholipid, the weight ratio of two phospholipid and lysophospholipid ranges from about 1:10 to about 10: 1, including about 1 : 9, about 1 : 8, about 1 : 7, about 1 : 6, about 1 :5, about 1 : 4, about 1:3, about 1:2, about 1 :1, about 2:1, about 3: 1, about 4:1, about 5: 1, about 6: 1, about 7:1, about 8:1, about 9: 1, to about 10:1, including all values and ranges therebetween.

[0276] In embodiments, the structure and properties of the HDL-derived nanoparticles (e.g., particle size, rigidity, viscosity, loading, etc.) can be modified by incorporating a hydrophobic matrix. As used herein, hydrophobic matrix refers to a core or filler or structural modifier of the nanoparticle. Non-limiting examples of suitable hydrophobic matrix molecules include, triglycerides, fatty acid esters, hydrophobic polymers, sterol esters, or combinations thereof.

[0277] Any suitable synthetic or natural fatty acid or fatty acid ester, known in the art are contemplated for use in the HDL-derived nanoparticles of the present disclosure. Non-limiting examples of fatty acids of use include: arachidonic acid, oleic acid, arachidic acid, lauric acid, sad, capric acid, myristic acid, palmic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, three decanoins, glycerin mono-fatty acid ester, Dilaurin, 1 -SunSoft 767, laurocapram (1-dodecyl-aza- cycloheptane-2-ketone), acylcarnitines, acyl group choline or Ci-Cioarr costab (such as isopropyl myristate IPM), monoglyceride, diglyceride or its pharmaceutically acceptable salt.

[0278] In embodiments, the HDL-derived nanoparticles comprise one or more triglycerides.

[0279] In embodiments of the HDL-derived nanoparticles provided herein, the triglyceride may be any triglyceride or any combination of triglycerides.

[0280] Any suitable synthetic or natural triglycerides, known in the art are contemplated for use in the HDL-derived nanoparticles of the present disclosure. Non-limiting examples of triglycerides of use include: tricaprylin, tristearin, triolein, tripalmitin, 1 ,2-dipalmitoolein, 1,3- dipalmitoolein, 1 -palmito-3-stearo-2-olein, 1 -palmito-2-stearo-3-olein, 2-palmito- 1 -stearo-3- olein, trilinolein, 1,2-dipalmitolinolein, 1-palmito-dilinolein, 1 -stearo-dilinolein, 1,2- diacetopalmitin, 1,2-distearo-olein, 1,3-distearo-olein, trimyristin, trilaurin and combinationsthereof. In embodiments, the triglyceride is tricaprylin. Suitable triglycerides may be added to the present compositions in neat form. Additionally, or alternatively, oils and / or processed oils containing suitable triglycerides may be added to the compositions. Non-limiting examples of oils include coconut oil, corn germ oil, olive oil, palm seed oil, cottonseed oil, palm oil, rapeseed oil, sunflower oil, whale oil, soybean oil, peanut oil, linseed oil, tall oil, and combinations thereof.

[0281] In embodiments, the HDL-derived nanoparticles comprise cholesterol-alpha linolenate.

[0282] In embodiments, the HDL-derived nanoparticles comprise isopropanol and acetonitrile. In embodiments, the HDL-derived nanoparticles comprise isopropanol. In embodiments, the HDL-derived nanoparticles comprise MeCN.

[0283] The hydrophobic polymer or polymers may be selected from the group of polymers approved for human use (i.e. biocompatible and FDA-approved). Such polymers include, for example, but are not limited to the following polymers, derivatives of such polymers, copolymers, block co-polymers, branched polymers, and polymer blends: polyalkenedicarboxlates, polyanhydrides, polyfaspartic acid), polyamides, polybutylenesuccmates (PBS), polybutylenesuccinates-co-adipate (PBSA), poly(e-caprolactone) (PCL), polycarbonates including poly-alkylene carbonates (PC), polyesters including aliphatic polyesters and polyesteramides, polyethylenesuccinates (PES), polyglycolides (PGA), polyimines and poly alkyleneimines (Pl, PAI), polylactides (PLA (polylactic acid), PLLA, PDLLA), polylactic-co-glycolic acid (PLGA), poly(l-lysme), polymethacrylates, polypeptides, polyorthoesters, poly-p-dioxanones (PPDO), (hydrophobic) modifiedpolysaccharides, polysiloxanes and poly-alkyl-siloxanes, polyureas, polyurethanes, and polyvinyl alcohols, and biodegradable polyalkyl-cyanoacrylate.

[0284] In embodiments of the HDL-derived nanoparticles provided herein, the HDL- derived nanoparticle has a PDI of about 0.01 to about 0.5, including about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4 to about 0.5, including all subranges and values therebetween. In embodiments of the HDL-derived nanoparticles provided herein, the HDL-derived nanoparticle has a PDI ofabout 0.1 to about 0.3. The PDI can be measured by for example DLS (dynamic light scattering) techniques, known in the art.

[0285] In embodiments, the IIDL-derived nanoparticle ranges from about 5 nm to about 400 nm in diameter, including about 5 nm, about 6 nm, about 7 nm, about 8 nm, about 9 nm, about 10 nm, about 11 nm, about 12 nm, about 13 nm, about 14 nm, about 15 nm, about 16 nm, about 17 nm, about 18 nm, about 19 nm, about 20 nm, about 21 nm, about 22 nm, about 23 nm, about 24, about 25 nm, about 26 nm, about 27 nm, about 28 nm, about 29, about 30 nm, about 31 nm, about 32 nm, about 33 nm, about 34, about 35 nm, about 36 nm, about 37 nm, about 38 nm, about 39, about 40 nm, about 41 nm, about 42 nm, about 43 nm, about 44 nm, about 45 nm, about 46 nm, about 47 nm, about 48 nm, about 49 nm, about 50 nm, about 51 nm, about 52 nm, about 53 nm, about 54 nm, about 55 nm, about 56 nm, about 57 nm, about 58 nm, about 59 nm, about 60 nm, about 61 nm, about 62 nm, about 63 nm, about 64, about 65 nm, about 66 nm, about 67 nm, about 68 nm, about 69 nm, about 70 nm, about 71 nm, about 72 nm, about 73 nm, about 74 nm, about 75 nm, about 76 nm, about 77 nm, about 78 nm, about 79 nm, about 80 nm, about 81 nm, about 82 nm, about 83 nm, about 84 nm, about 85 nm, about 86 nm, about 87 nm, about 88 nm, about 89, about 90 nm, about 91 nm, about 92 nm, about 93 nm, about 94, about 95 nm, about 96 nm, about 97 nm, about 98 nm, about 99 nm, about 100 nm, about 101 nm, about 102 nm, about 103 nm, about 104 nm, about 105 nm, about 106 nm, about 107 nm, about 108 nm, about 109 nm, about HO nm, about 111 nm, about 112 nm, about 1 13 nm, about 114 nm, about 115 nm, about 116 nm, about 117 nm, about 118 nm, about 1 19 nm, about 120 nm, about 121 nm, about 122 nm, about 123 nm, about 124 nm, about 125 nm, about 126 nm, about 127 nm, about 128 nm, about 129 nm, about 130 nm, about 131 nm, about 132 nm, about 133 nm, about 134 nm, about 135 nm, about 136 nm, about 137 nm, about 138 nm, about 139 nm, about 140 nm, about 141 nm, about 142 nm, about 143 nm, about 144 nm, about 145 nm, about 146 nm, about 147 nm, about 148 nm, about 149 nm, about 150 nm, about 160 nm, about 170 nm, about 180 nm, about 190 nm, about 200 nm, about 210 nm, about 220 nm, about 230 nm, about 240 nm, about 250 nm, about 260 nm, about 270 nm, about 280 nm, about 290 nm, about 300 nm, about 310 nm, about 320 nm, about 330 nm, about 340 nm, about 350 nm, about 360 nm, about 370 nm, about 380 nm, about 390 nm, to about 400 nm including all ranges and values therebetween. In embodiments of the HDL- derived nanoparticles provided herein, the HDL-derived nanoparticle is about, 5 nm to about 30nm in diameter, 5 nm to about 150 nm in diameter, about 20 nm to about 150 nm in diameter, about 15 nm to about 250 nm in diameter, or about 30 nm to about 100 nm in diameter. In embodiments of the HDL-derived nanoparticles provided herein, the HDL-derived nanoparticle is about 20 nm to about 100 nm in diameter. In embodiments of the HDL-derived nanoparticles provided herein, the HDL-derived nanoparticle is about 25 nm to about 60 nm in diameter. In embodiments, the HDL-derived nanoparticle diameters are measured by dynamic light scattering (DLS).

[0286] In embodiments, the HDL-derived nanoparticle diameters are measured by (cryo) TEM measurements.

[0287] In embodiments, the HDL-derived nanoparticles of the present disclosure are spherical or close to spherical. In embodiments the HDL-derived nanoparticle morphology is visualized by (cryo)-transmission electron microscopy (TEM).

[0288] In embodiments of the HDL-derived nanoparticle of the present disclosure may comprise cholesterol. Typically, the HDL-derived nanoparticle comprises from about 1 mol% to about 100 mol% of cholesterol relative to lipid, including about 1% mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol %, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, about 55 mol%, about 60 mol%, about 65 mol%, about 70 mol%, about 75 mol%, about 80 mol%, about 85 mol%, about 90 mol%, about 95 mol%, to about 100 mol% (i.e. 1:1 mol / mol mixture of cholesterol and lipid (e.g. phospholipid and / or lysophospholipid) including all ranges and values therebetween. In embodiments, the HDL-derived nanoparticle comprises from about 1 mol% to about 30 mol% cholesterol. In embodiments, the HDL-derived nanoparticle comprises from about 15 mol% to about 25 mol% cholesterol. In embodiments, the HDL-derived nanoparticle comprises about 20 mol% cholesterol. In embodiments, the HDL -derived nanoparticle comprises from about 10 mol% to about 35 mol% cholesterol. In embodiments, the HDL-derived nanoparticle comprises from about 15 mol% to about 30 mol% cholesterol.I l l

[0289] In embodiments, the HDL-derived nanoparticle is cholesterol free.

[0290] In embodiments, the molar ratio of cholesterol: lipid (e.g., phospholipid and / or lysophospholipid), in the HDL-derived nanoparticle is about 0: 1 , about 0.025: 1 , about 0.05: 1 , about 0.075: 1, about 0.1 : 1 , about 0.125: 1, about 0.15: 1, about 0.175: 1, about 0.2: 1 , about 0.225: 1, about 0.25: 1, about 0.275: 1, about 0.3: 1, about 0.325: 1, about 0.35: 1, about 0.375: 1, about 0.4: 1, about 0.425: 1, about 0.45: 1, about 0.475: 1 or about 0.5: 1, including all values therebetween. In embodiments, the molar ratio of cholesterol: lipid (e.g., phospholipid and / or lysophospholipid), ranges from about 0: 1 to about 0.5: 1, including about 0: 1, about 0.025: 1, about O.05: 1, about 0.075: L about O. l: 1, about 0.125: l, about 0.15: 1, about 0.175: l, about 0.2: 1, about 0.225: 1, about 0.25: 1, about 0.275: 1, about 0.3: I, about 0.325: 1, about 0.35: 1, about 0.375: 1, about 0.4: 1, about 0.425: 1, about 0.45: 1, about 0.475:1 to about 0.5: 1, including all ranges therebetween. In embodiments, the molar ratio of cholesterol: lipid (e.g., phospholipid and / or lysophospholipid), ranges from about 0.05: 1 to about 0.25: 1. In embodiments, the molar ratio of cholesterol is about 0.2: 1.

[0291] In embodiments, the HDL-derived nanoparticle comprises one or more phospholipids and / or iysophospholipids and cholesterol in a molar ratio in the range of about 1:0.05 to about 1 :0.25. In embodiments, the HDL-derived nanoparticle comprises one or more phospholipids and / or Iysophospholipids and cholesterol in a molar ratio of about 1 : 0.2.

[0292] In embodiments, the weight percentage of cholesterol ranges from about 0% (w / w) to about 15% (w / w) of the nanoparticle, lipid, or composition, including from about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w7w), about 5% (w7w), about 5.5% (w / w), about 6% (w / w), about 6.5% (w / w), about 7% (w / w), about 7.5% (w / w), about 8% (w / w), about 8.5% (w / w), about 9% (w / w), about 9.5% (w / w), about 10% (w / w), about 10.5% (w / w), about 11% (w / w7), about 11.5% (w / w), about 12% (w / w), about 12.5% (w / w), about 13% (w / w), about 13.5% (w / w), about 14% (w / w), about 14.5% (w / w), to about 15% (w / w). In embodiments, the weight percentage of cholesterol ranges from about 0% (w / w) to about 15%, (w / w) of the nanoparticle, lipid, or composition, including from about 1 % (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w),about 6% (w / w), about 6.5% (w / w), about 7% (w / w), about 7.5% (w / w), about 8% (w / w), about 8.5% (w / w), about 9% (w / w), about 9.5% (w / w), about 10% (w / w), about 10.5% (w / w), about 11% (w / w / ), about 11.5% (w / w), about 12% (w7w), about 12.5% (w / w), about 13% (w7w), about 13.5% (w / w), about 14% (w / w), about 14.5% (w / w), to about 15% (w / w). In embodiments, the weight percentage is the weight percentage of cholesterol relative to lipid (e.g., phospholipid and / or lysophosphohpid). In embodiments, the weight percentage of cholesterol ranges from about 1 to 10% cholesterol (w / w%) of the composition, the weight percentage of cholesterol ranges from about 2 to 8% cholesterol (w / w%) of the composition. In embodiments, the weight percentage of cholesterol ranges from about 3.5 to 7.5% cholesterol (w7w%) of the composition. In embodiments, the weight percentage of cholesterol ranges from about 5 to 10% cholesterol (w / w%) of the composition. In embodiments, the weight percentage of cholesterol is about 3.6(w / w’%) of the composition. In embodiments, the weight percentage of cholesterol is about 7.2(w / w%) of the composition. In embodiments, the weight percentage of cholesterol is about 5.9(w / w%) of the composition.

[0293] In embodiments, the HDL-derived nanoparticle comprises from about a 5: 1 to 1000:1 ratio (e.g., on a molar basis) of lipid (e.g., phospholipid and / or lysophosphohpid): apoA-I or a mimetic of apoA-I, including about 5: 1, about 10: 1, about 20:1, about 30: 1, about 40:1, about 50: 1, about 60: 1, about 70:1, about 80:1, about 90:1, about 100: 1, about 110: 1, about 120: 1, about 130: 1, about 140: 1 , about 150: 1 , about 160: 1 , about 170: 1 , about 180: 1 , about 190: 1 , about 200: 1 , about 210: 1, about 220: 1 about 230:1, about 240:1, about 250: 1, about 260: 1, about 270: 1, about 280: 1, about 290: 1, about 300: 1, about 310: l, about 320: l, about 330:1, about 340: 1, about 350: l, about 360: 1, about 370: 1, about 380:1, about 390:1, about 400: 1, about 410:1 , about 420: 1 , about 430: 1 , about 440: 1 , about 450: 1, about 460: 1 , about 470: 1 , about 480: 1, about 490: 1 , about 500: 1, about 510: 1 , about 520: 1, about 530:1, about 540: 1, about 550: 1, about 560:1, about 570:1 , about 580: 1 , about 590: 1 , about 600: 1, about 610: 1 , about 620: 1 , about 630: 1, about 640: 1 , about 650: 1 , about 660:1, about 670: 1, about 680: 1, about 690: 1 , about 700:1 , about 710:1, about 720: 1 about 730: 1 , about 740: 1 , about 750: 1 , about 760: 1 , about 770: 1 , about 780: 1 , about 790: 1 , about 800: 1 , about 810:1, about 820:1, about 830:1, about 840: 1, about 850: 1, about 860:1 , about 870: 1 , about 880: 1 , about 890:1, about 900: 1, about 910: 1 , about 920:1, about 930:1, about 940: 1 , about 950:1, about 960:1, about 970: 1, about 980: 1, about 990: 1 , to about 1000: 1, including all subranges andvalues therebetween. In embodiments, the HDL-derived nanoparticle comprises from about a 10: 1 to 1000:1 ratio (e.g., on a molar basis) of lipids (e.g., phospholipid and / or lysophospholipid): apoA-I or a mimetic of apoA-I. In embodiments, the HDL-derived the nanoparticle comprises from about a 70: 1 to 125:1 ratio (e.g., on a molar basis) of lipid (e.g., phospholipid and / or lysophospholipid): apoA-I. In embodiments, the HDL-derived the nanoparticle comprises from about a 5:1 to 10: 1 ratio (e.g., on a molar basis) of mimetic of apoA-I.

[0294] In embodiments, the HDL-derived nanoparticle comprises from about a 2: 1 to 3 : 1 ratio by weight of lipid (e.g., phospholipid and / or lysophospholipid): apoA-I or a mimetic of apoA- I.

[0295] In embodiments, the HDL-derived nanoparticle comprises apolipoprotein A-l: lipid (e.g., phospholipid and / or lysophospholipid) ranges from about 5% to about 250% weight percent, including about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, to about 250% weight percent, including all values and subranges therebetween.

[0296] In embodiments, the HDL-derived nanoparticle comprises triglycerides (e.g., tricaprylin): lipid (e.g., phospholipid and / or lysophospholipid) in an amount ranging from 0% to about 1000% weight percent, including 0%, about 25%, about 50%, about 75%, about 100%, about 125%, about 150%, about 175%, about 200%, about 225%, about 250%, about 275%, about 300%, about 325%, about 350%, about 375%, about 400%, about 425%, about 450%, about 475%, about 500%, about 525%, about 550%, 575%, about 600%, about 625%, about 650%, about 675%, about 700%, about 725%, about 750%, about 775%, about 800%, about 825%, about 850%, about 875%, about 900%, about 925%, about 950%, about 975% to about 1000%, including all values and subranges therebetween.

[0297] In embodiments, the HDL-derived nanoparticle comprises from about, or at least about 1 :0 w / w to 10: 1 w / w of a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (I-B-l), (l -B-2). (I-C), (I-C-A), (I-C-B), (II), (11-2), (II- A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G). (II-H), (III), (III-2), (III-A), (III-B), (III-C), (IV), (IV-2), (IV- A ), (V), (V-2), (V-A), (VI), (VI-2), (VI-A), Table 2, or Table 1). relative to triglycerides including aboutl : 0, about 1: 1, about 2:1, about 3: 1, about 4: 1, about 5:1, about 6: 1, about 7:1, about 8:1, about 9: 1, to about 10: 1.

[0298] In embodiments, the HDL-derived nanoparticle comprises from about, or at least about 1 :0 w / w to 10: 1 w / w of a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (1-B-l), (l-B-2), (I-C), (I-C-A), (I-C-B), (II), (II- A), (II-B), (III), (III-A), (IV), (IV- A), (V), (V-A), (VI), or (VI-A) or Table 1) relative to triglycerides including aboutl: 0, about 1:1, about 2: 1, about 3:1, about 4: 1, about 5:1, about 6: 1, about 7: 1, about 8:1, about 9: 1, to about 10: 1.

[0299] In embodiments, the HDL-derived nanoparticle comprises from about, or at least about 1 :0 w / w to 10:1 w / w of a compound of the present disclosure (e.g., a compound ofFormula (I), (I- A), (I-B), (I-B-l), (l-B-2), (I-C), (I-C-A), (I-C-B), (II-2), (II- A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (HI-2), (III-A), (III-B), (III-C), (IV-2), (I V- A), (V-2), (V-A), (VI-2), (VI-A), or Table 2). relative to triglycerides including aboutl : 0, about 1: 1, about 2:1, about 3:1, about 4:1, about 5: 1, about 6:1, about 7: 1, about 8:1, about 9:1, to about 10:1.

[0300] In embodiments, the HDL-derived nanoparticle comprises from about, or at least about 0.1 mol% to about 100 niol% of a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (I-B-l), (l-B-2), (I-C), (I-C-A), (I-C-B), (II), (II-2), (II- A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (III), (111-2). (III-A), (III-B), (III-C), (IV), (IV-2), (IV-A), (V), (V-2), (V-A), (VI), (VI-2), (VI-A), Table 2, or Table 1). relative to lipid (e.g., phospholipid and / or lysophospholipid) including about, or at least about 0,1 mol%, about or at least about 0.5 mol%, about or at least about 0.75 mol%, about, or at least about 1% mol%, about, or at least about 2 mol%, about, or at least about 3 mol%, about, or at least about 4 mol%, about, or at least about 5 mol%, about, or at least about 6 mol%, about, or at least about 7 mol%, about, or at least about 8 mol%, about, or at least about 9 mol%, about, or at least about 10 mol %, about, or at least about11 mol%, about, or at least about 12 mol%, about, or at least about 13 mol%, about, or at least about 14 mol%, about, or at least about 15 mol%, about, or at least about 16 mol%, about, or at least about 17 mol%, about, or at least about 18 mol%, about, or at least about 19 mol%, about, or at least about 20 mol%, about, or at least about 21 mol%, about, or at least about 22 mol%, about, or at least about 23 mol%, about, or at least about 24 mol%, about, or at least about 25 mol%, about, or at least about 26 mol%, about, or at least about 27 mol%, about, or at least about 28 mol%, about, or at least about 29 mol%, to about, at least about 30 mol%, about or at least about or at least about 35 mol%, about or at least about 40 mol%, about or at least about 45 mol%, about or at least about 50 mol%, about or at least about 55 mol%, about or at least about 60 mol%, about or at least about 65 mol%, about or at least about 70 mol%, about or at least about 75 mol%, about or at least about 80 mol%, about or at least about 85 mol%, about or at least about 90 niol%, about or at least about 95 mol%, to about or at least about 100 niol% (1:1 mol / mol mixture of compound and lipid (e.g., phospholipid and / or lysophospholipid)) including all ranges and values therebetween. In embodiments, the HDL-derived nanoparticle comprises from about 10 mol% to about 30 mol% of a compound of the present disclosure (e.g., a compound Formula (I), (LA), (I-B), (LB-1), (LB-2), (I-C), (LC-A), (LC-B), (II), (IL 2), (ILA), (ILB), (ILC), (II-D), (ILE), (ILF), (II-G), (ILH), (III), (IIL2), (IILA), (IILB), (IILC), (IV), (IV-2), (IV-A), (V), (V-2), (V-A), (AT), (VL2), (VLA), Table 2, or Table 1 ). In embodiments, the HDL-derived nanoparticle comprises from about 12 mol% to about 25 mol% a compound of the present disclosure (e.g., a compound of Formula (I), (LA), (LB), (LB-1), (LB-2), (I-C), (I-C-A), (LC-B), (II), ( 11 -2), (ILA), (ILB), (II-C), (ILD), (ILE), (ILF), (ILG), (ILH), (III), (III-2), (IILA), (IILB), (IILC), (IV), (IV-2), (IV-A), (V), (V-2), (V-A). (VI), (AT -2), (VLA), Table 2, or Table 1).

[0301] In embodiments, the HDL-derived nanoparticle comprises from about, or at least about 0.1 mol% to about 100 mol% of a compound of the present disclosure (e.g., a compound of Formula (I), (LA), (LB), (LB-1 ), (LB-2), (I-C), (LC-A), (LC-B), (II), (ILA), (ILB), (III), (III-A), (IV), (IV- A), (V), (V-A), (VI), or (VLA) or Table 1) relative to lipid (e.g., phospholipid and / or lysophospholipid) including about, or at least about 0.1 mol%, about or at least about 0.5 mo1%, about or at least about 0.75 mol%, about, or at least about 1% mol%, about, or at least about 2 mol%, about, or at least about 3 mol%, about, or at least about 4 mol%, about, or at least about 5 mol%, about, or at least about 6 mol%, about, or at least about 7 mol%, about, or at least about 8mol%, about, or at least about 9 mol%, about, or at least about 10 mol %, about, or at least about 11 mol%, about, or at least about 12 mol%, about, or at least about 13 mol%, about, or at least about 14 mol%, about, or at least about 15 mol%, about, or at least about 16 mol%, about, or at least about 17 mol%, about, or at least about 18 mol%, about, or at least about 19 mol%, about, or at least about 20 mol%, about, or at least about 21 mol%, about, or at least about 22 mol%, about, or at least about 23 mol%, about, or at least about 24 mol%, about, or at least about 25 mol%, about, or at least about 26 mol%, about, or at least about 27 mol%, about, or at least about 28 mol%, about, or at least about 29 mol%, to about, at least about 30 mol%, about or at least about or at least about 35 moi%, about or at least about 40 mol%, about or at least about 45 mol%, about or at least about 50 mol%, about or at least about 55 moi%, about or at least about 60 mol%, about or at least about 65 moi%, about or at least about 70 mol%, about or at least about 75 moi%, about or at least about 80 mol%, about or at least about 85 moi%, about or at least about 90 mol%, about or at least about 95 mol%, to about or at least about 100 mol% (1:1 mol / mol mixture of compound and lipid (e.g., phospholipid and / or lysophospholipid)) including all ranges and values therebetween. In embodiments, the HDL-derived nanoparticle comprises from about 10 mol% to about 30 mol% of a compound of the present disclosure (e.g., a compound of Formula (I), (I- A), (I-B), (1-B-l), (LB-2), (LC), (LC-A), (I-C-B), (II), (ILA), (II-B), (III), (III-A), (IV), (IV-A), (V), (V-A), (VI), or (VI-A)or Table 1). In embodiments, the HDL-derived nanoparticle comprises from about 12 mol% to about 25 mol% a compound of the present disclosure (e.g., a compound of Formula (I), (LA), (LB), (1-B-l), (LB-2), (LC), (LC-A), (LC-B), (II), (ILA), (II-B), (III), (III- A), (IV), (IV-A), (V), (V-A), (VI), or (VLA) or Table 1).

[0302] In embodiments, the HDL-derived nanoparticle comprises from about, or at least about 0. 1 mol% to about 100 mol% of a compound of the present disclosure (e.g., a compound of Formula (I), (LA), (LB), (LB-1), (LB-2), (LC), (LC-A), (I-C-B), (IL2), (ILA), (II-B), (ILC), (II- D), (ILE), (ILF), (ILG), (ILH), (III-2), (III-A), (III-B), (III-C), (IV-2), (IV-A), (V-2), (V-A), (VI- 2), (VLA), or Table 2). relative to lipid (e.g., phospholipid and / or lysophospholipid) including about, or at least about 0.1 mol%, about or at least about 0.5 mol%, about or at least about 0.75 mol%, about, or at least about 1% mol%, about, or at least about 2 mol%, about, or at least about 3 mol%, about, or at least about 4 mol%, about, or at least about 5 mol%, about, or at least about 6 mol%, about, or at least about 7 mol%, about, or at least about 8 mol%, about, or at least about9 mol%, about, or at least about 10 mol %, about, or at least about I I mol%, about, or at least about 12 mol%, about, or at least about 13 moi%, about, or at least about 14 mol%, about, or at least about 15 mol%, about, or at least about 16 moi%, about, or at least about 17 mol%, about, or at least about 18 mol%, about, or at least about 19 mol%, about, or at least about 20 mol%, about, or at least about 21 mol%, about, or at least about 22 moi%, about, or at least about 23 mol%, about, or at least about 24 mol%, about, or at least about 25 mol%, about, or at least about 26 mol%, about, or at least about 27 mol%, about, or at least about 28 mol%, about, or at least about 29 mol%, to about, at least about 30 mol%, about or at least about or at least about 35 mol%, about or at least about 40 moi%, about or at least about 45 mol%, about or at least about 50 moi%, about or at least about 55 mol%, about or at least about 60 moi%, about or at least about 65 mol%, about or at least about 70 moi%, about or at least about 75 mol%, about or at least about 80 moi%, about or at least about 85 mol%, about or at least about 90 mol%, about or at least about 95 mol%, to about or at least about 100 mol% (1:1 mol / mol mixture of compound and lipid (e.g., phospholipid and / or lysophospholipid)) including all ranges and values therebetween. In embodiments, the HDL-derived nanoparticle comprises from about 10 niol% to about 30 mol% of a compound of the present disclosure (e.g., a compound of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), ( II -2 ), (II- A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (III-2), (III-A), (III-B), (III-C), (IV-2), (IV- A), (V-2), (V-A), (VI-2), (VI- A), or Table 2). In embodiments, the HDL- derived nanoparticle comprises from about 12 mol% to about 25 mol% a compound of the present disclosure (e.g., a compound of Formula (I), (I-A), (I-B), (I-B-l), (I-B-2), (I-C), (I-C-A), (I-C-B), (11-2), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), ( II 1-2 ), (III-A), (III-B), (III-C), (IV- 2), (IV-A), (V-2), (V-A), (VI-2), (VI-A), or Table 2).

[0303] Stability of the HDL-derived nanoparticle can be assessed by performing DLS measurements. In embodiments, the HDL-derived nanoparticle is stable for at least about 1 week, or at least about 2 weeks, or at least about 5 weeks e.g., by DLS.

[0304] In embodiments, the nanobiologic composition inhibits aspects of the innate immune response in a subject in need thereof. In embodiments, the response is inhibited for at least about 7 to about 30 days. In embodiments, the response is inhibited for at least 30 to 100 days. In embodiments, the response is inhibited for more than 100 days and up to 3 years. In embodiments.the nanobiologic composition is administered once and wherein the response is inhibited for at least 30 days. In embodiments, the nanobiologic composition is administered at least once per day in each day of a multiple-dosing regimen, and wherein the response is inhibited for at least 30 days. In embodiments, the subject has a stimulated innate immune response, prior to administration, due to an existing disease or disorder, or other medical conditions, such as a transplant. Such stimulated immune responses are deemed hyper-responsive relative to a desired level of immune response and the compositions disclosed herein have useful effects in reducing the hyper-responsive condition, restoring a desired level of immune response. Typically, the elevated response has an inflammation component.

[0305] Production methods can prepare uniform size HDL-derived nanoparticles, or a non-uniform sized mixture of HDL-derived nanoparticles, either by not filtering, or by preparing a range of different sized HDL-derived nanoparticles and re-combining them in a post-production step. The larger the size of the HDL-derived nanoparticles, the more drug can be incorporated. However, larger sizes e.g. >120 nm, can limit, prevent or slow diffusion of the HDL-derived nanoparticles into the tissues of the patient being treated. Smaller HDL-derived nanoparticles do not hold as much drug per particle, but are able to access the bone marrow, blood, or spleen, or other localized tissue or cells affected by trained immunity, e.g. myeloid cells, myeloid progenitor cells, and hematopoietic stem cells in the bone marrow, blood and / or spleen, and so forth (biodistribution). Using a non-uniform mixture of nanoparticles sizes in a single administration or regimen can produce an immediate reduction in activity of cells that regulate the innate immune system, and simultaneously produce a durable, long-term reduction in innate immune activity (e.g. dampening of inflammation) that can last days, weeks, months, and years, wherein the nanoparticle has reversed, modified, or reregulated pathways of one or mnore hematopoietic stem cells (HSC) types, the common myeloid progenitors (CMP), or the myeloid cells such as monocytes, macrophages and other short-lived circulating cells.

[0306] In embodiments, the maximum loading capacity of the HDL-derived nanoparticle can be determined dividing the volume of the interior of the HDL -derived nanoparticle by the volume of a drug-load spheroid.

[0307] Particle: assume a lOOnm spherical particle having 2.2 nm-3.0 nm phospholipid wall, yielding a 94 nm diameter interior with volume (L) @ 4 / 3n(r)3.

[0308] Drug: assume STIMULATOR at 12x12x35 Angstrom or as a cylinder 1 .2x1.2x3.5 nm, where multiple drug molecule cylinders, e.g. seven or nine, etc. could assume a 3.5nm diameter spheroid having a radius of 1 ,75nm Vol(small) @ 4 / 3n(r)3.

[0309] Maximum Loading Capacity (calc): -487k 3.5 nm spheroids within a lOOnm particle.

[0310] When employed as pharmaceuticals, the compounds and HDL-derived nanoparticles of the present disclosure can be administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. In embodiments, the pharmaceutical composition is a nanobiologic composition of the present disclosure, comprising a nanoparticle and a pharmaceutically acceptable carrier.

[0311] Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound 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 actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0312] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, intraocular, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, directly into cerebrospinal fluid, intratracheal, and intranasal. Depending on the intended route of deliver}', the compounds of this invention are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration. In embodiments, the composition is administered intravenously or intraarterially. In embodiments, the composition is for pulmonary delivery (e.g., inhaled as an aersol).

[0313] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. 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. 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. In such compositions, a compound as described herein is usually a minor component (from about 0.1 to about 50% by weight or preferably from about I to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0314] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0315] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0316] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0,01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0317] Nanoparticles described herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0318] The above-described components for orally administrable, injectable or topically admmistrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17ihedi tion, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0319] For injection, nanoparticles described herein can be provided in an injection grade saline solution, in the form of an injectable liposome solution, slow-release polymer system or the like.

[0320] Nanoparticles described herein can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0321] Therapeutic Use

[0322] Provided herein are methods of treating a subject susceptible to or afflicted with immune-related diseases and conditions, including, for example, prophylaxis of organ or tissue rejection and other conditions caused by defective trained immunity.

[0323] In embodiments, the compounds and compositions of the present disclosure maybe used to treat or prevent a disease or condition, treat a subject suffering from a disease or condition, or treat the symptoms of a disease or condition, selected from organ or tissue transplant rejection, autoimmune and inflammatory diseases and cardiovascular diseases.199

[0324] Transplanted organ or tissue include but are not limited to heart transplant, kidney transplant, liver transplant, retinal transplant, corneal transplant, skin transplant, pancreatic transplant, intestinal transplant, genital transplant, ovary transplant, tendon transplant, bone marrow transplant, or vascular tissue transplant.

[0325] Autoimmune and inflammatory diseases include but are not limited to arthritis, inflammatory bowel disease including Crohn’s disease and ulcerative colitis, diabetes e.g., type I and type II diabetes, coeliac disease, hidradenitis suppurativa, multiple sclerosis, thyroiditis, Grave's disease, systemic lupus erythematosus, scleroderma, psoriasis, rheumatoid arthritis, alopecia areata, ankylosing spondylitis, Churg-Strauss Syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, dermatomyositis, glomerulonephritis, Guillain-Barre syndrome, irritable bowel syndrome (IBS), lupus nephritis, myasthenia gravis, myocarditis, pemphigus / pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, rheumatic fever, sarcoidosis, Sjogren's syndrome, uveitis, vitiligo, Parkinson’s disease, Alzheimer’s disease, non-alcoholic steatohepatitis, and Wegener's granulomatosis.

[0326] Cardiovascular diseases include but are not limited to angina pectoris, atherosclerotic conditions (such as coronary atherosclerosis, diabetic atherosclerosis), stroke, stenosis, restenosis, hypertension, heart failure, left ventricular hypertrophy, acute coronary’ syndrome, transient ischemic attack, impaired circulation, heart disease, intermittent claudication, myocardial ischemia, cholesterol and plaque formation, ischemia, ischemia reperfusion injury, peripheral vascular disease, cardiac disease, cardiopulmonary' resuscitation, kidney’ failure, thrombosis (e.g., venous thrombosis, deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, arterial thrombosis etc., thrombus formation, thrombotic event or complication, Budd-Chiari syndrome, Paget-Schroetter disease, coronary artery disease, need for coronary’ revascularization, peripheral artery’ disease, a pulmonary circulatory disease, pulmonary embolism, a cerebrovascular disease, cellular proliferation and endothelial dysfunction, graft occlusion or failure, need for or an adverse clinical outcome after peripheral bypass graft surgery', need for or an adverse clinical outcome after coronary’ artery’ graft failure, vein graft failure, autologous vein grafts, vein graft occlusion, ischemic diseases, intravascular coagulation, cerebrovascular disease or any other cardiovasculardisease related to obesity or an overweight condition or myocardial infarction or combinations thereof.

[0327] In embodiments, the compounds and compositions of the present disclosure may be used to treat a patient who is suffering from cytokine storm syndrome, or acute respiratory distress syndrome e.g., associated with direct lung injury or indirect lung injury. Examples of direct lung injury include pneumonia, aspiration (inhalation of stomach contents into the lungs), inhalation of toxic substances, bruising of the lungs caused by chest trauma, fat embolism (when a clot of fat enters the pulmonary circulation) and lung transplantation. Direct lung injury can also be caused by infections with: viruses including but not limited to SARS-CoV-2 (the coronavirus that causes COVID-19), influenza A / B / C viruses, respiratory syncytial virus (RSV) and human metapneumovirus; bacteria including but not limited to Streptococcus pneumoniae, Staphylococcus aureus, Legionella, Mycoplasma and Chlamydia spp: fungi including but not limited to Aspergillus, Histoplasnia spp. Conditions that cause indirect lung injury’ include sepsis, severe trauma to the body, massive blood transfusion, pancreatitis (inflammation of the pancreas), cardiopulmonary' bypass (heart- lung bypass surgery), or drug overdose.

[0328] In embodiments, provided herein is a method for prophylaxis of organ or tissue rejection in a patient in need thereof, comprising administering a compound of the present disclosure or the composition of the present disclosure.

[0329] In embodiments, provided herein is a method for inducing transplant tolerance in a patient in need thereof, comprising administering a compound of the present disclosure or the composition of the present disclosure.

[0330] In embodiments of the methods of the present disclosure, the patient has undergone an organ or tissue transplant, and the transplanted tissue is lung tissue, heart tissue, kidney tissue, liver tissue, -retinal tissue, corneal tissue, skin tissue, pancreatic tissue, intestinal tissue, genital tissue, ovary? tissue, bone tissue, tendon tissue, bone marrow, or vascular tissue.

[0331] In embodiments of the methods of the present disclosure, the transplanted tissue is an intact organ.

[0332] In embodiments of the methods of the present disclosure, the organ or tissue transplant is an allogeneic tissue or organ transplant.

[0333] In embodiments of the methods of the present disclosure, the compound or composition is for administration prior to performance of an allogeneic tissue or organ transplant.

[0334] In embodiments of the methods of the present disclosure, the compound or composition is for administration in conjunction with an allogeneic tissue or organ transplant.

[0335] In embodiments of the methods of the present disclosure, the compound or composition is for administration within at least two weeks after an allogeneic tissue or organ transplant.

[0336] In embodiments of the methods of the present disclosure, the method further comprises administering to the patient one or more immunosuppressant agents.

[0337] In embodiments of the methods of the present disclosure, the immunosuppressant agent is cyclosporine A or FK506.[0033S] In embodiments of the methods of the present disclosure, the composition is administered intravenously or intra-arterially.NUMBERED EMBODIMENTS1. A compound of Formula (I):(I) or a pharmaceutically acceptable salt thereof, wherein:R!is -heterocyclyl-L;R2is C2-3 alkylene;R is hydrogen, alkyl, aryl or alkenyl;Y is an -Cui 2 alkylene;L is alkyl, alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=:O)-W, --alkylene-N- (alkylene-C(=O)-NR5-alkylene-NR5-C(=O)-W)2, or --alkylene-N-(alkylene-C(=O)-W)2; andR5is independently hydrogen, or alkyl;W is alkyl, -O“alkylene-C(H)(OR6)-alkylene~OR7, or a sterol;R6and R7are each independently R8or -C(=O)-R8; andR8is alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyclyl is optionally substituted. The compound of embodiment 1, wherein the compound is of Formula (I- A):(I-A) or a pharmaceutically acceptable salt thereof. The compound of embodiment 1 or 2, wherein R!is -heteroaryl-L.The compound of any one of embodiments 1 -3. wherein each alkyl, alkylene, alkenyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more RAsubstituents; wherein RAis independently selected for each occurrence from the group consisting of hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(RC)(RD), -C(O)N(Rc)(R°), - N(RC)C(O)RB, -OC(O)NRCRD, -NRCC(O)ORB, -OC(O)RB, -C(O)ORB, -C(O)RB, -CO I L -NO2, -SH, S(O)xRB, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and RB;Rcand Ri Jare independently selected for each occurrence from the group consisting of hydrogen, alkyl, haloalkyl -C(O)RB, and ~C(O)ORB; or Rcand RDare taken together with the nitrogen to which they are attached to form a heterocyclic ring optionally substituted with RA;RBis alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro; and x is 0, 1, or 2.The compound of any one of embodiments 1-4, wherein the compound is of Formula (I-B):(I-B) or a pharmaceutically acceptable salt thereof wherein:X1is -IN- and Xzis -C-; or X1is -C- and X2is -N-. The compound of embodiment 5, wherein the compound is of Formula (I-C):(I-C) or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 1 -6, wherein the compound is of Formula (I- C-A):(l-C-A) or a pharmaceutically acceptable salt thereof.The compound of any one of embodiments 1-6, wherein the compound is of Formula (I-(I-C-B): or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 1 -8, wherein R2is a -C2alkylene. The compound of any one of embodiments 1-8, wherein R2is -CH2CH2-. The compound of any one of embodiments 1-10, wherein R3is Ci-ealkyl or hydrogen. The compound of embodiment 11, wherein R3is H. The compound of embodiment 11, wherein R3is -CH3. The compound of any one of embodiments 1 -13, wherein Y is Ci-salkylene. The compound of embodiment 14, wherein Y is -CII2- or -CH2CH2CH2-. The compound of any one of embodiments 1-15, wherein L is alkyl, -alkylene-C(=O)-W, or -alkylene-O-C(=O)-W. The compound of any one of embodiments 1 -16, wherein L is -Ci2-24alkyl. The compound of embodiment 17, wherein L is -CH2(CH2CH2)s-CH,3. The compound of any one of embodiments 1-16, wherein L is -alkylene-O-C(=O)-W.The compound of embodiment 19, wherein L is -Cialkylene-O-C(=O)-W.The compound of embodiment 20, wherein L is -CH2-O-C(:::O)-W.The compound of any one of embodiments 1 -16, wherein L is -Ci-6alkylene-C(:::O)-W.The compound of embodiment 22, wherein L. is -Cialk.ylene-C(=O)-W.The compound of embodiment 23, wherein L is -CH2-C(=O)-W.The compound of any one of embodiments 1-24, wherein W is a sterol.The compound of embodiment 25, wherein the sterol is:wherein R8and R8’ is each independently -Cs-soalkyl.The compound of embodiment 27, wherein R8and R8is each independently a -Cs-2oalkyl.The compound of embodiment 27, wherein R8and R8are both -(CH2CH2)s-CH3.The compound of embodiment 27, wherein R8and R8' are both -(CH2CH2)s-CH3The compound of any one of embodiments 1 -30, wherein the compound isor a pharmaceutically acceptable salt thereof, wherein:R2is C2-6 alkylene;R-’ is hydrogen, alkyl, aryl or alkenyl;Y is an -C1-6 alkylene or absent;R1is -C(==O)-W or W; andW is C6-C30 alkyl or a sterol; wherein each aforementioned alkyl, alkylene, aryl, and alkenyl is optionally substituted. The compound of embodiment 32, wherein R2is C2-4 alkylene. The compound of embodiment 32 or 33, wherein the compound is a compound of Formula (11- A):or a pharmaceutically acceptable salt thereof wherein n is 2 or 3. The compound of any one of embodiments 32-34, the compound is a compound of Formula(n-B):(II-B) or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 32-35, wherein R3is Ci-salkyl or hydrogen. The compound of embodiment 36, wherein R3is H. The compound of embodiment 36, wherein R3is -CHa. The compound of embodiment 36, wherein R3is --(CfeCHz^CfeCHs. The compound of embodiments 32-39, wherein R1is W. The compound of embodiment 40, wherein R1is Cs-Cis alkyl. The compound of embodiment 40 or 41, wherein R1is -Cs alkyl. The compound of embodiment 40 or 41, wherein Rlis -Cis alkyl. The compound of embodiment 42, wherein R!is ---(CH2CH2)3CH2CH3. The compound of embodiment 43, wherein R1is -(CHzCI-b^sCHzCI-b. The compound of any one of embodiments 32-39, wherein Rlis -C(=::O)-W. The compound of embodiment 46, wherein W is a sterol. The compound of embodiment 47, wherein the sterol is:s 32-45, wherein Y is absent. s 32-48, wherein ¥ is -CH?.. s 32-50, wherein the compound is:or a pharmaceutically acceptable salt thereof, wherein:RC!is H or -C(::::O)-RC3; andRc2and Rc" are each independently an optionally substituted Ci-soalkyl or Qcoalkenyl. The compound of embodiment 52, wherein the compound is of Formula (III-A):or a pharmaceutically acceptable salt thereof. The compound of embodiment 52 or 53, wherein RC2and R53are each independently an optionally substituted Cu-soalkyl or Cii-3oalkenyl.The compound of any one of embodiments 52-54, wherein RC2and RC3are each independently an Cn-nalkyL The compound of any one of embodiments 52-55, wherein RC2and RCjare the same. The compound of embodiment 56, wherein RC2and RCJare both Cn alkyl. The compound of any one of embodiments 52 or 53, wherein RC1is hydrogen and RC2is t-butyl,A compound selected from:or a pharmaceutically acceptable salt thereof; wherein:Rb’!is hydrogen, -C(=O)NRD4-alkyl or -C(=O)NRD4-alkenyl;RD2IS hydrogen, alkyl, aryl or alkenyl;alkyl;RD4is hydrogen, alkyl, aryl or alkenyl; wherein each aforementioned alkyl, aryl, and alkenyl is optionally substituted. The compound of embodiment 60, wherein the compound is of Formula (IV- A):or a pharmaceutically acceptable salt thereof. The compound of embodiment 60 or 61, wherein RD1is hydrogen or -C(=O)NRD4-alkyl , The compound of any one of embodiments 60-62, whereinHis hydrogen. The compound of any one of embodiments 60-62, wherein RD!is -C(=O)NRD4-alkyl. The compound of embodiment 64, wherein RD1is -C(=0)NH-Cs-3oalkyi. The compound of embodiment 65, wherein RD1is:The compound of any one of embodiments 60-66, wherein RD3is -C8-24alkyl. The compound of embodiment 67, wherein RDJis -Cisalkyl. The compound of any one of embodiments 60-64, wherein RDJis:The compound of any one of embodiments 60-69, wherein the compound is:or a pharmaceutically acceptable salt thereof; wherein:RE1is hydrogen or -C(-O)ORE3;RE2is -Cs-Cso alkyl or -Cs-Cso alkenyl;REJIS -Ce-Cso alkyl or -Ce-Cso alkenyl; wherein each aforementioned alkyl and alkenyl is optionally substituted.The compound of embodiment 71, wherein the compound is of Formula (V-A):(V-A) or a pharmaceutically acceptable salt thereof. The compound of embodiment 71 or 72, wherein Rklis hydrogen.erein Rfclis -C(=;O)ORE3. n REJis -Cs-24alky1. n RE3is -Cisalkyl. s 71-76, wherein RE2is -Cs-24alkyl. n RE2is -Cisalkyl. s 71-78, wherein the compound is:or a pharmaceutically acceptable salt thereof; wherein RF!is an optionally substituted Ce-aoalkyl or optionally substituted Csooalkenyl. The compound of embodiment 80, wherein the compound is of Formula (VI-A):or a pharmaceutically acceptable salt thereof. The compound of embodiment 80 or 81, wherein the compound is:A composition, comprising a high-density lipoprotein (HDL)-derived nanoparticle, wherein the nanoparticle comprises a compound of any one of embodiments 1-82. The composition of embodiment 83, wherein the HDL-derived nanoparticle comprises a phospholipid. The composition of embodiment 83 or 84, herein the HDL-derived nanoparticle comprises a lysophospholipid. The composition of embodiment 85, wherein the phospholipid and lysophospholipid are present in a weight ratio from about 2: 1 to about 4: 1 . The composition of any one of embodiments 83-86, wherein the phospholipid is selected from the group consisting of l,2-dimyristoyl-sn-glycero-3 -phosphatidylcholine (DMPC) and l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). The composition of any one of embodiments 83-87, wherein the lysophospholipid is selected from the group consisting of l-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), and 1 -palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC). The composition of any one of embodiments 83-88, wherein the HDL-derived nanoparticle comprises apoA-I or a peptide mimetic of apoA-I.The composition of any one of embodiments 83-89, wherein the HDL-derived nanoparticle further comprises one or more triglycerides, fatty acid esters, hydrophobic polymers, sterol esters, or combinations thereof. The composition of any one of embodiments 83-90, wherein the HDL-derived nanoparticle further comprises cholesterol. A pharmaceutical composition comprising a compound of any one of embodiments 1 -82 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method for prophylaxis of tissue rejection in a patient in need thereof, comprising administering a compound of any one of embodiments 1-82 or the composition of any one of claims 83-92. A method of inducing transplant tolerance in a patient comprising administering a compound of any one of embodiments 1-82 or the composition of any one of embodiments 83-92. The method of embodiment 93 or 94, wherein the patient has undergone an organ or tissue transplant and the transplanted tissue is lung tissue, heart tissue, kidney tissue, liver tissue, -retinal tissue, corneal tissue, skin tissue, pancreatic tissue, intestinal tissue, genital tissue, ovary tissue, bone tissue, tendon tissue, bone marrow, or vascular tissue. The method of any one of embodiments 93-95, wherein the transplanted tissue is an intact organ. The method of any one of embodiments 93-96, wherein the organ or tissue transplant is an allogeneic tissue or organ transplant, The method of any one of embodiments 93-97, wherein the compound or composition is for administration prior to performance of an allogeneic tissue or organ transplant. The method of any one of embodiments 93-97, wherein the compound or composition is for administration in conjunction with an allogeneic tissue or organ transplant.100. The method of any one of embodiments 93-97, wherein the compound or composition is for administration within at least two weeks after an allogeneic tissue or organ transplant.101. The method of any one of embodiments 93-100, further comprising administering to the patient one or more immunosuppressant agents.102. The method of embodiment 101, wherein the immunosuppressant agent is cyclosporine A or FK506.103. A method for treating an autoimmune disease, an inflammatory disease, or a cardiovascular disease in a subject in need thereof comprising administering to the subject a compound of any one of embodiments 1-82 or the composition of any one of embodiments 83-92.104. The method of any one of embodiments 93-103, wherein the composition is administered intravenously or intra-arterially.EXAMPLES

[0339] The therapeutic agents described herein and nanoparticles comprising the same may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.Materials and methods

[0340] All chemicals - including lauric anhydride [645-66-9], 3-azido-propylamine [88192-19-2], N-methyl-octadecylamine [2439-55-6] and dioctylamine [1120-48-5] - were purchased from commercial sources and used without further purification. Cholesteryl azidoacetate ([1819361 -63-1], Uriel et al, Org. Lett. 2021, 23(7), 6801-6806), DSG-azidoacetate ([2923537-41 -9], W02022198101 Al), propargyl octadecanoate ([38003-60-0], Jishkariani et al, JACS, 2025, 137(33), 10728-10734), stearyl azide ([121955-20-2], Fang et al, Org, Let. 2022, 24(48), 8920-8924) and octadecyl chloroformate ([51637-93-5], Kawase et al.. Journal of Oleo Science, 2010, 59(4), 191-201) were synthesized as according to literature procedures. Starting from (S)-3-hydroxypropane-l,2-diyl didodecanoate DLG-azidoacetate was prepared in a similar way as DSG-azidoacetate. Cholesteryl N-methylglycme (trifluoroacetate salt) was prepared bycoupling of N-Boc-N-methyl-glycine with cholesterol with subsequent deprotection of the Boc- group using IT A.

[0341] All reagents, chemicals, materials, and solvents were obtained from commercial sources and were used without, further purification. Drying of solvents, when necessary, was done using molsieves. Reactions were run under an inert, argon atmosphere whenever appropriate. 1H- NMR and 13C-NMR spectroscopy were performed using a Broker AVANCE III HD spectrometer running at 400 MHz and 298 K. All shifts are reported with respect to the 1H signal of TMS at 0 ppm. Infrared spectroscopy was performed on a Perkin-Elmer Spectrum Two FT-IR spectrometer equipped with an UATR Two setup. GC / MS was measured on a Shimadzu GC-2010 gas chromatograph, equipped with a GCMS-QP202 mass spectrometer. HPLC (ACN / H2O) was measured using an integrated Thermo Scientific Vanquish integrated HP! .(' system combined with a Thermo Scientific LTQ XL MS detector, with eluents A: H2O and B: ACN, both with 0.1% formic acid and a gradient from 5 to 100% B, at 0.3 niL / min using a 50 x 2.1 mm Phenomenex Kinetex 5 gm EVO C18 100 A column (00B-4633-AN) at 40 °C. HPLC (IPA / ACN / H2O) was measured on a Shimadzu Nexera-i LC-2040C 3D integrated liquid chromatography system alternatively equipped with a Shimadzu LCMS-2020 mass spectrometer or an Alltech 3300 ELSD detector, with eluents A: H2O and B: IPA'ACN / H2O (80: 15:5), both with 20 mM ammonium formate and 0.1% formic acid and a gradient from 60 to 90% B at 0.3 mL / min using a 50 x 2.1 mm Phenomenex Kinetex 5 gm EVO Cl 8 100 A column (00B-4633-AN) at 40 °C. MA.LDI-TOF was measured on a Broker autoflex speed system. TsCl = tosyl chloride, DCM = dichloromethane. IP A = isopropanol. ACN = acetonitrile. THF = tetrahydrofuran.

[0342] Dry solvents were obtained with an MBRAUN Solvent Purification System (MB- SPS). Toluene was dried over 4A molecular sieves before use. Glassware used for reactions carried out under argon atmosphere was dried with a heat gun prior to use. Thin-layer chromatography (TLC) was performed using 60-F254 silica gel plates from Merck and visualized by UV light at 254 nm, permanganate staining and / or cerium molybdate (CeMo) staining. Normal and reversed- phase automated column chromatography was conducted on a Biotage Isolera One or Grace Reveleris X2 Flash Chromatography System using Biotage Sfar Silica, Buchi FlashPure ID Silica or Buchi FlashPure ID Cl 8 columns. Elution gradients are specified in column volumes (CVs).

[0343] NMR spectra were recorded on Brisker 400 MHz Ultrashield spectrometer (400 MHz for ’H XMR.). Deuterated solvents used are indicated in each case. Chemical shifts (5) are expressed in ppm and are referred to the residual peak of the solvent. Peak multiplicity is abbreviated as s: singlet; d: doublet; t: triplet; dt: doublet of triplets; ddt: doublet of doublets of triplets; td: triplet of doublets; tt: triplet of triplets; q: quartet; ABq: AB quartet; dq: doublet of quartets; qd: quartet of doublets; sept: septet; m: multiplet; bs: broad singlet.

[0344] Matrix assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectra were obtained on a PerSeptive Biosystems Voyager DE-PRO spectrometer using a-cyano- 4-hydroxycinnamic acid (CHCA) or trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]- malononitrile (DCTB) as matrix.

[0345] Gas chromatography-mass spectrometry (GC-MS) measurements were conducted on a Shimadzu GC-17A gas chromatograph with a Shimadzu AOC-20i auto injector, Shimadzu GCMS-QP5000 gas chromatograph mass spectrometer and Phenomenex Zebron ZB-35 column (1 = 30 meters, ID = 0.25 mm, film thickness = 0.25(um).100346] High performance liquid chromatography mass spectrometry (HPLC-MS) experiments using a water / acetonitrile gradient were performed on a Shimadzu setup with 2x LC- 20 AD pumps, DGU-20A3 degasser, SIL-20AC autosampler, SPD-M20A PDA and ThermoScientific LCQ fleet MS. Column: Phenomenex Kinetex 5 uni EVO C18 IOOA LC (50X2.1 mm). Gradient: water / MeCN (+ 0.1% formic acid) from 5 to 100% MeCN, 0.30 niL / min. Other HPLC-MS experiments with a water / THF or water / MeOH gradient were performed on a Shimadzu Nexera-i LC-2040C 3D Plus with Shimadzu LCMS-8045. Column: Alltech Alltima C18 (150x3.2mm; 5 um; no. 88383). Flow’: 0.40 niL / min. This HPLC setup was also used in combination with ELSD (evaporative light scattering detection). Yet other HPLC (IPA / ACN / H2O) measurements were performed on a Shimadzu Nexera-i LC-2040C 3D integrated liquid chromatography system equipped with a Shimadzu LCMS-2020 mass spectrometer or an Alltech 3300 ELSD detector, with eluents A: H2O and B: IPA / ACN / H2O (80: 15:5), both with 20 mM ammonium formate and 0.1% formic acid and using a gradient from 60 to 90% B. Column: Phenomenex Kinetex 5 um EVO Cl 8 100A LC (50x2. 1 mm). Flow: 0.30 mL / min.

[0347] Abbreviations

[0348] HPLC “ high performance liquid chromatography, ELSD = evaporative light scatering detection, ESI-MS = electrospray ionization mass spectrometry; SIM = selected ion mode, NMR::::nuclear magnetic resonance, NHS = N-hydroxy succinimide; PyBOP = (benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate), DMTMM = (4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methyl-morphohnium chloride); SPPS = solid phase peptide synthesis. TEA ~ triethyl-amine; DiPEA = di-isopropyl-amine; DMAP = 4- dimethylaminopyridine; THF =;:tetrahydrofuran; MeOH = methanol; IPA:;= iso-propanol; DMF = dimethylformamide; DCM = dichloromethane or methylene chloride; ACN or MeCN = acetonitrile; FA ~ formic acid; TFA = trifluoro-acetic acid.

[0349] Building blocks

[0350] Rapamycin hemi-succisiate

[0351] Rapamycin hemi-succmate was prepared following literature procedures: Jianxm Gu, Mark E. Ruppen, Ping Cai, Org. Let. 2005, 7, 18, 3945-3948. Rapamycin (0.572 g, 0.63 mmol, 1.00 eq) and succinic anhydride (0.282 g, 2.82 mmol, 4.50 eq) were dissolved in toluene (30 mL, -0.02 M). Novozyme 435 (1 .1 g) was then added to the solution. The mixture was flushed with argon and stirred at 45 °C for 120 h. Consumption of the starting material and formation of the product were observed by TLC (chloroform / MeOH 90 / 10). The reaction mixture was filtered through a glass frit filter and rinsed with toluene (20 mL). The filtrates were combined and concentrated in vacuo, giving a crude white solid product. The crude was purified by automatedcolumn chromatography (product: silica 1:120; detector: 200-400 nm) and eluted with chloroform / MeOH 99 / 1-97 / 3 over 30 CV), giving a white solid hemi-succinate (0.463 g, 73%) containing approximately 5% rapamycin starting material.

[0352] 13CNMR (101 MHz, CDC13): <5 === 214.95, 208.23, 208.23, 207.68, 196.18, 192.94, 176.88, 172.72, 171.77, 169.77, 169.26, 166.72, 165.80, 140.53, 139.87, 136.11, 135.88, 135.78, 133.49, 133.31, 130.21, 130.01, 129.36, 129.20, 126.51, 126.37, 98.75, 98.51, 86.34, 84.84, 84.38, 84.28, 80.87, 75.60, 75.46, 67.78, 67.20, 59.07, 59.03, 57.47, 56.32, 55.88, 55.86, 51.91 , 51.28,46.59, 46.06, 44.22, 41.54, 40.85, 40.64, 40.45, 40.22, 38.98, 38.68, 38.34, 35.96, 35.78, 35.46,34.97, 34.49, 33.85, 33.26, 32.86, 31.36, 31.18, 30.94, 29.63, 29.32, 28.98, 28.72, 27.89, 27.19,27.04, 26.91, 25.25, 24.29, 21.61, 21.41, 20.68, 16.40, 16.19, 15.98, 15.91, 15.88, 14.74, 13.52,13.40, 13.17, 10.34, 10.18 ppm. LCMS (water / acetonitrile): t = 5.81 min; calcd. for C55H82NO16 1012.56, found 1012.83 [M-H 1.

[0353] NHS-Glut-OH

[0354] A mixture of NHS (1.06 g, 9.2 mmol) and glutaric anhydride (1.00 g, 0.95 eq.) were heated under reflux in THF (5 mL) for 16 hours to afford the crude product. The crude material was diluted with DCM and then purified by column chromatography (50 g SiO2 Biotage® Star, 0 — > 10% MeOH in CHCh), affording 1.64 g (77%) of the desired product.

[0355] !I -I-NMR (CDCh) 5: 2.92-2.78 (m, 4H), 2.73 (t, J === 7.2 Hz, 2H), 2.54 (t, J === 7.2Hz, 2H), 2.08 (p, J === 7.3 Hz, 2H) ppm.i3C-NMR (CDCh) 8: 178.15, 169.19, 168.02, 32.31, 29.92, 25.57, 19.49 ppm.

[0356] NHS-Glut-Ci

[0357] Oxalyl chloride (0.34 mL, 3.9 mmol) and a drop of DMF were added to a stirring solution of NHS-glut-OH (0.7 g, 3 mmol) in DCM (7 mL), leading to instantaneous gas evolution. After 80 minutes the solvent was removed as NMR indicated quantitative conversion, affording 0.56 g (74%) of the desired compound.

[0358] 1H AMR (CDCh) 8: 3.10 (t, J - 7.2 Hz, 2H), 2.85 (s, 4H ), 2.73 (t, J - 7.1 Hz, 2H).2.14 (p, J - 7.2 Hz, 2H) ppm.13C-NMR (CDCh) 5: 173.19, 168.96, 167.60, 45.31, 29.35, 25.59, 20.02 ppm. IR (FT-IR) v: 2950, 1785, 1733, 1430, 1406, 1367, 1205, 1069, 1048, 994, 966, 938, 869, 831, 752, 722, 681, 648, 576 cm -1.

[0359] Octyl Chloroformate

[0360] Pyridine (0.8 mL, 1 eq.) in 2.5 mL DCM v / as slowly added to a stirring solution of octanol (1.31 g, 10 mmol) and triphosgene (1.01 g, 0.33 eq.) in 2.5 mL DCM that was submerged in a water bath acting as a heatsink. After 80 minutes the reaction mixture was diluted with 10 mL chloroform, dissolving all the precipitate that had formed, extracted rapidly with water, dried over MgSCh, and evaporated to dryness, yielding a pink oil. This oil was then dissolved in heptane and rapidly run over a SiOz column, with heptane, yielding 0.64 g (33%) of the desired chloroforniate that was 98% pure according to NMR.

[0361] ’H NAIR (400 MHz, CDCh) 8: 4.31 (t, J= 6.7 Hz, 2H), 1.72 (dt, J= 8.2, 6.5 Hz, 2H), 1.61-1.07 (m, 10H), 0.89 (t, 3H) ppm.13C NMR ( 101 MHz. CDCh) 8: 150.63, 150.61, 72.37, 31.87, 31.70, 29.05, 29.01, 28.85, 28.27, 25.49, 22.68, 22.59, 14.08, 14.03 ppm. IR(ATR) v: 2958, 2927, 2858, 1775, 1467, 1379, 1137, 940, 830, 803, 723, 689, 477 cm h

[0362] 9-Heptadecimyi chloroformate

[0363] Pyridine (135 p.L, 1 eq.) in 1 mL DCM was slowly added to a stirring solution of 9-heptadecanol (0.42 g, 1.64 mmol) and triphosgene (0.16 g, 0.33 eq.) in 1 mL DCM, that was submerged in a water bath acting as a heatsink. After 1 hour the reaction mixture was diluted with 5 mL chloroform, extracted with 5 mL water, 5 mL brine, dried over MgSOr, and evaporated to dryness yielding an oil. This oil was dissolved in heptane and rapidly run over a S1O2 column, with heptane, yielding 185 mg (35%) of the desired chloroformate, with a purity of 97% according to XMR..

[0364] !H NMR (400 MHz, CDCh) 5: 4.90 (It, J === 7.4, 5. 1 Hz, 1H), 1.80-1 .50 (m, 4H), 1.29 (m, . / 11.0 Hz, 24H), 0.88 (t, . / 6.8 Hz, 6H) ppm.13C NMR (101 MHz. CDCh) 5: 150.22, 84.88, 84.86, 38.52, 33.74, 31.93, 31.81 , 31.64, 29.70, 29.66, 29.47, 29.37, 29.32, 29.24, 29.17, 26.49, 25.23, 25.07, 22.63, 22.45, 14.05 ppm. IR (ATR) v: 2925, 2856, 1774, 1466, 1378, 1159, 1121, 956, 886, 834, 722, 687, 475 cnr1.

[0365] Rapamycin-GIut-NHS

[0366] A solution of NHS-glut-Cl (26 mg, 1 .7 eq.) in DCM (1 mL) was added to a reaction vessel containing rapamycin (57 mg, 62 pmol). Immediately after addition pyridine (20 pL, 4 eq.) was added to the reaction mixture. After about 2 hours the reaction was quenched with MeOH (25|1L, ~10 eq.) and evaporated to dryness. The resulting crude material was purified by column chromatography (1: 10 g SiOz Biotage Star 0 — > 100% EtOAc in CHCh, 2: 10 g SiOz Biotage Sfar0 —> 55% EtOAc in CHCh), affording 38 mg (54%) of the desired product.

[0367] lH-NMR (CDCh): complex spectrum in line with the expected structure.13C- NMR(CDCh) 8: 215.44, 208.17, 207.67, 192.51, 172.00, 169.23, 169.06, 169.01 , 168.14, 166.75, 140.16, 135.99, 135.60, 133.62, 130.16, 129.55, 126.64, 126.40, 98.47, 86.42, 84.78, 84.33, 80.86, 76.24, 75.41, 67.16, 59.33, 57.29, 55.89, 51.28, 46.60, 44.22, 41.47, 40.57, 40.20, 38.90, 38.37, 35.83, 35.63, 35.12, 33.74, 33.18, 33.10, 32.83, 31.26, 29.83, 29.73, 27.25, 27.04, 25.58, 25.29, 21.51, 20.67, 19.96, 16.25, 16.04, 15.92, 13.68, 13.17, 12.98, 10.16 ppm. HPLC-MS (ACN / HzO, gradient: 5-100% B): t[prod] = 5.60 min; m / z = 1147.75 [M+Na]+. MALDI (CeoHssNzOis) calculated mass: 1124.60, found mass: 1147.60 [M+Na]+, 1163.57 [M+K]+.

[0368] Rapamycin- Propargyl- 1

[0369] Rapamycin hemi-succinate (50 mg, 49 umol, 1.00 eq) solution in DCM (1 mL, -0.05 M) was prepared under argon atmosphere. PyBOP (36 mg, 69 gmol, 1.40 eq) and N,N- diisopropylethylamine (13 mg, 17 pL, 99 pmol, 2.00 eq) were then added to the solution. The reaction mixture was stirred for 10 min at room temperature. Next, propargylamine (4.3 mg, 5.1 pmL, 79 pmoi, 1.60 eq) was added and stirred at room temperature for 1 hour. Full conversion of the rapamy cin hemisuccinate starting material was observed by TLC (chloroform / MeOH 90 / 10) and LCMS analysis (water / acetonitrile). The reaction mixture was diluted with chloroform (10 mL) and washed with IM citric acid (10 mL) and brine (10 mL). The washed product was driedwith MgSCh and concentrated in vacuo, giving crude product as a light-yellow wax. The crude was purified by automated column chromatography (product: silica 1: 140; detector: 200-400 nm), eluting with chloroform / 'MeOH 100 / 0-96 / 4. Pure fractions were lyophilized, yielding product (0.050 g, 96%) as a white solid containing approx. 5% rapamycin. The product was used for further reactions as-is.

[0370] lH NMR (400 MHz, CDCh) and13C NMR (101 MHz, CDCh) r the complex spectra are in line with the structure. HPLC-MS (water / MeCN): tfprod] = 5.80 mm; m / z = 1073.58 [M+Na]+.

[0371] Rapamycin-Propargyi-2

[0372] DiPEA (22 pL, 2 eq.) was added to rapamycin hemi-succinate (50 mg, 49 pmol) and DMTMM (24 mg, 1.7 eq.) in DCM. After 15 minutes of pre-activation N-methyl propargyl amine (7.5 uL, 1.8 eq.) was added to the reaction mixture that was stirred for a further 2 hours. The mixture was then diluted with 5 m chloroform, extracted with 5 mL 1 M citric acid, 5 mL water, 5 mL brine, dried with MgSO<i, and evaporated to dryness. The crude material was then purified by column chromatography (10 g S1O2 Biotage Star, 0 5% MeOH in CHCh), dissolved in 0.5 mL dioxane, lyophilized, stirred with 4 mL heptane for 16 hours, decanted, dried, redissolved in 0.5 mL chloroform, precipitated with 5 mL heptane, stirred for 16 hours, decanted again, and dried to afford 28 mg (54%) of the desired product.

[0373] ‘H-NMR (CDCh): complex spectrum in line with the expected structure.13C-NMR(CDCh) 8: 215.49, 215.31, 208.22, 207.67, 196.41, 192.52, 172.59, 171.18, 171.03, 169.24,166.78, 165.71, 140.78, 140.18, 136.20, 136.06, 135.55, 133.66, 133.40, 130.16, 129.98, 129.60, 129.34, 126.66, 126.40, 98.77, 98.49, 84.80, 84.36, 80.93, 78.78, 77.94, 77.25, 77.20, 76.54, 75.64, 75.54, 72.84, 71.81, 67.83, 67.18, 59.36, 59.26, 57.69, 56.25, 55.95, 55.89, 51.27, 46.61 , 46.09,44.22, 41.47, 40.70, 40.48, 40.21 , 39.28, 38.89, 38.29, 36.31, 36.05, 35.63, 35.12, 34.57, 34.18,33.75, 33.54, 33.23, 33.01, 32.91, 31.88, 31.48, 31.35, 31.27, 29.71, 29.57, 29.02, 28.28, 27.97,27.26, 27.06, 25.30, 22.69, 21.72, 21.52, 20.67, 16.38, 16.26, 16.19, 16.06, 15.93, 15.87, 14.98,14.12, 13.73, 13.15, 13.00, 10.33, 10.17 ppm. HPLC-MS (ACN / H2O, gradient: 5-100% B): tfprod] = 5.60 mm; m / z = 1087.83 [M+Na]+. MALDI (CssHssNzOis) calculated mass: 1064.62, found mass: 1087.61 [M+Na]+, 1103.59 [M+K]+.

[0374] Rapamycin-OC(O)PNP and Rapamycin-(OC(O)PNP)2

[0375] Rapamycin (90 mg, 0. 1 mmol) and pyridine (40 pL, 5 eq.) were dissolved in DCM (0.5 mL) and cooled in an ice-bath, PNP chloroformate (57 mg, 3 eq.) dissolved in DCM (0.5 mL) was added slowly to this solution under stirring, resulting in the immediate formation of a white precipitate. After addition of the chloroformate, the mixture was stirred for another 25 minutes and subsequently quenched by the addition of 5 mL of 1 M citric acid (aq). The resulting mixture was diluted with 5 mL chloroform and separated. The organic phase was washed with 1 M citric acid (5 mL), water (5 mL), and brine (5 mL), dried with MgSOr, and evaporated to dryness to afford a crude mixture of both title compounds. These were separated and purified by column chromatography (10 g S1O2 Biotage® Sfar 0 — > 40% EtOAc in chloroform) to afford 50 mg (40%) of the monosubstituted compound, and 48 mg (34%) of the disubstituted compound.

[0376] Monosubstituted compound:lH-NMR (CDCb): complex spectrum in line with the expected structure.13C-NMR (CDCb) 5: 215.47, 215.30, 208.17, 192.56, 169.91, 169.28, 166.77, 165.63, 155.67, 152.04, 145.27, 140.16, 136.15, 136.07, 135.66, 133.60, 133.42, 130.19, 129.96, 129.52, 129.33, 126.64, 126.43, 125.24, 121.76, 98.80, 98.48, 86.35, 84.70, 84.46, 84.33, 81.80,80.73, 80.68, 77.20, 75.54, 75.36, 67.84, 67.19, 67.08, 59.39, 59.29, 57.40, 57.38, 56.21, 55.88,51.27, 46.60, 46.06, 44.21, 41.51, 40.46, 40.18, 38.91, 38.58, 38.23, 35.64, 35.44, 35.17, 34.59,33.76, 33.12, 32.91, 32.72, 31.25, 31.08, 29.44, 27.25, 27.03, 25.27, 24.24, 21.72, 21.52, 20.65,16.41, 16.24, 16.21, 15.97, 15.89, 15.84, 14.99, 13.75, 13.15, 13.02, 10.32, 10.16 ppm. HPLC-MS (ACN / H2O, gradient: 5-100% B): tfprod] = 5.95 mm; m / z = 1101.92 [M+Na]+, 1123.50 [M+formate]'. MALDI (C58H82N2O17) calculated mass: 1078.56, found mass: 1101.55 [M+Nap, 1117.53 [M+K]+.

[0377] Disubstituted compound:TH-NMR (CDCb): complex spectrum in line with the expected structure.!3C-NMR (CDCb) 5: 210.99, 207.43, 193.11, 169.64, 169.32, 166.61, 155.67, 155.39, 155.36, 152.04, 151.49, 145.60, 145.28, 139.63, 136.35, 133.22, 132.31, 130.27, 128.97, 128.75, 126.75, 125.41, 125.34, 125.25, 121.99, 121.78, 98.67, 98.49, 84.02, 83.47, 82.40, 81.75,80.66, 77.21, 74.69, 67.90, 67.21, 67.09, 59.74, 57.40, 57.32, 55.93, 51.34, 46.35, 44.20, 41.66,40.96, 39.92, 39.17, 38.19, 35.48, 35.35, 35.13, 34.64, 33.94, 33.46, 32.59, 31.09, 31.02, 29.37,27.23, 26.92, 25.21, 21.52, 20.68, 16.22, 16.08, 15.84, 15.75, 15.36, 14.41, 13.94, 13.27, 10.44,10.30 ppm. HPLC-MS (ACNZH2O, gradient: 5-100% B): tfprod] = 6.23 min; m / z = 1266.58 [M+Na]'h. MALDI (CesHssNsChi) calculated mass: 1243.57, found mass: 1266.56 [M+Nap, 1282.52 [M+Kp.

[0378] Rapamycin azide

[0379] Rapamycin hemi-succmate was coupled to 3 -azi do-propylamine using amide coupling chemistry, as is known in the art. The product was isolated after extraction and silica column chromatography. The product was pure as according to 1H-NMR and chromatographic analysis.Example 1A. Rapa-C 18 [Click]

[0380] Rapamycin-propargyl-1 (25.7 mg, 25 pmol) and stearyl azide (9.6 mg, 32 pmol.1.3 eq) were dissolved in DCM (0.4 mL). Under vigorous stirring, 0.4 M ascorbic acid (0.13 mL, 2 eq) and 0.2 M CuSOrSHcO (0.13 mL, 1 eq) were added. The resulting two-phase system was vigorously stirred at room temperature for additional 22 h. Next, the organic layer was separated with H2O (4 mL) and DCM (3 mL) while the aqueous layer was extracted with chloroform (2 x 2 mL). The extracted organic layers were combined and washed with H2O / brine 1 :1 (4 mL), driedusing NazSCh, and concentrated in vacuo. The resulting colorless solid was subjected to column chromatography (flash SiOz.) using an elution gradient of 1 % to 4 % MeOH in chloroform. This yielded impure product (26 mg) consisting of the desired product, residual non-functionalized rapamycin and stearyl azide. The crude product was again purified by automated column chromatography (reversed-phase (Cis); product:Ci8-silica 1:440; detection: 200-400 nm), eluting with water / THF 50 / 50-35 / 65. Pure fractions v / ere combined and most I'HF removed in vacuo. The remaining water- rich solution was lyophilized, giving pure product as a fluffy , white solid (17 mg, 52%).

[0381] ’H NMR (400 MHz, CDCb): complex spectrum is in line with structure.13C NMR (101 MHz, CDCh): d == 215.20, 215.12, 208.15, 208.15, 207.66, 192.66, 172.27, 172.25, 171.54, 171.50, 169.83, 169.24, 166.75, 165.71, 144.62, 144.58, 140.70, 140.07, 136.19, 136.05, 135.70, 133.58, 133.38, 130.18, 129.98, 129.47, 129.29, 126.54, 126.44, 122.02, 121.98, 107.92, 98.78, 98.49, 98.43, 86.40, 84.79, 84.42, 84.31, 80.85, 75.59, 75.41, 67.83, 67.67, 67.41, 67.19, 59.26,59.20, 57.40, 56.26, 55.94, 55.90, 51.29, 50.39, 46.61, 46.08, 44.23, 41.51, 40.88, 40.55, 40.22,38.97, 38.64, 38.39, 35.93, 35.74, 35.58, 35.09, 34.57, 33.80, 33.27, 33.19, 32.98, 32.85, 31.93,31.40, 31.24, 31.18, 31.00, 30.27, 30.11, 30.07, 29.70, 29.66, 29.62, 29.54, 29.40, 29.36, 29.15,29.02, 27.89, 27.25, 27.06, 26.51, 25.29, 24.29, 23.92, 23.40, 22.69, 21.69, 21.50, 21.10, 20.69,16.41, 16.25, 16.22, 16.02, 15.91, 15.88, 14.93, 14.13, 13.67, 13.26, 13.09, 10.34, 10.19, 10.19 ppm. HPLC-MS (water / THF, gradient: 65-95% THF): t[prod] = 4.80 min; m / z = 1346.9 [M+H]+and 1368.9 [M+Naf (SIM mode). MALDI: calcd for CzsHizsNsOisNa 1368.89, found: 1368.91 [M+Na]+. CLogP = 15.5.Example IB. RapatiVMeC18[Oick|

[0382] Rapamycin-propargyl-2 (22 mg. 20 pmol) and octadecyl azide (9 mg, 1.3 eq.) were dissolved in 0.33 mL DCM. After flushing the reaction vessel with argon 100 pL 0.4 M ascorbic acid and 100 p.L 0.2 g CuSOi were added. After again flushing with Ar, the mixture was stirred vigorously for 16 hours. The reaction mixture was then diluted with 3 mL chloroform and 3 mL water. The organic phase was separated, and the water phase was washed 2 more times with 3 mL chloroform. The combined organic phases were then washed with 3 mL water, 3 mL brine, dried with NazSCL, and evaporated to dryness. The crude material was then purified by column chromatography (10 g SiOz Biotage® Sfar, 0 — > 5% MeOH in CHCh), affording 17 nig (62%) of the desired product with a purity of >99% according to HPLC-ELSD (IPA / ACNZHzO).

[0383] lH-NMR (CDCh): complex spectrum in line with the expected structure.l 3C- NMR (CDCh) 5: 215.44, 215.23, 210.13, 208.19, 207.66, 196.41, 192.55, 172.82, 172.65, 171.28, 171.16, 169.86, 169.24, 166.78, 165.70, 144.12, 143.87, 140.76, 140.17, 136.19, 136.07, 135.60, 133.65, 133.40, 130.17, 129.99, 129.57, 129.33, 126.64, 126.41, 122.63, 121.44, 98.78, 98.49, 86.43, 84.79, 84.36, 80.94, 77.24, 77.19, 76.51, 75.49, 67.84, 67.19, 59.35, 59.25, 57.74, 57.66,56.25, 55.95, 55.89, 51.28, 50.54, 50.36, 46.61, 46.08, 45.41, 44.22, 43.04, 41.48, 40.83, 40.62,40.21, 38.91, 38.35, 36.08, 35.92, 35.62, 35.42, 35.13, 34.58, 33.76, 33.69, 33.20, 33.02, 32.93,31.93, 31.28, 30.28, 30.22, 29.70, 29.66, 29.62, 29.53, 29.40, 29.36, 29.01, 28.22, 27.93, 27.26,27.06, 26.52, 26.50, 25.31, 24.28, 22.69, 21.72, 21.53, 20.68, 16.41, 16.26, 16.19, 16.05, 15.92,15.87, 14.98, 14.13, 13.74, 13.17, 13.04, 10.33, 10.17 ppm. HPLC-MS (IPA / ACN / HzO, gradient: 60-90% B): tfprod] = 4.02 min; m / z = 1360.9 [M+H]+, 1382.9 [M+Na]^ (SIM mode). MALDI(C77H125N5O15) calculated mass: 1359.92, found mass: 1382.91 [M+Na]+, 1398.89 [M+K]+.CLogP 15.7.

[0384] A 10 mL round-bottomed flask was charged with a solution of rapamycin- propargyl-1 (0.070 g, 0.067 mmol, 1.00 eq) and DLG-azidoacetate (0.047 g, 0.087 mmol, 1.30 eq) in chloroform (1.3 mL, -0.05 M). A 0.4 M aq. solution of L-ascorbic acid (333 pL, 0.13 mmol ascorbic acid, 2.00 eq) was added, followed by a 0.2 M aq. solution of copper(II) sulfate pentahydrate (333 uL, 0.067 mmol Cu, 1.00 eq). The flask was purged with argon, and the resulting light green / yellow emulsion stirred at 700 rpm at room temperature. After 16 h, LCMS (water / MeOH) showed full conversion of the alkyne starting material and formation of the product. Subsequently, the reaction mixture was concentrated in vacuo, and the resulting white / green solid taken up in THF and impregnated on celite (250 mg, -1:2 loading ratio). The material was purified by automated column chromatography (reversed-phase (Cl 8); product: C18-silica 1:100; detection: 200-400 nm), eluting with water / THF 60 / 40-30 / 70. Product containing fractions were combined and most THF removed in vacuo. The remaining water-rich solution was lyophilized, giving a mixture of product and residual DLG-azidoacetate. The material was again purified by automated column chromatography (normal phase; product: silica 1: 150; detection: 200-400 nm), eluting with chloroform / MeOH 100 / 0- 98 / 2. Pure fractions were combined and concentrated in vacuo, giving the desired product (0.050 g, 47%) as a white solid.

[0385] ’H NMR (400 MHz, CDCI3) and13C NMR (101 MHz, CDCls): the complex spectra are in line with the structure. HPLC-MS (water / 'MeOH, gradient: 90-100% MeOH): t[ prod ] == 8.22 mm; m / z = 1613.0 [M+Na]+(SIM mode). MALDI: calcd for (NrHwNsChiNa 1612.99, found: 1612.92 [M+Naf; calcd for CMHi 39N5O: 21 K 1628.96, found: 1629.92 [M+K]+. CLogP == 17.4.Example ID. Rapa-DSG [Click]

[0386] A 10 mL round-bottomed flask was charged with a solution of rapamycin- propargyl-1 (28 mg, 0.027 mmol, 1.00 eq) and DSG-azidoacetate (25 mg, 0.035 mmol, 1.30 eq) in chloroform (0.5 mL, -0.05 M). A 0.2 M aq. solution of copper(II) sulfate pentahydrate (133 uL, 0.027 mmol Cu, 1.00 eq) was added, followed by a 0.4 M aq. solution of L-ascorbic acid (133 uL, 0.053 mmol, 2.00 eq). The flask was purged with argon, and the resulting yellowish emulsion was stirred at 700 rpm at room temperature. After 17 h, LCMS (water / THF) showed full conversion of the alkyne starting material and formation of the product. Subsequently, the reaction mixture was concentrated in vacuo, resulting in a white / green solid. The crude product was purified by automated column chromatography (product: silica 1 :200; detection: 200-400 nm), eluting with chloroform / MeOH 100 / 0-96 / 4. The resulting white material (34 mg) consisted of a mixture of the desired product, residual non-functionalized rapamycm and DSG-azidoacetate. The mixture was further purified by automated column chromatography (reversed-phase (Cl 8); product: Cl 8- silica 1:350; detection: 200— 400 nm), eluting with water / THF 50 / 50-15 / 85. The combined pure fractions were concentrated in vacuo and lyophilized, giving pure product as a fluffy, white solid (18 mg, 60%).

[0387] ’H NMR (400 MHz, CDCb,) and13C NMR (101 MHz, CDCb): the complex spectra are in line with the structure.13C NMR (101 MHz, CDCb): 5 - 215.21, 215.07, 208.16, 207.63, 192.67, 173.38, 173.34, 172.99, 172.37, 172.33, 171.67, 171.49, 169.83, 169.25, 166.74, 165.88, 165.80, 145.54, 145.39, 140.68, 140.09, 136.04, 135.71, 133.58, 133.37, 130.19, 130.00, 129.48, 129.26, 126.57, 126.44, 123.74, 123.58, 107.93, 98.78, 98.50, 98.45, 86.36, 84.78, 84.31, 80.97, 80.95, 75.60, 75.41, 68.27, 67.98, 67.83, 67.68, 67.43, 67.20, 64.07, 61.84, 61.71, 59.28,59.18, 57.51, 56.29, 55.94, 55.90, 51.83, 51.30, 50.68, 47.84, 46.61, 46.07, 44.23, 41.51, 40.89,40.52, 40.22, 38.98, 38.68, 38.37, 36.13, 35.95, 35.58, 35.12, 35.09, 34.56, 34.14, 34.03, 33.81,33.27, 33.17, 32.99, 32.88, 31.93, 31.25, 31.19, 31.06, 30.70, 30.05, 29.71, 29.67, 29.64, 29.52,29.50, 29.37, 29.29, 29.13, 29.09, 27.90, 27.25, 27.06, 25.61, 25.30, 25.16, 24.86, 24.85, 24.30,23.92, 23.38, 22.70, 21.68, 21.51, 20.69, 16.40, 16.25, 16.20, 16.02, 15.90, 14.90, 14.13,13.67, 13.25, 13.10, 10.35, 10.19 ppm. HPLC-MS (water / THF, gradient: 65-95% THF): tfprod] = 5.81 min; m / z = 1781.2 [M+Nap (SIM mode). MALDI: calcd for CaaHissNsChiNa 1781.17, found: 1781.22 [M+Napi CLogP = 23.8.Example IE. Rapa-ChoI[CJick]

[0388] A 10 mL round-bottomed flask was charged with a solution of rapamycin- propargyl-1 (0.046 g, 0.043 mmol, 1.00 eq) and cholesteryl-azidoacetate (0.027 g, 0.056 mmol, 1.30 eq) in chloroform (0.6 mL, -0.07 M). A 0.4 M aq. solution of L-ascorbic acid (217 pL, 0.087 mmol ascorbic acid, 2.00 eq) was added, followed by a 0.2 M aq. solution of copper(II) sulfate pentahydrate (217 pL, 0.043 mmol, 1.00 eq). The flask was purged with argon, and the resulting light green / yellow emulsion was stirred at 1200 rpm at room temperature. After 3 hr, LCMS(water / THF) showed full conversion of the alkyne starting material and formation of the product. Subsequently, the reaction mixture was concentrated in vacuo, and the resulting white / green solid was taken up in THF and impregnated on celite (200 mg, -4:3 loading ratio). The material was purified by automated column chromatography (reversed-phase (C18); product: Cl 8-silica 1:200; detection: 200---400 nm), eluting with water / THF 75 / 25-35 / 65. Product containing fractions were combined and most THF removed in vacuo. The remaining water-rich solution was lyophilized, giving product with a trace of copper salts (faint blue color). The material was again purified by automated column chromatography (normal phase; product: silica 1:200; detection: 200-400 nm), eluting with chloroform / MeOH 100 / 0-96 / 4. Pure fractions were combined and concentrated in vacuo, giving pure product (0.048 g, 73%) as a white solid.

[0389] ’H XMR (400 MHz, CDCh) and53C NMR (101 MHz, CDCb): the complex spectra are in line with the structure. HPLC-MS (water / THF, gradient: 70-95% THF): t[prod] = 4.34 min; m / z = 1543.0 [M+Nap (SIM mode). MALDI: calcd for CsvHissNsOnNa 1542.96, found: 1542.92 [M+Na]+. CLogP = 16.9.Example IF. Rapa-C18[invCIick]

[0390] A 10 ml. round-bottomed flask was charged with a solution of rapamycin-azide (0.043 g, 0.039 mmol, 1.00 eq) and propargyl octadecanoate (0.014 g, 0.043 mmol, 1.10 eq) in chloroform (0.8 mL, -0 05 M). A 0.4 M aq. solution of L-ascorbic acid (196 uL, 0,078 mmol ascorbic acid, 2.00 eq) was added, followed by a 0.2 M aq. solution of copper(II) sulfate pentahydrate (196 uL, 0.039 mmol Cu, 1.00 eq). The flask was purged with argon, and the resulting light green. / yellow emulsion stirred at 1200 rpm at room temperature. After 17 h, LCMS(water / MeOH) showed full conversion of the azide starting material and formation of the product. Subsequently, the reaction mixture was concentrated in vacuo, and the resulting white / green solid taken up in THF and impregnated on celite (150 mg, ~ 1 :3 loading ratio). The material was purified by automated column chromatography (reversed-phase (Cl 8); product: Cl 8-silica 1:200; detection: 200-400 nm), eluting with water / THF 50 / 50-30 / 70. Product containing fractions were combined and most THF removed in vacuo. The remaining water-rich solution was lyophilized, giving pure product (0.030 g, 54%) as a white solid.

[0391] lH NMR (400 MHz, CDCh) and13C NMR (101 MHz, CDCb): the complex spectra are in line with the structure. HPLC-MS (water / MeOH, gradient: 90-100% MeOH): t[prod] = 8.02 mm; ni / z = 1418.9 [M+H]+and 1440.9 [M+Na]+(SIM mode). MALD1: calcd for C79Hi27N50nNa 1440.91, found: 1440.92 [M+Na]+; calcd for C^HizrNsOwNa 1456.89, found: 1456.89 [M-K] CLogP = 15.6.Example 2A. Rapa-SucNHC18

[0392] DiPEA (22 gL, 127 gmol, 2.4 eq.) was added to a stirring solution of rapamycin hemi-succinate (53 mg, 52 pmol), octadecyl amine (16 mg, 60 gmol, 1.15 eq.) and PyBOP (32 nig, 62 gniol, 1.2 eq.) in dry DCM (0.5 mL). After 1 hour the reaction was diluted with 5 mL chloroform and extracted with IM citric acid (5 mL), water (5 mL) and brine (5 mL), dried with MgSOi, and evaporated to dryness. The crude product was purified by silica column chromatography (10 g Biotage Star, 0— *70% EtOAc in chloroform) to afford 41 mg (63%) of the desired compound with a purity of >99% according to HPL.C-ELSD (IPA'ACN / HzO).

[0393] ’H-NMR (CDCh): complex spectrum in line with the expected structure.l 3C- NMR (CDCh) 5: 215.53, 215.30, 208.21, 207.68, 192.51, 172.62, 172.58, 171.36, 169.87, 169.24, 166.78, 165.69, 140.78, 140.19, 136.18, 136.08, 135.56, 133.66, 133.41, 130.17, 129.98, 129.60, 129.34, 126.67, 126.40, 98.79, 98.49, 86.43, 84.78, 84.45, 84.37, 80.92, 80.87, 77.24, 77.21, 76.60, 75.63, 75.52, 67.84, 67.18, 59.38, 59.27, 57.50, 56.24, 55.95, 55.89, 51.27, 46.61, 46.08, 44.23,41.48, 40.94, 40.85, 40.64, 40.47, 40.21, 39.68, 38.89, 38.59, 38.31, 35.89, 35.62, 35.14, 34.59,33.75, 33.19, 32.99, 32.89, 31.93, 31.47, 31.32, 31.27, 31.01, 30.30, 30.26, 29.71, 29.66, 29.61 ,29.56, 29.37, 29.31, 27.88, 27.27, 27.06, 26.92, 25.30, 24.27, 22.70, 21.72, 21.53, 20.67, 16.41,16.26, 16.18, 16.05, 15.91, 15.86, 15.15, 15.00, 14.13, 13.75, 13.14, 13.02, 10.33, 10.17 ppm. HPLC-MS (IPA / ACN / H2O, gradient: 60-90% B): tfprod] = 4.54 min; m / z = 1287.85 [M+Na]^ (SIM mode). MALDI (C73H120N2O15) calculated mass: 1264.87, found mass: 1287.85 [M+Na]^, 1303.83 [M+K]+. CLogP = 16.2.Example 2B. Rapa-SucNMeC18

[0394] Rapamycin hemi-succinate (50 mg, 50 pmol), N-methyl-octadecyl amine (18 mg, 1.3 eq.), and PyBOP (30 mg, 1.5 eq.) were dissolved in DCM (mol sieves). After the addition of DiPEA (13 iiL, 1.5 eq.) the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was subsequently diluted with 5 niL CHCI3, extracted with 5 mL 1 M citric acid, 5 niL brine, dried with MgSCh, and evaporated to dryness. The crude product was purified by column chromatography (1: 10 g S1O2 Biotage Sfar, 0 — •> 10% MeOH in CHCI3, 2: 10 g S1O2 Biotage Sfar, 0 —> 3% MeOH in CHCI3, 3: 10 g SiO?. Biotage Sfar, 0 — •> 70% EtOAc in CHCI3).Because the resulting product contained a small amount of HOBt , it was dissolved in 5 mL chloroform and extracted with saturated NaHCCh (2x5 mL), dried with MgSO4, and evaporated to dryness to afford 18 mg (29%) of the desired product with a purity of 98% according to HPLC- ELSD (IPA / ACN / H2O).

[0395] ’H-NMR (CDCh): complex spectrum in line with the expected structure.l 3C- NMR (CDCh) 5: 215.58, 215.32, 208.20, 207.65, 192.44, 172.82, 170.88, 170.81, 169.21 , 166.77, 140.20, 136.06, 135.48, 133.67, 130.14, 129.62, 128.17, 126.69, 126.36, 110.04, 98.47, 84.80, 84.37, 80.94, 76.46, 75.58, 67.82, 67.16, 59.38, 59.26, 57.72, 55.94, 55.88, 51.25, 49.86, 47.96,47.06, 46.60, 44.21, 41.44, 40.73, 40.20, 38.85, 38.26, 36.03, 35.64, 35.12, 34.56, 33.72, 33.50,33.22, 33.01, 32.92, 31.92, 31.39, 31.27, 29.69, 29.65, 29.57, 29.44, 29.39, 29.35, 28.38, 27.77,27.33, 27.26, 27.05, 26.89, 26.81, 26.38, 26.29, 25.30, 22.68, 21.72, 21.52, 20.65, 16.25, 16.07,15.93, 14.97, 14.12, 13.73, 13.10, 12.98, 10.15 ppm. HPLC-MS (IP.VACX I LO. gradient: 60- 90% B): t[prod] = 5.03 min; m / z = 1301.90 [M+Nap (SIM mode). MALDI (C74H122N2O15) calculated mass: 1278.88, found mass: 1301.87 [M+Nap, 1317.83 [M+K]+. CLogP = 16.6.

[0396] DiPEA (20 uL, 2 eq.) was added to a suspension of rapamycin hemi -succinate (49 mg, 49 pmol) and DMTMM (22 mg, 1.6 eq.) in DCM. After 15 minutes of pre-activation, dioctyl amine (25 gL, 1.8 eq.) was added and the resulting mixture was stirred for another 105 minutes.The reaction mixture was then diluted with 5 mL chloroform, extracted with 5 mL IM citric acid, 5 mL brine, dried with MgSCh, and evaporated to dryness. The product was purified by column chromatography (10 g SiOz Biotage Sfar, 0 —>■ 5% MeOH in CHCh). The resulting material, still contaminated with a triazine derivative from the coupling reagent , was dissolved in 10 mL EtOAc and extracted with 5 mL water, 5 mL brine, dried with MgSO4, and evaporated to dryness. The product was then again purified by column chromatography (10 g SiOz Biotage Sfar, 0 — > 70% EtOAc in CHCh), dissolved in EtOAc extracted with 2x5 mL IM citric acid, 5 mL brine, dried with MgSOr, and evaporated to dryness, redissolved in dioxane, filtered of a cotton plug, and lyophilized to afford 30 mg of the desired product with a purity of 95% according to HPLC-ELSD (IPA'ACN / HzO).

[0397] ’H-NMR. (CDCh): complex spectrum in line with the expected structure.{3C- NMR (CDCh) 8: 214.85, 208.51, 193.39, 175.40, 172.95, 172.92, 172.26, 170.92, 169.83, 169.37, 166.86, 140.54, 139.88, 136.52, 136.14, 135.86, 133.51, 130.29, 129.38, 126.60, 126.25, 98.58, 85.04, 84.33, 80.99, 77.32, 76.56, 75.63, 72.86, 67.87, 67.22, 67.11, 58.99, 57.68, 57.64, 55.93,51.34, 50.24, 50.03, 49.82, 49.60, 49.39, 49.17, 48.96, 48.03, 46.62, 46.29, 46.17, 44.26, 42.68,41.59, 40.87, 40.63, 40.26, 39.10, 38.30, 35.96, 35.02, 33.97, 33.43, 32.92, 31.84, 31.80, 31.38,31.17, 29.89, 29.72, 29.43, 29.35, 29.28, 29.26, 28.97, 28.01, 27.78, 27.20, 27.08, 26.98, 25.28,22.67, 22.65, 21.58, 21.43, 20.74, 16.43, 16.15, 16.03, 15.95, 15.87, 15.83, 14.81, 14.10, 13.58,13.51, 13.18, 10.36, 10.21 ppm. HPLC-MS (IPA / ACN / H2O, gradient: 60-90% B): t[prod] = 3.71 min; m / z = 1259.8 [M+Nap (SIM mode), MALDI (C71H116N2O15) calculated mass: 1236.84, found mass: 1259.83 [M+Na]+, 1275.80 [M K i CLogP = 15.1.Example 2D. Rapa-SucChol

[0398] A 10 mL round-botomed flask was filled rapamycin hemi-succinate (0.060 g, 0.06 mmol, 1.00 eq), and dissolved in a mixture of dry DCM (0.4 mL) and acetonitrile (0.2 mL) under argon atmosphere. Next, N,N-diisopropylethylamme (0.023 g, 31 pL, 0.18 mmol, 3.00 eq) was added to the solution. HATU (0.031 g, 0.08 mmol, 1.40 eq) was then added, and the resulting clear solution was stirred at RT for 5 min. Afterwards, solid cholesteryl N-methylglycinate (trifluoroacetate salt) (0.051 g, 0.09 mmol, 1.50 eq) was added to the mixture and was stirred at room temperature for 18 hours. The resulting clear solution was diluted with chloroform and washed with water (10 mL). The aqueous layer was extracted with chloroform (10 mL). The organic layers were combined, washed with brine (10 mL) and dried with MgSOv Removal of the solvent in vacuo gave the crude product as a light yellow glassy wax (0.109 g). The crude was purified by automated column chromatography (product: silica 1 :110; detector: 265 nm), eluting with toluene / EtOAc 80 / 20-20 / 80. Pure product (0.063 g, 73%) was obtained as an amorphous, white solid.

[0399] !H VW (400 MHz, CDCls) andi3C NMR (101 MHz, CDCh): the complex spectra are in line with the structure.5JC NMR (101 MHz, CDCls): 5 = 215.48, 215.28, 208.18, 207.63, 196.37, 192.49, 172.59, 171.95, 171.76, 169.84, 169.22, 168.71, 168.33, 166.76, 140.17, 139.43, 139.13, 136.06, 135.80, 135.51, 133.65, 133.38, 130.14, 129.98, 129.59, 129.31, 126.65, 126.38, 123.11, 122.80, 98.76, 98.48, 86.43, 84.80, 84.35, 80.92, 77.25, 76.52, 75.58, 74.99, 67.82, 67.17, 59.35, 59.25, 57.71, 57.69, 56.68, 56.25, 56.13, 55.95, 55.89, 51.76, 51.26, 49.98, 49.67, 46.59, 46.07, 44.22, 42.31, 41.46, 40.75, 40.20, 39.71, 39.51, 38.88, 38.29, 38.05, 36.92, 36.56,36.31, 36.18, 36.03, 35.78, 35.12, 35.03, 34.56, 33.74, 33.25, 32.91, 31.90, 31.84, 31.39, 31.27, 29.70, 29.56, 28.22, 28.08, 28.01 , 27.75, 27.26, 27.06, 25.30, 24.28, 23.82, 22.83, 22.57, 21.73, 21.53, 21.03, 20.67, 19.30, 18.72, 16.37, 16.26, 16.07, 15.94, 14.96, 13.74, 13.14, 13.00, 11.86, 10.33, 10.17 ppm. HPLC-MS (water / THF, gradient: 65-95% THF): tfprod] = 5.25 mm; m / z = 1475.9 [M+Nap (SIM mode). MALDI: calcd for CsdlrnNzNaOn 1475.94, found: 1475.99 ps i ■ X a| . CLogP == 18.4.

[0400] A solution of rapamycin-glut-NHS (64 mg, 56 mmol) in CDCh (0.5 mL) was placed in a reaction vessel. After addition of a solution of N -methyl octadecyl amine (18.5 mg, 1.15 eq.) in DCM (0.5 mL) and DiPEA (24 pL, 2.4 eq.), the resulting reaction mixture was stirred for 2 hours, after which LC / MS showed conversion >90%. The reaction mixture was then diluted with 5 mL chloroform, extracted with a mixture of 1 : 1 brine and 1 M citric acid, and evaporated to dryness. The crude material was purified by column chromatography (1 : 10 g SiOz Biotage Star 050% EtOAc in CHCI3, 2: 10 g SiCh Biotage Sfar 0 30 50% EtOAc in CHCI3), affording32 mg (44%) of the desired product, with a purity of >99% according to HPLOELSD (IPA / ACN / H2O).

[0401] TH-NMR (CDCh): complex spectrum in line with the expected structure.5JC- NMR(CDCh) 5: 215.45, 215.21, 208.20, 207.65, 196.41, 192.53, 172.98, 172.91, 171.97, 171.86, 169.84, 169.23, 166.77, 165.71, 140.75, 140.16, 136.19, 136.07, 135.55, 133.64, 133.38, 130.16, 129.98, 129.57, 129.31, 126.75, 126.64, 126.39, 98.76, 98.48, 86.44, 84.79, 84.43, 84.35, 80.95, 80.91, 77.25, 77.18, 76.07, 76.04, 75.61, 75.52, 67.82, 67.17, 59.34, 59.23, 57.54, 57.50, 56.24,55.93, 55.87, 51.26, 49.92, 47.76, 46.60, 46.07, 44.21, 41.46, 40.92, 40.79, 40.65, 40.46, 40.20,38.88, 38.59, 38.32, 35.93, 35.61 , 35.23, 35.12, 34.56, 33.97, 33.90, 33.74, 33.33, 33.20, 32.99,32.90, 32.45, 31.92, 31.83, 31.49, 31.35, 31.26, 30.98, 29.80, 29.69, 29.65, 29.59, 29.57, 29.55,29.43, 29.40, 29.35, 28.49, 27.88, 27.30, 27.25, 27.04, 26.90, 26.77, 25.29, 24.27, 22.68, 21.70,21.51, 20.70, 20.66, 20.45, 16.37, 16.24, 16.15, 16.04, 15.90, 15.86, 14.98, 14.12, 13.73, 13.14,12.99, 10.32, 10.16 ppm. HPLC-MS (IPA / ACNAIzO, gradient: 60-90% B): tfprod] - 4.61 min; m / z == 1315.9 [M- + N< (SIM mode). MALDI (C75I ImN 2O15) calculated mass: 1292.90, found mass: 1315.86 [M+Na]+. CLogP == 16.9.Example 2F. Rapa-glut-NHC18

[0402] Octadecyl amine (14 mg, 1.17 eq.) in 0.8 niL DCM, immediately followed by DiPEA (17.5 gL, 2.2 eq.), were added to a reaction vessel charged with rapamycin-glut-NHS (50 nig, 44 gmol), and stirred. The reaction mixture was briefly clear, formed a precipitate, was diluted with another 0.5 mL of DCM, and subsequently slowly became clear again. After 2 hours t reaction mixture was diluted with 5 mL CHCI3, extracted with a 1 :1 mixture of 1 M citric acid and brine (2x5 mL), evaporated to dryness, redissolved in CHCh, and evaporated again. The resulting crude material was purified by column chromatography (1 : 10 g SiO2 Biotage Star 0 — » 50% EtOAc in CHC13, 2: 10 g S1O2 Biotage Sfar 0 -> 50% EtOAc in CHCh, 2: 10 g SiO2 Biotage Sfar 0 45%EtOAc in CHC13 ), collected, and lyophilized from a minimal amount of dioxane, affording 17 mg (30%) of the desired product, with a purity of >99% according to HPLC-ELSD (IPA / ACNZH2O).

[0403] ’H-NMR. (CDCh) 5: complex spectrum in line with the expected structure. 13C- NMR (CDCh) 5: 215.46, 208.19, 207.65, 192.54, 172.85, 172.09, 169.25, 166.76, 140.16, 136.07,135.60, 133.63, 130.17, 129.55, 126.65, 126.40, 98.76, 98.48, 84.75, 84.35, 80.81, 77.21, 77.19,75.90, 75.49, 67.18, 59.37, 59.21 , 57.04, 55.94, 55.88, 51.25, 46.59, 44.21, 41.47, 40.59, 40.20,39.56, 38.89, 38.31, 35.71, 35.40, 35.13, 33.75, 33.62, 33.13, 32.88, 31.92, 31.33, 31.25, 29.78,29.69, 29.65, 29.60, 29.56, 29.35, 29.30, 27.25, 27.05, 26.94, 25.29, 22.68, 21.70, 21.52, 21.27,20.65, 16.40, 16.24, 16.02, 15.92, 15.87, 14.89, 14.12, 13.72, 13.14, 13.07, 10.33, 10.16 ppm. HPLC-MS (IPA. / ACN / H2O, gradient: 60-90% Bi. t[prod] == 4.45 mm; m / z == 1301.90 [M+Na]+(SIM mode). MALDI (C74HI22N2O15) calculated mass: 1278.88, found mass: 1301.88 [M+Na]+, 1317.85 [M-i-K]+.Example 2.G. Rapa-g!ut-NC8C8

[0404] Dioctyl amine (17 p.L, 1 eq.) in 0.6 ml DCM , immediately followed by DiPEA (20 pL, 2 eq.), were added to a reaction vessel charged with rapamycin-glut-NHS (61 mg, 55 pmol) and stirred. After 90 minutes HPLC indicated a conversion of about 80%. The reaction mixture was subsequently diluted with 5 mL CHCh, extracted with 1 M citric acid (2x5 mL), brine (5 mL), dried with MgSO4, and evaporated to dryness. The resulting crude material was purified with column chromatography (10 g SiO?. Biotage Sfar 30 -+ 40% EtOAc in CHCB), collected, and lyophilized from a minimal amount of dioxane, affording 33 mg (48%) of the desired product, with a purity of >99% according to HPLC-ELSD (IPA / ACN / H2O).

[0405] lH-NMR (CDCh) 8: complex spectrum in line with the expected structure.!3C- XMR. (CDCh) 8: 215.62, 208.19, 192.39, 172.94, 171.59, 169.21, 166.77, 140.21, 136.07, 135.47, 133.68, 130.13, 129.63, 126.71, 126.36, 98.77, 98.47, 84.78, 84.38, 80.94, 77.22, 76.06, 75.56,67.16, 59.41, 59.28, 57.56, 56.22, 55.94, 55.88, 51.25, 47.88, 46.61, 45.91, 44.21, 41.45, 40.69,40.20, 38.84, 38.28, 35.93, 35.12, 33.98, 33.70, 33.19, 33.01, 32.91, 32.00, 31.80, 31.76, 31.39,31.28, 29.80, 29.39, 29.32, 29.26, 29.21, 29.10, 27.81, 27.27, 27.08, 27.05, 26.91, 25.30, 22.63,22.61, 21.52, 20.74, 20.65, 16.38, 16.26, 16.16, 16.07, 15.91, 15.85, 14.99, 14.09, 13.75, 13.08,12.97, 10.31, 10.15 ppm. HPLC-MS (IPA / ACN / H2O, gradient: 60-90% B): tfprod] === 3.85 mm; m / z = 1273.85 [M+Na]+(SIM mode). MALDI (C72H118N2O15) calculated mass: 1250.85, found mass: 1273.83 [M+Naf, 1289.80 [M+K]+.Example 3 A. Rapa-C12C12

[0406] A 5 mL round-bottomed flask was charged with a solution of rapamycin (0.034 g, 0.037 mmol, 1.00 eq), dodecanoyl dodecanoate (0.036 g, 0.093 mmol, 2.50 eq) and DMAP (0.45 mg, 0.0037 mmol, 0.10 eq) in chloroform (0.75 ml, -0.05 M). Next, 7V,y-diisoProPy!et!,yiamins(0.014 g, 0.019 ml.,, 0.11 mmol, 3.00 eq) was added and stirred overnight at room temperature under argon atmosphere. Completion of the reaction was confirmed by TLC (heptaneZEtOAc 80 / 20) after 17 h. The reaction mixture was then purified by automated column chromatography (normal phase; product: silica 1:200; detection: 200-400 nm), eluting with chloroform / EtOAc 100 / 0-75 / 25. The fractions containing product were combined and concentrated in vacuo, giving a mixture of product and lauric aid. The material was purified twice by automated column chromatography (reversed-phase (Cl 8); product: C 18-silica 1 :350; detection: ELSD), eluting with water / THF50 / 50—15 / 85. Pure fractions were combined and THF was removed in vacuo. The remaining waterrich solution was lyophilized, giving pure product (0.028 g, 59%) as a white solid.

[0407] Purity of the compound was confirmed by!H NMR (400 MHz, CDCh) andi3CNMR (101 MHz, CDCh). HPLC-MS (water / THF, gradient: 70-95% THF): t[prod] === 3.65 min; m / z ------ 1300.9 | M Xa | (SIM mode). MALDI: calcd for CvsHizaNOnNa 1300.88, found: 1300.90 ps i ■ \ a| . CLogP == 19.4.Example 3B. Rapa-CHC8C6

[0409] M LNMR (CDCh) 8: ppm.i ;('-NXIR (CDCh) 8: ppm. MALDI (CseHsiNOu) calculated mass: 997.61. LCMS. CLogP = 9.2.Example. 3D, Rapa-C18

[0410] A 25 mL flask was charged with rapamycin (0,070 g, 0.08 mmol, 1.00 eq) and vinyl stearate (0,119 g, 0.38 mmol, 5.00 eq). Dry toluene (7 mL) was added, resulting in a colorless, clear solution. Novozyme 435 (35 mg) was added and the resulting suspension agitated under reduced pressure (-500 mbar) at 45 °C using a rotary evaporator for 50 hours. Care was taken that no solvent evaporated. Conversion was checked with TLC (toluene / EtOAc 80 / 20). Usually, the rapamycin is not fully consumed. The reaction mixture was then filtered through a glass frit filter, filter rinsed with toluene (5 mL) and the combined filtrates concentrated in vacuo. The residual crude material (white solid) is purified by automated column chromatography (product: silica 1 :60, detector: 265 nm), eluting with toluene / EtOAc 90 / 10- 70 / 30). This resulted in pure product (69 mg, 72%). Purity was confirmed by NMR, MALDI-TOF and LCMS (water / THF).

[0411] !H NAIR (400 MHz, CDC13): (complex) spectrum is available.13C NAIR (101 MHz, CDC13): 8 === 215.39, 215.21 , 208.22, 207.67, 196.40, 192.52, 173.41 , 173.36, 169.84, 169.23, 166.76, 165.70, 140.76, 140.13, 136.17, 136.03, 135.56, 133.63, 133.39, 130.15, 129.97, 129.56, 129.33, 126.70, 126.60, 126.39, 98.77, 98.47, 86.44, 84.79, 84.44, 84.34, 80.96, 75.94, 75.91, 75.61, 75.49, 67.82, 67.17, 59.31 , 59.22, 57.53, 57.51, 56.25, 55.94, 55.88, 51.27, 46.61, 46.08, 44.22, 41.49, 40.94, 40.82, 40.65, 40.47, 40.20, 38.89, 38.60, 38.37, 36.04, 35.88, 35.61 , 35.10,34.75, 34.57, 33.75, 33.23, 33.03, 32.93, 31.92, 31.47, 31.32, 31.27, 31.00, 29.81, 29.69, 29.65,29.62, 29.49, 29.36, 29.31, 29.09, 27.89, 27.26, 27.05, 25.30, 25.09, 25.06, 24.27, 22.69, 21.70,21.50, 20.67, 16.40, 16.25, 16.21, 16.05, 15.93, 15.87, 14.98, 14.13, 13.71, 13.19, 13.04, 10.32,10.17 ppm. HPLC-MS (water / THF, gradient: 65-95% B): t[prod] = 5.77 min; ni / z = 1202.8[M+Na]+(SIM mode). MALDI: ((P^HiiaNNaOu) calculated mass: 1202.81, found mass: 1202.82

[0412] Oleoyl chloride (51 mg, 1.18) in DCM (0.5 mL), immediately followed by pyridine (25 pL, 2.2 eq.), was added to a reaction vessel charged with rapamycin (129 mg, 0.141 mmol), and stirred. After 2 hours the reaction mixture was quenched with MeOH (55 pL, ~10 eq.), stirred briefly, and evaporated to dryness. The resulting crude product was purified bycolumnchromatography (1 : 10 g SiO2 Biotage® Star 0 30% EtOAc in chloroform, 2: 10 g SiO2Biotage® Sfar 0 — > 30% EtOAc in chloroform), collected, and lyophilized from a minimal amount of dioxane to afford 120 mg (72%) of the desired ester, with a purity of >99% according to HPLC- ELSD (IPA / ACN / H2O).

[0413] lH-NMR (CDC13) 5: complex spectrum in line with the expected structure.13C- NMR (CDC13) 8: 215.53, 215.34, 208.20, 207.65, 192.44, 173.37, 169.87, 169.22, 166.76, 140.18, 136.17, 136.03, 135.52, 133.66, 133.40, 130.14, 129.98, 129.75, 129.60, 129.34, 126.67, 126.38, 98.76, 98.47, 86.42, 84.76, 84.36, 80.95, 80.90, 77.20, 75.91, 75.50, 67.83, 67.16, 59.37, 59.27, 57.52, 56.22, 55.94, 55.88, 51.25, 46.61, 46.07, 44.21, 41.47, 40.81, 40.65, 40.20, 38.87, 38.35,36.03, 35.63, 35.11, 34.72, 34.57, 33.71, 33.21, 33.03, 32.93, 31.89, 31.32, 31.27, 29.80, 29.75,29.70, 29.51, 29.31, 29.20, 29.12, 29.05, 27.26, 27.21, 27.16, 27.04, 25.30, 25.06, 22.67, 21.71,21.51, 20.66, 16.37, 16.25, 16.21, 16.05, 15.94, 15.85, 14.97, 14.11, 13.71, 13.12, 12.98, 10.31,10.15 ppm. HPLC-MS (IPA / ACNZH2O, gradient: 60-90% B): t[prod] - 5.27 mm; m / z = 1200.80| M \a | (SIM mode). MALDI (Ced-IiiiNOii) calculated mass: 1177.80, found mass: 1200.77 | \ l ■ \a| . 1216.74 | M K | .Example 3F. Rapa-CHC2C2

[0414] 2-Ethylbutanoyl chloride (17 pL, 1.1 eq.), immediately followed by pyridine (20 pL, 2.2 eq.), was added to a stirring solution of rapamycin (100 mg, 0.109 mmol) in 0.5 mL DCM. After 2 hours the reaction mixture was quenched with MeOH (50 pL), stirred briefly, and evaporated to dryness. The crude product was purified by column chromatography (1 : 10 g SiCh Biotage® Star 0 — > 30 40% EtOAc in chloroform, 2: 10 g SIOT Biotage® Sfar 0 30 40% EtOAc in chloroform), collected, and lyophilized from a minimal amount of dioxane to afford 67 mg (61%) of the desired ester with a purity of >99% according to HPLC-ELSD (IPA / ACN / H2O).

[0415] ^I-NAIR (CDCh) 5: complex spectrum in line with the expected structure.1JC- NMR (CDCh) 8: 215.49, 208.23, 207.67, 192.46, 175.74, 169.22, 166.76, 140.16, 136.02, 135.54, 133.65, 133.40, 130.15, 129.58, 126.64, 126.38, 98.47, 86.42, 84.76, 84.35, 80.97, 77.21 , 77.18, 75.49, 67.16, 67.08, 59.34, 57.40, 55.88, 51.26, 50.87, 49.34, 46.61, 44.22, 41.48, 40.61, 40.20, 38.87, 38.39, 36.03, 35.10, 33.72, 33.23, 32.93, 31.28, 29.89, 27.25, 27.04, 25.23, 25.15, 21.50, 20.66, 16.25, 16.06, 15.93, 13.70, 13.14, 12.96, 11.72, 11.69, 10.15 ppm. HPLC-MS (ACN / ILO,gradient: 5-100% B): tfprod] = 6.14 min; m / z = 1035.17 (M+Na]*, 1056.75 [M+formate] . MALDI (C57H89NO14) calculated mass: 1011.63, found mass: 1034.61 [M+Na]+, 1050.59 [M+K]+.

[0416] Rapamyommg, 55 jimol), octadecyl isocyanate (43 mg, 2.5 eq.), and dibutyltin dilaurate (~5 mg) were stirred in a mixture of DMF (0.5 mL) and chloroform (0.5 mL) for 16 hours at room temperature. The resulting turbid reaction mixture was evaporated to dryness and purified by silica column chromatography (1 : 10 g SiCh Biotage® Star 0-->5% MeOH in chloroform, 2: 10 g SiOz Biotage® Star 0-->50% EtOAc in chloroform), affording 22 mg (33%) of the desired compound with a purity of 98% according to HPLC-UV / Vis (IPA / ACN / H2O).

[0417] ^-{-NMR (CDCh): complex spectrum in line with the expected structure.:’C-NMR (CDCI3) 8: 215.41, 215.22, 208.22, 207.65, 196.35, 192.50, 169.83, 169.22, 166.76, 165.72, 156.15, 140.74, 140.14, 136.17, 136.01, 135.54, 133.64, 133.38, 130.14, 129.98, 129.57, 129.31 , 126.74, 126.60, 126.39, 98.75, 98.47, 86.44, 84.77, 84.42, 84.34, 81.09, 77.22, 77.15, 76.46, 75.60, 75.50, 67.82, 67.16, 59.30, 59.22, 57.25, 56.24, 55.94, 55.88, 51.26, 46.60,46.06, 44.21 , 41.48, 41.02, 40.79, 40.68, 40.47, 40.20, 38.89, 38.60, 38.37, 36.01, 35.61, 35.08, 34.55, 33.73, 33.27,33.04, 32.96, 31.91, 31.49, 31.34, 31.26, 30.97, 30.27, 29.97, 29.68, 29.64, 29.59, 29.55, 29.35,29.30, 27.88, 27.25, 27.04, 26.93, 26.76, 25.29, 24.27, 22.68, 21.69, 21.49, 20.66, 20.57, 16.39,16.25, 16.18, 16.06, 15.94, 15.86, 14.95, 14.11, 13.68, 13.63, 13.17, 13.01 , 10.63, 10.31, 10.15 ppm. HPLC-MS (IPA / ACN / H2O, gradient: 60-90% B): t[prod]:;= 5.53 min; m / z = 1231.85[M+Na]+(SIM mode). MALDI (C70H116N2O14) calculated mass: 1208.84, found mass: 1231.84 [M+Naf, 1247.81 IM K| . CLogP 16.7.Example 4B. Rapa-BisCarbamate-CIS

[0418] Rapamycin (52 mg), octadecyl isocyanate (192 mg, 11.4 eq.) and dibutyltin dilaurate (3 mg) were stirred in chloroform (1 mL) at 45°C for 20 hours. The crude reaction mixture was purified by silica column chromatography (10 g SiOz Biotage® Sfar 0 —> 25% EtOAc in chloroform), dissolved in chloroform and filtered over a coton plug, evaporated to ‘lry!KSS, and lyophilized from a minimal amount of dioxane affording 48 mg (56%) of the desired compound with a purity of >99% according to HPLC-ELSD (IPA / ACN / HzO).

[0419] ’ H-NMR (CDCb): complex spectrum in line with the expected structure.eC-NMR(CDCh) 5: 213.22, 212.88, 210.85, 208.15, 193.16, 169.12, 166.56, 166.09, 156.17, 154.64, 140.66, 139.06, 136.20, 134.44, 133.21, 130.20, 129.01, 126.83, 126.52, 126.22, 98.51, 98.43, 86.73, 84.34, 84.02, 81.14, 77.21, 75.52, 67.98, 67.20, 59.02, 58.64, 57.21, 56.29, 55.93, 55.83,51.16, 46.79, 46.39, 44.16, 41.22, 41.03, 40.41, 39.15, 38.33, 34.34, 34.00, 33.89, 32.84, 31.92,31.41, 31.11, 30.30, 29.98, 29.79, 29.69, 29.65, 29.62, 29.59, 29.56, 29.44, 29.35, 29.30, 27.23,26.91, 26.76, 26.73, 25.24, 24.77, 22.68, 21.63, 21.07, 20.71, 16.20, 16.01, 15.74, 14.38, 14.11,13.69, 10.48, 10.19 ppm. HPLC-MS (IPAACN / HzO, gradient: 60-90% B): tfprod] = 9.96 min;m / z = 1527.15 [M+Na]e(SIM mode). MALDI (CssHissNsOn) calculated mass: 1504.13, found mass: 1527.05 [M+Na]+. CLogP = = 26.3.Example 4C. Rapa-Carbamate-C8C8

[0420] A solution of rapamycin-OC(O)PNP (35 mg, 32 gmol) and dioctyl amine (21 gL, 2.1 eq.) was stirred in DCM (0.5 mL) for 16 hours, after which HPLC indicated 60% conversion to the carbamate (or urethane), combined with 35% hydrolysis of the internal ester. Theresulta»s reaction mixture was evaporated to dryness and purified by silica column chromatography (10 g SiOz Biotage Sfar 0 40% EtOAc in chloroform) to afford 16 mg product with about 75% purity.This was combined with 23 mg of the same material from previous batches and purified again by column reverse-phase chromatography (12 g Cl 8 Biotage Sfar 50— *100% isopropanol in water). The resulting material was isolated and lyophilized from a minimal amount of dioxane to afford 18 nig (overall, 29%) of the desired compound, with a purity of >99% according to HPLC-ELSD (IPA / ACN / H2O).

[0421] 1H-NMR (CDCls): complex spectrum in line with the expected structure.5JC-NMR (CDCb) 8: 215.42, 208.27, 192.49, 169.22, 166.76, 155.93, 140.13, 136.03, 135.52, 133.66, 130.13, 129.59, 126.59, 126.38, 98.75, 98.47, 84.79, 84.34, 81.47, 77.21, 77.14, 75.53, 67.16, 59.29, ” 46, 57.43, 55.89, 51.25, 46.62, 44.22, 41.48, 40.73, 40.20, 38.88, 38.34, 36.01, 35.05, 33.72, 33.33, 32.97, 31.82, 31.41, 31.27, 30.36, 29.39, 29.26, 27.25, 27.05, 26.88, 25.30, 22.65, 21.48, 20.66, 16.25, 16.09, 15.93, 14.93, 14.09, 13.66, 13.18, 10.15 ppm. HPLC-MS(IPA / ACN / H2O, gradient: 60-90% B): t[prod] = 4.57 min; ni / z = 1203.8 [M+Na]+(SIM mode). MALDI (C68HU2N60I 4) calculated mass: 1180.81 found mass: 1203.83 (M+Na]+. CLogP - 15.7.Rapa-carbonate-CHC8C8

[0422] Pyridine (24 pL, 2,5 eq.) was added to a stirring solution of rapamycin (106 mg.0.116 mmol) and 9-heptadecanyl chloroformate (49 mg, 1.3 eq.) in 1 mL DCM cooled in an ice bath. After the addition of the pyridine the reaction mixture was allowed to warm too room temperature. After 105 minutes the reaction was quenched with methanol (50 pL), diluted with 5 mL chloroform, washed with 1 M citric acid (2x5 mL), dried over MgSCh, and evaporated to dryness. The crude product wasp'“rifiedby column chromatography (1 : 10 g SiCh Biotage® Sfar 0 — > 40% EtOAc in chloroform, 2: 10 g SiCh Biotage® Sfar 0 35% EtOAc in chloroform), collected, and lyophilized from a minimal amount of dioxane to afford 56 mg (40%) of the desired carbonate with a purity of >99% according to HPLC-ELSD (IPA / ACNZH2O).

[0423] ^I-NAIR (CDCI3) 5: complex spectrum in line with the expected structure.1JC- NMR (CDCh) 8: 215.70, 208.20, 207.63, 192.34, 169.87, 169.20, 166.78, 165.64, 154.92, 140.24, 136.07, 135.42, 133.70, 133.41, 130.12, 129.95, 129.67, 126.73, 126.34, 98.77, 98.47, 86.43, 84.79, 84.40, 81.13, 79.70, 78.90, 77.21 , 75.55, 67.15, 59.42, 59.31, 57.64, 57.62, 56.21, 55.94,55.88, 51.25, 46.61, 44.21, 41.43, 40.70, 40.19, 38.81, 38.26, 35.87, 35.64, 35.12, 34.17, 33.68,33.20, 33.08, 32.96, 32.84, 31.84, 31.37, 31.29, 31.00, 29.72, 29.52, 29.49, 29.46, 29.22, 27.27,27.05, 25.30, 25.26, 25.15, 22.65, 21.72, 21.53, 20.65, 16.37, 16.26, 16.17, 16.08, 15.93, 15.84,15.01, 14.09, 13.77, 13.05, 12.94, 10.31, 10.14 ppm. HPLC-MS (IPA / ACN / H2O, gradient: 60-90% B): t[prod] == 5.94 mm; m / z == 1218.80 [M+Na]+(SIM mode). MALDI (CssHinNOn) calculated mass: 1195.81, found mass: 1218.80 [M+Na]+, 1234.76 [M+K]+.Example 5A, Rapa-Carbonate-CIS

[0424] Pyridine (25 uL, 0.3 mmol, 3 eq.) was slowly added to a solution of octadecyl chloroformate (53 mg, 0.16 mmol, 1,6 eq.) and rapamycin (92 mg, 0.10 mmol) m 0.5 mL dry DCM. After addition of pyridine the reaction mixture was allowed to warm to room temperature and was stirred for an additional 45 minutes. The reaction mixture was then diluted with 5 mL chloroform, extracted with 1 M citric acid (2x5 mL) and brine (5 mL), dried over MgSCh, and evaporated to dryness to afford a mixture of crude lx and 2x reacted product and other sideproduct. The crude material was purified by silica column chromatography (10 g Biotage® Sfar, 0-->30% EtOAc in chloroform, twice) to separate the mono-carbonate and the di-carbonate from unreacted rapamycin and hydrolyzed side-products. This yielded 63 mg (52%) of the mono- octadecyl-carbonate, with a purity of >99% according to HPLC-ELSD (IPA / ACN / H2O), and 15 mg (10%) of the di-octadecyl-carbonate, with a purity of >99% according to HPLC-ELSD.

[0425] Mono-carbonate:lH-NMR (CDCh): complex spectrum in line with the expected structure.i ;C-NXIR (CDCh) 8: 215.60, 215.34, 208.20, 207.69, 192.43, 169.87, 169.22, 166.78, 165.67, 154.97, 154.91, 140.82, 140.22, 136.16, 136.08, 135.96, 135.47, 133.68, 133.41, 130.13, 129.95, 129.63, 129.36, 126.68, 126.35, 98.79, 98.47, 86.45, 84.81, 84.38, 80.89, 80.83, 79.97, 77.22, 77.19, 75.63, 75.54, 68.10, 67.82, 67.16, 59.39, 59.28, 57.56, 57.54, 56.22, 55.94, 55.87,51.25, 46.60, 46.06, 44.21, 41.44, 40.84, 40.68, 40.20, 38.84, 38.56, 38.24, 35.79, 35.62, 35.12,34.58, 33.71, 33.19, 33.01, 32.91 , 32.81, 31.92, 31.43, 31.32, 31.27, 31.01, 29.68, 29.65, 29.63,29.56, 29.49, 29.35, 29.24, 28.66, 27.26, 27.04, 25.69, 25.29, 22.68, 21.72, 21.53, 20.65, 16.40,16.25, 16.18, 16.06, 15.92, 15.84, 15.00, 14.12, 13.77, 13.10, 12.99, 10.31, 10.15 ppm. HPLC-MS(IPA / ACN / H2O, gradient: 60-90% B): tfprod] = 5.97 min; m / z = 1232.85 [M+Na]+(SIM mode). MALDI (C70H115NO15) calculated mass: 1209.83 found mass: 1232.79 [M+Na]+. CLogP = 16.9.Example 5B. Rapa-BisCarbonate-C18

[0426] See the description of Rapa-Carbonate-C18. Di-carbonate: ’H-NMR (CDCI3): complex spectrum in line with the expected structure.bC-NMR (CDCh) 8: 212.23, 211.09, 207.70, 192.98, 169.25, 166.59, 154.97, 153.96, 139.68, 135.80, 133.39, 130.15, 129.30, 128.22, 126.65, 98.54, 84.17, 84.14, 80.90, 80.74, 79.95, 77.21 , 75.36, 68.57, 68.09, 67.18, 59.33, 57.50, 57.44, 55.87, 51.22, 46.63, 44.1 1 , 41.18, 40.1 1, 38.22, 35.63, 34.86, 33.83, 33.62, 32.75, 31.92,31.31, 31.13, 29.69, 29.65, 29.63, 29.59, 29.57, 29.50, 29.42, 29.35, 29.25, 29.23, 28.66, 28.58,28.55, 27.29, 26.92, 25.70, 25.61 , 25.22, 22.68, 21.42, 20.61, 16.21, 15.96, 15.72, 15.46, 14.60,14.1 1, 13.54, 10.20 ppm. HPLC-MS (IPA / ACN / H2O, gradient: 60-90% B): t[prod] - 11.17 min; m / z::::1529.10 [M+Na]+(SIM mode). MALDI (CssNisiNOi?) calculated mass: 1506.10 found mass: 1530.07 d \l • \a j "e CLogP::::26.7.Example SC. Rapa-carbonate-C8

[0427] Pyridine (25 pL, 2,5 eq.) was added to a stirring solution of rapamycin (103 mg, 0.113 mmol) and octyl chloroformate (29 mg, 1 ,1 eq.) in 1 mL. DCM cooled in an ice bath. After the addition of the pyridine the reaction mixture was allowed to warm to room temperature. After 90 minutes the reaction was quenched with MeOH (50 pL), stirred briefly, diluted with 5 mL chloroform, extracted with IM citric acid (2x5 mL), brine (5 mL), dried over MgSOr and evaporated to dryness. The crude product was purified by column chromatography (1: 10 g SiOz Biotage® Sfar 0 50% EtOAc in chloroform, 2: 10 g S1O2 Biotage® Star 0 50% EtOAc in chloroform), collected, and lyophilized from a minimal amount of dioxane to afford 55 mg (42%) of the desired carbonate ester with a purity of >99% according to HPLC-ELSD (IPA / ACN / H2O).

[0428] fl-I-NN'IR (CDCh) 5: complex spectrum in line with the expected structure.1JC- NMR (CDCh) 8: 215.65, 215.43, 208.19, 207.65, 192.39, 169.88, 169.22, 166.77, 154.96, 140.83, 140.23, 136.16, 136.07, 135.46, 133.68, 133.41, 130.13, 129.95, 129.64, 129.36, 126.72, 126.35, 98. / 8, 98.47, 86.43, 84.78, 84.47, 84.38, 80.89, 80.82, / 9.97, / / .21, / 5.54, 68.08, 67.84, 67.16,59.42, 59.32, 57.56, 56.21, 55.95, 55.88, 51.25, 46.60, 46.06, 44.21, 41.44, 40.83, 40.68, 40.19,38.83, 38.24, 35.80, 35.65, 35.13, 33.70, 33.18, 33.02, 32.81, 31.75, 31.43, 31.31, 29.69, 29.18,29.14, 28.65, 27.26, 27.05, 25.68, 25.30, 22.61, 21.73, 21.53, 20.65, 16.37, 16.26, 16.19, 16.05,15.92, 15.00, 14.07, 13.77, 13.07, 12.95, 10.30, 10.15 ppm. HPLC-MS (IPA / ACN / ILO, gradient: 60-90% B): tfprod] - 1.88 mm; m / z - 1092.65 [M+Na];(SIM mode). MALDI iCA DNOri calculated mass: 1069.67, found mass: 1092.65 [M+Na]+, 1108.62 [M+K]+.

[0429] A suspension of octadecanol (143 mg, 0.53 mmol) in toluene (0.3 mL, stored on molsieves) with DiPEA (100 uL, 0.58 mmol, 1.1 eq.) was placed in a water bath (functioning as a heat sink). Triflic anhydride (90 pL, 0.54 mmol, 1.02 eq) was then carefully and slowly added to the stirring suspension, causing most of the alcohol to dissolve, resulting in a tan solution. More DiPEA (100 gL, 0.58 mmol, 1.1 eq.) was added to this reaction mixture, after which rapamycin (121 mg, 0.13 mmol, 0.25 eq.) was added as a solid. Residual solid clinging to the walls of the reaction vessel was washed into the reaction mixture with a small amount of toluene (0.1 mL). This mixture was stirred at 40°C for 16 hours, quenched with 1 mL saturated NaHCCh, and diluted with 5 mL water and 8 mL EtOAc. After transfer to a separator}' funnel the organic phase was separated. The water phase was adjusted to pH = 8 with more saturated NaHCO3 and extracted 2 more times with 5 mL EtOAc. The combined organic phases were washed with saturated NaHCO3 and brine, dried with Na2SO4, and evaporated to dryness. The crude product was purified by column chromatography (25 g SiO2 Biotage Sfar, 0 20% EtOAc in CHC13) affording 44 mg(29%) of desired product with a purity' of >99% according to HPLC-ELSD (IPA / ACN / H2O).

[0430] ’H-NMR (CDCh): complex spectrum in line with the expected structure.{3C- NMR (CDCh) 5: 215.72, 208.19, 192.42, 169.23, 166.78, 140.24, 136.05, 135.45, 133.70, 130.16, 129.99, 129.67, 126.84, 126.37, 98.76, 98.49, 84.84, 84.42, 83.10, 82.71, 75.76, 70.13, 67.17,59.48, 59.30, 58.17, 55.88, 51.25, 46.56, 46.06, 44.21, 41.41, 40.80, 40.23, 38.82, 38.33, 36.59,35.16, 33.71, 33.19, 33.12, 31.93, 31.88, 31.29, 30.36, 30.13, 29.70, 29.66, 29.53, 29.37, 27.28,27.08, 26.20, 25.32, 22.70, 21.75, 21.55, 20.65, 16.27, 16.06, 15.95, 14.98, 14.13, 13.79, 13.06,10.35, 10.16 ppm. HPLC-MS (IPA / ACN / HzO, gradient: 60-90% B): t[prod] = 7.06 min; m / z =1188.8 [M-i-Na]" (SIM mode). MALDI (C69H115NO13) calculated mass: 1165.84, found mass: 1188.81 | M Nai and 1204.78 i \T K| . CLogP 16.7.Example 8. Preparation of Nanopartide Compositions

[0431] Compositions containing Spherical nanoparticles of the present disclosure can be prepared according to the following protocol:

[0432] Materials:

[0433] 1. Phospholipid monolayer by combining POPC (l-pahnitoyl-2-oleoyl-sn- glycero-3-phosphocholine), and PHPC (1 -palmitoyl- 2-hydroxy-sn-glycero-3-phosphocholine) in a molar ratio ranging from 1 :0 to 1: 1.

[0434] 2. Integrating apolipoprotein Al (apoAl), weight percentage (relative to phospholipids) ranging from 5% to 250%.

[0435] 3. Enclosing a core of triglycerides (TG, tricaprylin), weight percentage (relative to phospholipids) ranging from 0% to 1000%.

[0436] 4. The core in which additionally compounds (e.g., a compound in Table 1) are incorporated at weight ratios varying from a 1 :0 compound / TG to 1 : 10 compound / TG.

[0437] Method: using a microfluidic setup, an aqueous solution of apoAl and an acetonitrile / m ethanol mixture containing 1, 3 and 4 is injected into a herringbone mixer, with a flow rate of X ml / min for the lipid solution and a rate of 8X ml / min for the apoAl solution. The obtained product is concentrated and filtered through to obtain compound-loaded nanoparticles.Example 9. Evaluation of Nanoparticle Compositions in Heart Transplant Model

[0438] BALB / c hearts are transplanted as fully vascularized heterotopic grafts intoC57BL / 6 mice as previously described (Corry et ah, 1973), Hearts are transplanted into recipients’ peritoneal cavities by establishing end-to-side anastomosis between the donor and recipientperitoneal cavities by establishing end-to-side anastomosis between the donor and recipient aortae and end-to-side anastomosis between the donor pulmonary trunk and the recipient inferior vena cava.

[0439] Transplant recipient mice are treated with 3 intravenous injections of the exemplary nanoparticle compositions at about 5 mg / kg test compound (e.g., a compound of Formula (I), (II), (III), (IV), or Table 1), at the day of transplantation as well as on postoperative days 2 and 5. The myeloid cell compartment in the allograft, blood and spleen of the mice receiving treatment or placebo is profiled.Example 10. Evaluation of Nanopartide Compositions in Acute Respiratory Distress(ARDS) model

[0440] The composition used in the study is shown in the table below:

[0441] Table A. Nanopartide composition (mTOR-HDL)

[0442] Study design:

[0443] As outlined in FIG. 1 mice received LPS (0.1 mg / Kg) intratracheally (i.t.) to induce lung inflammation, (a model for acute respiratory distress syndrome, ARDS). At 30 minutes and 2 hours following LPS administration, mice were intravenously treated with the Compound 1 A containing nanoparticle (5 mg / kg). To study metabolic activity in the bone marrow and lung inflammation quantitatively, mice received 2-deoxy-2-[18F]fluoro-D-glucose (FDG), a radiolabeled sugar analogue. FDG uptake in the bone marrow is reflective of (metabolic) activity. It’s the source of the systemic inflammatory response in the lungs. FDG uptake in the lungs is reflective of inflammation. Six mice were also administered no LPS / no nanoparticle as a control group.

[0444] Results

[0445] FIG. 2 depicts percent injected dose of FDG per gram tissue. As shown in FIG. 2 bone marrow of mice with LPS-induced lung inflammation showed a significantly higher FDG uptake compared to control mice. Bone marrow of LPS treated mice that intravenously received the Compound lA-containing nanoparticles, had a similar (low') metabolic activity as control animals. These data indicate that the Compound I A- nanoparticles, silence metabolic activity in the bone when ARDS is induced in mice.

[0446] FIGs. 3A-C depicts percent injected dose of FDG per gram tissue. FDG uptake in the lungs is reflective of inflammation. The lungs of animals that received intratracheal LPS showed a four-fold increased uptake of FDG, indicative of severe lung inflammation. In animals that were treated with the Compound 1A nanoparticles, the LPS-induced increased lung inflammation was significantly reduced, and only somewhat higher than untreated mice (See FIGs. 3A-C).Example 11. Evaluation of Nanopartide Compositions in model

[0447] The composition of the mTOR inhibitor compositions used in the study is shown in the table below:

[0448] Table B. Nanopartide composition (mTOR-HDL)

[0449] Study design:

[0450] As outlined in FIG. 4 mice received LPS (0. 1 mg / kg) intraperitoneally. At 1 hour following LPS treatment, mice received the Compound 1A nanoparticles intravenously, after which FDG, a radiolabeled sugar analogue, was administered. FDG uptake in the bone marrow is reflective of (metabolic) activity. It’s the source of the systemic inflammatory response. A control group was administered no LPS / no nanoparticles.

[0451] Results

[0452] FIG. 5 depi cts percent injected dose of FDG per gram tissue. The bone marrow of mice with LPS-induced lung inflammation showed a significantly higher FDG uptake as compared to control mice. Bone marrow of LPS treated mice that intravenously received the Compound 1 A nanoparticles had a similar (low) metabolic activity as control animals (see FIG. 4 and FIG. 5). These data indicate that the Compound 1A nanoparticles silence metabolic activity in the bone after LPS induced cytokine storm in mice.Example 12. Stability Studies of Compounds in Solution and Formulated in Compositions

[0453] This example provides stability data for the compounds of Table C and stability after subsequent incorporation into a nanoparticle composition.

[0454] Table C. Select Compounds of the Present Disclosure

[0455] Stability of Compounds in Solution

[0456] The compounds of Table C were dissolved in a 9:1 THF / water + 0.25% TEA solution. A high-level overview of the study is shown in Table D,

[0457] Table D. Overview of Stability Study of Compounds in Solution

[0458] Analytical Method for Measuring Compound Stability: Samples were measured with HPLC using both UV / Vis and MS detection. The UV / Vis detector is used to quantify the remaining parent material (= compound) and the degradation products, whenever possible. The MS detector (primarily used in SIM mode) is used to identify the different species. Two degradation products, rapamycin and secorapamycm, overlap with this HPLC setup and are indicated in the data as (seco-)rapamycm when they were detected. The species included in SIM are rapamycin, the parent molecule, the parent molecule +18, and the parent molecule minus one (or more) apolar substituent(s), where relevant, as M+Nah, XI \ 114 molecular ions.

[0459] Data Analysis: To quantify the stability of the compounds, the fraction of intact compound was determined as a function of the fraction of the total integral of the UV / Vis data at 278 nm, the Xmax of rapamycin. Based on the MS data, degradation products were assigned to the individual peaks (were possible) and individually plotted for each timepoint.

[0460] Stability7Data of Compounds in Solution: All compounds, with exception of Rapa- DLG[click], Rapa-bis~carbonate-C18, and Rapa-DSG[ click], showed a similar degradation rate in which the amount of intact compound that remained after 16 days varied between 40 - 60% (FIG. 7).

[0461] Formulation of Compounds in a Nanoparticle Composition

[0462] The formulation is shown below in Table E, For formulation and storage, a PBS buffer with pH of 6 is used as hydrolysis of the macrocyclic ester of rapamycin occurred at pH >6.

[0463] Table E. Nanopartide Formulation

[0464] Formulation Process: Formulations were performed using a stainless-steel three- way junction (ID=1. 59 mm (1 / 16”)) connected to two syringe pumps. Subsequent concentration and diafiltration of the nanoparticles was achieved using Vivaspin filters with a regenerated cellulose (RC) membrane with a 10 kDa MW cutoff. Afterwards, concentrated trehalose solution (50 w / v%) is added as a cryoprotectant (to 5 w / v% final concentration), and the nanoparticles are passed through a 0.2 pm filter to obtain the final product (at approximately 2-4 mg compound / mL).

[0465] In an alternative example to the formulation described in Table E, the organic phase may be isopropanol.

[0466] Stability7of Formulated Compounds

[0467] The analytical methods used to measure the stability of the formulations were a combination of HPLC-RP-UV+CAD, HPLC-SEC-RI, and DLS.

[0468] All of the compounds were formulated into the nanoparticles as described above, all samples were released in accordance with the following target conditions:

[0469] Compound recovery: >30% (i.e., = starting amount of the compound / concentration of the compound after HPLC-RP-UV+CAD analysis X final volume of nanoparticles ) X 100%.

[0470] Z-average by DLS: 30 - 90 nm.

[0471] PDI by DLS: < 0.3.

[0472] After release, a forced degradation study was initiated in which samples were aliquoted in 200 mM tris, pH 8.5 and stored at 22 °C in the dark. Testing was performed as outlined in Table F.

[0473] Table F. Stability Study Design and Tested Parameters

[0474] Throughout the stability study, the nanoparticles remained size and shape remained unchanged, indicating stability of the nanoparticles and compatibility of the compounds with the nanoparticle carrier components. In contrast with the stability profiles of the compounds in solution, differences were observed in the stability of the compounds when incorporated into the nanoparticle formulations (FIG. 8A). The stability at different timepoints for each compound is shown at FIG. 88.

[0475] Potency of the Formulated Compounds

[0476] .Assay description:

[0477] The nanoparticles inhibit trained immunity via inhibition of mechanistic target of rapamycin (mTOR) to treat inflammation driven diseases such as inflammatory bowel disease (IBD) or Hidradenitis suppurativa (HS). To determine the potency of individual nanoparticles formulated using different compounds of the present disclosure, a medium to high-throughput in vitro potency assay was developed to determine the half maximal inhibitory concentration (ICso). The assay focuses on measuring inhibition of LPS-induced MCP-1 secretion from THP-1 cell, which reflects a biologically relevant functional readout since MCP-1 levels serve as an indicator of mTOR pathway inhibition and trained immunity modulation by rapamycin derivatives. Briefly, THP-1 cells were plated, and nanoparticles were titrated in triplicate in a range from 0.028 - 5000 nM. In addition to nanoparticles, a fixed concentration of EPS was included to induce maximum MCP-1 levels. Cells were incubated for 24 hours and subsequently the cell cultured supernatant was collected for quantification of MCP-1 levels using ELISA.

[0478] A total of 14 culture plates were tested at once. In FIG. 9, the ICso for all compounds is displayed. All formulated compounds exhibiting an ICso value below 100 nM were subjected to a secondary assay to validate the accuracy of the initial ICso measurements and to determine whether the most potent candidates (Rapa-suc-NHGs and Rapa-glut-NHCis) maintained superior activity' in the follow-up experiment (FIG. 9). In all cases the ICso was below 100 nM, re-confirming the potency of the compounds. ICso’s measured in the second experiment showed a narrower distribution, with no distinct top performer. Consequently, all tested compounds in the second experiment were considered to possess comparable potency.

Claims

CLAIMSWhat is claimed:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:R1is -heterocyclyl-L;R2is -C2-3 alkylene;R-’ is -hydrogen, -alkyl, -aryl or -alkenyl;Y is an -C1-12 alkylene;L is -alkyl, -alkenyl, -alkylene-C(=O)-W, -alkylene-O-C(=O)-W, -alkylene-N- (alkylene-C(:=:O)-NR3-alkylene-NR’>-C(=;O)-W)2, or -alkylene-N-(alkylene-C(=:O)-W)2; andR5is independently -hydrogen or -alkyl;W is -alkyl, -O-alkylene-C(H)(OR6)-alkylene-OR7, or a sterol;R6and R' are each independently R8or ~C(=O)~R8; andR8is -alkyl; wherein each aforementioned alkyl, alkylene, alkenyl, aryl, and heterocyclyl is optionally substituted.The compound of claim 1, wherein the compound is a compound of Formula (I- A):(I-A) or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R1is -heteroaryl -L.

4. The compound of any one of claims 1-3, wherein each alkyl, alkylene, alkenyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more RAsubstituents; wherein RAis independently selected for each occurrence from the group consisting of hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(RC)(RD), -C(O)N(R‘' )(RD), - N(RC)C(O)RB, -OC(O)NRCRD, -NRCC(O)ORB, -OC(O)RB, -C(O)ORB, -C(O)RB, •CO I L -NO2, -SH, S(O)xRB, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and RB;Rcand RDare independently selected for each occurrence from the group consisting of hydrogen, alkyl, haloalkyl -C(O)RB, and -C(O)ORB; or Rcand RDare taken together with the nitrogen to which they are attached to form a heterocyclic ring optionally substituted with RA;RBis alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro; and x is 0, 1, or 2.

5. The compound of any one of claims 1-4, wherein the compound is a compound of Formula (I-B):(I-B) or a pharmaceutically acceptable salt thereof wherein:X1is -N- and X2is -C-; or X1is -C- and X2is -N-.

6. The compound of claim 5, wherein the compound is a compound of Formula (I-C):or a pharmaceutically acceptable salt thereof.The compound of any one of claims 1-6, wherein the compound is a compound of Formula (I-C-A):or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-6, wherein the compound is a compound of Formula (I-C-B-2):(I-C-B): or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1 -8, wherein Rzis a -C2 alkylene.

10. The compound of any one of claims 1-8, wherein R2is -CH2CH2-.

11. The compound of any one of claims 1-10, wherein R3is -C1-6 alkyl or -hydrogen.

12. The compound of claim 1 1, wherein R3is -hydrogen.

13. The compound of claim 11, wherein RJis -CHs.

14. The compound of any one of claims 1-13, wherein Y is Ci-6 alkylene.

15. The compound of claim 14, wherein Y is -CEb- or -CH2CH2CH2-.

16. The compound of any one of claims 1-15, wherein L is -alkyl, -alkylene-C(:=:())-\V, or - alkylene-O-C(=O)-W.

17. The compound of any one of claims 1-16, wherein L is -C12-24 alkyl.

18. The compound of claim 17, wherein L is -CH2.(CH2CH2)8-CH3.

19. The compound of any one of claims 1-16, wherein L is -alkylene-O-C(=O)-W.

20. The compound of claim 19, wherein L is -Ci alkylene-O-C(=O)-W.

21. The compound of claim 20, wherein L is -CH2-O-C(=O)-W.

22. The compound of any one of claims 1-16, wherein L is -Ci-s alkylene-C(=O)-W.

23. The compound of claim 22, wherein L is -Ci alkylene-C(=O)-W.

24. The compound of claim 23, wherein L is -CH2-C(=O)-W.

25. The compound of any one of claims 1-24, wherein W is a sterol.

26. The compound of claim 25, wherein the sterol is:27 The compound of any one of claims 1-24, wherein W is:wherein R8and R8’ is each independently -C5-30 alkyl.

28. The compound of claim 27, wherein R8and R8is each independently a -Cs-zoalkyl.

29. The compound of claim 27, wherein R8and R8’ are both -(CH2CH2)5-CH3.

30. The compound of claim 27, wherein R8and R8are both ~(CH2CH2)a~CH3.

31. The compound of any one of claims 1-30, wherein the compound is( ) or a pharmaceutically acceptable salt thereof, wherein:R2is -C2-6 alkylene;R3is -hydrogen, -alkyl, -aryl or -alkenyl;Y is an -C1-6 alkylene or absent;R1is -C(=O)-W or -W; andW is -Co-Cao alkyl or a sterol; wherein each aforementioned alkyl, alkylene, aryl, and alkenyl is optionally substituted, and wherein the compound is not:

33. The compound of claim 32, wherein R2is -C2-4 alkylene.

34. The compound of claim 32 or 33, wherein the compound is a compound of Formula (II- A-2):(II-A) or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.

35. The compound of any one of claims 32-34, wherein the compound is a compound of Formula (II-B):or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.

36. The compound of any one of claims 32-35, wherein the compound is a compound of Formula (II-C):(II-C) or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 32-35, wherein the compound is a compound ofFormula (II-D):or a pharmaceutically acceptable salt thereof.

38. The compound of any one of claims 32-35, wherein the compound is a compound of Formula (II-E):(II-E) or a pharmaceutically acceptable salt thereof.

39. The compound of any one of claims 32-35, wherein the compound is a compound of Formula (II-F):(II -F) or a pharmaceutically acceptable salt thereof.

40. The compound of any one of claims 32-35, wherein the compound is a compound ofFormula (II-G):(II-G) or a pharmaceutically acceptable salt thereof.

41. The compound of any one of claims 32-35, wherein the compound is a compound of Formula (II-H):or a pharmaceutically acceptable salt thereof.

42. The compound of any one of claims 32-35 or 38-41 , wherein R’ is -Ci-8 alkyl or hydrogen.

43. The compound of any one of claims 32-35 or 38-41, wherein R3is -hydrogen.

44. The compound of any one of claims 32-35 or 38-41, wherein R3is -CH?,.

45. The compound of any one of claims 32-35 or 38-41, wherein R3is ---(CH2CH2 )?,CH2CH?,.

46. The compound of claim 32-45, wherein Rlis W.

47. The compound of claim 46, wherein R!is -Cs-Cis alkyl.

48. The compound of claim 46 or 47, wherein R’!is -Cs alkyl.

49. The compound of claim 46 or 47, wherein R{is -Ci 8 alkyl.

50. The compound of claim 47, wherein Rlis -(CH2CH2)3CH2CH3.

51. The compound of claim 47, wherein R!is -(CH2CH2)sCH2CH,3.

52. The compound of any one of claims 32-45, wherein R1is -C(=0)-W.

53. The compound of claim 52, wherein W is a sterol.

54. The compound of claim 53, wherein the sterol is:The compound of any one of claims 32-51, wherein Y is absent.

56. The compound of any one of claims 32-54, wherein Y is -CHz.

57. The compound of any one of claims 32-56, wherein the compound is:

58. A compound of Formula ( 111 -2 ).or a pharmaceutically acceptable salt thereof; wherein:RC1is H or -C( O)-R' : andRC2and RCjare each independently an optionally substituted -C4-30 alkyl or -C4-30 alkenyl, wherein the compound is not:

59. The compound of claim 52, wherein the compound is of Formula (III- A):or a pharmaceutically acceptable salt thereof.

60. The compound of claim 42, wherein the compound is of Formula (III-B):(II-B) or pharmaceutically acceptable salt thereof wherein RC1is H or -C(::::())-Rc3; andRC2is -C4-30 alkenyl.

61. The compound of any one of claims 58-60, wherein RC2is -C15-30 alkenyl.

62. The compound of any one of claims 58-60, wherein RC2is -C15-20 alkenyl.

63. The compound of any one of claims 58-60, wherein RC2is C17 alkenyl.

64. The compound of claim 42, wherein the compound is of Formula (III -C):or pharmaceutically acceptable salt thereof, wherein Rl 2is -C4-30 alkenyl.

65. The compound of any one of claims 58-64, wherein R'2is -C15-30 alkeny l.

66. The compound of any one of claims 58-64, wherein RC2is -C 15-20 alkenyl.

67. The compound of any one of claims 58-64, wherein RC2is -C17 alkenyl.

68. The compound of any one of claims 58-63, wherein RC2and RC3are each independently an optionally substituted -Cu-30 alkyl or -Cu-30 alkenyl.

69. The compound of any one of claims 58-63, wherein RC2and RC3are each independently an -Cu-nalkyl.

70. The compound of any one of claims 58-63, wherein RC2and RC3are the same.

71. The compound of claim 70, wherein RC2and RCjare both -C11 alkyl.

72. The compound of any one of claims 58-63, wherein R.' ' is a branched -alkyl.

73. The compound of any one of claims 58-63, wherein R'2is a linear -alkyl.

74. The compound of claim 73, wherein RC2is a linear -Cu alkyl.

75. The compound of any one of claims 58-68, wherein RC2is a -C’4-30 alkenyl.

76. The compound of claim 72, wherein RC2is a branched -C15 alkyl or -C4 alkyl.

77. The compound of any one of claims 58-60, wherein RC1is hydrogen and RC2is t-butyl, or79. A compound of Formula (IV-2):or a pharmaceutically acceptable salt thereof; wherein:RD!IS -hydrogen, -C(=O)NRD4-alkyi or -C(=O)NRD4-alkenyl;RD2is -hydrogen, -alkyl, -aryl or -alkenyl;RD3IS -Ce-Cso alkyl;RD4IS -hydrogen, -alkyl, -aryl or -alkenyl.

80. The compound of claim 79, wherein the compound is a compound of Formula (IV- A):(IV-A) or a pharmaceutically acceptable salt thereof.

81. The compound of claim 79 or 80, wherein RDsis -hydrogen or -C(:::O)NRD4-alkyl.

82. The compound of any one of claims 79-81, wherein Rljlis -hydrogen.

83. The compound of any one of claims 79-81, wherein R: )iis -C(:=:O)NRD4-alkyl.

84. The compound of claim 81, wherein RD1is -C(:=:0)NH-Cs-3oalkyl.

85. The compound of claim 81, wherein RD!is:

86. The compound of any one of claims 79-85, wherein RD3is -Cs-z-ralkyl.

87. The compound of claim 86, wherein RD3is -CisalkyL88. The compound of any one of claims 79-87, wherein RD3is:

89. The compound of any one of claims 79-88, wherein the compound is:(V-2) or a pharmaceutically acceptable salt thereof; wherein:RE1is hydrogen or -fl OJOR1RE2is -Cs-Cso alkyl;RE3IS -C6-C30 alkyl or -C6-C30 alkenyl; wherein each aforementioned alkyl and alkenyl is optionally substituted.

91. The compound of claim 90, wherein the compound is of Formula (V-A-2):or a pharmaceutically acceptable salt thereof.

92. The compound of claim 90 or 91, wherein RElis -hydrogen.

93. The compound of claim 90 or 91, wherein RE’!is -C(:=:O)ORE3.

94. The compound of claim 91, wherein RE3is -CS-ZN alkyl.

95. The compound of claim 91, wherein REJis -C18 alkyl.

96. The compound of any one of claims 90-95, wherein R&2is -Cs-24 alkyl.

97. The compound of claim 96, wherein RE2is -Cis alkyl.

98. The compound of claim 96, wherein RE2is -Cs alkyl.

99. The compound of any one of claims 90-98, wherein the compound is:

100. A compound of Formula (VI-2):or a pharmaceutically acceptable salt thereof; wherein Rf lis an optionally substituted Csoo alkyl, wherein R! !is not -Cs, -Cs, -C9, -C17, and -Cis alkyl.

101. The compound of claim 100, wherein the compound is of Formula (VI- A):(VI-A) or a pharmaceutically acceptable salt thereof.

102. A composition, comprising a high-density lipoprotein (HDL)-derived nanoparticle, wherein the nanoparticle comprises a compound of any one of claims 1-101.

103. The composition of claim 102, wherein the HDL-derived nanoparticle comprises a phospholipid.

104. The composition of claim 102 or 103, herein the HDL-derived nanoparticle comprises a lysophospholipid.

105. The composition of claim 104, wherein the phospholipid and lysophospholipid are present in a weight ratio from about 2: 1 to about 4: 1.

106. The composition of any one of claims 103-105, wherein the phospholipid is selected from the group consisting of l,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC).

107. The composition of any one of claims 104-106, wherein the lysophospholipid is selected from the group consisting of l-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), and 1 -palmitoyl-2-hydroxy-sn~glycero-3-phosphocholine (PHPC).

108. The composition of any one of claims 102-107, wherein the HDL-derived nanoparticle comprises apoA-I or a peptide mimetic of apoA-I.

109. The composition of any one of claims 102-108, wherein the HDL-derived nanoparticle further comprises one or more triglycerides, fatty acid esters, hydrophobic polymers, sterol esters, or combinations thereof997110. The composition of any one of claims 102-109, wherein the HDL-derived nanoparticle further comprises cholesterol.

111. A pharmaceutical composition comprising a compound of any one of claims 1-101 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

112. A method for prophylaxis of tissue rejection in a patient in need thereof, comprising administering a compound of any one of claims 1-101 or the composition of any one of claims 102-110.

113. A method of inducing transplant tolerance in a patient comprising administering a compound of any one of claims 1-101 or the composition of any one of claims 102-110.

114. The method of claim 112 or 113, wherein the patient has undergone an organ or tissue transplant and the transplanted tissue is lung tissue, heart tissue, kidney tissue, liver tissue, -retinal tissue, corneal tissue, skin tissue, pancreatic tissue, intestinal tissue, genital tissue, ovary’ tissue, bone tissue, tendon tissue, bone marrow, or vascular tissue.

115. The method of claim 114, wherein the transplanted tissue is an intact organ.

116. The method of claim 114, wherein the organ or tissue transplant is an allogeneic tissue or organ transplant.

117. The method of any one of claims 112-116, wherein the compound or composition is for administration prior to performance of an allogeneic tissue or organ transplant.

118. The method of any one of claims 112-116, wherein the compound or composition is for administration in conjunction with an allogeneic tissue or organ transplant.

119. The method of any one of claims 112-116, wherein the compound or composition is for administration within at least two weeks after an allogeneic tissue or organ transplant.

120. The method of any one of claims 112-119, further comprising administering to the patient one or more immunosuppressant, agents.

121. The method of claim 120, wherein the immunosuppressant agent is cyclosporine A or FK506.

122. A method for treating an autoimmune disease, an inflammatory disease, or a cardiovascular disease in a subject in need thereof comprising administering to the subject a compound of any one of claims I -101 or the composition of any one of claims 94-103.

123. The method of any one of claims 112-122, wherein the composition is administered intravenously or intra-arterially.

124. A method for reducing inflammation in a subject in need thereof comprising administering to the subject a compound of any one of claims 1-101 or the composition of any one of claims 94-103, optionally when the inflammation is autoinflanimation.

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