Compounds for modulating trained immunity and methods of use thereof

Abstract

Provided herein are compounds of formula (I), as well as compositions comprising compounds of formula (I) and uses thereof. [Formula 1] TIFF2024511067000110.tif2552

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 163,428, filed March 19, 2021, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] Description of electronically submitted text files The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: Computer-readable copy of the Sequence Listing (Filename: TRAI_005_00US_SeqList_ST25.txt, Recording Date: March 17, 2021, File Size: 105 KB). [Background technology]

[0003] The immune system plays a crucial role in the pathophysiology of major diseases, including atherosclerosis, diabetes, and cancer. However, most currently developed immunotherapeutic strategies focus either on effector molecules such as cytokines or on T lymphocytes, cells from the adaptive immune system (Mulder et al. Nat. Rev. Drug Discov. 2019, 18(7), 553-566; Pardoll et al. Nat. Immunol., 2012, 13, 1129-1132). While anti-cytokine therapy can neutralize bioactive cytokines in autoimmune and autoinflammatory diseases, the most commonly used immunotherapies for cancer patients involve the application of checkpoint inhibitors. Although the innate immune system was long thought to have no memory, recent studies have shown that innate immune cells undergo metabolic and epigenetic rewiring to adjust their functional programs in a process termed "trained immunity," which is involved in exerting antitumor effects (Buffen et al., 2014, PLoS Pathog. 10, e1004485; Netea et al., J. Leukoc Biol. 2017, 102, 1323-1332).

[0004] A series of pattern recognition receptors (PRRs), including TLRs, NOD2, dectin-1, and inflammasomes, can be involved in promoting trained immunity. In addition, in vitro studies have demonstrated that BCG and several other PAMPs and DAMPs, including peptidoglycan and β-glucan, can be therapeutically utilized as trained immunity stimulators. However, the in vivo therapeutic use of molecules that regulate trained immunity has been hindered by toxicity, immune-related adverse effects, and poor bioavailability, which target relevant myeloid cells and their progenitor cells.

[0005] There is a need for therapeutic agents and compositions thereof that involve the innate immune system and modulate trained immunity to treat cancer and other diseases and conditions caused by defective trained immunity. Summary of the Invention

[0006] In embodiments, provided herein is a compound of formula (I):

[0007] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is -H or -C(O)-R X and; R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5 , and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; R 7 is C 9~30 Fatty acid chain, -YN(R 11 )-C(O)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , -C(R 10 )(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 16~30 Fatty acid chain, -(CR 10 R 10 )2-OP(O)(OH)-O-alkylene-C(R 10 )(OR Z )-Alkylene-OR Z’ or -Y-triazolyl-L; R Z and R Z’ are each independently C 8~30 Fatty acids or -C(O)-C 16~30 is a fatty acid chain; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R X and; R 10 , R 22 , R 33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ are each independently H or R A and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, aryl, and triazolyl may be selected from one or more R A is optionally replaced by R A is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B(wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle; R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro; R 7 C 9~30 If it is a fatty acid chain, R 2 is -H) is.

[0008] In embodiments, the compound of formula (I) has formula (IA):

[0009] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 55 , R 5’ , R 55’ , R 33 , R 33’ , R 44 , R 44’ , R 6 , and R 7 is defined herein) is.

[0010] In embodiments, the compound of formula (I) has formula (IB):

[0011] [ka] is. (In the formula, R 2 , R 3 , R 4 , R 6 , and R 7 is defined herein)

[0012] In embodiments, the compound of formula (I) has formula (II):

[0013] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 , R 3 , R 4 , R 5 , R 5’ , R 6 , Y, X 1 , X 2 , R A , L is defined herein) is.

[0014] In an embodiment, the compound of formula (II) is

[0015] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 , R 3 , R 4 , R 5 , R 5’ , R 6 , Y, X 1 , X 2 and L is defined herein). is.

[0016] In embodiments, the compound of formula (I) has formula (IIA):

[0017] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 , R 3 , R 4 , R 5 , R 5’ , R 6 , Y, X 1 , X 2 , L, and R A is defined herein) is.

[0018] In an embodiment, the compound of formula (IIA) is

[0019] [ka] is. (In the formula, R 2 , R 3 , R 4 , R 5 , R 5’ , R 6 , Y, X 1 , X 2 and L is defined herein).

[0020] In embodiments, the present disclosure provides a nanobiological composition comprising high density lipoprotein (HDL)-derived nanoparticles, the nanoparticles having formula (I);

[0021] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is -H or -C(O)-R X and; R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5, and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; R 7 is the fatty acid chain, -YN(R 6 )-C(O)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , -YN(R 6 )-C(O)-R X , -YOP(O)(OH)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 or -Y-triazolyl-L; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R X and; R 10 , R 22 , R 33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ are each independently H or R A and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, aryl, and triazolyl may be selected from one or more R A is optionally replaced by RA is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocyclic ring; R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro Includes:

[0022] In embodiments, the present disclosure provides a method for treating a cell proliferative disorder, or sepsis, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or nanobiological composition disclosed herein. [Brief explanation of the drawings]

[0023] [Figure 1]1 shows cryo-TEM photographs of HDL-derived nanoparticles from entries A to F in Table 8 of Example 24. The 50 nm bar applies to all six photographs. [Figure 2] 1 shows the DLS-determined Z-average diameter and PDI values ​​of nanoparticles in Formulations A to F of Formulation 1 in Example 23. [Figure 3] 2 is a graph showing OD values ​​as a function of test article concentration in the NOD2 activation assay described in Example 25. [Figure 4] AE show tumor growth curves for the study described in Example 26. [Figure 5] 4A-C show tumor growth curves for the study described in Example 27. DETAILED DESCRIPTION OF THE INVENTION

[0024] definition For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0025] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are incorporated by reference in their entireties into this disclosure in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. This disclosure shall control in the event of a conflict between the cited patents, patent applications, and publications and this disclosure.

[0026] The term "about" immediately preceding a numerical value refers to a range of plus or minus a value within the acceptable range of variation in the art. In embodiments, unless otherwise indicated or contradicted by the context of this disclosure, the term "about" encompasses 10% of the value, e.g., "about 50" refers to 45 to 55, "about 25,000" refers to 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ~," "about 50" refers to a range spanning less than half the interval between the preceding and following values, e.g., 49.5 or greater and less than 52.5. Furthermore, the phrases "less than approximately a value" or "greater than approximately a value" should be understood in light of the definition of the term "about" provided herein.

[0027] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0028] "Salts" include salts formed by reacting a compound that functions as a base with an inorganic or organic acid, or a compound that functions as an acid with an inorganic or organic base. "Salts" include derivatives of active agents, where the active agent is modified by making its acid or base addition salt. Preferably, the salt is a pharmaceutically acceptable salt. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, Examples of suitable amine salts include ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, sulfates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, and ketoglutarates.Examples of base addition salts include, but are not limited to, ethylenediamine, N-methylglucamine, 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, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine dicyclohexylamine, etc. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts, etc. Examples of ammonium salts and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc. Standard methods for preparing 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, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0029] The terms "carrier" or "vehicle," as used interchangeably herein, include carriers, excipients, adjuvants, and diluents, or any combination thereof, and refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in the carrying or transport of a drug from one organ or part of the body to another. In addition to adjuvants, excipients, and diluents known to those skilled in the art, carriers include nanoparticles of organic and inorganic nature.

[0030] For example, in embodiments, the present disclosure provides nanoparticle carriers (e.g., HDL-derived nanoparticles) as delivery vehicles for active agents (e.g., compounds of Formula (I), (IA), (IB), (II), (II-1), (II-2), (IIA), (IIA-1), (IIA-2), or Table 1). In embodiments, the agent is encapsulated within the nanoparticle carrier. In other embodiments, the agent is bound to the surface of the nanoparticle carrier. Association of the agent with the nanoparticle carrier can be achieved by various means, including non-covalent bonding and entrapment of the agent within the delivery vehicle. In embodiments, the association is sufficiently stable so that the agent remains associated with the delivery vehicle until delivered to the target site of treatment.

[0031] As used herein, the terms "pharmaceutical combination," "therapeutic combination," or "combination" refer to a single dosage form containing at least two therapeutically active agents, or separate dosage forms containing at least two therapeutically active agents, together or separately, for use in combination therapy. Administration of combination therapy includes sequential, simultaneous, or consecutive administration via the same or different routes, in the same or different compositions and / or combinations. For example, one therapeutically active agent may be formulated in one dosage form, and the other therapeutically active agent may be formulated in a single or different dosage form. For example, one therapeutically active agent may be formulated in a solid oral dosage form, and the second therapeutically active agent may be formulated in 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.

[0032] As used herein, the phrase "disorders characterized by cell proliferation" or "conditions characterized by cell proliferation" includes, but is not limited to, cancers, benign and malignant tumors. Examples of cancers and tumors include, but are not limited to, cancers or tumor growths of the bladder, blood vessels, bone, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovary, pancreas, prostate, rectum, colorectum, skin, stomach, testicles, throat, thyroid, urothelium, and uterus.

[0033] The terms "treat," "treating," or "treatment" with respect to a particular disease or disorder include prevention of the disease or disorder and / or reduction, amelioration, remission, or arrest of the symptoms and / or pathology of the disease or disorder. Generally, the term as used herein refers to amelioration, alleviation, relief, and elimination of the symptoms of a disease or condition. The candidate compounds described herein can be present in a formulation or medicament in a therapeutically effective amount, which is an amount that can cause a biological effect such as apoptosis of certain cells (e.g., cancer cells), reduced proliferation of certain cells, or lead to the amelioration, alleviation, relief, or elimination of symptoms of a disease or condition, such as sepsis. The term can also refer to a reduction in the rate or cessation of cell proliferation (e.g., slowing or stopping tumor growth), or a reduction in the number of proliferating cancer cells (e.g., eliminating some or all of a tumor).

[0034] As used herein, the term "patient" or "subject" includes all mammals, and more specifically, humans. The methods described herein may be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.

[0035] As used herein, "prevention" or "preventing" refers to a reduction in the risk of contracting a given disease or disorder, e.g., preventing the development of at least one clinical symptom of a disease in a subject who may be exposed to or predisposed to the disease but who has not yet experienced or displayed symptoms of the disease.

[0036] As used herein, "therapeutically effective amount" means the amount of a compound or therapeutically active agent that, when administered to a subject for treating a disease or other undesirable medical condition, is sufficient to produce a beneficial effect with respect to the disease or condition. The therapeutically effective amount will vary depending on the type of compound or therapeutically active agent selected, the disease or condition and its severity, and the age, weight, etc. of the patient receiving treatment.

[0037] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes examples in which the event or circumstance occurs and examples in which it does not occur. For example, "optionally substituted aryl" includes both "aryl" and "substituted aryl," as defined below. With respect to any group containing one or more substituents, those of skill in the art will understand that such groups are not intended to introduce substitutions or substitution patterns that are sterically impractical, synthetically impractical, and / or inherently unstable.

[0038] It is further noted that the claims may be drafted to exclude optional elements, and therefore, this statement is intended to serve as a predicate for using exclusive terminology, such as "solely," "only," and the like, in connection with the recitation of claim elements or the use of a "negative" limitation.

[0039] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, C1-C6 alkyl means C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0040] The term "acyl," as used herein, refers to the group RC(O)-, including, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, where the group is attached to the parent molecular structure via a carbonyl functionality. In embodiments, this refers to the carbonyl carbon of the acyl and the C, which refers to the total number of chain or ring atoms in, for example, the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl moiety. 1~10 An acyl radical. For example, a C4-acyl has a carbonyl and three other ring or chain atoms.

[0041] An "alkyl" or "alkyl group" is a fully saturated, straight or branched hydrocarbon chain. In embodiments, an alkyl group contains 1 to 30 carbon atoms. In embodiments, an alkyl group has 1 to 12 carbon atoms and is attached to the rest of the molecule by a single bond. For example, alkyls containing any number of carbon atoms from 1 to 12 are included. Alkyl containing up to 12 carbon atoms is C1-C 12 Alkyl, containing up to 10 carbon atoms, is C1-C 10An alkyl is a C1-C6 alkyl, where an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl containing up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes all of the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9 and C 10 Alkyl is also included. Similarly, C1-C 12 Alkyl includes all of the above moieties, except C 11 and C 12 Alkyl is also included. C1~C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specified herein, alkyl groups can be optionally substituted. In embodiments, "alkyl" is a straight-chain hydrocarbon. In embodiments, "alkyl" is a branched-chain hydrocarbon.

[0042] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain. In embodiments, an alkylene group has 1 to 12 carbon atoms. C1-C 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, etc. 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 in the specification, alkylene chains can be optionally substituted.

[0043] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain. In embodiments, an alkenyl group contains 1 to 30 carbon atoms. In embodiments, an alkenyl group contains 2 to 12 carbon atoms and has one or more carbon-carbon double bonds, e.g., a straight or branched group of 2 to 8 carbon atoms, referred to herein as a C2-C8 alkenyl. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C8 alkenyls. 12 Alkenyl, containing up to 10 carbon atoms, is C2-C 10 An alkenyl group containing up to 6 carbon atoms is a C2-C6 alkenyl, and an alkenyl containing up to 5 carbon atoms is a C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties listed above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10 Alkenyl includes all of the moieties listed above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 Alkenyl is also included. Similarly, C2-C 12 Alkenyl includes all of the above moieties, except that C 11 and C 12 Alkyl is also included. C2~C 12Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-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, and 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 in the specification, an alkyl group can be optionally substituted.

[0044] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain. In embodiments, an alkynyl group contains 1 to 30 carbon atoms. In embodiments, an alkynyl group contains 2 to 12 carbon atoms and has one or more carbon-carbon triple bonds, e.g., a straight or branched group of 2 to 8 carbon atoms, referred to herein as a C2-C8 alkynyl. Each alkynyl group is attached to the remainder of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C2-C8 alkynyl groups. 12 Alkynyl, containing up to 10 carbon atoms, is C2-C 10An alkynyl group containing up to 6 carbon atoms is C2-C6 alkynyl, and an alkynyl containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkynyl includes all of the moieties listed above for C2-C5 alkynyl, but also includes C6 alkynyl. C2-C 10 Alkynyl includes all of the moieties listed above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9 and C 10 Alkynyl is also included. Similarly, C2-C 12 Alkynyl includes all of the above moieties, except that C 11 and C 12 Alkynyl is also included. C2-C 12 Non-limiting examples of alkenyl include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0045] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, attached to the rest of the molecule by a single bond. For purposes of the present invention, aryl can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other polycyclic ring system, and can include fused or bridged ring systems. Aryl includes, but is 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 triphenyl. Unless otherwise specified herein, aryls can be optionally substituted.

[0046] An "aralkyl" or "arylalkyl" is a group of the formula -R b -R c R refers to the group bis an alkylene group as defined above, and R c is one or more aryl as defined above, for example, benzyl, diphenylmethyl, etc. Unless stated otherwise in the specification, an aralkyl group can be optionally substituted.

[0047] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon and which is attached to the rest of the molecule by a single bond. A carbocyclic ring can contain from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryl, as defined herein, as well as cycloalkyl, cycloalkenyl, and cycloalkynyl. Unless otherwise specified herein, a carbocyclyl group can be optionally substituted.

[0048] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon, consisting solely of carbon and hydrogen atoms, which may include fused, spirocyclic, or bridged ring systems, has 3 to 20 carbon atoms, and is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyls 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 specified in the specification, cycloalkyl groups can be optionally substituted.

[0049] "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 may include fused, spirocyclic, or bridged ring systems, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and attached to the remainder of the molecule by a single bond. Monocyclic cycloalkenyls 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 specified in the specification, cycloalkenyl groups can be optionally substituted.

[0050] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon, consisting solely of carbon and hydrogen atoms, having 3 to 20 carbon atoms, and having one or more carbon-carbon triple bonds, which may include fused, spirocyclic, or bridged ring systems, and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkynyls include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specified in the specification, cycloalkynyl groups can be optionally substituted.

[0051] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered aromatic or non-aromatic ring consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocycle can be aromatic (heteroaryl) or non-aromatic. Unless otherwise specified herein, a heterocyclyl can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other polycyclic ring system, which can include fused, spirocyclic, or bridged ring systems; the nitrogen, carbon, or sulfur atoms in a 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 dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, biotinyl, dihydrofuranyl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, pyranyl, pyrazolinyl, thiopyranyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, and 2-oxopiperazinyl. Examples of heterocyclyl groups include, but are not limited to, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydroisoquinolyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, heterocyclyl groups can be optionally substituted.

[0052] "Heteroaryl" refers to a 5- to 20-membered ring system containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this disclosure, a heteroaryl can be monocyclic, bicyclic, tricyclic, or tetracyclic, which can include fused or bridged ring systems; a heteroaryl can contain one or more non-aromatic rings (e.g., cycloalkyl or heterocyclyl) fused to an aromatic ring. The nitrogen, carbon, or sulfur atoms in a heteroaryl can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indophenyl, and indophenyl. linyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-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 in the specification, a heteroaryl group may be optionally substituted.

[0053] "Heteroarylalkyl" refers to a group of the formula -R b -R f R refers to the group b is an alkylene chain as defined above, and R f is heteroaryl as defined above. Unless stated otherwise in the specification, a heteroarylalkyl group may be optionally substituted.

[0054] The term "substituted," as used herein, means any of the above groups (i.e., alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, N-heterocyclyl, heteroaryl, etc.) in which at least one hydrogen atom has been replaced by a bond to a non-hydrogen atom, such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" refers to any of the above groups in which one or more hydrogen atoms have been replaced by a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile, through a higher bond (e.g., double or triple bond). For example, "substituted" refers to any group in which one or more hydrogen atoms have been replaced by a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. g R h , N.R. g C(=O)R h , N.R.g C(=O)NR g R h , N.R. g C(=O)OR h , N.R. g SO2R h , OC(=O)NR g R h , OR g , S.R. g , SOR g , SO2R g , OSO2R g , SO2OR g , =NSO2R g , and SO2NR g R h "Substituted" includes any of the above groups replaced with one or more hydrogen atoms. g , C(=O)OR g , C(=O)NR g R h , CH2SO2R g , CH2SO2NR g R h , and any of the above groups substituted with R g and R hare the same or different and are 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" also refers to any of the above groups in which one or more hydrogen atoms are replaced by 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 groups. Additionally, "substituted" refers to any of the above groups in which two hydrogen atoms have each been replaced with a bond to form a fused ring system containing the atom to which the hydrogens are attached. Furthermore, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0055] The compounds of the present disclosure contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. As used herein, the term "stereoisomer" consists of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated with the symbols "R" or "S," depending on the arrangement of substituents around the stereogenic carbon atoms. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated by "(±)" in nomenclature, although one of skill in the art will recognize that the structure may implicitly indicate a chiral center. In embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0056] In embodiments, the compound is a racemic mixture of the (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds wherein the individual compounds of the mixture are present predominantly in the (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In other embodiments, the compound mixture has an (S)-enantiomeric excess of from about 55% to greater than about 99.5%, from about 60% to greater than about 99.5%, from about 65% to greater than about 99.5%, from about 70% to greater than about 99.5%, from about 75% to greater than about 99.5%, from about 80% to greater than about 99.5%, from about 85% to greater than about 99.5%, from about 90% to greater than about 99.5%, from about 95% to greater than about 99.5%, from about 96% to greater than about 99.5%, from about 97% to greater than about 99.5%, from about 98% to greater than about 99.5%, from about 99% to greater than about 99.5%, or even greater. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of from about 55% to greater than about 99.5%, from about 60% to greater than about 99.5%, from about 65% to greater than about 99.5%, from about 70% to greater than about 99.5%, from about 75% to greater than about 99.5%, from about 80% to greater than about 99.5%, from about 85% to greater than about 99.5%, from about 90% to greater than about 99.5%, from about 95% to greater than about 99.5%, from about 96% to greater than about 99.5%, from about 97% to greater than about 99.5%, from about 98% to greater than about 99.5%, from about 99% to greater than about 99.5%, or even greater.

[0057] Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing an asymmetric or stereogenic center, or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified as follows: (1) coupling of the enantiomeric mixture to a chiral auxiliary, recrystallization or chromatographic separation of the resulting diastereomeric mixture, and liberation of the optically pure product from the auxiliary; (2) salt formation utilizing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0058] Geometric isomers may also exist in the compounds of the present disclosure. The present disclosure encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbon ring. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds include both E and Z isomers.

[0059] Substituents around a carbon-carbon double bond are sometimes referred to as "cis" or "trans," with "cis" referring to substituents on the same side of the double bond and "trans" referring to substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring is designated as "cis" or "trans." The term "cis" refers to substituents on the same side of the plane of the ring and the term "trans" refers to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are located on both the same and opposite sides of the plane of the ring is designated "cis / trans."

[0060] The compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended to be encompassed within the scope of the disclosure, even if only one tautomeric structure is shown.

[0061] As used herein, the term "isotopically enriched variant" is meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Such compounds may be useful, for example, as analytical tools, probes in biological assays, or therapeutic agents. For example, an "isotopically enriched variant" of a compound may be an isotopic variant of a compound that differs only in the presence of one or more isotopically enriched atoms, for example, deuterium ( 2 H or D), carbon 13 ( 13 C), nitrogen 15( 15 In such isotopically substituted compounds, the following atoms, if present, may be changed, for example, hydrogen is 2 H / D, carbon 13 C, nitrogen 15 It is understood that the presence and location of such atoms may be N, and the determination of such atoms is within the skill of the art. Similarly, the present invention may include the preparation of isotopic variants with radioactive isotopes, for example, when the resulting compounds may be used in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose due to their ease of incorporation and rapid means of detection. Additionally, positron-emitting isotopes, e.g., 11 C. 18 F 、15O and 13 Compounds substituted with N, etc., can also be prepared and may be useful in positron emission tomography (PET) experiments to examine substrate receptor occupancy.

[0062] As used herein, the term "triglyceride" refers to an ester derived from glycerol and three fatty acids. The fatty acids may be the same or different. The notation used to describe triglycerides herein is the same as that used to describe fatty acids below. The fatty acids can be attached to the glycerol molecule in any order; for example, any fatty acid can react with any hydroxyl group on the glycerol molecule to form an ester bond. For example, in a non-limiting example, a triglyceride can contain glycerol with any combination of the following fatty acids: C18:1, C14:1, C16:1, polyunsaturated, and saturated. A triglyceride of C18:1 fatty acids simply means that the fatty acid component of the triglyceride is derived from or based on a C18:1 fatty acid. That is, a C18:1 triglyceride is an ester of glycerol and three fatty acids, each having 18 carbon atoms, each with one double bond. Similarly, a C14:1 triglyceride is an ester of glycerol and three fatty acids, each having 14 carbon atoms, each fatty acid having one double bond. Similarly, a C16:1 triglyceride is an ester of glycerol and three fatty acids, each having 16 carbon atoms, each fatty acid having one double bond. A combination of a triglyceride of C18:1 fatty acid with a C14:1 and / or C16:1 fatty acid means: (a) a C18:1 triglyceride mixed with a C14:1 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 on a C18:1 fatty acid, and the other two are derived from or based on a C14:1 fatty acid and / or a C16:1 fatty acid.

[0063] The term "fatty acid" and similar terms refer to a carboxylic acid having a long aliphatic tail, either saturated or unsaturated. The terms "long aliphatic tail" and "fatty acid chain" are used interchangeably herein. Fatty acids and fatty acid chains can be esterified into phospholipids and triglycerides. As used herein, fatty acid chain lengths include C4-C30 (e.g., C6-C30), saturated or unsaturated, cis or trans, unsubstituted or substituted, branched or unbranched hydrocarbon chains (e.g., fatty acid chain lengths include C4-C30 (e.g., C6-C30), saturated or unsaturated, cis or trans, unsubstituted or substituted with 1-6 side chains). For example, in embodiments, exemplary fatty acid chains include, but are not limited to, saturated or unsaturated, cis or trans, unsubstituted or substituted hydrocarbon chains of C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, or C30. Unsaturated fatty acids and fatty acid chains have one or more double bonds between carbon atoms. Saturated fatty acids and fatty acid chains do not contain double bonds. In embodiments, fatty acids are described herein by the capital letter "C" representing a carbon atom, followed by a number representing the number of carbon atoms in the fatty acid, followed by a colon and another number representing the number of double bonds in the fatty acid. For example, C16:1 refers to a 16-carbon fatty acid with one double bond, such as palmitoleic acid. The number after the colon in this notation does not indicate the position of the double bond within the fatty acid, nor does it indicate whether the hydrogen atoms attached to the carbon atoms of the double bond are cis to each other. Other examples of this notation include C18:0 (stearic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3 (α-linolenic acid), and C20:4 (arachidonic acid).

[0064] The term "sterol," such as, but not limited to, cholesterol, can also be utilized in the methods and compounds described herein. Sterols are animal or plant steroids containing only a hydroxyl group at C-3 and no other functional groups. Generally, sterols contain 27-30 carbon atoms and a double bond at the 5 / 6 position, and occasionally at the 7 / 8, 8 / 9, or other positions. In addition to these unsaturated species, other sterols are saturated compounds obtained by hydrogenation. One example of a suitable animal sterol is cholesterol. Typical examples of suitable phytosterols that are preferred from an application standpoint are ergosterol, campesterol, stigmasterol, brassicasterol, and preferably sitosterol or sitostanol, more specifically β-sitosterol or β-sitostanol. In addition to the phytosterols mentioned, their esters are also preferably used. The acid component of the ester may be a carboxylic acid corresponding to the formula (CA-I): RI CO-OH (CA-I); where RI CO is an aliphatic, linear or branched acyl group containing 2 to 30 carbon atoms and O and / or 1, 2, or 3 double bonds. Typical examples are acetic acid, propionic acid, hexanoic acid, butyric acid, valeric acid, caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, cyclopentanepropionic acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, conjugated linoleic acid (CLA), linolenic acid, eleostearic acid, arachidic acid, gadoleic acid, behenic acid, and erucic acid.

[0065] The term "phospholipid" refers to an amphiphilic compound consisting of two hydrophobic fatty acid "tails" and a hydrophilic "head" consisting of a phosphate group. The two components are joined by a glycerol molecule. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine, or serine. Choline refers to an essential bioactive nutrient with the chemical formula R-(CH2)2-N(CH2)4. When the phosphorylated moiety is R-, it is called a phosphocholine.

[0066] As used herein, "lysolipid" includes, in non-limiting embodiments (acyl, single chain), by way of example, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (MHPC), 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC), and 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (SHPC).

[0067] The terms "apolipoprotein AI" or "apo AI" and also "apoliprotein A1" or "apoA1" refer to the protein that in humans is encoded by the APOAI gene.

[0068] Detailed Description Traditionally, the vertebrate immune system is subdivided into two parts. The first part, the innate immune system, provides an initial response to infection within minutes to hours. Its cellular components include natural killer (NK) cells, innate lymphoid cells (ILCs), and phagocytes such as monocytes, macrophages, and neutrophils. The innate immune system is triggered through the recognition of either pathogen or endogenous danger signals by pattern recognition receptors (PRRs) and acts as a rapid first line of defense. Upon detecting pathogen-associated molecular patterns (PAMPs), PRRs initiate the innate immune response, which includes antigen presentation, costimulation, and subsequent activation of the adaptive immune system through cytokine secretion. In addition, PRRs recognize damage-associated molecular patterns (DAMPs), triggering non-infectious inflammatory responses. The second phase of the response to infection involves the adaptive response, a second part of the immune system, in which T and B lymphocytes specifically recognize, proliferate, and are activated against the pathogen. These cells also build immunological memory for that specific infection. The specificity of adaptive immune system responses is mediated by immunoglobulin gene recombination at the lymphocyte level. Immunological memory results in a more rapid and quantitatively superior immune response to previously encountered antigens (compared to a primary response alone). While it was long thought that the innate immune system lacked memory, recent studies have shown that innate immune cells undergo metabolic and epigenetic rewiring to adjust their functional programs in a process termed "trained immunity," which can be considered a de facto innate immune memory.

[0069] Trained immunity is defined by a secondary, long-term hyperresponsiveness, manifested by increased cytokine secretion caused by metabolic and epigenetic rewiring of myeloid cells and their progenitor and stem cells in the bone marrow, spleen, and blood upon restimulation after a primary insult. Trained immunity (also called innate immune memory) is also defined by the long-term increased responsiveness (e.g., high cytokine production) of myeloid innate immune cells following secondary restimulation, induced by a primary insult that stimulates these cells or their progenitor and stem cells in the bone marrow and spleen, and mediated by epigenetic, metabolic, and transcriptional rewiring.

[0070] Trained immunity is regulated and maintained through the induction of training properties in progenitor cells in the bone marrow, resulting in persistent reprogramming that extends beyond the lifespan of bone marrow cells in the bloodstream. Trained immunity can be induced in cultured bone marrow cells using various "training agents," but its systemic induction requires the involvement of bone marrow progenitor cells.

[0071] In one aspect, the present disclosure provides compounds that activate nucleotide-binding oligomerization domain-containing protein 2 (NOD2) (e.g., compounds of Formula (I), (IA), (IB), (II), (II-1), (II-2), (IIA), (IIA-1), (IIA-2), or Table 1). The present disclosure also provides nanobiological compositions comprising nanoparticle carriers (e.g., HDL-derived nanoparticles) comprising a compound of the present disclosure (e.g., of Formula (I), (IA), (IB), (II), (II-1), (II-2), (IIA), (IIA-1), (IIA-2), or Table 1). Nanobiological compositions of the present disclosure comprising compounds of the present disclosure (e.g., of Formula (I), (IA), (IB), (II), (II-1), (II-2), (IIA), (IIA-1), (IIA-2), or Table 1) that activate nucleotide-binding oligomerization domain-containing protein 2 (NOD2) are designed to exhibit bone marrow proclivity. These nanomaterials can be administered (e.g., intravenously) to promote trained immunity. Therapeutic induction of trained immunity may find use, for example, in overcoming immune paralysis in sepsis and infection, treating cell proliferation disorders (such as cancer), enhancing immune responses, etc.

[0072] compound In embodiments, the present disclosure provides a compound of formula (I):

[0073] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is -H or -C(O)-R X and; R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5 , and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; R 7 is the fatty acid chain, -YN(R 6 )-C(O)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , -YN(R 6 )-C(O)-R X , -YOP(O)(OH)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 or -Y-triazolyl-L; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R X and; R 22 , R 33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ are each independently H or R A and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, aryl, and triazolyl may be selected from one or more R A is optionally replaced by R A is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(RC )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle; R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro to provide.

[0074] In embodiments, the present disclosure provides a compound of formula (I):

[0075] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is -H or -C(O)-R X and; R 2 and R 3are each independently selected from the group consisting of -H, alkyl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5 , and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; R 7 is C 9~30 Fatty acid chain, -YN(R 11 )-C(O)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , -C(R 10 )(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 16~30 Fatty acid chain, -(CR 10 R 10 )2-OP(O)(OH)-O-alkylene-C(R 10 )(OR Z )-Alkylene-OR Z’ or -Y-triazolyl-L; R Z and R Z’ are each independently C 8~30 Fatty acid chain or -C(O)-C 16~30 is a fatty acid chain; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R Xand; R 10 , R 22 , R 33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ are each independently H or R A and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, aryl, and triazolyl may be selected from one or more R A is optionally replaced by R A is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle; R Bis alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro; R 7 C 9~30 If it is a fatty acid chain, R 2 is -H) to provide.

[0076] In an embodiment of the compound of formula (I), the compound has the formula (IA):

[0077] [ka] (In the formula, R 1 is -H or -C(O)-R X and; R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5 , and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; R 7 is C 9~30 Fatty acid chain, -YN(R 11 )-C(O)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , -C(R 10 )(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 16~30 Fatty acid chain, -(CR 10 R 10 )2-OP(O)(OH)-O-alkylene-C(R 10 )(OR Z )-Alkylene-OR Z’ or -Y-triazolyl-L; R Z and R Z’ are each independently C 8~30Fatty acid chain or -C(O)-C 16~30 is a fatty acid chain; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R X and; R 10 , R 22 , R 33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ are each independently H or R A and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, aryl, and triazolyl may be selected from one or more R A is optionally replaced by R A is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B, -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle; R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro; R 7 C 9~30 If it is a fatty acid chain, R 2 is -H) or a pharmaceutically acceptable salt thereof.

[0078] In embodiments, the compound of formula (I) has formula (IB):

[0079] [ka] or a pharmaceutically acceptable salt thereof.

[0080] In embodiments of compounds of Formula (I), (IA), or (IB), Y is —C(O)N(R C )(R D In embodiments, Y is alkylene optionally substituted with -C 1~6 In an embodiment, Y is -CH2-. In an embodiment, Y is -CH2- or

[0081] [ka] In an embodiment, Y is

[0082] [ka] In an embodiment, Y is

[0083] [ka] is.

[0084] In embodiments of compounds of formula (I), (IA), or (IB), R 7 is -Y-triazolyl-L.

[0085] In embodiments of compounds of formula (I), (IA), or (IB), R 7 comprises a cholesteryl moiety or at least one fatty acid chain containing at least 17 carbons. 7 contains a cholesteryl moiety. In embodiments, R 7 comprises at least one fatty acid chain containing at least 17 carbons. 7 comprises at least two fatty acid chains containing at least 17 carbons. 7 At least two C 17 In embodiments, C 17 The fatty acid chains are derived from stearic acid or oleic acid. 17 The fatty acid chain is derived from stearic acid. 17 The fatty acid chain is derived from oleic fatty acid. 7 is a compound derived from stearic acid. 17 Contains fatty acid chains.

[0086] In embodiments of compounds of formula (I), (IA), or (IB), R 7 is an alkyl group having at least 16 carbons. In embodiments of compounds of formula (I), (IA), or (IB), R7 is an alkenyl group having at least 16 carbons. In embodiments of compounds of formula (I), (IA), or (IB), R 7 is an alkyl group having at least 18 carbons. In an embodiment of the compound of Formula (I), R 7 is an alkenyl group having at least 18 carbons.

[0087] In embodiments of compounds of formula (I), (IA), or (IB), R 7 is C 9~30 In an embodiment of the compound of formula (I), R 7 -C 9~30 Alkyl or C 9~30 In embodiments, R is an alkenyl. 7 -C 9~30 Alkyl or C 9~30 alkenyl, provided that R 7 -C 9~30 For alkyl, R 2 is —H. In an embodiment of the compound of formula (I), R 7 -C 9~30 In embodiments, R 7 -C 9~30 alkyl, and R 2 is —H. In an embodiment of the compound of formula (I), R 7 -C 9~30 In embodiments, R is an alkenyl. 7 -C 15~30 In embodiments, R 7 -C 15~30 is an alkyl group, and R 2 is —H. In embodiments, R 7 -C 15~30 In embodiments, R is an alkenyl group. 7 -C 17~19 In embodiments, R 7 -C 17~19 alkyl, and R 2 is —H. In embodiments, R 7 -C 17~19 In embodiments, R is an alkenyl.7 -C 18 In embodiments, R 7 -C 18 is an alkyl group, and R 2 is —H. In embodiments, R 7 -C 18 It is an alkenyl group.

[0088] In embodiments of compounds of formula (I), (IA), or (IB), R 7 teeth,

[0089] [ka] is.

[0090] In embodiments of compounds of formula (I), (IA), or (IB), R 7 teeth,

[0091] [ka] is.

[0092] In embodiments of compounds of formula (I), (IA), or (IB), R 7 teeth,

[0093] [ka] and R 2 is -H.

[0094] In embodiments of compounds of formula (I), (IA), or (IB), R 7 is -YN(R 11 )-C(O)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 is.

[0095] In embodiments of compounds of formula (I), (IA), or (IB), R 7 is -C(R 10)(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 16~30 In embodiments, R 7 is -C(H)(C(O)NH2)-C5 alkylene-N(R 11 )-C(O)-C 17~30 In embodiments, R 7 is -C(H)(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 17~30 It is a fatty acid.

[0096] In embodiments of compounds of formula (I), (IA), or (IB), R 7 is -C(R 10 )(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 16~30 In embodiments, R 7 is -C(R 10 )(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 17~30 In embodiments, R 7 is -C(H)(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 17~30 In embodiments, R 7 is -C(H)(C(O)NH2)-C4 alkylene-N(R 11 )-C(O)-C 17~30 In an embodiment of the compound of formula (I), R 7 is -C(R 10 )(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 16~30 alkyl, and R 2 is alkylene-aryl (e.g., benzyl). In embodiments, R 7 is -C(R 10 )(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 17~30 alkyl, and R 2 is alkylene-aryl (e.g., benzyl). In embodiments, R 7is -C(H)(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 17~30 alkyl, and R 2 is alkylene-aryl (e.g., benzyl). In embodiments, R 7 is -C(H)(C(O)NH2)-C4 alkylene-N(R 11 )-C(O)-C 17~30 alkyl, and R 2 is alkylene-aryl (e.g., benzyl).

[0097] In embodiments of compounds of formula (I), (IA), or (IB), R 7 is -(CR 10 R 10 )2-OP(O)(OH)-O-alkylene-C(R 10 )(OR Z )-Alkylene-OR Z In an embodiment of the compound of formula (I), R 7 is -CH2CH2-OP(O)(OH)-O-CH2-C(H)(OR Z )-CH2-OR Z’ In an embodiment, R Z and R Z’ are each independently C 12~20 Alkyl or -C(O)-C 16~30 In embodiments, R Z and R Z’ are each independently C 18 Alkyl or -C(O)-C 17 In embodiments, R Z and R Z’ are each independently -C 16~30 In embodiments, R Z and R Z’ are both -C 17 It is alkyl.

[0098] In embodiments of compounds of formula (I), (IA), or (IB), R 7 is -YN(R 6 )-C(O)-O-alkylene-C(H)(OR8 )-Alkylene-OR 9 In an embodiment, R 8 and R 9 are each independently 8~30 Alkyl or -C(O)-C 8~30 In embodiments, R 8 and R 9 are each independently 12~20 Alkyl or -C(O)-C 11~20 In embodiments, R 8 and R 9 are each independently 18 Alkyl or -C(O)-C 17 In embodiments, R 8 and R 9 are both -C(O)-C 17 It is alkyl.

[0099] In embodiments of compounds of formula (I), (IA), or (IB), R A is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B wherein X is 0, 1, or 2, and is independently selected at each occurrence from the group consisting of aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl.

[0100] In embodiments of compounds of formula (I), (IA), or (IB), R Ais halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B wherein X is 0, 1, or 2, and is independently selected at each occurrence from the group consisting of aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl.

[0101] In embodiments, the compound of formula (I) has formula (II):

[0102] [ka] or a pharmaceutically acceptable salt thereof (In the formula, X1 is -N- and X2 is -C-; or X1 is -C- and X2 is -N-; R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, aryl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5 , and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R X and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, and aryl may be selected from one or more R A is optionally replaced by R A is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)ORB or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle; R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro is.

[0103] In an embodiment, the compound of formula (II) is

[0104] [ka] is.

[0105] In an embodiment, the compound of formula (II) has the formula (II-1):

[0106] [ka] or a pharmaceutically acceptable salt thereof.

[0107] In an embodiment, the compound of formula (II-1) is

[0108] [ka] or a pharmaceutically acceptable salt thereof.

[0109] In an embodiment, the compound of formula (II) has the formula (II-2):

[0110] [ka] is a compound of

[0111] In an embodiment, the compound of formula (II-2) is

[0112] [ka] or a pharmaceutically acceptable salt thereof.

[0113] In embodiments, the compound of formula (I) has formula (IIA):

[0114] [ka] or a pharmaceutically acceptable salt thereof (In the formula, X1 is -N- and X2 is -C-; or X1 is -C- and X2 is -N-; R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, aryl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5 , and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R X and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, and aryl may be selected from one or more R A is optionally replaced by R A is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle; R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro is.

[0115] In an embodiment, the compound of formula (IIA) is

[0116] [ka] is.

[0117] In embodiments, the compound of formula (IIA) is a compound of formula (IIA-1), or a pharmaceutically acceptable salt thereof.

[0118] [ka]

[0119] In embodiments, the compound of formula (IIA-1) is

[0120] [ka] or a pharmaceutically acceptable salt thereof.

[0121] In embodiments, the compound of formula (IIA) is a compound of formula (IIA-2), or a pharmaceutically acceptable salt thereof:

[0122] [ka]

[0123] In embodiments, the compound of formula (IIA-2) is

[0124] [ka] or a pharmaceutically acceptable salt thereof.

[0125] In an embodiment of a compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1), or (IIA-2), Y is alkylene. In an embodiment of a compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1), or (IIA-2), Y is C 1~6 In an embodiment, Y is C 1~5 In an embodiment, Y is C 1~3In embodiments, Y is —C(O)N(R C )(R D ), and R C and R D is defined herein. In an embodiment, Y is -CH2-. In an embodiment, Y is

[0126] [ka] In an embodiment, Y is

[0127] [ka] is.

[0128] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R A is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B and independently selected at each occurrence from the group consisting of:

[0129] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R A is halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B and independently selected at each occurrence from the group consisting of:

[0130] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), alkyl, alkylene, alkylene-aryl, and aryl are each independently selected from the group consisting of one or more R A is optionally replaced by

[0131] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle.

[0132] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro.

[0133] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R A is -H.

[0134] In some embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1), or (IIA-2), R 2 is alkyl, aryl, or alkylene-aryl. In embodiments, the aryl is optionally substituted with alkyl.

[0135] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, aryl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl.

[0136] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R 2 is —H or benzyl. In an embodiment of the compound of formula (I), R 2 -H ’ In an embodiment, R 2 is benzyl.

[0137] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R 4 , R 5 , and R 5’ are each alkyl.

[0138] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R 4 is alkyl. In embodiments, R 4 is methyl.

[0139] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R 3 is —H. In embodiments, R 6 is —H. In embodiments, R 3 and R 6 are both -H.

[0140] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R 10 , R 22 , R 33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ are -H, respectively.

[0141] In embodiments of the compounds of Formula (I), (II), (IA), (IB), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L comprises a cholesteryl moiety or at least one fatty acid chain containing at least 13 carbons. In embodiments, L comprises a cholesteryl moiety. In embodiments, L comprises at least one fatty acid chain containing at least 13 carbons. In embodiments, L comprises at least two fatty acid chains containing at least 15 carbons. In embodiments, L comprises at least one C 17 In an embodiment, L comprises at least two C 17 In an embodiment, L is C 17 Alkyl or C 17 In embodiments, L comprises at least one fatty acid chain independently selected from the group consisting of alkenyl, C 17 Alkyl or C 17 In embodiments, the C 17 The fatty acid chains are derived from stearic acid or oleic acid. 17 The fatty acid chain is derived from stearic acid. 17 The fatty acid chains are derived from oleic fatty acids. In embodiments, L is a hydroxyl group consisting of two C hydroxyl groups derived from stearic acid. 17 Contains fatty acid chains.

[0142] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2.

[0143] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is C8~30 Fatty acid chain, -CH2-C(O)-W, -CH2-OC(O)-W, -CH2CH2-N-CH2CH2-C(O)-NR 11 -CH2CH2-NR 11 -C(O)-W)2, and -CH2CH2-N-(CH2CH2-C(O)-W)2.

[0144] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is C 8~30 In an embodiment, L is a C 8~30 Alkyl or C 8~30 In embodiments, L is C 15~20 Alkyl or C 15~20 It is alkenyl.

[0145] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is selected from the group consisting of -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, or -alkylene-N-(alkylene-C(O)-W)2.

[0146] In an embodiment of a compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is -alkylene-C(O)-W. In an embodiment, L is -C 1~6 alkylene-C(O)-W. In embodiments, L is -CH2-C(O)-W.

[0147] In an embodiment of a compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is -alkylene-OC(O)-W. In an embodiment, L is -C 1~6alkylene -OC(O)-W. In embodiments, L is -CH2-OC(O)-W.

[0148] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 In an embodiment, L is -C(O)-W). 2~6 Alkylene-N-(-C 2-6 Alkylene-C(O)-NR 11 -C 2~6 Alkylene-NR 11 In an embodiment, L is -CH-CH-N-(CH-CH-C(O)-NR 11 -CH2-CH2-NR 11 -C(O)-W)2.

[0149] In an embodiment of a compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is -alkylene-N-(alkylene-C(O)-W). In an embodiment, L is -C 1~6 Alkylene-N-(C 1~6 alkylene-C(O)-W). In embodiments, L is -CH-CH-N-(CH-CH-C(O)-W).

[0150] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), L is C 18 In an embodiment, L is a C 18 Alkyl or C 18 In an embodiment, L is -CH2(CH2CH2)8-CH3.

[0151] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols.

[0152] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), W is C 8~30 In an embodiment, W is a C 8~30 Alkyl or C 8~30 In embodiments, W is C 8~30 In an embodiment, W is C 8~30 In embodiments, W is C 12~18 In an embodiment, W is a C 12~18 Alkyl or C 12~18 In embodiments, W is C 12~18 In an embodiment, W is C 12~18 In embodiments, W is C 18 In an embodiment, W is a C 17 In an embodiment, W is a C 17 Alkyl or C 17 In embodiments, W is C 17 In an embodiment, W is C 17 In embodiments, W is alkenyl. In embodiments, W is -(CH2CH2)8-CH3. In embodiments, W is a fatty acid chain containing at least 15 carbons. In embodiments, W is a fatty acid chain containing at least 18 carbons. In embodiments, W is a fatty acid chain containing at least 17 carbons. In embodiments, W is a fatty acid chain containing at least 18 carbons.

[0153] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), W is

[0154] [ka] In an embodiment, R X and R X’ are each independently a fatty acid chain. X and R X’ are each independently a fatty acid chain containing at least 15 carbons. X and R X’ are each independently a fatty acid chain containing at least 17 carbons. X and R X’ are each independently -C 8~30 In embodiments, R X and R X’ are each independently -C 8~30 Alkyl or -C 8~30 In embodiments, R is an alkenyl. X and R X’ are both -C 8~30 In embodiments, R X and R X’ are both -C 8~30 In embodiments, R is an alkenyl. X and R X’ are each independently C 12~18 In embodiments, R X and R X’ are each independently -C 12~18 Alkyl or -C 12~18 In embodiments, R is an alkenyl. X and R X’ -C 12~18 In embodiments, R X and R X’ -C 12~18 In embodiments, R is an alkenyl. X and R X’ are each independently C 17 In embodiments, R X and R X’ are each independently C17 Alkyl or C 17 In embodiments, R is an alkenyl. X and R X’ is C 17 In embodiments, R X and R X’ is C 17 In embodiments, C is alkenyl. 17 The chains are each independently derived from stearic acid or oleic acid. 17 The chain is derived from stearic acid. 17 The chain is derived from oleic acid. X and R X’ are both -(CH2CH2)8-CH3.

[0155] In an embodiment of compound (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), W is a sterol.

[0156] In an embodiment of compound (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), W is cholesterol.

[0157] [ka]

[0158] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1), or (IIA-2), W is a phospholipid selected from the group consisting of phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), and lysophosphatidylcholine. In embodiments, W is phosphatidylcholine (PC). In embodiments, W is phosphatidylglycerol (PG). In embodiments, W is phosphatidylserine (PS). In embodiments, W is phosphatidylethanolamine (PE). In embodiments, W is phosphatidic acid (PA). In embodiments, W is lysophosphatidylcholine.

[0159] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), W is

[0160] [ka] is. (In the formula, Y Q1 , Y Q2 , and Y Q3 are each independently alkylene. Q1 is C 2~6 is alkylene, and Y Q2 and Y Q3 are each independently -C 1~3 In embodiments, R X and R X’ are each independently a fatty acid chain having at least 15 carbons, or in certain embodiments, R X and R X’ are each independently a fatty acid chain having at least 17 carbons. X and R X’ are each independently C 8~30 In embodiments, RX and R X’ are each independently C 8~30 Alkyl or C 8~30 In embodiments, R is an alkenyl. X and R X’ are each independently C 15~30 Alkyl or C 15~30 In embodiments, R is an alkenyl. X and R X’ are each independently C 15~20 Alkyl or C 15~20 In embodiments, R is an alkenyl. X and R X’ are each independently C 17 Alkyl or C 17 In embodiments, R is an alkenyl. X and R X’ are both -(CH2CH2)8-CH3.

[0161] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), W is

[0162] [ka] is.

[0163] In an embodiment of the compound of (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), W is

[0164] [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R X and R X’ are each independently C 8~30 In embodiments, the fatty acid is saturated. X and R X’ are each independently C8~30 Alkyl or C 8~30 In embodiments, R is an alkenyl. X and R X’ are each independently C 15~20 Alkyl or C 15~20 In embodiments, R is an alkenyl. X and R X’ are each independently C 17 Alkyl or C 17 In embodiments, R is an alkenyl. X and R X’ are both -(CH2CH2)8-CH3.

[0165] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R 8 and R 9 are each independently R X or -C(O)-R X is.

[0166] In embodiments of compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2), R 6 and R 11 are each independently —H or alkyl.

[0167] In embodiments, the present disclosure provides

[0168] [ka]

[0169] [ka] a compound selected from the group consisting of or a stereoisomer thereof (eg, an alpha or beta anomer thereof, or a tautomer thereof).

[0170] In embodiments, the present disclosure provides:

[0171] [ka] a compound selected from the group consisting of or a stereoisomer thereof (eg, an anomer thereof, or a mixture of anomers thereof).

[0172] In embodiments, the present disclosure provides compounds of formula (I), (IA), (IB), (II), (II-1), (II-2), (IIA), (IIA-1), (IIA-2), or stereoisomers thereof.

[0173] In embodiments, the present disclosure provides compounds of formula (I), (IA), (IB), (II), (II-1), (II-2), (IIA), (IIA-1), (IIA-2), or diastereomers or tautomers thereof.

[0174] In embodiments, provided herein is one or more compounds selected from Table 1.

[0175] In embodiments, provided herein are one or more pharmaceutically acceptable salts of a compound selected from Table 1.

[0176] In embodiments, provided herein are one or more compounds selected from Table 1, stereoisomers, or pharmaceutically acceptable salts thereof.

[0177] [Table 1-1]

[0178] [Table 1-2]

[0179] [Table 1-3]

[0180] [Table 1-4]

[0181] [Table 1-5]

[0182] Muramyl tripeptide phosphatidylethanolamine; N-(N-acetylmuramoyl)-L-alanyl-D-alpha-glutaminyl-N-[(7R)-4-hydroxy-4-oxido-10-oxo-7-[(1-oxohexadecyl)oxy]-3,5,9-trioxa-4-phosphapentacos-1-yl]-L-alaninamide (MTP-α-DPPE or mifamurtide): Molecular weight: 1238 Daltons. CLogP = 10.59 (uncharged) and 4.80 (negatively charged). Mifamurtide (CAS No. [83461-56-7]) was prepared according to literature procedures (e.g., DE; Wade, R. (1985) J Label Compd Radiopharm. 22 (1): 29-35. doi:10.1002 / jlcr.2580220105). The lipophilicity of this molecule is relatively low in physiological environments, with a CLogP of 4.80.

[0183] N-acetylmuramyl-L-alanyl-D-isoglutamine-6-O-stearoyl (MDP-C18[mur]) molecular weight: 759 daltons. C LogP = 5.39 (uncharged) and 1.39 (negatively charged). MDP-C18[mur] (CAS No. [60398-08-5]) was prepared according to literature procedures (e.g., Matsumoto K. et al. (1981) Infect Immun. 32(2):748-58). The lipophilicity of this molecule is low in physiological environments, with a C LogP of 1.39, which is unlikely to be sufficient to ensure reliable incorporation into HDL-derived nanoparticles.

[0184] Romurtide (CAS No. [78113-36-7]) has a molecular weight of 887 daltons. It has a lipophilicity with a CLogP of 3.90 (uncharged) and 0.61 (negatively charged) (in physiological environments, the CLogP is 0.61). This compound has low lipophilicity, with a CLogP close to 0 for charged molecules.

[0185] Murabutide (CAS number [74817-61-1]) molecular weight: 549 daltons. CLogP=-1.53 ​​(uncharged), which is a negative CLogP value. This molecule is hydrophilic because its CLogP value is less than 0.

[0186] In embodiments, compounds of the disclosure (e.g., compounds of Formula (I), (IA), (IB), (II), (II-1), (II-2), (IIA), (IIA-1), (IIA-2) or Table 1) activate nucleotide-binding oligomerization domain-containing protein 2 (NOD2).

[0187] Anomers and open / closed structures In embodiments, molecules of the present disclosure bear an —OH substituent at the anomeric hemiacetal carbon of the muramyl sugar group, i.e., when R═H, it is understood that both anomeric isomers alpha and beta are included in the compounds of the present disclosure.

[0188] Furthermore, in those cases where R = H, it is known in the art that such molecules actually exist (in aqueous environments) in both closed and open ring isomers. Again, it is understood that both open and closed ring isomers are included in the compounds of the present disclosure.

[0189] In the non-limiting examples below, the top structures show the alpha and beta anomers, and the bottom structures show the general anomeric closed (left) and open (right) ring structures.

[0190] [ka]

[0191] molecular weight The compounds of the invention preferably have a molecular weight of greater than 500 daltons, greater than 700 daltons, greater than 950 daltons, or greater than 1,200 daltons.

[0192] The compounds of the present invention preferably have a molecular weight of less than 10,000 daltons, less than 5,000 daltons, less than 2,500 daltons, or less than 1,750 daltons.

[0193] Hydrophobic In certain embodiments, the compounds of the present disclosure are essentially hydrophobic.Hydrophobicity can be estimated by calculating CLogP value.This can be performed using software programs such as Perkin Elmer's ChemDraw or ChemDraw Professional (v18).The higher the CLogP value of a compound, the more hydrophobic the compound is.

[0194] In embodiments, compounds of the present disclosure have a CLogP value of greater than about 1, greater than about 3, greater than about 5, greater than about 7, greater than about 9, or greater than about 11.

[0195] The CLogP value represents the n-octanol / water partition coefficient (Log Po / w) of a molecule and is a calculated value, as opposed to a LogP value, i.e., an experimentally determined value. Therefore, CLogP values ​​may deviate from LogP values. Importantly, however, CLogP values ​​provide a good comparison between the lipophilicity of molecules. CLogP values ​​can be evaluated for molecules in either the uncharged or charged state. This is the case for molecules with ionogenic groups, such as those with carboxylic acid (-COOH) or phosphate (-OP(O)OH-O-) groups. At physiological pH (approximately 7.4), these particular groups are deprotonated and therefore charged. Also, alkyl(ated)amine groups are charged at physiological pH, in this case by protonation.

[0196] At physiological pH, the molecules of the invention have CLogP values ​​of less than 20, or less than 15, or less than 10. Additionally, at physiological pH, the molecules of the invention have CLogP values ​​of greater than 3, or greater than 4, or greater than 5, or greater than 5.5.

[0197] Nanobiological Compositions Provided herein are nanobiological compositions comprising a nanoparticle carrier and one or more compounds of the present disclosure (such as compounds (I), (IA), (IB), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2) as disclosed herein or in Table 1).

[0198] In embodiments, the compounds of the present disclosure can be formulated in nanoparticle carriers, including colloidal dispersion systems such as polyplexes, polymer complexes, nanocapsules, microspheres, beads, and lipid-based systems such as oil-in-water emulsions, micelles, mixed micelles, liposomes, lipoplexes, lipid nanoparticles, lipid nanocapsules, lipidoids, rapid-clearing lipid nanoparticles (reLNPs), micro- and nanoemulsions, HDL-derived nanoparticles, polymeric nanoparticles such as poly(lactic-co-glycolic acid) (PLGA) nanoparticles, including PLGA microspheres, poly(lactide) (PLA) nanoparticles, poly(ε-caprolactone) (PCL) nanoparticles, poly(butylcyanoacrylate) (PBCA) nanoparticles, dendrimers (de Examples of suitable nanoparticles include, but are not limited to, nanoparticles, nanowires, gold nanoparticles, magnetic nanoparticles, core-shell nanoparticles, carbon nanotubes, nanocrystals, hyaluronidase, and combinations thereof.

[0199] In embodiments, the compounds of the present disclosure may be formulated in nanoparticle carriers such as those described in U.S. Pat. Nos. 5,567,434, 5,552,157, 5,565,213, 5,738,868, 5,795,587, 10,485,884, U.S. Patent Application Publication No. 2018 / 0263907, U.S. Patent Application Publication No. 2016 / 0317647, U.S. Patent Application Publication No. 2019 / 0290593, U.S. Patent Application Publication No. 2020 / 0253884, U.S. Patent Application Publication No. 2020 / 0376146, and WO 2018 / 071549, the contents of each of which are incorporated herein by reference.

[0200] In embodiments, the nanoparticle carrier is a high-density lipoprotein (HDL)-derived nanoparticle. High-density lipoprotein (HDL)-derived nanoparticles are envisioned as delivery vehicles that, for example, improve the therapeutic index of small molecule immunomodulatory compounds and / or provide innate immune cell-specific delivery. By conferring targeting specificity to innate immune cells (such as bone marrow cells, bone marrow progenitor cells, and hematopoietic stem cells in the bone marrow, blood, and / or spleen), therapeutic agents encapsulated or incorporated into HDL-derived nanoparticles can be delivered in a concentrated and localized manner. In embodiments, the high-density lipoprotein (HDL)-derived nanoparticles comprise apoA-I or a peptidomimetic of apoA-I. In embodiments, the high-density lipoprotein (HDL)-derived nanoparticles comprise apoA-I.

[0201] 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 includes synthesizing apoA-I by recombinant protein expression, for example, in Escherichia coli (E. coli) organisms. When expressed in bacteria, apoA-I may contain an N-terminal methionine or formylmethionine. The presence of a methionine group can be assessed by mass spectrometry (MS) methods known in the art. The location of methionine in the protein sequence can be assessed by digestion of apoA-I followed by analysis of the peptide mixture by MS, as is also known in the art.

[0202] In embodiments, purification of apoA-I, including any of its variations, can involve any method known in the art (e.g., the use of hydrophobic interaction chromatography, ion exchange columns, precipitation, etc.) The production method may or may not include the use of an affinity tag that allows for purification of the protein, such a tag needing to be removed after purification to restore the identity of human apoA-I.

[0203] In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise ApoA-1 Milano.

[0204] Suitable apoA-I mimetic polypeptides can have the sequences shown in Table 2 (SEQ ID NOS: 256-263, and 342-346) or SEQ ID NOS: 1-341.

[0205] [Table 2]

[0206] In embodiments, the apoA-I mimetic is DWLKAFYDKVAEKLKEAF (SEQ ID NO: 256). In embodiments, the apoA-I mimetic is Ac-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 257). In embodiments, the apoA-I mimetic is Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ ID NO: 260).

[0207] In embodiments, the apoA-I mimic is optionally acetylated at the N-terminus or optionally amidated at the C-terminus. In embodiments, the apoA-I mimic is acetylated at the N-terminus. In embodiments, the apoA-I mimic is amidated at the C-terminus. In embodiments, the apoA-I mimic is acetylated at the N-terminus and amidated at the C-terminus. In embodiments, the HDL-derived nanoparticles of the present disclosure comprise one or more phospholipids. All phospholipids, ranging in chain length from C4 to C30, saturated or unsaturated, cis or trans, unsubstituted or substituted with 1 to 6 side chains, and with or without the addition of lysolipids, are contemplated for use in the nanoparticles described herein. Additionally, other synthetic variants and variants with other phospholipid head groups are also contemplated. In embodiments, the HDL-derived nanoparticles comprise phospholipids. In embodiments, the HDL-derived nanoparticles comprise phospholipids and lysolipids.

[0208] Non-limiting examples of phospholipids that can be used in the present composition include phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylethanolamine (PE).In embodiments, phosphatidic acid / ester (PA) can be used.

[0209] In embodiments, the phospholipid or lysolipid is one or more of the following: DDPC CAS-3436-44-0 1,2-didecanoyl-sn-glycero-3-phosphocholine, DEPA-NA CAS-80724-31-8 1,2-dierucoyl-sn-glycero-3-phosphate (sodium salt), DEPC CAS-56649-39-9 1,2-dierucoyl-sn-glycero-3-phosphocholine, DEPE CAS-988-07-2 1,2-dierucoyl-sn-glycero-3-phosphoethanolamine, DEPG-NA 1,2-dierucoyl-sn-glycero-3-phospho-rac-(1-glycerol) (sodium salt), DLOPC CAS-998-06-1 1,2-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-glycero-3-phosphoethanolamine, DLPG-NA 1,2-Dilauroyl-sn-glycero-3-phospho-rac-(1-glycerol) (sodium salt), DLPG-NH4 1,2-Dilauroyl-sn-glycero-3-phospho-rac-(1-glycerol) (ammonium salt), DLPS-NA 1,2-Dilauroyl-sn-glycero-3-phosphoserine (sodium salt), DMPA-NA CAS-80724-3 1,2-Dimyristoyl-sn-glycero-3-phosphate (sodium salt), DMPC CAS-18194-24-6 1,2-Dimyristoyl-sn-glycero-3-phosphocholine, DMPE CAS-988-07-2 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine, DMPG-NA CAS-67232-80-8 1,2-Dimyristoyl-sn-glycero-3-phospho-rac-(l-glycerol) (sodium salt), DMPG-NH4 1,2-Dimyristoyl-sn-glycero-3-phospho-rac-(l-glycerol) (ammonium salt), DMPG-NH4 / NA 1,2-Dimyristoyl-sn-glycero-3-phospho-rac-(l-glycerol) (sodium / ammonium salt), DMPS-NA1,2-Dimyristoyl-sn-glycero-3-phosphoserine (sodium salt), DOPA-NA 1,2-Dioleoyl-sn-glycero-3-phosphate (sodium salt), DOPC CAS-4235-95-4 1,2-Dioleoyl-sn-glycero-3-phosphocholine, DOPE CAS-4004-5-1 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine, DOPG-NA CAS-62700-69-0 1,2-Dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (sodium salt), DOPS-NA CAS-70614-14-1 1,2-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 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine, DPPG-NA CAS-67232-81-9 1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-(l-glycerol) (sodium salt), DPPG-NH4 CAS-73548-70-6 1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-(l-glycerol) (ammonium salt), DPPS-NA 1,2-Dipalmitoyl-sn-glycero-3-phosphoserine (sodium salt), DSPA-NA CAS-108321-18-2 1,2-Distearoyl-sn-glycero-3-phosphate (sodium salt), DSPC CAS-816-94-4 1,2-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-(1-glycerol) (sodium salt), DSPG-NH4 CAS-108347-80-4 1,2-Distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) (ammonium salt), DSPS-NA1,2-Distearoyl-sn-glycero-3-phosphoserine (sodium salt), EPC egg-PC, HEPC hydrogenated egg-PC, HSPC hydrogenated soybean PC, LYSOPC myristic (CAS-18194-24-6) l-myristoyl-sn-glycero-3-phosphocholine, LYSOPC palmitic (CAS-17364-16-8) l-palmitoyl-sn-glycero-3-phosphocholine, LYSOPC stearic (CAS-19420-57-6) l-stearoyl-sn-glycero-3-phosphocholine, milk sphingomyelin, MPPC l-myristoyl-2-palmitoyl-sn-glycero-3-phosphocholine, MSPC l-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, PMPC 1-Palmitoyl-2-myristoyl-sn-glycero-3-phosphocholine, POPC CAS-26853-31-6 l-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPE 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, POPG-NA CAS-81490-05-3 l-Palmitoyl-2-oleoyl-sn-glycero-3[phospho-rac-(1-glycerol)](sodium salt), PSPC 1-Palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, SMPC 1-Stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, SOPC1-Stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, SPPC1-Stearoyl-1-2-palmitoyl-sn-glycero-3-phosphocholine. In some preferred embodiments, non-limiting examples of phospholipids include dimyristoylphosphatidylcholine (DMPC), soy lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dilaurylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dilaurylolphosphatidylglycerol (DLPG), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylglycerol (DSPG ...oleoylphosphatidylcholine (DOPC), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylglycerol (DOPC), dioleoylphosphatidylglycerol (DOPC), dioleoylphosphatidylglycerol (DOPC), dioleoylphosphatidylglycerol (DOPC), dioleoylphosphatidylglycerol (DOPC), dioleoylphosphatidylglycerol (DOPC), dioleoylphosphatidylglycerol (DOPC), dioleoylphosphatidylglycerol (DOPC), dioleoylphosphat Oleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidic acid (DMPA), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), dipalmitoylphosphatidic acid (DPPA), dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylserine (DMPS), dipalmitoylphosphatidylserine (DPPS), dipalmitoylsphingomyelin (DPSP), distearoylsphingomyelin (DSSP), and mixtures thereof.

[0210] In embodiments, the phospholipid is 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and the lysolipid is 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC).

[0211] In embodiments, the phospholipid is 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the lysolipid is 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC).

[0212] In embodiments, when the composition comprises (or consists essentially of, or consists of) two or more types of lipids (e.g., phospholipids, or lysolipids), the weight ratio of the two types of phospholipids ranges from about 1:10 to about 10:1, e.g., 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.

[0213] In embodiments, the HDL-derived nanoparticles comprise DMPC and MHPC, and the weight ratio of DMPC to MHPC can range from about 1:10 to about 10:1, about 2:1 to about 4:1, about 1:1 to about 5:1, about 2:1 to about 5:1, about 6:1 to about 10:1, about 7:1 to about 10:1, about 8:1 to about 10:1, about 7:1 to about 9:1, or about 8:1 to about 9:1. The weight ratio of DMPC to MHPC can be about 1:10, 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, or about 10:1, including all values ​​and ranges therebetween.

[0214] In embodiments, the HDL-derived nanoparticles comprise POPC and PHPC, and the weight ratio of POPC to PHPC may range from about 1:10 to about 10:1, about 2:1 to about 4:1, about 1:1 to about 5:1, about 2:1 to about 5:1, about 6:1 to about 10:1, about 7:1 to about 10:1, about 8:1 to about 10:1, about 7:1 to about 9:1, or about 8:1 to about 9:1. The weight ratio of POPC to PHPC may be about 1:10, 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, or about 10:1.

[0215] In embodiments, the phospholipids in the nanoparticles of the present disclosure comprise (or consist essentially of, or consist of) a mixture of double-chain diacyl phospholipids and single-chain acyl phospholipids / lysolipids.

[0216] In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise apoA-I or a peptidomimetic of apoA-I, and a phospholipid. In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise apoA-I or a peptidomimetic of apoA-I, a phospholipid, and a compound of Formula (I), (II), (II-1), (II-2), (II-A), (IIA-1), or (IIA-2).

[0217] In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise i) apoA-I or a peptidomimetic of apoA-I; ii) a phospholipid; iii) a lysolipid, and iv) cholesterol. In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise i) apoA-I or a peptidomimetic of apoA-I; ii) a phospholipid; iii) a lysolipid, iv) cholesterol, and a compound of Formula (I), (II), (II-1), (II-2), (II-A), (IIA-1), or (IIA-2).

[0218] In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise i) apoA-I or a peptidomimetic of apoA-I; ii) a phospholipid; and iii) cholesterol. In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise i) apoA-I or a peptidomimetic of apoA-I; ii) a phospholipid; iii) cholesterol, and a compound of Formula (I), (II), (II-1), (II-2), (II-A), (IIA-1), or (IIA-2).

[0219] In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise i) apoA-I or a peptidomimetic of apoA-I; ii) a phospholipid; iii) a lysolipid, iv) a hydrophobic matrix core, and v) cholesterol. In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise i) apoA-I or a peptidomimetic of apoA-I; ii) a phospholipid; iii) a lysolipid, iv) a hydrophobic matrix core, v) cholesterol and a compound of Formula (I), (II), (II-1), (II-2), (II-A), (IIA-1), or (IIA-2).

[0220] In embodiments, the high density lipoprotein (HDL)-derived nanoparticles comprise i) apoA-I or a peptidomimetic of apoA-I; ii) a phospholipid; iii) a lysolipid; iv) a triglyceride; v) cholesterol and a compound of formula (I), (II), (II-1), (II-2), (II-A), (IIA-1) or (IIA-2).

[0221] In embodiments, the structure and properties (e.g., particle size, rigidity, viscosity, loading, etc.) of HDL-derived nanoparticles can be modified by incorporating a hydrophobic matrix. As used herein, a hydrophobic matrix refers to the core, filler, or structural modifier of a nanobiological preparation. Non-limiting examples of suitable hydrophobic matrix molecules include triglycerides, fatty acid esters, hydrophobic polymers, sterol esters, or combinations thereof.

[0222] For example, the inclusion of one or more triglycerides and / or one or more polymers in the nanoparticles disclosed herein can facilitate control of nanoparticle size (e.g., from about 10 nm to over 100 nm) and shape (from discoid to spherical). The size, rigidity, and viscosity of HDL-derived nanoparticles can also affect loading and biodistribution. In a non-limiting example, HDL-derived nanoparticles containing phospholipids and apoA-I can have a diameter of about 10 nm to about 50 nm, and the addition of hydrophobic matrix molecules (such as triglycerides) can swell the HDL-derived nanoparticles from a minimum of about 10 nm to at least about 30 nm. The addition of further triglycerides can further increase the diameter of the HDL-derived nanoparticles to at least 50 nm, at least 75 nm, at least 100 nm, at least 150 nm, at least 200 nm, at least 300 nm, and up to 400 nm, including all values ​​and ranges therebetween.

[0223] Any suitable synthetic or natural fatty acid or fatty acid ester known in the art is contemplated for use in the HDL-derived nanoparticles of the present disclosure. Non-limiting examples of fatty acids that may be used include arachidonic acid, oleic acid, arachidic acid, lauric acid, SAD, capric acid, myristic acid, palmic acid, stearic acid, linoleic acid, linolenic acid, dicapric acid, decanoin 3, glycerin mono-fatty acid ester, dilaurin, 1-Sunsoft 767, laurocapram (1-dodecyl-aza-cycloheptane-2-ketone), acylcarnitine, acylcholine, or C1-C6 fatty acids. 10 arrcostab (such as isopropyl myristate IPM), monoglycerides, diglycerides or pharmaceutically acceptable salts thereof.

[0224] Any suitable synthetic or natural triglyceride known in the art is contemplated for use in the HDL-derived nanoparticles of the present disclosure.Non-limiting examples of triglycerides that can be used include: tricaprylin, tristearin, triolein, tripalmitin, 1,2-dipalmitolein, 1,3-dipalmitolein, 1-palmito-3-stearo-2-olein, 1-palmito-2-stearo-3-olein, 2-palmito-1-stearo-3-olein, trilinolein, 1,2-dipalmitrinolein, 1-palmito-dilinolein, 1-stearo-dilinolein, 1,2-diacetopalmitin, 1,2-distearo-olein, 1,3-distearo-olein, trimyristin, trilaurin, and combinations thereof.Suitable triglycerides can be added to the compositions of the present invention in raw form. Additionally or alternatively, oils and / or processed oils containing suitable triglycerides may be added to the composition.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.

[0225] The hydrophobic polymer or polymers can 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 copolymers, branched polymers, and polymer blends: polyalkene dicarboxylates, polyanhydrides, poly(aspartic acid), polyamides, polybutylene succinate (PBS), polybutylene succinate-co-adipate (PBSA), poly(ε-caprolactone) (PCL), polycarbonates including polyalkylene carbonates (PC), aliphatic polyesters, and polyesteramides. These include polyesters, polyethylene succinate (PES), polyglycolide (PGA), polyimines and polyalkyleneimines (Pl, PAI), polylactides (PLA (polylactic acid), PLLA, PDLLA), polylactic-co-glycolic acid (PLGA), poly(L-lysine), polymethacrylates, polypeptides, polyorthoesters, poly-p-dioxanone (PPDO), (hydrophobically) modified polysaccharides, polysiloxanes and polyalkylsiloxanes, polyureas, polyurethanes, polyvinyl alcohol, and biodegradable polyalkylcyanoacrylates.

[0226] In embodiments of HDL-derived nanoparticles of the present disclosure, the addition of cholesterol to the nanoparticle carrier stabilizes the composition and improves entrapment efficiency. Typically, HDL-derived nanoparticles contain about 1 mol% to about 100 mol% cholesterol relative to the phospholipid (e.g., relative to DMPC), including all ranges and values ​​therebetween, such as 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%, and the like. %, 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% cholesterol (i.e., a 1:1 mol / mol mixture of cholesterol and phospholipid (e.g., DMPC)). In embodiments, the HDL-derived nanoparticles contain about 1 mol% to about 30 mol% cholesterol. In embodiments, the HDL-derived nanoparticles contain about 15 mol% to about 25 mol% cholesterol relative to the phospholipid. In embodiments, the HDL-derived nanoparticles contain about 20 mol% cholesterol relative to the phospholipid. In an embodiment, the HDL-derived nanoparticles comprise about 10 mol% to about 35 mol% cholesterol relative to the phospholipid. In an embodiment, the HDL-derived nanoparticles comprise about 15 mol% to about 30 mol% cholesterol relative to the phospholipid. In an embodiment, the HDL-derived nanoparticles comprise about 15 mol% to about 25 mol% cholesterol relative to the phospholipid. In an embodiment, the HDL-derived nanoparticles comprise about 28 mol% to about 23 mol% cholesterol relative to the phospholipid. In an embodiment, the HDL-derived nanoparticles comprise about 20 mol% to about 27 mol% cholesterol relative to the phospholipid.

[0227] In embodiments, the HDL-derived nanoparticles are cholesterol-free. In embodiments, the cholesterol:phospholipid molar ratio in the HDL-derived nanoparticles is 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. The cholesterol:phospholipid molar ratio can range from about 0:1 to about 0.5:1, e.g., 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 to about 0.5:1, including all ranges therebetween. In embodiments, the cholesterol:phospholipid molar ratio is from about 0.05:1 to about 0.25:1. In embodiments, the molar ratio of cholesterol is about 0.2:1.

[0228] In embodiments, the HDL-derived nanoparticles comprise one or more phospholipids and cholesterol in a molar ratio ranging from about 1:0.05 to about 1:0.25, and in embodiments, the HDL-derived nanoparticles comprise one or more phospholipids and cholesterol in a molar ratio of 1:0.2.

[0229] In embodiments, the weight percentage of cholesterol ranges from about 0% (w / w) to about 15% (w / w) of the nanoparticle, lipid, or composition, e.g., 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% (w / w), about 12.5% ​​(w / w), about 13% (w / w), about 13.5% (w / w), about 14% (w / w), and in the range of 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, e.g., 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% (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 percentages are the weight percentages of cholesterol relative to the phospholipid. 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 (w / w%) of the composition.In embodiments, the weight percentage of cholesterol ranges from about 5-10% 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.

[0230] In embodiments, the size and circulation time of nanoparticles can be modulated, for example, by controlling the lipid to APOA1 ratio and the lipid to polymer or lipid to triglyceride ratio.

[0231] In embodiments, the HDL-derived nanoparticles are present in a ratio of about 5:1 to 1000:1 (e.g., on a molar basis), e.g., 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 Approximately 230:1, approximately 240:1, approximately 250:1, approximately 260:1, approximately 270:1, approximately 280:1, approximately 290:1, approximately 300:1, approximately 310:1, approximately 320:1, approximately 330:1, approximately 340:1, approximately 350:1, approximately 360:1, approximately 370:1, approximately 380:1, approximately 390:1, approximately 400:1, approximately 410:1, approximately 420:1, approximately 430:1, approximately 440:1, approximately 450:1, approximately 460:1, approximately 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 phospholipid:apoA-I or apoA-I mimetic ratios of 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 and values ​​therebetween. In embodiments, the HDL-derived nanoparticles comprise a phospholipid:apoA-I or apoA-I mimetic ratio (e.g., on a molar basis) of about 10:1 to 1000:1. In embodiments, the HDL-derived nanoparticles comprise a phospholipid:apoA-I ratio (e.g., on a molar basis) of about 70:1 to 125:1. In embodiments, the HDL-derived nanoparticles comprise an apoA-I mimetic ratio (e.g., on a molar basis) of about 5:1 to 10:1.

[0232] In embodiments, the HDL-derived nanoparticles comprise a weight ratio of about 2:1 to 3:1 phospholipid:apoA-I or apoA-I mimetic.

[0233] In embodiments, the HDL-derived nanoparticles comprise about or at least about 0.1 mol% to about 100 mol% of a compound of Formula I relative to the phospholipid (e.g., DMPC), e.g., 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 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 is 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 or at least about 30 mol%, 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 mol%, about or at least about 95 mol% to about or at least about 100 mol% of the compound of Formula I (a 1:1 mol / mol mixture of the compound and a phospholipid (e.g., DMPC)), including all ranges and values ​​therebetween. In embodiments, the HDL-derived nanoparticles comprise about 10 mol% to about 30 mol% of the compound of Formula I relative to the phospholipid.In an embodiment, the HDL-derived nanoparticles contain about 12 mol % to about 25 mol % of the compound relative to the phospholipid.

[0234] In embodiments, the nanoparticle size ranges from about 5 nm to about 500 nm in diameter, e.g., about 5 nm, about 10 nm, about 15 nm, about 20 nm, about 25 nm, about 30 nm, about 35 nm, about 40 nm, about 50 nm, about 55 nm, about 60 nm, about 65 nm, about 70 nm, about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm to about 100 nm, about 110 nm, about 120 nm, about 130 nm, about 140 nm, about 150 nm The nanoparticle size ranges from 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, about 400 nm, about 410 nm, about 420 nm, about 430 nm, about 440 nm, about 450 nm, about 460 nm, about 470 nm, about 480 nm, about 490 nm to about 500 nm, including all ranges and values ​​therebetween. In embodiments, the nanoparticle size is less than about 50 nm. In embodiments, the nanoparticle size is about 50 nm to about 100 nm, or about 5 nm to about 30 nm. In embodiments, the nanoparticle size is measured by dynamic light scattering (DLS). In embodiments, nanoparticles with long blood half-lives and small size (<50 nm) can be used to target immune cells in tissues with limited access to the circulation. In embodiments, nanoparticles with short blood half-lives and large size (about 100 nm) can be used to target immune cells in well-perfused tissues. These tissues include the spleen, liver, kidney, lung, and bone marrow.

[0235] In embodiments, the HDL-derived nanoparticles are disc-shaped. In embodiments, the HDL-derived nanoparticles are spherical. In embodiments, the morphology of the HDL-derived nanoparticles is visualized by transmission electron microscopy (TEM).

[0236] In embodiments, the HDL-derived nanoparticles are about 5 to about 100 nm in length, e.g., about 5 nm, about 10 nm, about 15 nm, about 20 nm, about 25 nm, about 30 nm, about 35 nm, about 40 nm, about 50 nm, about 55 nm, about 60 nm, about 65 nm, about 70 nm, about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm to about 100 nm in length, including all ranges and values ​​therebetween. In embodiments, the HDL-derived nanoparticles are about 10 nm to 80 nm in length. In embodiments, the HDL-derived nanoparticles are about 15 nm to 50 nm in length. In embodiments, the HDL-derived nanoparticles are greater than about 10 nm or greater than about 15 nm. In embodiments, the HDL-derived nanoparticles have a thickness of about 1 nm to 10 nm, e.g., about 1 nm, about 2 nm, about 3 nm, about 4 nm, about 5 nm, about 6 nm, about 7 nm, about 8 nm, about 9 nm to about 10 nm, including all ranges and values ​​therebetween. In embodiments, the thickness of the HDL particles is about 1 to 10 nm, or 2 to 7 nm, or 3 to 6 nm. In embodiments, the dimensions (e.g., length and thickness) are recorded by cryo-TEM. In embodiments, the HDL particles have a worm-like morphology as determined by cryo-TEM.

[0237] In embodiments, the HDL-derived nanoparticles are disk-shaped with diameters of about 5 nm to about 50 nm (e.g., as measured by dynamic light scattering (DLS)), e.g., diameters of about 5 nm, about 10 nm, about 15 nm, about 20 nm, about 25 nm, about 30 nm, about 40 nm to about 50 nm, including all subranges and values ​​therebetween. In embodiments, the nanodiscs are about 5 nm to about 30 nm in diameter.

[0238] In embodiments, the HDL-derived nanoparticles are spherical with a diameter of about 10 nm to about 400 nm (e.g., as measured by dynamic light scattering (DLS)), e.g., diameters of about 10 nm, about 15 nm, about 20 nm, about 30 nm, about 40 nm, about 50 nm, about 60 nm, about 70 nm, about 80 nm, about 100 nm, about 110 nm, about 120 nm, about 130 nm, about 140 nm, about 150 nm, about 160 nm, about 170 nm, and the like. The nanospheres may be 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 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 values ​​and ranges therebetween. In embodiments, the nanospheres are between about 15 nm and about 250 nm in diameter. In embodiments, the nanospheres are between about 30 nm and about 100 nm in diameter.

[0239] The stability of the HDL-derived nanoparticles can be assessed by performing DLS measurements. In embodiments, the HDL-derived nanoparticles are stable, e.g., by DLS, for at least about 1 week, or at least about 2 weeks, or at least about 5 weeks.

[0240] In embodiments, the nanobiological composition promotes a hyper-reactive innate immune response in a patient in need thereof. In embodiments, the hyper-reactive innate immune response is promoted for at least about 7 to about 30 days. In embodiments, the hyper-reactive innate immune response is promoted for at least 30 to 100 days. In embodiments, the hyper-reactive innate immune response is promoted for more than 100 days and up to 3 years. In embodiments, the nanobiological composition is administered once, and the hyper-reactive innate immune response is promoted for at least 30 days. In embodiments, the nanobiological composition is administered at least once daily on each day of a multiple-dose regimen, and the hyper-reactive innate immune response is promoted for at least 30 days.

[0241] The production method can produce uniformly sized HDL-derived nanoparticles or a mixture of heterogeneous sized HDL-derived nanoparticles, either by not filtering or by preparing HDL-derived nanoparticles of various sizes and then recombining them in a post-production step. The larger the size of the HDL-derived nanoparticles, the more drug they can incorporate. However, larger sizes (e.g., >120 nm) may limit, hinder, or delay the diffusion of HDL-derived nanoparticles into the tissues of patients undergoing treatment. Smaller HDL-derived nanoparticles do not carry as much drug per particle, but can access bone marrow cells, bone marrow progenitor cells, and hematopoietic stem cells (biodistribution), such as bone marrow, blood, or spleen, or other local tissues affected by trained immunity.

[0242] The use of heterogeneous mixtures of nanoparticle sizes in a single dose or regimen can immediately reduce innate immune hyperresponsiveness, while providing durable and long-term relief of innate immune hyperresponsiveness that can last for days, weeks, months, and years. Nanobiologics reverse, modify, or re-regulate metabolic, epigenetic, and inflammasome pathways in hematopoietic stem cells (HSCs), common myeloid progenitor cells (CMPs), and myeloid cells, e.g., monocytes, macrophages, and other short-lived circulating cells.

[0243] In embodiments, the maximum loading capacity of HDL-derived nanoparticles can be determined by dividing the internal volume of the HDL-derived nanoparticles by the volume of the drug-loaded spheroids. Particles: Assuming 100 nm spherical particles with 2.2 nm to 3.0 nm phospholipid walls, with an inner diameter of 94 nm and a volume (large) @ 4 / 3n(r)3. The drug:stimulator (STIMULATOR) is envisioned as a 12 x 12 x 35 Å, or 1.2 x 1.2 x 3.5 nm, cylinder, and the multi-drug molecule cylinder is envisioned as a 3.5 nm diameter spheroid with a radius of 1.75 nm and a volume (small) @ 4 / 3n(r), e.g., 7 or 9. Maximum packing capacity (calculated): 3.5 nm spheroids within 100 nm particles is approximately 487 kJ.

[0244] formulation When used as a pharmaceutical, the compound of the present disclosure and HDL-derived nanoparticles are typically administered in the form of pharmaceutical compositions.This composition can be prepared by a method well known in the pharmaceutical field, and comprises at least one active compound.In embodiments, pharmaceutical compositions comprise the nanobiological composition of the present disclosure and pharmaceutically acceptable carriers.

[0245] Generally, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of compound actually administered will typically be determined by a physician taking into account the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0246] The pharmaceutical compositions of the present invention can be administered by various routes, including oral, rectal, intraocular, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, directly into cerebrospinal fluid, intratracheal, and intranasal.Depending on the intended delivery route, the compounds of the present invention are preferably formulated as either an injectable or oral composition, or as a salve, lotion, or patch, all for transdermal administration.In embodiments, the compositions are administered intravenously or intraarterially.

[0247] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect in association with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the compounds described herein are typically minor components (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0248] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms can include, for example, the following ingredients: 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 cornstarch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring, or any of compounds of a similar nature.

[0249] Injectable compositions are typically based on injectable sterile saline, phosphate-buffered saline, or other injectable carriers known in the art. As noted above, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable carrier, etc.

[0250] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, more 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 ingredient is typically combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream, for example, using an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance the stability of the active ingredient or formulation for skin penetration. All such known transdermal formulations and ingredients are within the scope of the present invention.

[0251] The nanoparticles described herein can also be administered by a transdermal device. Thus, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0252] The above ingredients for oral, injectable, or topical compositions are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17 th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.

[0253] For injection, the nanoparticles described herein can be provided in injectable saline solutions, in the form of injectable liposomal solutions, slow-release polymer systems, and the like.

[0254] The 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.

[0255] method Provided herein are methods of treating subjects susceptible to or suffering from immune-related diseases and conditions, including, for example, immunoparalysis in sepsis and infection, cell proliferation disorders (such as cancer), and other diseases and conditions caused by defects in trained immunity.

[0256] In embodiments, the present disclosure provides methods for treating a cell proliferation disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a nanobiological composition comprising high-density lipoprotein (HDL)-derived nanoparticles comprising a compound of the present disclosure, such as a compound of Formula I. In embodiments, the compounds, compositions provided herein are useful for treating cancer by inducing trained immunity.

[0257] In embodiments, the cell proliferation disorder is cancer. In embodiments, the cancer is one or more of the following cancers: aggressive malignancies, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C and D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, tumor, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous adenocarcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, hormone-refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma. In embodiments, the cancer is selected from the group consisting of bladder cancer, vascular cancer, bone cancer, brain cancer, breast cancer, cervical cancer, breast cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, colorectal cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, urothelial cancer, and uterine cancer. In embodiments, the cancer is selected from the group consisting of breast cancer, prostate cancer, melanoma, colorectal cancer, lung cancer, pancreatic cancer, and glioblastoma. In embodiments, the cancer is metastatic. In embodiments, the cancer is refractory or resistant to chemotherapy or radiation, particularly thalidomide.

[0258] In embodiments, the cancer is selected from the group consisting of bladder cancer, vascular cancer, bone cancer, brain cancer, breast cancer, cervical cancer, breast cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, colorectal cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, urothelial cancer, and uterine cancer.

[0259] In embodiments, the cancer is selected from the group consisting of breast cancer, prostate cancer, melanoma, colorectal cancer, lung cancer, pancreatic cancer, and glioblastoma.

[0260] In embodiments, the present disclosure provides a method for treating sepsis, comprising administering to a subject in need thereof a therapeutically effective amount of a nanobiological composition of the present disclosure, in embodiments, the patient has sepsis associated with a bacterial, viral, or fungal infection of the lungs, abdomen, kidney, or bloodstream.

[0261] The compounds of the present disclosure and their carriers disclosed herein can be used to enhance immune responses.Accordingly, disclosed herein is a method for inducing an immune response, comprising administering to a subject an immunogenic composition, wherein the composition comprises (i) at least one antigen and (ii) a compound disclosed herein, optionally in a nanoparticle carrier, such as HDL-derived nanoparticles or liposomes.

[0262] The antigen is typically derived from a pathogen, but neoantigens derived from a subject with cancer can also be used. Exemplary pathogen antigens can be derived from viruses, bacteria, parasites, or yeast. In some embodiments, the antigen can be secreted by the pathogen; for example, it can be an exotoxin or endotoxin.

[0263] Examples of viruses include adenovirus, adeno-associated virus (AAV), chikungunya, dengue, influenza, Ebola, Epstein-Barr, hantavirus, hepatitis (e.g., hepatitis A, B, C, D, E), CMV, HPV (e.g., one or more of HPV1-18), coronavirus (e.g., SARS, MERS, COVID-19), polio, rabies, and Zika. Examples of bacteria include Vibrio cholerae, Escherichia coli (E. coli), Salmonella spp., Neisseria gonorrhea (N. gonorrhea), Neisseria meningitidis (N. meningitidis), Streptococcus pyogenes, Mycobacterium tuberculosis, Legionella pneumophila, Brucella bortus, and Listeria monocytogenes.

[0264] The antigen may be, for example, a polypeptide, including a glycosylated peptide, or a carbohydrate. In embodiments, the immunogenic composition may include a nucleic acid encoding the antigen, typically a polypeptide transcribed and / or translated from a nucleic acid. The nucleic acid may be DNA or RNA, or may be a derivative of DNA or RNA. Common RNA derivatives include covalent modifications to the molecule to enhance stability and / or expression. In embodiments, the nucleic acid encoding the polypeptide may be in a plasmid or viral vector, such as an adenovirus vector, an adeno-associated virus vector, a baculovirus vector, or a lentivirus vector.

[0265] In some embodiments, administration may be prophylactic, e.g., to vaccinate a subject prior to exposure to a pathogen. In other embodiments, administration may be therapeutic, e.g., to induce an immune response against a neoantigen-bearing tumor in a subject suffering from cancer. In embodiments, the nanobiological composition is administered to a patient in a treatment regimen comprising two or more doses to generate drug accumulation in bone marrow cells, myeloid progenitor cells, and hematopoietic stem cells in the bone marrow, blood, and / or spleen.

[0266] In embodiments, the nanobiological composition is administered intravenously or intraarterially.

[0267] Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 2 g / day for a human patient weighing 40 to 80 kg.

[0268] Oral dosage levels range from about 0.01 to about 20 mg / kg of a compound of the invention, including all ranges and values ​​therebetween. For example, dosage levels range from about 0.1 to about 10 mg / kg, or from about 1 to about 5 mg / kg.

[0269] The transdermal dose is generally selected to provide a blood level that is comparable to or lower than that achieved by an injection dose.Appropriate administration modes for mucosal sites are also contemplated herein, including but not limited to anal swabs, enemas, nasal sprays, and aerosolized or vaporized compounds and / or compositions for delivery to pulmonary mucosa.Those skilled in the art will select an appropriate delivery model based on various parameters, including the organ or tissue site of the patient with the disease or condition that is most severely affected by the disease or condition.

[0270] The compounds of the present invention can be administered as the sole active agent or in combination with one or more additional agents, including other compounds that exhibit the same or similar therapeutic activity, and such combined administration has been determined to be safe and effective. In embodiments, the additional agent is an inhibitor of a checkpoint protein. In embodiments, the methods provided herein further include co-administering an anti-cancer drug with the nanobiological composition as a combination therapy.

[0271] A compound or composition described herein can be provided in a kit. In some embodiments, the kit includes (a) a compound described herein or a composition comprising a compound described herein (in which case, for example, the compound can be a NOD2 modulator described herein), and optionally (b) informational material. The informational material can be descriptive, instructional, marketing, or other material related to the methods described herein and / or the use of the compounds or compositions described herein for the methods described herein. In embodiments, the informational material can include information regarding the production of the compound. In embodiments, the informational material relates to methods of administering the compound. In embodiments, the informational material can include instructions for administering a compound or composition described herein in a suitable manner, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein), for carrying out the methods described herein. In embodiments, the informational material can include instructions for administering a compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein.

[0272] The kit can include one or more containers for the composition containing the compound or composition described herein. In embodiments, the kit contains separate containers, dividers, or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet. In embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial, or syringe to which informational material in the form of a label is attached. In embodiments, the kit includes multiple (e.g., packs) of individual containers, each containing one or more unit dosage forms (e.g., dosage forms described herein) of the compounds or compositions described herein. For example, the kit includes multiple syringes, ampoules, foil packets, or blister packs, each containing a single unit dose of a compound described herein. The containers of the kit can be airtight, waterproof (e.g., impermeable to changes in moisture or evaporation), and / or light-tight.

[0273] Also provided herein is a process for producing the nanobiological composition of the present disclosure, the process comprising: a) forming, under conditions effective to form a lipid membrane, a lipid membrane comprising: i) a compound of the present disclosure; ii) one or more phospholipids; optionally, iii) a hydrophobic matrix comprising one or more triglycerides, fatty acid esters, hydrophobic polymers, or sterol esters, or combinations thereof; and optionally iv) cholesterol; and b) dissolving the lipid membrane in a solvent to form a lipid solution; and contacting the lipid solution with apoA-I or a peptidomimetic of apoA-I under conditions effective to form HDL-derived nanoparticles containing a compound of the present disclosure.

[0274] In embodiments, provided herein are nanobiological compositions prepared according to the methods disclosed herein. [Example]

[0275] The therapeutic agents described herein and nanoparticles containing same can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis.

[0276] material and method All chemicals were purchased from commercial suppliers and used without further purification unless otherwise specified. N-Methylmorpholine was redistilled, and the fraction between 110 and 112 °C was collected. Cholesterol azidoacetate, similar to 1-azidooctadecane, was synthesized according to a known procedure (RSC Adv. 2015, 5, 12094). Dry solvents were obtained using an MBRAUN solvent purification system (MB-SPS). Toluene was dried over 4 Å molecular sieves before use. Glassware used in reactions conducted under an argon atmosphere was dried with a heat gun before use. Thin-layer chromatography (TLC) was performed using Merck 60-F254 silica gel plates and visualized by 254 nm UV light, permanganate stain, and / or cerium molybdate (CeMo) stain. Normal-phase and reverse-phase automated column chromatography was performed on a Biotage Isolera One or Grace Reveleris X2 flash chromatography system using Biotage Sfar Silica, Buchi FlashPure ID Silica, or Buchi FlashPure ID C18 columns. Elution gradients are specified in column volumes (CV). Unstabilized THF was used for the water / THF gradient.

[0277] NMR spectra were recorded on a Bruker 400 MHz Ultrashield spectrometer (400 MHz for 1H NMR). The deuterated solvent used is indicated in each case. Chemical shifts (δ) are expressed in ppm and refer to residual solvent peaks. Peak multiplicities are abbreviated as follows: s: singlet; d: doublet; t: triplet; dt: doublet of triplets; ddt: doublet of triplet doublet; 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. Matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectra were acquired on a PerSeptive Biosystems Voyager DE-PRO spectrometer using α-cyano-4-hydroxycinnamic acid (CHCA) or trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]-malononitrile (DCTB) as the matrix. Gas chromatography-mass spectrometry (GC-MS) measurements were performed on a Shimadzu GC-17A gas chromatograph equipped with a Shimadzu AOC-20i autoinjector, a Shimadzu GCMS-QP5000 gas chromatograph-mass spectrometer, and a Phenomenex Zebron ZB-35 column (l = 30 m, ID = 0.25 mm, film thickness = 0.25 μm). High-performance liquid chromatography-mass spectrometry (HPLC-ESI-MS) experiments using a water / acetonitrile gradient were performed on a Shimadzu setup equipped with 2xLC-20AD pumps, a DGU-20A3 degasser, a SIL-20AC autosampler, an SPD-M20A PDA, and a ThermoScientific LCQ fleet MS. Column: Phenomenex Kinetex 5um EVO C18 100Å LC (50 x 2.1 mm). Gradient: water / MeCN (+0.1% formic acid) 5 to 100% MeCN, 0.300 mL / min. Electrospray ionization (ESI) was used to generate charge for MS detection.HPLC-MS and HPLC-ELSD experiments using a water / THF or water / MeOH gradient were performed on a Shimadzu Nexera-iLC-2040C 3D Plus equipped with a Shimadzu LCMS-8045. Column: Alltech Alltima C18 (150 × 3.2 mm; 5 μm; no. 88383). Gradient: water / THF (+0.1% TFA) or water / MeOH (+0.1% TFA) at 0.400 mL / min. This HPLC setup was coupled with ELSD (evaporative light scattering) detection.

[0278] Alternatively, HPLC-MS (SIM) and HPLC-ELSD were performed on a Phenomenex Kinetex 5 micrometer EVO C18 100A LC column (50 × 2.1 mm) using a gradient from eluent A to B: A = 20 mM NH4HCO2 in HO containing 0.1 v / v% formic acid, and B = 2-propanol / MeCN / HO 85:15:5, also containing 20 mM NH4HCO2 and 0.1 v / v% formic acid.

[0279] Abbreviation HPLC = high performance liquid chromatography; ELSD = evaporative light scattering detection; ESI-MS = electrospray ionization mass spectrometry; SIM = selected ion mode; NMR = nuclear magnetic resonance.

[0280] [ka]

[0281] MDP = muramyl dipeptide muramyl (or N-acetylmuramyl-L-alanyl-D-isoglutamine) CAS [53678-77-6]. Prepared according to standard peptide synthesis or purchased from commercial sources.

[0282] NHS = N-hydroxysuccinimide; DiC or DIC = N,N'-diisopropylcarbodiimide; EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (use the hydrochloride salt); PyBOP = (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate); SPPS = solid phase peptide synthesis.

[0283] TEA = triethylamine; THF = tetrahydrofuran; MeOH = methanol; DMF = dimethylformamide; FA = formic acid; TFA = trifluoroacetic acid.

[0284] Building Blocks DSPE-azidoacetate (DSPE-CO-CH2-N3)

[0285] [ka] (2R)-3-(((2-aminoethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-distearate (260 mg, 0.35 mmol), 2,3,5,6-tetrafluorophenyl 2-azidoacetate (prepared by D. J. Vugts et al., Bioconjugate Chem. 2011, 22, 2072-2081; 87 mg, 0.35 mmol, 1 equiv.), and N,N-diisopropylethylamine (184 μL, 1.1 mmol, 3 equiv.) were combined in chloroform (2 mL). The mixture was stirred at 50 °C for 1 h, during which time the white suspension became clear. Chloroform (200 mL) was added, and the organic layer was gently washed twice with 1 M HCl (100 mL). After drying over MgSO, filtration, and removal of the solvent in vacuo, the compound was purified by column chromatography (flash SiO) using an elution gradient of 5% to 40% MeOH in chloroform to afford pure DSPE-azidoacetate (244 mg, 0.29 mmol, 84%) as a white solid. 1H-NMR (400 MHz, CDCl3 / CD3OD 9:1): δ = 5.23 (dt, J = 9.0, 4.6 Hz, 1H), 4.35 (dd, J = 12.0, 3.7 Hz, 1H), 4.22-3.99 (m, 5H), 3.95 (s, 2H), 3.53 (t, J = 5.1 Hz, 2H), 2.33 (q, J = 7.6 Hz, 4H), 1.61 (td, J = 7.4, 4.2 Hz, 4H), 1.48-1.16 (m, 56H), 0.88 (t, J = 6.7 Hz, 6H). 13 C-NMR (101 MHz, CDCl3): δ = 173.7, 173.4, 168.3, 69.7, 69.6, 66.1, 66.0, 65.2, 62.1, 52.5, 40.01, 39.95, 34.3, 34.2, 34.1, 32.1, 29.9, 29.80, 29.7, 29.62, 29.59, 29.50, 29.47, 29.46, 29.4, 29.30, 29.26, 25.00, 24.97, 24.9, 22.8, 14.2. 31 P-NMR (162 MHz, CDCl3): δ = -0.48. MALDI-TOF MS: m / z C 43 H 83 Calculated value for N4O9P: 830.59; Found value [M+Na] + 853.62, [M-H+2Na] + 875.58.

[0286] MDP-propargyl

[0287] [ka] A 50 mL round-bottom flask was charged with MDP (0.113 g, 0.23 mmol, 1.00 equiv.) This material was dissolved in dry DMF (approximately 1.5 mL, 0.15 M) and the flask was purged with argon.

[0288] EDC.HCl (0.066 g, 0.34 mmol, 1.50 equiv.), N,N-diisopropylethylamine (0.050 g, 0.068 mL, 0.39 mmol, 1.70 equiv.), and 4-(N,N-dimethylamino)pyridine (0.0028 g, 0.023 mmol, 0.10 equiv.) were added, and the resulting clear solution was stirred at room temperature for 5 min. Next, prop-2-yn-1-amine (0.018 g, 0.021 mL, 0.32 mmol, 1.40 equiv.) was added via syringe. Stirring was continued at room temperature. After 21 h of reaction time, LC-MS (water / MeOH) analysis confirmed complete conversion of the MDP starting material. The reaction mixture was concentrated in vacuo to give the crude product as a yellow glass. This material was purified twice by automated column chromatography (reverse phase (C18); product: C18-silica 1:100; detection: 200-400 nm) eluting with water / MeOH 90 / 10-82 / 18. Pure fractions were lyophilized to give the pure product as a white solid (0.050 g, 41%). 1 H NMR (400 MHz, MeOD) δ 5.16 (d, J = 3.4 Hz, 1H), 4.42 - 4.23 (m, 3H), 3.95 (t, J = 2.3 Hz, 2H), 3.94 - 3.57 (m, 5H), 3.52 - 3.39 (m Hz, 1H), 2.58 (t, J = 2.6 Hz, 1H), 2.33 - 2.26 (m, 2H), 2.25 - 2.13 (m, 1H), 2.00 - 1.85 (m, 4H), 1.45 - 1.33 ppm (m, 6H). 13C NMR (100 MHz, MeOD) δ 175.26, 174.83, 173.89, 173.06, 172.08, 91.01, 79.15, 78.92, 76.68, 71.86, 70.83, 70.21, 63.35, 61.22, 54.13, 52.66, 49.48, 31.54, 28.11, 27.10, 23.85, 21.46, 18.31, 16.21 ppm. HPLC-MS (water / MeCN): t (product) = 0.76 and 1.02 min. Found: m / z = 512.08 [M-HO+H] + ; 552.33 [M+Na] + (yang mode); 325.17 [M-muramil]- (yin mode).

[0289] MDP(Bn)

[0290] [ka] MDP(Bn) was synthesized using standard SPPS techniques in a 100 mL glass reaction vessel equipped with a glass-fritted filter bottom. A constant stream of argon was applied through the glass-fritted filter to ensure thorough stirring of the reaction mixture, while excess reagents and wash solutions were removed by vacuum filtration. Crude MDP(Bn) was purified twice by automated column chromatography (reverse-phase (C18); product: C18-silica 1:200; detection: 200-400 nm) eluting with water / MeCN + 0.1% formic acid 90 / 10 to 82 / 18. Pure fractions were lyophilized to afford the pure product as a fluffy white material (0.309 g, 67%). 1H NMR (400 MHz, DMF-d7) δ 8.18 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 6.5 Hz, 1H), 7.53 - 7.28 (m, 6H), 7.11 - 7.03 (m, 1H), 4.86 (d, J = 3.5 Hz, 1H), 4.76 (d, J = 12.3 Hz, 1H), 4.72 - 4.56 (m, 1H), 4.51 (d, J = 12.3 Hz, 1H), 4.47 - 4.32 (m, 3H), 4.01 (ddd, J = 10.7, 8.4, 3.5 Hz, 1H), 3.83 (dd, J = 11.6, 2.2 Hz, 1H), 3.78 - 3.61 (m, 3H), 3.60 - 3.40 (m, 1H), 2.39 (t, J = 7.8 Hz, 2H), 2.24 - 2.12 (m, 1H), 1.97 - 1.83 (m, 4H), 1.40 (d, J = 7.0 Hz, 3H), 1.34 ppm (d, J = 6.7 Hz, 3H). 13 C NMR (100 MHz, DMF-d7) δ 174.30, 173.74, 173.60, 172.82, 170.19, 138.47, 128.58, 127.93, 127.79, 97.05, 80.16, 77.36, 73.94, 70.66, 68.61, 61.76, 53.64, 52.59, 49.41, 35.63, 30.57, 30.47, 27.78, 22.65, 19.05, 18.04 ppm. HPLC-MS (water / MeCN): t(product) = 3.11 min. Measured value: m / z = 583.08 [M+H] + .

[0291] MDP(Bn)-プロパルギル

[0292]

change

[0293] MTP-b on resin

[0294]

change

[0295] MTP-b-N3

[0296] [ka] A 20 mL PE syringe equipped with a PE frit was loaded with MTP-b resin (429 mg, approximately 0.15 mmol of MTP-b), and the resin was swollen in 12 mL of DMF for 30 min. The resin was treated twice with 2% hydrazine hydrate solution in 12 mL of DMF for 15 min. After filtration, the resin was washed with 4 x 12 mL of DMF for 1 min. A solution of CuSO4·5H2O (0.6 mg, 2.4 μmol, 1.5 mol%), imidazole-1-sulfonyl azide HCl salt (170 mg, 0.77 mmol, 5 equiv.), and N,N-diisopropylethylamine (0.34 mL, 1.9 mmol, 12 equiv.) in 12 mL of DMF was added to the resin, and the beads were stirred at room temperature for 24 h (a slight overpressure was occasionally released). After filtration, the resin was washed with DMF (5 × 12 mL) for 1 min and dichloromethane (4 × 10 mL) for 1 min. The resin was then subjected to cleavage in TFA / TIPS / HO 95:2.5:2.5 (4 mL) for 2 h. After filtration, the resin was washed with TFA (4 mL) for 5 min. The combined TFA filtrates were concentrated in vacuo (the temperature was kept as low as possible to avoid TFA ester formation). The impure compound was obtained by automated column chromatography (reverse-phase (C18); detection: λ = 200 nm) using an elution gradient of 5% to 60% MeCN in HO (both containing 0.1% TFA). This was further purified by RP-HPLC using an elution gradient of 26% to 35% MeCN in HO (both containing 0.1% TFA) to give the pure product (37.5 mg, 51 μmol, 34%) as a white fluffy solid after lyophilization. 1H-NMR (400 MHz, DMF-d7 / D2O 9:1): δ = 8.45 (t, J = 9.1 Hz, 2H), 8.26 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 6.5 Hz, 1H), 7.81 (d, J = 2.8 Hz, 2H), 7.64-7.45 (m, 5H), 7.31 (d, J = 17.2 Hz, 2H), 5.82 (d, J = 6.3 Hz, 1H), 5.03 (d, J = 3.5 Hz, 1H), 4.93 (d, J = 12.4 Hz, 1H), 4.68 (d, J = 12.4 Hz, 1H), 4.63-4.46 (m, 4H), 4.19 (dd, J = 10.7, 3.6 Hz, 1H), 4.00 (dd, J = 6.8, 6.3 Hz, 1H), 3.92-3.79 (m, 3H), 3.66 (t, J = 9.0 Hz, 1H), 3.52 (t, J = 6.8 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.37 (dtd, J = 16.5, 7.9, 4.3 Hz, 1H), 2.10 (s, 3H), 2.09-1.93 (m, 2H), 1.88-1.55 (m, 5H), 1.58 (d, J = 7.1 Hz, 3H), 1.52 (d, J = 6.7 Hz, 3H). 13 C-NMR (100 MHz, DMF-d7 / D2O 9:1): δ = 174.9, 174.24, 174.17, 174.00, 173.93, 173.14, 173.06, 172.9, 172.8, 170.90, 170.8, 138.2, 128.6, 127.9, 127.8, 96.8, 80.0, 77.3, 73.7, 70.3, 68.6, 61.5, 53.6, 53.5, 53.2, 53.13, 53.10, 52.7, 52.6, 51.2, 49.4, 49.3, 32.1, 31.7, 28.5, 28.2, 23.2, 22.53, 22.48, 18.9, 17.80, 17.76. ESI-MS: m / z C 32 H 49 N9O 11Calculated value 735.36; Found value [M+H] + 736.25, [M+Na] + 758.42.

[0297] DSG 4-Nitrophenyl Carbonate

[0298] [ka] A 25 mL round-bottom flask was charged with a solution of commercially available [(2S)-3-hydroxy-2-octadecanoyloxypropyl]octadecanoate (0.601 g, 0.96 mmol, 1.00 equiv.) in chloroform (6.5 mL, approximately 0.15 M). Pyridine (0.122 g, 0.125 mL, 1.54 mmol, 1.60 equiv.) was added, and the resulting clear solution was cooled in ice water. Next, solid 4-nitrophenyl chloroformate (0.252 g, 1.25 mmol, 1.30 equiv.) was added portionwise. The pale yellow reaction mixture was stirred overnight at room temperature. Complete conversion of the alcohol was confirmed by precipitation. 1 The reaction mixture was confirmed by H NMR (CDCl). The reaction mixture was then precipitated in MeOH (100 mL) and collected by filtration through a glass filter. The material was washed with MeOH (30 mL total) and EtO (10 mL total) and dried in a vacuum oven at 30 °C. The product (0.713 g, 94%) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 9.1 Hz, 2H), 7.39 (d, J = 9.1 Hz, 2H), 5.38 (p, J = 5.2 Hz, 1H), 4.50 (dd, J = 11.7, 3.9 Hz, 1H), 4.41 - 4.32 (m, 2H), 4.22 (dd, J = 12.0, 5.6 Hz, 1H), 2.35 (dt, J = 9.8, 7.5 Hz, 4H), 1.68 - 1.58 (m, 4H), 1.37 - 1.17 (m, 56H), 0.88 ppm (t, J = 6.7 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.24, 172.92, 155.35, 152.29, 145.56, 125.36, 121.76, 68.33, 66.97, 61.63, 34.16, 34.03, 31.93, 29.71, 29.68, 29.64, 29.49, 29.37, 29.29, 29.13, 29.07, 24.87, 22.70,14.12 ppm.

[0299] 2,3,5,6-Tetrafluorophenyl stearate

[0300] [ka] Triethylamine (2.8 mL, 5 equiv.) was slowly added to a solution of stearoyl chloride (1.26 g, 4.2 mmol) and tetrafluorophenol (0.72 g, 1.04 equiv.) in DCM (10 mL), resulting in the immediate formation of a white precipitate. The heterogeneous reaction mixture was stirred for an additional 2 h, diluted with 25 mL of DCM, extracted with water (50 mL), 0.1 M HCl (2 × 50 mL), dried over MgSO4, and evaporated to dryness. The resulting solid was redissolved in 50 mL of diethyl ether and extracted again with 1 M NaHCO3 (50 mL), 0.1 M HCl (50 mL), water (50 mL), and brine (2 × 50 mL). The organic phase was dried over MgSO4 (with the addition of a small amount of activated charcoal) and evaporated to dryness. The resulting crude material was redissolved in chloroform, flashed onto a silica plug and evaporated to dryness again to give 1.2 g (67%) of the desired compound as a white solid. 1 H NMR (400 MHz, CDCl3) δ 6.98 (tt, J = 9.9, 7.0 Hz, 1H), 2.66 (t, J = 7.4 Hz, 2H), 1.78 (p, J = 7.4 Hz, 2H), 1.26 (s, 28H), 0.88 (t, J = 6.7 Hz, 3H) ppm. 19F NMR (376 MHz, CDCl3) δ -139.21 (ddd, J = 24.0, 11.8, 7.8 Hz), -153.03 - -153.20 (m). 13 C NMR (101 MHz, CDCl3) δ 169.56, 147.23 (m), 144.74 (m), 141.94, 141.86 (m), 139.41 (m), 129.78 (m), 103.01 (t), 33.42, 31.92, 29.69, 29.65, 29.61, 29.54, 29.39, 29.36, 29.14, 28.85, 24.78, 22.68, 14.09 ppm.

[0301] synthetic アプローチ First Approach: The compounds of the present invention can be prepared by using the starting reactants MDP or MDP(Bn) (see above). These molecules have a functional carboxylic acid group derived from the glutamic acid (Glu) building block. The COOH group allows for conjugation to an amine-functional reactant containing a lipophilic group. Such a lipophilic group can be, for example, a C18 moiety derived from stearic acid, oleic acid, stearyl alcohol, oleyl alcohol, stearylamine, or oleylamine; or a sterol moiety, such as cholesterol. Saturated linear lipophilic moieties are preferred, as are moieties derived from cholesterol. Particularly useful building blocks are PE phospholipids such as DSPE ([1069-79-0]) or DOPE ([4004-05-1]); these molecules are already amine-functionalized. Mixed acyl PE-phospholipids can also be useful (e.g., 16:0 to 18:1 PE, or 18:0 to 18:1 PE, or 18:0 to 16:0 PE). Another useful building block is cholesterol. Yet another useful building block is a diglyceride, such as 1,2-dioctadecanoyl-sn-glycerol (18:0 DG [51063-97-9]) or 1-2-dioleoyl-sn-glycerol (18:1 DG [24529-88-2]). Mixed acyl diglycerides can also be used (e.g., 16:0 to 18:1 DG, or 18:0 to 18:1 DG, or 18:0 to 16:0 DG). PE-phospholipids and diglycerides have two lipophilic chains, and such building blocks are preferably used in this approach. This first approach is illustrated in Examples 10-19.

[0302] Second Approach: A particularly suitable alternative modular approach uses copper-catalyzed azide-alkyne cycloaddition ("click reaction") to connect MDP (or MTP) reactants to lipophilic reactants. Here, MDP, MDP(Bn), MTP, or MTP(Bn) building blocks bearing azide (-N3) or alkyne (-C≡CH) functional groups are used. Non-limiting examples of such molecules are MDP-propargyl, MDP(Bn)-propargyl, or MTP-b-N3 (see above). In a copper-catalyzed click reaction, these molecules can be coupled with alkyne- or azide-functional molecules containing lipophilic groups. The click reaction targets stable azide- or alkyne-functional intermediates that are modular and easy to prepare. This allows for easy isolation and storage of the intermediates. Furthermore, copper-catalyzed click cycloaddition reactions can be performed, and are most successful, in aqueous environments (e.g., THF / water or tBuOH / water) or aqueous biphasic liquid / liquid solvent combinations (e.g., dichloromethane / water). These reaction media favorably dissolve both hydrophilic MDP (or MTP) reactants (with or without a Bn group) and lipophilic reactants, significantly improving the ease of conjugation and reaction yield. In this click approach, the lipophilic group contained in the azide or alkyne reactant can be a C14, C16, or C18 moiety, such as stearic acid, palmitic acid, myristic acid, oleic acid, palmitoleic acid, myristoleic acid, stearyl alcohol or amine, palmityl alcohol or amine, myristyl alcohol or amine, oleyl alcohol or amine, palmitoleic alcohol or amine, or myristoleic alcohol or amine; or a sterol moiety, such as one derived from cholesterol. Saturated linear lipophilic moieties are preferred, as are moieties derived from cholesterol. Particularly useful building blocks are PE-phospholipids containing C14, C16 and / or C18 moieties, mixed acyl PE-phospholipids, diglycerides (DG) or mixed acyl diglycerides, and cholesterol.Lipophilic azide or alkyne reactants containing two lipophilic chains or containing a cholesteryl group are preferred. This second approach is illustrated in Examples 1-9.

[0303] Note that both approaches allow the introduction of an additional amino acid unit linked to the glutamic acid unit of MDP or MDP(Bn). Preferred amino acid units are those derived from L-lysine or L-alanine. Once the additional amino acid unit is attached, the MDP (muramyl dipeptide) moiety, with or without the Bn group, is converted to an MTP (muramyl tripeptide) moiety. Examples are shown in Examples 9-10, 13-15, and 17-18.

[0304] [Example 1] Synthesis of MDP-C18 [click] (1)

[0305] [ka] Molecular weight: 825 daltons. CLogP=4.15. This synthesis demonstrates the general conditions for Cu click-type reactions.

[0306] A 5 mL vial was charged with MDP-propargyl (0.011 g, 0.02 mmol, 1.00 equiv.). To this was added L-ascorbic acid (0.4 M aqueous solution, 104 μL, 41.5 μmol ascorbic acid, 2.00 equiv.). To the resulting slightly opaque solution was added a solution of 1-azidooctadecane (0.012 g, 0.04 mmol, 2.00 equiv.) in DCM (0.8 mL), followed by aqueous copper(II) sulfate pentahydrate (0.2 M, 104 μL, 20.8 μmol Cu, 1.00 equiv.). The biphasic reaction mixture was then stirred at 1400 rpm at room temperature, resulting in a pale yellow / green emulsion. After 16 h, the reaction mixture was concentrated under a stream of N2 to give the crude product as a light brown sludge. This material was dissolved in chloroform / MeOH (4:1) and impregnated onto Celite (90 mg, approximately 1:5 loading ratio). Purification by automated column chromatography (product:silica 1:500; detection: 200-400 nm) eluting with chloroform / MeOH / water (90 / 9 / 1 to 70 / 27 / 3) afforded the product (0.005 g, 31%) as a white solid. 1 H NMR (400 MHz, MeOD) δ 7.64 - 7.61 (m, 1H), 5.33 (d, J = 3.4 Hz, 1H), 4.58 - 4.21 (m, 7H), 3.85 - 3.46 (m, 6H), 2.35 - 2.26 (m, 2H), 2.23 - 2.08 (m, 1H), 2.06 - 1.84 (m, 6H), 1.42 - 1.36 (m, 6H), 1.35 - 1.22 (m, 30H), 0.88 ppm (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, MeOD) δ 175.75, 174.66, 174.04, 173.58, 171.91, 144.63, 122.53, 91.00, 76.01, 71.84, 71.18, 67.16, 61.98, 54.15, 52.98, 50.67, 34.78, 32.20, 32.03, 30.34, 29.80, 29.76, 29.72, 29.65, 29.52, 29.46, 29.12, 27.49, 26.60, 22.83, 22.79, 22.69, 19.34, 16.95, 16.57, 14.15 ppm. HPLC-MS (water / MeCN): t (product) = 5.64 min. Observed value: m / z = 825.33 [M+H]+.

[0307] [Example 2] Synthesis of MDP-DSPE [click] (2)

[0308] [ka] Molecular weight: 1361 Daltons. CLogP = 11.56 (uncharged) and 5.78 (negatively charged).

[0309] MDP-propargyl (24.4 mg, 46 μmol) was dissolved in 0.4 M ascorbic acid (0.24 mL, 2 equiv.) and a solution of DSPE-azidoacetate (38.5 mg, 46 μmol, 1 equiv.) in dichloromethane (0.5 mL) was added. With vigorous stirring, 0.2 M CuSO 5HO (0.24 mL, 1 equiv.) was added, and the biphasic system was vigorously stirred at room temperature for 19 h. The solvent was removed in vacuo, and the greenish solid was subjected to column chromatography (flash SiO ) using an elution gradient of 20% to 50% MeOH in chloroform, ending with chloroform (45% MeOH + 5% HO). (A significant amount of the compound elutes only after the addition of HO.) This yielded an impure product, which was purified by automated column chromatography (reverse-phase (C 18 );Product:C 18-silica 1:200; detection: λ = 210 nm) using an elution gradient of 25% to 70% THF in HO, which gave the pure product (19.5 mg, 14 μmol, 31%) as a white fluffy solid after lyophilization. 1 H NMR (400 MHz, CDCl3+MeOD) δ 7.93 (s, 1H), 5.29 - 5.22 (m, 2H), 5.16 (s, 2H), 4.51 - 4.41 (m, 4H), 4.38 - 4.25 (m, 2H), 4.20 (dd, J = 12.1, 6.8 Hz, 1H), 4.05 - 3.89 (m, 4H), 3.88 - 3.77 (m, 2H), 3.77 - 3.63 (m, 6H), 3.55 - 3.42 (m, 3H), 2.34 (q, J = 7.3 Hz, 6H), 2.22 (dddd, J = 18.4, 13.5, 8.4, 5.7 Hz, 1H), 1.98 (d, J = 5.7 Hz, 4H), 1.93 (s, 0H), 1.62 (q, J = 6.4 Hz, 5H), 1.46 - 1.36 (m, 6H), 1.28 (s, 61H), 0.89 (t, J = 6.8 Hz, 6H). The peak between 4.9 and 4.6 ppm is not visible due to overlap with the HO peak. MALDI-TOF MS: m / z C 65 H 118 N9O 19 Calculated P 1359.83; Found [M+Na] + 1382.83, [M-H+2Na] + 1404.84. HPLC-MS (H2O / THF, gradient: 65-95% THF): t (product) = 2.33 min; m / z = 1360.80 [M+H] + (SIM mode).

[0310] [Example 3] Synthesis of MDP-chol [click] (3)

[0311] [ka] Molecular weight: 999 daltons. CLogP=5.04.

[0312] MDP-propargyl (25 mg, 47 μmol) was dissolved in 0.4 M ascorbic acid (0.24 mL, 2 equiv.) and cholesterol azide acetate (26.6 mg, 57 μmol, 1.2 equiv.) in dichloromethane (0.5 mL) was added. With vigorous stirring, 0.2 M CuSO 5HO (0.24 mL, 1 equiv.) was added, and the biphasic system was stirred vigorously at room temperature for 17 h. HO / brine 1:1 (50 mL) was added, and the bluish aqueous layer was extracted with chloroform / MeOH 2:1 (5 × 20 mL). The combined organic layers were dried using NaSO, filtered, and the solvent was removed in vacuo. The resulting colorless solid was purified by repeated column chromatography (flash SiO) using an elution gradient of 6% to 20% MeOH in chloroform. This gave the pure product (24.4 mg, 24 μmol, 52%) as a white fluffy solid after lyophilization from THF / H 2 O. 1 H-NMR (400 MHz, THF-d8 / D2O 95:5): δ = 7.81 (s, 1H), 5.28 (d, J = 4.9 Hz, 1H), 5.16 (s, 2H), 5.10 (d, J = 3.4 Hz, 1H), 4.59-4.46 (m, 1H), 4.46-4.16 (m, 5H), 3.75-3.17 (m, 6H), 2.26 (d, J = 8.2 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 2.12-1.99 (m, 1H), 1.98-1.69 (m, 8H), 1.58-1.33 (m, 5H), 1.32-1.23 (m, 7H), 1.18 (s, 5H), 1.13-0.97 (m, 4H), 0.94 (s, 3H), 0.84 (d, J = 6.5 Hz, 3H), 0.77 (dd, J = 6.6, 1.4 Hz, 8H), 0.61 (s, 3H). 13C-NMR (100 MHz, THF-d8 / D2O 95:5): δ = 175.2, 174.9, 173.7, 173.4, 171.9, 166.6, 165.1, 139.6, 122.4, 91.0, 78.7, 76.7, 75.4, 72.0, 70.2, 61.1, 56.8, 56.2, 54.0, 52.6, 50.5, 50.2, 49.5, 42.2, 39.8, 39.4, 37.7, 36.8, 36.4, 36.1, 35.8, 34.4, 31.9, 31.8, 29.6, 28.1, 27.9, 27.5, 27.4, 22.5, 22.2, 22.1, 21.9, 20.9, 18.8, 18.7, 18.2, 16.8, 13.5, 11.3. 51 H 82 N8O 12 Calculated value 998.60; Found value [M+Na] + 1021.58. HPLC-MS (H2O / THF, gradient: 65-95% THF): t (product) = 2.20 min; m / z = 999.60 [M+H] + (SIM mode). Note: THF-d₂ / D₂O 95:5 was found to be the optimal solvent combination for NMR characterization. Nevertheless, the spectra have overlapping and are highly complex. Therefore, the integration is tentative.

[0313] [Example 4] Synthesis of MDP-DSPE2 [click] (4)

[0314] [ka] Molecular weight: 2192 daltons.

[0315] [Example 5] MDP-Chol2 [click]

[0316] [ka] Molecular weight: 1669 daltons. CLogP=15.31.

[0317] [Example 6] MDP-DSG [Click] (6)

[0318] [ka] Molecular weight: 1238 daltons. CLogP=12.45.

[0319] [Example 7] MDP(Bn)-DSPE[click](7)

[0320] [ka] Molecular weight: 1451 Daltons. CLogP=13.85 (uncharged) and 8.06 (negatively charged).

[0321] Following the general conditions for Cu-click reaction, MDP(Bn)-propargyl (0.028 g, 0.045 mmol, 1.00 equiv.) and DSPE-azidoacetate (0.039 g, 0.047 mmol, 1.05 equiv.) were reacted overnight. During the reaction, some material precipitated, resulting in a white suspension / emulsion. The reaction mixture was then diluted with chloroform / MeOH 1:1. The resulting clear solution was impregnated onto Celite (approximately 200 mg, loading ratio 1:3). The impregnated crude product was first purified by automated column chromatography (reverse-phase (C18); product: C18-silica 1:200; detection: ELSD and UV 200-400 nm) eluting with water / THF 60 / 40-20 / 80. The combined product fractions were lyophilized and then purified again by automated column chromatography (normal phase (silica); product:silica 1:300; detection:ELSD) eluting with chloroform / MeOH / water 90 / 9 / 1 to 75 / 22.5 / 2.5. The pure fractions were concentrated in vacuo, dissolved in water / THF 70 / 30, and lyophilized. This gave the pure product (0.027 g, 41%) as a white fluffy solid. 11H NMR (400 MHz, CDCl3+MeOD 1:1) δ 7.99 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H), 7.43 - 7.23 (m, 5H), 5.24 (m, 1H), 5.13 (s, 2H), 4.93 (d, J = 3.5 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 12.0 Hz, 2H), 4.48 - 4.40 (m, 2H), 4.37 - 4.15 (m, 3H), 4.05 - 3.89 (m, 5H), 3.86 - 3.73 (m, 2H), 3.71 - 3.53 (m, 3H), 3.49 - 3.42 (m, 2H), 2.37 - 2.28 (m, 6H), 2.25 - 2.11 (m, 1H), 2.05 - 1.89 (m, 4H), 1.67 - 1.56 (m, 4H), 1.52 - 1.19 (m, 72H), 0.89 ppm (t, J = 6.8 Hz, 6H). 13C NMR (100 MHz, MeOD) δ 174.97, 174.73, 173.93, 173.66, 173.57, 173.46, 171.92, 166.34, 137.16, 128.28, 128.09, 127.84, 124.43, 96.38, 79.09, 76.52, 72.55, 70.40, 69.75, 69.28, 63.66, 63.44, 62.56, 61.14, 53.18, 52.60, 52.13, 49.45, 40.52, 34.62, 34.19, 33.96, 31.81, 31.73, 29.57, 29.53, 29.43, 29.41, 29.23, 29.21, 29.03, 29.00, 27.12, 24.82, 24.77, 22.52, 22.20, 18.70, 16.75, 13.69 ppm. MALDI-TOF: m / z C 72 H 124 N9O 19 P + 2Na + -H + Calculated value for: 1494.85 [M+2Na-H] +; Found: 1494.94. HPLC-MS (water / THF, gradient: 55-95% THF): t (product) = 5.09 min; m / z = 1450.9 [M+H] + and 1472.9 [M+Na] + (SIM mode).

[0322] [Example 8] Synthesis of MDP(Bn)-chol [click] (8)

[0323] [ka] Molecular weight: 1089 daltons. CLogP=6.83.

[0324] Following the general conditions for the Cu-click reaction, MDP(Bn)-propargyl (0.030 g, 0.048 mmol, 1.00 equiv.) and cholesterol azide acetate (0.025 g, 0.053 mmol, 1.10 equiv.) were reacted overnight to yield a white emulsion. The reaction mixture was then concentrated in vacuo and impregnated onto Celite (150 mg). The impregnated crude product was purified by automated column chromatography (reverse-phase (C18); product: C18-silica 1:200; detection: 200-400 nm) eluting with water / THF 70 / 30 to 15 / 85. The combined product fractions were lyophilized and then purified again by automated column chromatography (normal-phase (silica); product: silica 1:350; detection: ELSD) eluting with chloroform / MeOH 96 / 4 to 86 / 14. The pure fractions were concentrated in vacuo to give the pure product as a white solid (0.028 g, 53%). 1H NMR (400 MHz, CDCl3+MeOD 1:1) δ 7.78 (s, 1H), 7.39 - 7.28 (m, 5H), 5.38 (d, J = 5.1 Hz, 1H), 5.16 (d, J = 1.6 Hz, 2H), 4.93 (d, J = 3.6 Hz, 1H), 4.70 (d, J = 11.8 Hz, 2H), 4.56 - 4.37 (m, 3H), 4.30 (dt, J = 8.9, 4.4 Hz, 1H), 4.27 - 4.17 (m, 2H), 4.02 (dd, J = 10.1, 3.6 Hz, 1H), 3.93 - 3.67(m, (24H), 3.67 - 3.53 (m, 3H), 3.40 (d, J = 3.2 Hz, 0H), 2.44 - 2.32 (m, 2H), 2.27 (td, J = 7.1, 3.7 Hz, 2H), 2.12 (dtd, J = 14.9, 7.5, 4.3 Hz, 1H), 2.07 - 1.74 (m, 8H), 1.72 - 1.42 (m, 5H), 1.38 (dd, J = 13.0, 7.0 Hz, 7H), 1.34 - 0.94 (m, 13H), 0.92 (d, J = 6.4 Hz, 3H), 0.87 (dd, J = 6.6, 1.8 Hz, 6H), 0.69 ppm (s, 3H). 13C NMR (100 MHz, CDCl3+MeOD 1:1) δ 175.17, 174.60, 173.71, 173.62, 171.76, 166.21, 145.18, 139.13, 137.21, 128.65, 128.37, 128.25, 124.35, 123.47, 96.91, 79.14, 76.83, 76.49, 72.44, 69.79, 61.63, 56.82, 56.28, 53.17, 52.57, 51.14, 50.14, 49.78, 42.45, 39.84, 39.65, 38.01, 36.97, 36.68, 36.32, 35.93, 34.85, 32.02, 31.97, 29.81, 28.34, 28.14, 27.74, 27.58, 24.39, 23.95, 22.87, 22.80, 22.77, 22.61, 21.16, 19.34, 18.98, 18.80, 16.90, 11.94 ppm. 58 H 88 N8O 12 +Na + Calculated value: 1111.64 [M+Na] + ; Found: 1111.65. HPLC-MS (water / THF, gradient: 65-95% THF): t (product) = 2.79 min; m / z = 1089.70 [M+H] + (SIM mode).

[0325] [Example 9] Synthesis of MTP-b-C18[invclick] (9)

[0326] [ka] Molecular weight: 1058 daltons. CLogP=5.68.

[0327] MTP-b-N3 (26 mg, 35 μmol) and prop-2-yn-1-yl stearate (11.3 mg, 35 μmol, 1 equiv.) were suspended in THF (0.36 mL) and 0.4 M ascorbic acid (0.18 mL, 2 equiv.) was added to obtain a clear solution. Prop-2-yn-1-yl stearate was prepared using a known procedure. Under vigorous stirring, 0.2 M CuSO4·5H2O (0.18 mL, 1 equiv.) was added, and the mixture was stirred vigorously at room temperature (initial gelation occurred, but gentle heating gave a yellow solution). After 1 h, HPLC-MS (THF / H2O) indicated the absence of starting compound, and the opaque solution was lyophilized. The crude product was adsorbed onto Celite from chloroform / MeOH 2:1 and subjected to column chromatography (flash SiO2) using an elution gradient of 10% to 25% MeOH in chloroform. Column chromatography was repeated using a similar gradient to give the pure product (31.5 mg, 30 μmol, 84%) as a white fluffy solid after lyophilization from THF / H 2 O. 11H-NMR (400 MHz, THF-d8 / D2O 4:1): δ = 7.92 (s, 1H), 7.31 (d, J = 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 5.04 (s, 2H), 4.74 (d, J = 3.5 Hz, 1H), 4.63 (d, J = 12.2 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 4.31 - 4.15 (m, 6H), 3.96 (dd, J = 10.5, 3.6 Hz, 1H), 3.66 (d, J = 3.2 Hz, 2H), 3.59 - 3.45 (m, 3H), 2.22 (dt, J = 15.3, 7.7 Hz, 4H), 2.09 (tt, J = 12.9, 6.0 Hz, 1H), 1.87 - 1.70 (m, 6H), 1.64 - 1.54 (m, 1H), 1.47 (q, J = 7.3 Hz, 2H), 1.32 (d, J = 7.2 Hz, 3H), 1.28 (d, J = 6.7 Hz, 3H), 1.18 (s, 30H), 0.78 (t, J = 6.6 Hz, 3H). 13 13C-NMR (100 MHz, THF-d8 / D2O 4:1): δ = 175.5, 174.9, 174.8, 173.73, 173.66, 173.2, 171.7, 142.3, 137.8, 128.1, 128.0, 127.4, 124.3, 96.6, 80.0, 77.3, 72.8, 69.1, 68.8, 60.9, 57.2, 53.2, 53.1, 52.2, 49.7, 49.5, 33.6, 31.8, 31.5, 30.9, 29.7, 29.54, 29.50, 29.4, 29.24, 29.20, 29.0, 27.7, 22.54, 22.49, 21.9, 18.6, 16.9, 13.5. MALDI-TOF MS: m / z C 53 H 87 N9O 13 Calculated value of 1057.64; Measured value [M+Na] + 1080.63, [M+K] +1096.65. HPLC-MS (H2O / THF, gradient: 65-95% THF): t (product) = 2.15 min; m / z = 1058.60 [M+H] + (SIM mode).

[0328] [Example 10] Synthesis of MTP-b-C18(10)

[0329] [ka] Molecular weight: 976 daltons. CLogP=5.31

[0330] A 10 mL PE syringe equipped with a PE frit was loaded with MTP-b on resin (137 mg, approximately 0.0493 mmol of MTP-b, 1.00 equiv.). The resin was allowed to swell in DMF (5 mL) for 30 min. The resin was then treated twice with a 2% solution of hydrazine hydrate in DMF (10 mL) for 15 min. The hydrazine solution was removed, and the resin was washed with DMF (4 × 5 mL). Next, a solution of 2,3,5,6-tetrafluorophenyl stearate (0.064 g, 0.15 mmol, 3.00 equiv.) and 4-methylmorpholine (0.030 g, 0.033 mL, 0.30 mmol, 6.00 equiv.) in DMF / DCM (1 + 1 mL; approximately 0.075 M) was added. The beads were stirred overnight at room temperature. The supernatant was then removed, and the resin was washed with 50 / 50 DMF / DCM (4 × 5 mL) and 2 × 5 mL DCM. The resin was then treated with 95 / 2.5 / 2.5 TFA / TIPS / water (200 μL) for 1 h. The filtrate was collected, and the resin was washed with additional cleavage cocktail. The combined filtrates were concentrated in vacuo to give the crude product as a white solid. This material was impregnated onto Celite (200 mg, 1:4 loading ratio) from a 95 / 5 THF / water solution. The impregnated crude product was purified by automated column chromatography (reverse-phase (C18); product: C18-silica 1:250; detection: ELSD) eluting with 50 / 50 to 10 / 90 water / THF. The combined product fractions were lyophilized and then re-purified by automated column chromatography (normal phase (silica); product:silica 1:500; detection:ELSD) eluting with dichloromethane / MeOH 90 / 10 to 70 / 30. Pure fractions were concentrated in vacuo to give the product as a white solid (0.016 g, 33%). 1H NMR (400 MHz, CDCl3+TFA-d3) δ 7.40 - 7.24 (m, 5H), 4.94 - 4.89 (m, 1H), 4.71 - 4.65 (m, 1H), 4.57 - 4.17 (m, 6H), 4.03 - 3.74 (m, 4H), 3.38 (bs, 2H), 2.60 - 2.22 (m, 5H), 2.30 (s, 1H), 2.11 - 1.55 (s, 11H), 1.50 - 1.17 (m, 36H), 0.87 ppm (t, J = 6.6 Hz, 3H). HPLC-MS (Water / MeCN): t (product) = 5.64 min. Actual value: m / z = 976.33 [M+H] + (Yang mode); 1020.25 [M+HCOO] - (Shadow mode).

[0331] [Example 11] Synthesis of MDP-C18 (11)

[0332] [ka] Molecular weight: 744 daltons. CLogP=4.79.

[0333] MDP (10 mg, 20 μmol), octadecylamine (5.2 mg, 0.95 equiv.), NHS (2.4 mg, 1 equiv.), and EDC-HCl (7.9 mg, 2 equiv.) were stirred in DMF (0.7 mL) at 50 °C for 3 h. The reaction mixture was then allowed to cool to room temperature and stirred for an additional 16 h. The resulting dispersion was heated to 40 °C to redissolve any precipitated solids and then precipitated with 5 mL of ether. The collected precipitate was washed two more times with ether, dried, then suspended in demineralized water, collected by centrifugation, resuspended in demineralized water, and collected again by centrifugation. The resulting solid was lyophilized to remove all water, yielding 13.8 mg (96%) of the desired compound as a white powder. 1¹H NMR (400 MHz, DMF-d⁷) δ 8.31 (d, J = 7.7 Hz, secondary anisotropy), 8.23 ​​(d, J = 8.0 Hz, primary anisotropy), 8.12 (d, J = 7.9 Hz, secondary anisotropy), 8.09 (d, J = 7.6 Hz, primary anisotropy), 7.96 (d, J = 6.6 Hz, secondary anisotropy), 7.90 (d, J = 6.5 Hz, primary anisotropy), 7.77 (m, ¹H), 7.47 (m, ¹H), 7.10 (m, secondary anisotropy), 7.01 (m, primary anisotropy), 6.86 (d, J = 6.0 Hz, (Secondary anisotropy), 6.74 (dd, J = 4.1, 1.2 Hz, primary anisotropy), 5.44 - 5.29 (m, 1H), 5.16 (t, J = 3.7 Hz, primary anisotropy), 4.79 (t, J = 6.1 Hz, secondary anisotropy), 4.60 (dd, J = 8.2, 6.0 Hz, secondary anisotropy), 4.57-4.22 (m, 4H), 3.93-3.57 (m, 5H), 3.45 (m, 1H), 3.13 (m, 2H), 2.42-2.07 (m, 3H), 2.00-1.78 (m, 4H), 1.56 - 1.07 (m, 38H), 0.88 (m, 3H) ppm. 13 C NMR (101 MHz, DMF-d7) δ 174.25, 174.20, 173.93, 173.89, 172.75, 172.56, 172.07, 172.02, 171.76, 170.11, 96.92, 91.66, 82.46, 79.55, 77.39, 77.00, 72.97, 71.30, 70.95, 62.05, 57.49, 54.49, 53.16, 53.03, 49.54, 39.26, 32.55, 32.05, 29.83, 29.49, 28.62, 28.41, 27.18, 22.86, 22.76, 22.73, 19.19, 17.80, 17.62, 13.93 ppm. ESI-MS: m / z 743.50 (calculated value), measured value 744.42 (M+H + ), 788.33 (M-FA - ).

[0334] [Example 12] Synthesis of MDP-DSPE (12)

[0335] [ka] Molecular weight: 1223 Daltons. CLogP = 12.96 (uncharged) and 7.18 (negatively charged).

[0336] MDP (14 mg, 29 μmol), NHS (5.6 mg, 1.7 equiv.), and DIC (7.3 mg, 2 equiv.) were stirred in 0.9 mL of DMF for 2 h to activate MDP. The resulting mixture was added to a dispersion of DSPE (17 mg, 0.8 equiv.) in 2.7 mL of tert-butanol containing TEA (9 mg, 3.1 equiv.) at 50 °C and stirred at that temperature for 3.5 h. The resulting mixture was evaporated to dryness, and the resulting material was repeatedly purified by column chromatography (SiO2, CHCl3 / MeOH / HO, 70 / 30 / 5, 5:4:1, and gradient 95 / 5 / 0 to 60 / 40 / 0) to afford 6 mg (21%) of the desired compound as a white fluffy material after lyophilization from water / THF. 1 H-NMR (400 MHz, CDCl3 / CD3OD 5:) δ 5.29 (d, major isomer), 5.24 (m, 1H), 4.54 (d, minor isomer), 4.47 (m, obscured by HDO), 4.41 (dd, obscured by HDO), 4.31 (m, obscured by HDO), 4.19 (dd, 1H), 4.00-3.90 (m, mixture of isomers), 3.87-3.75 (m, mixture of isomers), 3.72 (m, 1H), 3.63 (m, 1H), 3.53-3.30 (m, obscured by CD3OD), 2.37-2.26 (m, 5H), 2.25-2.10 (m, 2H), 2.10-1.92 (m, 4H), 1.61 (m, 4H), 1.50-1.15 (br.m, 62H), 0.88 (t, 6H) ppm. 31 P-NMR (162 MHz, CDCl3 / CD3OD 5:1) δ 0.14 (br.m) ppm.13 C-NMR (101 MHz, CDCl3 / CD3OD 5:1) δ 174.63, 174.00, 173.27, 173.08, 172.92, 172.89, 171.34, 90.19, 75.19, 71.09, 70.18, 69.73, 69.65, 63.24, 62.76, 61.86, 60.84, 53.13, 52.04, 48.77, 48.19, 39.71, 33.48, 33.32, 31.29, 31.14, 28.91, 28.87, 28.76, 28.74, 28.57, 28.54, 28.37, 28.34, 26.44, 24.14, 24.10, 21.88, 21.78, 18.35, 15.98, 13.14 ppm. MALDI-MS: m / z 1221.77 (calculated), found 1220.82 (MH - ), Negative mode. HPLC-ELSD (C18, 65-95% THF / H2O): Single peak + shoulder for alpha and beta isomers.

[0337] [Example 13] Synthesis of MTP-b-DSG (13)

[0338] [ka] Molecular weight: 1361 daltons. CLogP=15.05.

[0339] A 20 mL PE syringe equipped with a PE frit was loaded with MTP-b on resin (0.291 g, approximately 0.11 mmol of MTP-b, 1.00 equiv.). The resin was allowed to swell in DMF (5 mL) for 30 min. The resin was then treated twice with a 2% solution of hydrazine hydrate in DMF (5 mL) for 15 min. The hydrazine solution was removed, and the resin was washed with DMF (4 × 5 mL). Next, a solution of DSG 4-nitrophenyl carbonate (0.249 g, 0.32 mmol, 3.00 equiv.) and N,N-diisopropylethylamine (0.081 g, 0.110 mL, 0.63 mmol, 6.00 equiv.) in chloroform (4 mL) was added. The beads were stirred overnight at room temperature. The bright yellow supernatant was then removed, and the resin was washed with chloroform (3 × 5 mL), MeOH (3 × 5 mL), and chloroform (2 × 5 mL). The resin was treated with TFA / TIPS / water 95 / 2.5 / 2.5 (5 mL) for 45 min. The supernatant was poured into ice-cold diethyl ether (100 mL) with stirring, resulting in the slow formation of white aggregates. This cleavage and precipitation procedure was repeated twice. The solid was collected by filtration through a disposable PE filter, yielding the crude product as a white solid. This material was impregnated onto Celite (250 mg, loading ratio 1:2.5) from a chloroform / MeOH (1:2) solution. The impregnated crude product was purified by automated column chromatography (reverse-phase (C18); product: C18-silica 1:150; detection: 200–400 nm) eluting with water / THF 60 / 40–0 / 100. The combined product fractions were lyophilized and then purified again by automated column chromatography (normal phase (silica); product:silica 1:250; detection: 200-400 nm) eluting with chloroform / MeOH 95 / 5-60 / 40. Pure fractions were concentrated in vacuo to give the product as a white solid (0.030 g, 21%). 1H NMR (400 MHz, CDCl3+MeOD) δ 7.39 - 7.27 (m, 5H), 5.25 (p, J = 5.3 Hz, 1H), 4.89 (d, J = 3.5 Hz, 1H), 4.73 (d, J = 11.9 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 4.42 - 4.31 (m, 2H), 4.31 - 4.19 (m, 4H), 4.15 (dd, J = 11.9, 6.2 Hz, 2H), 4.10 - 3.97 (m, 1H), 3.87 - 3.75 (m, 2H), 3.72 - 3.53 (m, 3H), 3.12 (t, J = 6.9 Hz, 2H), 2.37 - 2.27 (m, 6H), 2.26 - 2.13 (m, 1H), 1.93 (s, 3H), 1.92 - 1.74 (m, 2H), 1.71 - 1.56 (m, 6H), 1.56 - 1.47 (m, 2H), 1.43 (d, 7.0 Hz, 3H), 1.40 (d, 7.0 Hz, 3H), 1.36 - 1.19 (s, 56H), 0.89 ppm (t, J = 6.7 Hz, 6H). 13C NMR (100 MHz, CDCl3+MeOD) δ 175.80, 174.79, 174.30, 173.86, 173.76, 173.44, 173.25, 171.70, 156.58, 137.07, 128.36, 128.14, 127.95, 96.52, 79.36, 76.83, 72.38, 69.48, 69.43, 69.37, 62.50, 62.29, 61.30, 53.52, 53.24, 51.71, 49.46, 40.33, 34.13, 33.97, 31.82, 31.29, 31.08, 29.58, 29.54, 29.52, 29.41, 29.39, 29.25, 29.20, 29.18, 29.09, 29.01, 28.98, 28.16, 24.80, 24.77, 22.88, 22.55, 22.35, 18.61, 16.89, 13.77 ppm. HPLC-MS (water / THF, gradient: 55-95% THF): t (product) = 6.20 min. Observed: m / z = 1360.9 [M+H] + and 1382.9 [M+Na] + (SIM mode).

[0340] [Example 14] Synthesis of MTP(Bn)-α-DPPE (14)

[0341] [ka] Molecular weight: 1328 Daltons. CLogP = 12.88 (uncharged) and 7.09 (negatively charged)

[0342] Building block (CBz)-Ala-DPPE N-CBz-protected L-alanine (390 mg, 1.7 mmol) and N-hydroxysuccinimide (222 mg, 1.89 mmol, 1.1 equiv.) were dissolved in chloroform (6 mL) to obtain a nearly clear solution. N,N'-Diisopropylcarbodiimide (DIC; 0.32 mL, 2.0 mmol, 1.2 equiv.) was added, and the mixture was stirred at room temperature for 40 min (after 1 min, the solution became cloudy; after 25 min, H-NMR indicated complete conversion). This solution was then added to a solution containing 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE; 1.06 g, 1.5 mmol, 0.9 equiv.) and triethylamine (600 μL, 0.71 mmol, 2.5 equiv.) in chloroform (12 mL; DPPE was dissolved under reflux and triethylamine was added at low temperature). The resulting clear solution was stirred at 60°C for 1 hour (the solution remained clear and 1 H-NMR indicated complete conversion. Chloroform (360 mL) was added, and the organic layer was gently washed with 0.1 M HCl (100 mL). The organic layer was dried using Na2SO4, filtered, and the solvent removed in vacuo. Column chromatography (flash SiO2) using an elution gradient of 2% to 30% methanol in chloroform afforded the title compound, partially contaminated with triethylamine. Impure fractions were dissolved in chloroform, and the organic layer was gently washed with 0.1 M HCl. The organic layer was dried using Na2SO4, filtered, and the solvent removed in vacuo. This effectively removed triethylamine, and the pure fractions were combined to give the pure product (1.22 g, 1.4 mmol, 91%) as a colorless, waxy solid. 1H-NMR (400 MHz, DMSO-d6): δ = 8.06 (t, J = 5.7 Hz, 1H), 7.47-7.22 (m, 6H), 5.15 (dq, J = 8.3, 4.6 Hz, 1H), 5.01 (q, J = 12.6 Hz, 2H), 4.28 (dd, J = 12.0, 3.2 Hz, 1H), 4.11 (dd, J = 12.1, 7.0 Hz, 1H), 4.06-3.92 (m, 3H), 3.82 (q, J = 6.4 Hz, 2H), 3.33-3.18 (m, 2H), 2.27 (dt, J = 12.8, 5.0 Hz, 4H), 1.50 (q, J = 6.9 Hz, 4H), 1.32-1.16 (m, 51H), 0.85 (t, J = 6.7 Hz, 6H). 31 P-NMR (162 MHz, DMSO-d6): δ = -1.4.

[0343] Building block Ala-DPPE In a two-neck round-bottom flask, (CBz)-Ala-DPPE (308 mg, 0.34 mmol) and Pd / C (374 mg, 10% Pd, pre-wetted Degussa / Evonik type) were mixed in chloroform / ethanol 1:2 (36 mL). The flask was evacuated and refilled with Ar three times. A H2 balloon was attached, the flask was evacuated and refilled with H2 three times, and the mixture was stirred under positive H2 pressure at room temperature for 3 h. The solution was filtered through Celite and washed thoroughly with ethanol, chloroform / ethanol 1:1, and chloroform. The combined filtrate was evaporated to dryness, and the resulting compound was dissolved in chloroform / ethanol 2:1 (90 mL) and dried using Na2SO4. The solution was filtered through Celite and washed thoroughly with chloroform / ethanol 2:1. The filtrate was evaporated to dryness to give the product (224 mg, 0.29 mmol, 86%) as a slightly yellowish waxy solid, which contained traces of Pd. 1H-NMR (400 MHz, DMSO-d6): δ = 8.60 (br, 1H), 8.08 (br, 2H), 5.15 (br, 1H), 4.28 (d, J = 13.2 Hz, 1H), 4.12 (dd, J = 6.9 Hz, 1H), 4.00 (m, 2H), 3.88 (m, 2H), 3.80 (br, 1H), 3.09 (br, 1H), 2.35-2.23 (m, 4H), 1.50 (br, 4H), 1.41-1.14 (m, 51H), 0.85 (t, J = 6.6 Hz, 6H). 31 P-NMR (DMSO-d): δ = -1.4.

[0344] MTP(Bn)-a-DPPE(14) MDP(Bn) (20.0 mg, 34 μmol) and Ala-DPPE (26.2 mg, 34 μmol, 1.0 equiv.) were mixed in DMAc (0.3 mL) and N,N-diisopropylethylamine (24 μL, 0.14 mmol, 4 equiv.), and PyBOP (22 mg, 41 μmol, 1.2 equiv.) was added sequentially. The resulting suspension was stirred at 50 °C for 1 h, after which the mixture became nearly clear. Volatiles were removed in vacuo (oil pump, 45 °C), and the mixture was flushed once with chloroform. This was followed by column chromatography (flash SiO2) using an elution gradient of 15% to 40% methanol in chloroform, followed by automated column chromatography (reverse-phase C18; product: C18-silica 1:200; detection: λ = 200-220 nm) using an elution gradient of 30% to 80% THF in HO. This gave product 14 (8.0 mg, 6 μmol, 18%) as a white fluffy solid after lyophilization. HPLC-MS: t[product]=3.92 min; m / z=1327.80[M+H] + (SIM mode). HPLC-ELSD: t[prod]=3.48 min; relative peak area 99.2%.

[0345] [Example 15] MTP-a-chol

[0346] [ka] Molecular weight: 1018 daltons. CLogP=5.64.

[0347] N-(2-aminoethyl)-cholesterol carbamate building block.

[0348] [ka] A solution of cholesterol chloroformate (0.95 g, 2.1 mmol) in 20 mL of DCM was slowly added to a solution of ethylenediamine (2 mL, 14 equiv.) in 30 mL of DCM over approximately 2 h. The reaction was allowed to proceed for an additional 30 min, after which the reaction mixture was evaporated to dryness. The resulting white material was purified by column chromatography (SiO, CHCl / MeOH / formic acid 78:20:2) to afford 720 mg (72%) of the desired compound as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.46 - 5.27 (m, 1H), 4.99 (br. s, 1H), 4.50 (br.m, 1H), 3.22 (q, J = 5.6 Hz, 2H), 2.82 (t, J = 5.9 Hz, 2H), 2.43 - 2.19 (m, 2H), 2.06 - 1.75 (m, 5H), 1.64 - 0.80 (m, 35H), 0.68 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 156.41, 139.83, 122.47, 74.31, 56.68, 56.13, 50.00, 43.63, 42.30, 41.79, 39.73, 39.51, 38.57, 36.99, 36.56, 36.18, 35.79, 31.90, 31.87, 28.22, 28.17, 28.00, 24.28, 23.82, 22.81, 22.55, 21.03, 19.33, 18.71, 11.85. MALDI: m / z = 472.40 (calculated), found: 495.39 (M+Na+). A prominent peak was observed at m / z=369.37, which is attributed to the 3.4 elimination product formed in MALDI (not observed in NMR).

[0349] This building block can be coupled to N-Boc-L-alanine (CAS[15761-38-3]) via amidation; the Boc group can then be deprotected; finally, the formed amine-functional molecule can be coupled with MDP to arrive at MTP-a-chol.

[0350] [Example 16] MDP(Bn)-chol

[0351] [ka] Molecular weight: 1037 daltons. CLogP=7.69.

[0352] The N-(2-aminoethyl)-cholesterol carbamate building block (see Example 15) can be conjugated to MDP(Bn) via amidation to arrive at the molecule MDP(Bn)-chol.

[0353] [Example 17] (MTP-a-DSPE)

[0354] [Example 18] (MTP(Bn)-a-DSPE)

[0355] [Example 19] (MDP(Bn)-DSPE)

[0356] [ka] MTP-a-DSPE: MW is 1294 Daltons. CLogP=12.70 and 6.92 (uncharged and charged). MTP(Bn)-α-DSPE: MW is 1384 Daltons. CLogP=14.99 and 9.21 (uncharged and charged). MDP(Bn)-DSPE: MW is 1313 Daltons. CLogP=15.25 and 9.46 (uncharged and charged).

[0357] 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE; CAS[1069-79-0]) can be connected to N-Boc-L-alanine (CAS[15761-38-3]) via amidation; the Boc group can then be deprotected; finally, the formed amine-functional molecule can be coupled to MDP to obtain MTP-α-DSPE or MDP(Bn) to obtain MTP(Bn)-α-DSPE.

[0358] Alternatively, DSPE can be attached to MDP(Bn) via amidation to arrive at the molecule MDP(Bn)-DSPE.

[0359] [Example 20] Lipophilicity studies The ClogP values ​​of exemplary compounds of the present disclosure were evaluated using Perkin Elmer ChemDraw Professional, version 18.0.0231 (4029) software. The results show values ​​ranging from approximately 4.15 to 18.28. At a physiological pH of approximately 7.4 (i.e., where the COOH and POH groups are charged), two molecules of the present invention have ClogP values ​​between 4 and 5, three have values ​​between 10 and 20, and the remaining molecule has a value between 5 and 10.

[0360] Experimentally, the lipophilicity of molecules can also be compared by running HPLC using the same elution gradient. Molecules that have a higher affinity for the hydrophobic C18 material of the column are more lipophilic and therefore have a longer retention time. The table below shows that the example molecules of the present invention (entries 1-4) have a longer retention time and are therefore more lipophilic than the comparative example molecules (entries 5 and 6).

[0361] Methods: HPLC-MS (SIM) and HPLC-ELSD were performed on a Phenomenex Kinetex 5 micrometer EVO C18 100A LC column (50 × 2.1 mm) using the same gradient from eluent A to B: A = 20 mM NH4HCO2 in H2O containing 0.1 v / v% formic acid, and B = 2-propanol / MeCN / H2O 85:15:5, also containing 20 mM NH4HCO2 and 0.1 v / v% formic acid.

[0362] [Table 3]

[0363] [Example 21] water solubility studies Compounds of the present disclosure were tested for solubility in PBS buffer and water applying low concentrations.

[0364] First, the compound was weighed into a vial and PBS buffer (137, 2.7, 10, and 1.8 mM in NaCl, KCl, NaHPO, and KHPO, respectively, pH=7.4) was added, resulting in a concentration of 0.2 mg / mL when fully dissolved. The sample was shaken, left for 1 hour, and shaken again before checking the appearance of the solution at room temperature (RT). The sample was then warmed in a 37°C water bath for 1 minute, and the appearance of the solution was checked again. The results are summarized in the table below.

[0365] None of the tested compounds spontaneously dissolved in PBS at either room temperature or 37°C. In contrast, the tested comparative compounds spontaneously dissolved under these conditions. Further treatment of the sample solutions with a heat gun did not dissolve items 4, 5, and 6, while items 2 and 3 gave cloudy solutions after cooling to room temperature.

[0366] [Table 4]

[0367] The compound was then weighed and dissolved in chloroform / methanol. The solution was allowed to dry in the vial, forming a film of material. The vial was placed under vacuum to remove traces of organic solvent. Demineralized water was added to give a compound concentration of 0.3 mM when fully dissolved (0.3 mM corresponds to 0.3 mg / mL of a compound with MW=1000 Daltons). The vial was sonicated briefly in a water bath, left overnight, and sonicated again (sonication at room temperature). The appearance of the solution at room temperature was checked to assess solubility. The results are summarized in the table below.

[0368] None of the tested compounds of the present disclosure are spontaneously soluble in water at room temperature. In contrast, the tested comparative compounds were spontaneously soluble under these conditions.

[0369] [Table 5]

[0370] Finally, Comparative Examples 1 and 2 were also tested for solubility in PBS (0.01 M, pH=7.4) and demineralized water at a level of 1 mg / mL. The same results as shown in the two tables above were found at this concentration.

[0371] Taken together, these results demonstrate that a series of compounds of the present invention are not spontaneously soluble in PBS or water at concentrations as low as 0.2 mg / mL (and higher). In contrast, the comparative materials are soluble in PBS or water, giving clear solutions at concentrations of at least 0.2 mg / mL, and even as high as 1 mg / mL.

[0372] Because the disclosed compounds have low solubility in aqueous solutions, their physicochemical properties find particular application in producing stable HDL-derived NPs. Without being bound by theory, it is believed that the disclosed compounds improve immobilization on NPs, reduce leakage, and provide products with improved stability and shelf life.

[0373] [Example 22] Degradation by enhanced oxidation test To achieve rapid degradation of the molecules by oxidation and mimic the slower oxidation phenomenon in vivo, the reference compounds MDP and MDP(Bn), as well as the Bn-substituted compounds from Example 7 (i.e., MDP(Bn)-DSPE [click] and Example 14 (i.e., MTP(Bn)-α-DPPE) were mixed with 12% hydrogen peroxide in water and heated at 80 °C for 4 h.

[0374] The resulting reaction mixture was diluted with acetonitrile and water (1:1) for MDP and MDP(Bn) test solutions, or with iPrOH, acetonitrile, and water (40:7.5:52.5) ​​containing 0.1% formic acid and 20 mM ammonium formate for MDP(Bn)-DSPE[click] and MTP(Bn)-α-DPPE solutions. Four diluted samples were analyzed by HPLC-MS. For reference, the four starting materials were also analyzed by HPLC-MS, as well as MDP-DSPE[click] and MTP-α-DPPE (i.e., debenzylated reference compounds for the Bn-substituted test molecules).

[0375] For all four test solutions, the unaffected starting compound was traced. Additionally, multiple derivatives with masses +14, +16, +28, +30, and +32 were found, indicating oxidation of CH to CO moieties (+14) and CH to C-OH moieties (+16), as well as combinations of these oxidation events. The tested MDP(Bn)-DSPE[click] and MTP(Bn)-α-DPPE compounds degraded primarily through oxidation of the Bn group to a benzoic acid group (+14) followed by hydrolysis of the benzoic acid (−104). This was evidenced by the presence of primarily debenzylated MDP-DSPE[click] and MTP-α-DPPE compounds as degradation products: enhanced retention times in HPLC and enhanced masses (−90 compared to the starting compounds) in MS.

[0376] The results indicate that the Bn group in the compounds of the present invention has the highest propensity for in vivo oxidative degradation. After oxidation and cleavage of Bn, a typical MDP or MTP group is formed, which degrades in vivo in a manner similar to other MDP / MTP groups known in the art.

[0377] [Example 23] Nanobiological Synthesis Method 1 - Membrane The phospholipid, (pro)drug, and optional triglyceride or polymer are dissolved (typically in chloroform, ethanol, or acetonitrile). This solution is then evaporated under vacuum to form a film of the components. A buffer solution is then added to hydrate the film and produce a vesicle suspension. The phospholipid, (pro)drug, and optional triglyceride or polymer are dissolved (typically in chloroform, ethanol, or acetonitrile). This solution is poured or added dropwise to a gently heated buffer solution with stirring until the organic solvent has completely evaporated and a vesicle suspension is produced.

[0378] To the vesicle suspension generated using A or B, add apolipoprotein AI (apoA-I) (note that apoA-I can also be already present in B) dropwise to avoid denaturation. Then, sonicate the resulting mixture for 30 minutes using a tip sonicator while completely cooling using an external ice-water bath. Transfer the resulting solution containing the nanobiological product and other by-products to a Sartorius Vivaspin tube with a molecular weight cutoff according to the estimated size of the nanobiological product (typically, a Vivaspin tube with a cutoff of 10,000-100,000 kDa is used). Centrifuge the tube until approximately 90% of the solvent volume passes through the filter. Then, add a volume of buffer approximately equal to the volume of the remaining solution, and rotate the tube again until approximately half of the volume passes through the filter. After repeating this process twice, pass the remaining solution through a polyethersulfone 0.22 pm syringe filter to obtain the final nanobiological solution.

[0379] Method 2 - Microfluidics In an alternative approach, phospholipids, (pro)drugs, and optional triglycerides, cholesterol, steryl esters, or polymers are dissolved (typically in ethanol or acetonitrile) and loaded into a syringe. A solution of apolipoprotein AI (apoA-I) in phosphate-buffered saline is then loaded into a second syringe. Using a microfluidics pump, the contents of both syringes are mixed using a microvortex platform. The resulting solution, containing the nanobiologic and other by-products, is transferred into a Sartorius Vivaspin tube with a molecular weight cutoff depending on the estimated particle size (typically, Vivaspin tubes with a cutoff of 10,000-100,000 kDa are used). The tube is centrifuged until approximately 90% of the solvent volume passes through the filter. A volume of phosphate-buffered saline approximately equal to the volume of the remaining solution is then added, and the tube is spun again until approximately half of the volume passes through the filter. This process is repeated twice, and the remaining solution is then passed through a polyethersulfone 0.22 pm syringe filter to obtain the final nanobiologic solution.

[0380] Method 3 - Microfluidizer Another method according to the present invention uses microfluidizer technology to prepare nanoscale assemblies and the final nanobiological composition. A microfluidizer is a device for preparing small particle sizes that operates based on the submerged jet principle. To obtain nanoparticles, a premix stream is passed by a high-pressure pump through a so-called interaction chamber, which consists of a channel system within a ceramic block that splits the premix into two streams. Precisely controlled shear, turbulence, and cavitation forces are generated within the interaction chamber during microfluidization. The two streams recombine at high speed, creating shear. The resulting product can be recycled back into the microfluidizer to obtain increasingly smaller particles. Advantages of microfluidization compared to traditional milling processes include significantly reduced contamination of the final product and easier scale-up of production.

[0381] Formulation 1 The following table provides details on the preparation of HDL-derived nanoparticle formulations. First, DMPC, cholesterol, and the compounds of the present invention were dissolved in ethanol (items A, B, and D) or ethanol / DMSO 4 / 1 (items C, E, and F) at a given molar ratio, while the protein apoA-1 was dissolved separately in PBS buffer (pH = 7.5). In these formulations, the weight of the applied apoA-1 correlated with the weight of DMPC. The organic solution was mixed with the PBS buffer solution by combining them via T-junction mixing.

[0382] The resulting solution was purified by TFF (tangential flow fractionation), whereby the organic solvent was removed and the nanoparticles were dissolved in PBS. Concentration of the NP solution was performed by spin filter centrifugation. Finally, the HDL-derived nanoparticle solution was filtered through a 0.2 micrometer Acrodisk PES filter.

[0383] The final HDL-derived nanoparticle solution had a typical recovery rate of over 80% for the compounds used (Examples 2, 3, 7, 8, and 13), DMPC, and cholesterol. Recovery rates were determined using HPLC (for compounds) and art-known assays (for DMPC and cholesterol). The concentration of the final HDL-derived nanoparticle solution was approximately 2-4 mg / mL of compound.

[0384] [Table 6]

[0385] Stability of nanobiologics assessed by dynamic light scattering (DLS). The formulations of Items A-F were characterized by DLS over an 8-week period. The nanoparticles in the formulations of Examples 2, 3, 7, and 13 had Z-average (intensity-weighted average hydrodynamic size) diameters of approximately 20, 30, 20, and 45 nm, respectively. The dimensions of these nanoparticles remained constant over time, and the particle size distribution (PDI) also remained constant. Unloaded particles (Item A) were also stable over time (diameter approximately 30 nm). The nanoparticles in the formulation of Example 8 showed a diameter increase from approximately 50 to approximately 225 nm from the 2-week time point to the 5-week time point. At the 5-week time point, the dimensions were stable. Using other processing conditions, this Example 8 material could most likely be formulated into stable 10-50 nm-sized particles.

[0386] The DLS-determined Z-average diameter and PDI values ​​of the nanoparticles of formulations A to F are shown in Figure 2 .

[0387] Tip sonication formulation A: DSPC ([816-94-4]; 2.7 mg), cholesterol (0.26 mg), and compound (0.46 mg) were dissolved in a glass vial using chloroform / methanol (9:1). The solvent was removed using a stream of argon gas, and the resulting film was dried in vacuo for >1 hour. ApoA-I PBS solution (6 mL) was added to the vial, followed by 5 minutes of bath sonication, 20 minutes of incubation at 37 °C, and then 10 minutes of tip sonication. The resulting dispersion was centrifuged to remove larger aggregates. The supernatant was transferred to a Vivapin 20 ultrafiltration unit (10 kDa cutoff) and spun down to a volume of approximately 1 mL. The resulting dispersion was diluted with PBS and spun down to 1 mL; this procedure was repeated twice. Finally, the volume was diluted to 2 mL using PBS to obtain the desired nanoparticle solution.

[0388] Tip sonication formulation B: DMPC (2.7 mg), cholesterol (0.30 mg), and compound (0.57 mg) were dissolved in a glass vial using chloroform / methanol (9:1). The solvent was removed using a stream of argon gas, and the resulting film was dried in vacuo for >1 hour. A solution of peptide-2F (apoA-I mimetic 18-mer; sequence 257 in Table 2) in 6 mL of PBS was added to the vial, followed by 5 minutes of bath sonication, 20 minutes of incubation at 37 °C, and then 5 minutes of tip sonication. The resulting dispersion was centrifuged to remove larger aggregates. The supernatant was transferred to a Vivapin 20 ultrafiltration unit (10 kDa cutoff) and spun down to approximately 1 mL. The resulting dispersion was diluted with PBS and spun down to 1 mL; this procedure was repeated twice. Finally, the volume was diluted to 2 mL using PBS to obtain the desired nanoparticle solution.

[0389] T-junction Formulation C: DMPC, cholesterol, and compound were dissolved in ethanol, while apoA-1 was dissolved in PBS buffer (pH = 7.5). T-junction mixing was applied to mix the organic solution with the buffer solution. Purification of the resulting solution was performed by TFF (tangential flow filtration), thereby removing the organic solvent. The sample was concentrated by spin-filtration. The final HDL-derived nanoparticle solution had a typical recovery rate of over 75% for compound, DMPC, and cholesterol. The concentration of the final HDL-derived nanoparticle solution was approximately 2-4 mg / mL of compound.

[0390] [Table 7]

[0391] *apoA-I or 2F-peptide used mg per mg phosphocholine PC; **apoA-I used mg per mg compound; #number average diameter.

[0392] The above examples highlight that DSPC can be used in place of DMPC (e.g., POPC can also be used), peptidomimetics can be used in place of apoA-I, and high levels of the compounds of the present disclosure can be incorporated. Additionally, tip sonication can also be used as a processing technique, e.g., in place of T-junction mixing or microfluidic mixing.

[0393] Isolation of apolipoprotein AI (apoA-I). Human apoA-I was isolated from human HDL concentrate (Bioresource Technology) according to a previously described procedure (Zamanian-Daryoush et al., 2013). Briefly, potassium bromide solution (density: 1.20 g / mL) was layered on top of the concentrate, and purified HDL was obtained by ultracentrifugation. The purified fraction was defatted by adding it to a chloroform / methanol solution. The resulting milky solution was filtered, and the apoA-I precipitate was allowed to dry overnight. The protein was refolded in 6 M guanidine hydrochloride, and the resulting solution was dialyzed against PBS. Finally, the apoA-I PBS solution was filtered through a 0.22 pm filter, and the protein identity and purity were confirmed by gel electrophoresis and size-exclusion chromatography.

[0394] [Example 24] Cryo-TEM measurements of HDL-derived nanoparticle formulations The molecular compounds of Examples 2 and 7, i.e., MDP-DSPE[click] and MDP(Bn)-DSPE[click], respectively, were formulated with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC; CAS [18194-24-6]) and APO-A1, and with varying amounts of cholesterol, to create HDL-derived nanoparticle formulations. The table below shows the relative molar amounts of DMPC, compound, and cholesterol components used. APO-A1 was used in twice the amount (in mg) of the compounds of the present invention (in mg). Dynamic scattering (DLS) data for the processed formulations are also shown; the reported diameters and errors in parentheses are based on number-averaged DLS data. The DLS-recorded polydispersity in particle dimensions is also shown.

[0395] [Table 8]

[0396] Formulation: DMPC, cholesterol, and compounds were dissolved in ethanol (items A, C, and E) or ethanol / DMSO (items B, D, and F), while apoA-1 was dissolved in PBS buffer (pH = 7.5). A T-junction mixer was applied to mix the organic solution with the buffer solution. Purification of the resulting solution was performed by TFF (tangential flow filtration), thereby removing the organic solvent. The sample was concentrated by spin-filtration. The final HDL-derived nanoparticle solution typically yielded greater than 75% recovery of the compounds used (Examples 2 and 7), DMPC, and cholesterol. Recovery rates were determined using HPLC (for compounds) and art-known assays (for DMPC and cholesterol). The concentration of the final HDL-derived nanoparticle solution was approximately 2-4 mg / mL of compound (Example 2 or 7).

[0397] Figure 1 shows cryo-TEM images recorded for HDL-derived nanoparticles from items A to F. The 50 nm bar applies to all six images. When 0% cholesterol is used, spherical, disc-shaped particles are primarily observed (A and B; approximately 5–10 nm in size). When 10% cholesterol is applied, slightly expanded disks are mostly observed (C and D; approximately 5–25 nm in length and approximately 5 nm in thickness). When 20% cholesterol is used, clearly elongated, worm-like particles are observed. These worm-like particles have lengths of approximately 20–50 nm and thicknesses of approximately 5 nm (photo C). In photo F, the worms have lengths of approximately 50–100 nm; again, their thickness is approximately 5 nm. In F, it is also observed that the worm-like particles aggregate into larger stacks.

[0398] The results highlight that the particle size of HDL-derived nanoparticles can be controlled not only using the cholesterol content of the formulation (compare C with E, and D with F), but also by the lipophilicity of the compound and / or the substitution at the R2 position in formula (I) of the compounds of the invention (clear: compare E with F; less clear: in D the particles appear a little more elongated than in C).

[0399] Methods: Immediately prior to sample processing, 200-mesh lacey carbon-supported copper grids (Electron Microscopy Sciences) were surface plasma treated for 40 seconds using a Cressington 208 carbon coater. Next, 3 μL of HDL-derived nanoparticle sample solution was transferred to the grid. A thin film of the sample solution was then vitrified onto the grid by plunge vitrification in liquid ethane using an automated vitrification robot (FEI Vitrobot Mark IV). The processed film was stored until measurements were performed. Cryo-TEM imaging of the prepared films was performed on a Cryo-TITAN microscope (Thermo Fisher) equipped with a field emission gun (FEG), a post-column Gatan imaging filter (Model 2002), and a post-GIF 2k × 2k Gatan CCD camera (Model 794).

[0400] [Example 25] In vitro NOD2 activation assay Stimulation of human NOD2 (hNOD2) by the disclosed compounds was studied by monitoring NF-κB activation in HEK-Blue™ hNOD2 cells (Invitrogen). 50,000 HEK-Blue™ hNOD2 cells were seeded in HEK-Blue™ detection medium in flat-bottom tissue culture plates. A range of test article concentrations (compounds diluted from DMSO solution (17.8 mmol / L) first in demineralized water and then in PBS to the desired concentration) were added to the cells in the tissue culture plates. The cells were incubated overnight at 37°C with 5% CO2. The next day, the supernatant was collected into an ELISA plate, and the OD was measured at 620 nm using a spectrophotometer.

[0401] The signal in this assay is based on NOD2 stimulation by ligands, which subsequently activates NF-κB and AP-1, resulting in the production of SEAP. SEAP levels were then determined using HEK-Blue™ Detection Medium (Invitrogen). Hydrolysis of a substrate in the medium by SEAP produced a purple / blue color, which was measured using an absorbance microplate reader. OD values ​​were mapped based on the concentration of the test article and are shown in Figure 3. Assay performance was validated using muramyl dipeptide (CAS number [53678-77-6]).

[0402] All of the test compounds (APIs) of the present invention can activate NOD2. The compounds of Examples 2, 3 and 7 have similar potencies. The compounds of Examples 8 and 13 can also activate NOD2, but to a lesser extent than the compounds of Examples 2, 3 and 7.

[0403] [Example 26] Combinatorial activity of (i) HDL-derived nanoparticles and (ii) immune checkpoint inhibition in the B16F10 mouse model 1. In Vivo Studies of Formulations Formulations for these in vivo studies were prepared by T-junction mixing followed by tangential flow filtration (TFF). Processing and purification procedures were applied as highlighted for formulations for cryo-TEM measurements (Table 8).

[0404] The compounds used were those of Examples 2, 3, 7, 8, and 13 (i.e., these example materials are collectively referred to as API in these descriptions of the in vivo studies). For the five formulations administered, the following relative ratios of components were used:

[0405] [Table 9]

[0406] Protocol and Results A panel of example APIs was formulated into HDL-derived nanoparticles (or nanobiologicals, NBs) that were screened for their antitumor activity in combination with immune checkpoint inhibitors in a B16F10 syngeneic mouse tumor model. To this end, B16F10 mouse melanoma cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Gibco) supplemented with 10% FBS (Gibco) and 1% penicillin / streptomycin (P / S). Cells were harvested on the day of injection and 1 x 10 viable cells were added to PBS containing 0.5% FBS. 6 Cells were resuspended at 1 × 10 cells / mL. During counting, cell viability was checked using trypan blue solution, 0.4% (Gibco). At the start of the experiment, 1 × 10 cells were resuspended in 100 μL PBS supplemented with 0.5% fetal bovine serum (FBS). 5 B16F10 tumor cells were injected subcutaneously into the flanks of 7-week-old female C57BL / 6 mice (The Jackson Laboratory).

[0407] Seven days after tumor inoculation, mice were randomized into groups with similar average group size (n=10). The average tumor size for the groups was 3.26 mm 3 After randomization, mice were ear-nicked and weighed. The dose was then calculated and aliquoted. The aliquoted doses were stored at 4°C until use.

[0408] The study consisted of a PBS control group, an immune checkpoint inhibitor (CI) group, and six treatment groups. Mice treated with immune checkpoint inhibitors received intraperitoneal injections of 200 μg of anti-CTLA-4 (clone 9H10, BioXcell) and / or 200 μg of anti-PD-1 (clone RMP1-14, BioXcell) on days 2, 4, and 8. Treatment groups consisted of NB prepared from the compound of Example 2, NB from Example 3, NB from Example 7, NB from Example 8, and NB from Example 13 in combination with the immune checkpoint inhibitor therapy (CI) described above. The dose for the treatment groups was approximately 9 mg MDP / kg (or approximately 27 mg / kg of each API contained in the NB) on days 0, 2, and 4.

[0409] Tumor growth curves are shown in Figures 4A-E, with the same PBS and CI groups mapped in each graph, allowing comparison between graphs.

[0410] PBS-treated animals or animals treated with immune checkpoint inhibitors alone did not exhibit tumor growth inhibition. All groups of animals treated with combination therapy exhibited tumor growth inhibition, which was most pronounced in groups in which the NBs of Example 2 (FIG. 4A), Example 7 (FIG. 4C), or Example 8 (FIG. 4D) were part of the combination therapy. It should be noted that the above results for the combination therapy were obtained with an applied formulation containing 10 mol% cholesterol relative to the applied 90 mol% DMPC; therefore, the dimensions of these particles were approximately 5 to a maximum of 10 nm (see cryo-TEM panels C and D in Figure 1) (see table above).

[0411] [Example 27] Single-agent activity of nanobiologics in the B16F10 mouse model Formulations for these in vivo studies were prepared by T-junction mixing followed by tangential flow filtration (TFF). Processing and purification procedures were applied as highlighted in the formulations for cryo-TEM measurements (Table 8). The table below shows the relative ratios of components used to prepare HDL-derived nanoparticles.

[0412] [Table 10]

[0413] Protocol and Results Two APIs (compounds of Example 2 and Example 7) were used to generate a series of different HDL-derived nanoparticle formulations (or nanobiologicals; nanobiologicals; NBs) and determine their efficacy. The resulting nanobiologicals were screened for single-agent antitumor activity in a B16F10 syngeneic mouse tumor model. To this end, B16F10 mouse melanoma cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Gibco) supplemented with 10% FBS (Gibco) and 1% penicillin / streptomycin (P / S). Cells were harvested on the day of injection and 1 x 10 viable cells were added to PBS containing 0.5% FBS. 6 Cells were resuspended at 1 × 10 cells / mL. During counting, cell viability was checked using a cell counter and analyzer (Casy). At the start of the experiment, 1 × 10 cells were resuspended in 100 μL PBS supplemented with 0.5% fetal bovine serum (FBS). 5 B16F10 tumor cells were injected subcutaneously into the flank of 7-week-old female C57BL / 6J mice (Charles River).

[0414] Seven days after tumor inoculation, mice were randomized into groups with similar average group sizes. Groups consisted of 8-10 mice. The average tumor size for the groups was 6.33 mm. 3 After randomization, mice were tattooed with numbers on their tails. The dose was then calculated and aliquoted. The aliquoted doses were stored at 4°C until use.

[0415] The study consisted of a PBS control group and five treatment groups: NB from Example 2 (formulation items 1, 3, and 4) and NB from Example 7 (formulation items 2 and 5). Treatment doses were approximately 3 mg MDP / kg (or approximately 9 mg / kg of each API contained in the NB) on days 0, 2, and 4. Tumor size was measured at designated times throughout the study. Tumor growth curves are shown in Figures 5A-C, with the same PBS group mapped on each graph to allow comparison between graphs. With the exception of NB from Example 2 (formulation item 1), all nanobiological formulations clearly demonstrated reduced tumor growth compared to the PBS control group. For both Example 2 (Figure 5A) and Example 7 (Figure 5B), the nanobiological formulation containing 20 mol% cholesterol performed best. Figure 5C shows that NB from Example 2 performed slightly better than NB from Example 7 (using formulation items 4 and 5, respectively).

[0416] In Figure 5A, the formulation of Example 2 containing 10 mol% cholesterol (item 1 in the table above) exhibited minimal single-agent activity (compared to PBS). Surprisingly, in comparison, the formulations of Example 2 containing 20 mol% cholesterol (items 3 and 4 in the table above) exhibited greatly enhanced tumor suppression. This can also be seen for the formulation of Example 7 (Figure 5B). Clearly, the dimensions of the formed particles play a crucial role in the activity of the prepared HDL-derived nanoparticles: the 10% cholesterol formulation yields spherical or slightly elongated, disc-shaped particles with dimensions of 5–10 nm, whereas the 20% cholesterol formulation yields elongated, worm-like particles approximately 15–50 nm in length and approximately 5 nm thick (compare panels C and E in Figure 1, cryo-TEM data).

[0417] The disclosed HDL-derived nanoparticles have certain dimensions, and these characteristics find particular use in generating stable and potent HDL-derived NPs. Without being bound by theory, it is believed that the disclosed HDL-derived nanoparticles improve the (multivalent) presentation of the MDP (or MDP(Bn) or MTP or MTP(Bn)) moiety to cells, dramatically improving their efficacy.

[0418] Embodiment 1. Formula (I):

[0419] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is -H or -C(O)-R X and; R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5 , and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; R 7 is C 9~30 Fatty acid chain, -YN(R 11 )-C(O)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , -C(R 10 )(C(O)NH2)-alkylene-N(R 11 )-C(O)-C 16~30 Fatty acid chain, -(CR 10 R 10 )2-OP(O)(OH)-O-alkylene-C(R 10 )(OR Z )-Alkylene-OR Zor -Y-triazolyl-L; R Z is C 8~30 Fatty acids or -C(O)-C 16~30 is a fatty acid chain; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R X and; R 10 , R 22 , R 33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ are each independently H or R A and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, aryl, and triazolyl may be selected from one or more R A is optionally replaced by R A is halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)RB , -C(O)OR B , -C(O)R B , -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle; R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro; R 7 C 9~30 If it is a fatty acid chain, R 2 is -H).

[0420] 2. The compound of formula (I) has the formula (IA):

[0421] [ka] or a pharmaceutically acceptable salt thereof.

[0422] 3. R 2 The compound of embodiment 1 or 2, wherein is —H or benzyl.

[0423] 4. R 2 The compound of any one of embodiments 1-3, wherein is —H.

[0424] 5. R 10 , R 22 , R33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ The compound of any one of embodiments 1-4, wherein each is —H.

[0425] 6. R 4 The compound of any one of embodiments 1-5, wherein is alkyl.

[0426] 7. R 4 The compound of any one of embodiments 1-6, wherein is methyl.

[0427] 8. R 3 and R 6 and R are both -H.

[0428] 9. Y is -C(O)N(R C )(R D The compound of any one of embodiments 1-8, wherein R is alkylene optionally substituted with .

[0429] 10. Y is -CH2- or

[0430] [ka] 10. The compound of embodiment 9, wherein:

[0431] 11. The compound of embodiment 10, wherein Y is -CH2-.

[0432] 12. R 7 The compound of any one of embodiments 1-11, wherein is -Y-triazolyl-L.

[0433] 13. The compound of formula (I) is a compound of formula (II):

[0434] [ka] or a pharmaceutically acceptable salt thereof (In the formula, X1 is -N- and X2 is -C-; or X1 is -C- and X2 is -N-. 13. The compound of any one of embodiments 1-12, wherein

[0435] 14. The compound of formula (I) has formula (IIA):

[0436] [ka] or a pharmaceutically acceptable salt thereof.

[0437] 15. Y is C 1~6 The compound of embodiment 13 or 14, wherein the compound is alkylene.

[0438] 16. R A The compound of any one of embodiments 13-15, wherein is —H.

[0439] 17. L is C 8~30 Fatty acid chain, -CH2-C(O)-W, -CH2-OC(O)-W, -CH2CH2-N-CH2CH2-C(O)-NR 11 -CH2CH2-NR 11 17. The compound of any one of embodiments 1-16, wherein the compound is selected from the group consisting of: —C(O)—W)2, and —CH2CH2—N—(CH2CH2—C(O)—W)2.

[0440] 18. L is C 12~18 The compound of embodiment 17, which is a fatty acid chain.

[0441] 19. The compound of embodiment 17, wherein L is -CH2(CH2CH2)8-CH3.

[0442] 20. W is C 8~30 The compound of any one of embodiments 1-19, which is a fatty acid chain.

[0443] 21. W is C 12~18 The compound of any one of embodiments 1-19, which is a fatty acid chain.

[0444] 22. W is,

[0445] [ka] 20. The compound of any one of embodiments 1-19, wherein:

[0446] 23. R X and R X’ However, each independently -C 8~30 The compound of embodiment 22, which is a fatty acid chain.

[0447] 24. R X and R X’ However, each independently C 12~18 The compound of embodiment 22 or 23, which is a fatty acid chain.

[0448] 25. R X and R X’ are both —(CH 2 CH 2 ) 8 —CH 3 .

[0449] 26. W is cholesterol:

[0450] [ka] 20. The compound of any one of embodiments 1-19, wherein:

[0451] 27. The compound of any one of embodiments 1-19, wherein W is a phospholipid selected from the group consisting of phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), and lysophosphatidylcholine.

[0452] 28. W is structure:

[0453] [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R X and R X’ are each independently C 8~30 fatty acid chains)

[0454] 29. R X and R X’ However, each independently C 12~18 The compound of embodiment 28, which is a fatty acid.

[0455] 30. The compound of embodiment 28 or 29, wherein the fatty acid is saturated.

[0456] 31. R X and R X’ are both —(CH 2 CH 2 ) 8 —CH 3 .

[0457] 32. R 7 -C(H)(C(O)NH2)-C5 alkylene-N(R 11 )-C(O)-C 17~30 12. The compound of any one of embodiments 1-11, which is a fatty acid.

[0458] 33. R 7 is -CH2CH2-OP(O)(OH)-O-CH2-C(H)(OR Z )-CH2-OR Z 12. The compound of any one of embodiments 1-11, wherein

[0459] 34.

[0460] [ka]

[0461] [ka]

[0462] [ka]

[0463] [ka] The compound of any one of embodiments 1-33, selected from the group consisting of:

[0464] 35. A nanobiological composition comprising high density lipoprotein (HDL)-derived nanoparticles, wherein the nanoparticles have formula (I):

[0465] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is -H or -C(O)-R X and; R 2 and R 3 are each independently selected from the group consisting of -H, alkyl, alkylene-aryl, -C(O)-alkyl, and -C(O)-aryl; R 4 , R 5 , and R 5’ are each alkyl; R 6 and R 11 are each independently —H or alkyl; R 7 is the fatty acid chain, -YN(R 6 )-C(O)-O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , -YN(R 6 )-C(O)-R X , -YOP(O)(OH)-O-alkylene-C(H)(OR8 )-Alkylene-OR 9 or -Y-triazolyl-L; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-OC(O)-W, -alkylene-N-(alkylene-C(O)-NR 11 -Alkylene-NR 11 -C(O)-W)2, and -alkylene-N-(alkylene-C(O)-W)2; W is a fatty acid chain, -O-alkylene-C(H)(OR 8 )-Alkylene-OR 9 , phospholipids, or sterols; R 8 and R 9 are each independently R X or -C(O)-R X and; R 10 , R 22 , R 33 , R 33’ , R 44 , R 44’ , R 55 , and R 55’ are each independently H or R A and; R X is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, aryl, and triazolyl may be selected from one or more R A is optionally replaced by R A is halo, alkoxy, haloalkoxy, cyano, hydroxyl, -N(R C )(R D ), -C(O)N(R C )(R D ), -N(R C )C(O)R B , -OC(O)NR C R D , -NR C C(O)OR B , -OC(O)R B , -C(O)OR B , -C(O)R B, -CO2H, -NO2, -SH, S(O) X R B (wherein X is 0, 1, or 2), aryl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B independently selected for each occurrence from the group consisting of: R C and R D is hydrogen, alkyl, haloalkyl-C(O)R B , and -C(O)OR B or R C and R D together with the nitrogen to which they are attached, form R A forming an optionally substituted heterocycle; R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro 1. A nanobiological composition comprising:

[0466] 36. A nanobiological composition comprising high density lipoprotein (HDL)-derived nanoparticles, wherein the nanoparticles comprise a compound according to any one of embodiments 1 to 34.

[0467] 37. The nanobiological composition of embodiment 35 or 36, wherein the HDL-derived nanoparticles comprise one or more phospholipids.

[0468] 38. The nanobiological composition of embodiment 37, wherein the phospholipids are independently selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, sphingomyelin or other ceramides, phospholipid-containing oils, phosphatidylglycerol, phosphatidic acid, lysophosphatidylcholine, and combinations thereof.

[0469] 39. The nanobiological composition of embodiment 35 or 36, comprising a phospholipid selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and a lysolipid selected from the group consisting of 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC) and 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC).

[0470] 40. The nanobiological composition of any one of embodiments 35 to 39, wherein the HDL-derived nanoparticles comprise apoA-I or a peptidomimetic of apoA-I.

[0471] 41. The nanobiological composition of any one of embodiments 35 to 40, wherein the HDL-derived nanoparticles further comprise one or more triglycerides, fatty acid esters, hydrophobic polymers, sterol esters, or combinations thereof.

[0472] 42. The nanobiological composition of any one of embodiments 35-41, wherein the HDL-derived nanoparticles further comprise cholesterol.

[0473] 43. The nanobiological composition of embodiment 42, wherein the HDL-derived nanoparticles comprise one or more phospholipids and cholesterol in a molar ratio ranging from about 1:0.05 to about 1:0.25.

[0474] 44. The nanobiological composition of embodiment 43, wherein the HDL-derived nanoparticles comprise one or more phospholipids and cholesterol in a molar ratio ranging from about 1:0.2.

[0475] 45. The nanobiological composition of any one of embodiments 1 to 44, wherein the HDL-derived nanoparticles are nanodiscs or nanospheres.

[0476] 46. ​​The nanobiological composition of embodiment 45, wherein the nanodiscs or nanospheres have a diameter of about 8 nm to about 400 nm.

[0477] 47. A pharmaceutical composition comprising a compound according to any one of embodiments 1-34 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0478] 48. A method for treating a cell proliferation disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the nanobiological composition described in any one of embodiments 35-46.

[0479] 49. The method of embodiment 48, wherein the cell proliferation disorder is cancer.

[0480] 50. The method of embodiment 49, wherein the cancer is selected from the group consisting of bladder cancer, vascular cancer, bone cancer, brain cancer, breast cancer, cervical cancer, breast cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, colorectal cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, urothelial cancer, and uterine cancer.

[0481] 51. The method of embodiment 49, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, melanoma, colorectal cancer, lung cancer, pancreatic cancer, and glioblastoma.

[0482] 52. The method of any one of embodiments 48-51, further comprising co-administering an anti-cancer drug with the nanobiological composition as a combination therapy.

[0483] 53. A method for treating sepsis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the nanobiological composition described in any one of embodiments 35-46.

[0484] 54. The method of embodiment 53, wherein the patient has sepsis associated with a bacterial, viral, or fungal infection of the lungs, abdomen, kidneys, or bloodstream.

[0485] 55. The method of any one of embodiments 48-54, wherein the nanobiological composition promotes a hyper-reactive innate immune response in a patient in need thereof.

[0486] 56. The method of embodiment 55, wherein the hyperreactive innate immune response is promoted for at least about 7 to about 30 days.

[0487] 57. The method of embodiment 55, wherein the hyperreactive innate immune response is promoted for at least 30 to 100 days.

[0488] 58. The method of embodiment 55, wherein the hyperreactive innate immune response is promoted for more than 100 days and up to 3 years.

[0489] 59. The method of embodiment 55, wherein the nanobiological composition is administered once and the hyperreactive innate immune response is promoted for at least 30 days.

[0490] 60. The method of embodiment 55, wherein the nanobiological composition is administered at least once daily on each day of a multiple-dose regimen, and the hyper-reactive innate immune response is promoted for at least 30 days.

[0491] 61. The method of any one of embodiments 48 to 58, wherein the nanobiological composition is administered to the patient in a treatment regimen comprising two or more doses to generate accumulation of the drug in bone marrow cells, bone marrow progenitor cells, and hematopoietic stem cells in the bone marrow, blood, and / or spleen.

[0492] 62. The method of any one of embodiments 48-61, wherein the nanobiological composition is administered intravenously or intraarterially.

[0493] 63. A method for activating the NOD2 receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the nanobiological composition described in any one of embodiments 35 to 46.

[0494] 64. A process for producing a nanobiological composition according to any one of embodiments 35-46, comprising: a) forming, under conditions effective to form a lipid membrane, a lipid membrane comprising: i) a compound of any one of embodiments 1-34; ii) one or more phospholipids; optionally, iii) a hydrophobic matrix comprising one or more triglycerides, fatty acid esters, hydrophobic polymers, or sterol esters, or combinations thereof; and optionally iv) cholesterol; and b) dissolving a lipid membrane in a solvent to form a lipid solution; and contacting the lipid solution with apoA-I or a peptidomimetic of apoA-I under conditions effective to form HDL-derived nanoparticles comprising a compound described in any one of embodiments 1 to 34.

[0495] 65. A nanobiological composition prepared according to embodiment 64.

[0496] 66. A kit comprising the nanobiological composition of any one of embodiments 35-46.

[0497] 67. The method of claim 52, wherein the anticancer drug is a checkpoint inhibitor.

[0498] 68. The method of claim 67, wherein the checkpoint inhibitor is selected from an anti-PD-1 antibody, an anti-CTLA-4 antibody, and a combination thereof.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, R １ is —H or —C(O)—R Ｘ and R ２ and R ３ are each independently selected from the group consisting of —H, alkyl, aryl, alkylene-aryl, —C(O)-alkyl, and —C(O)-aryl; R ４ , R ５ , and R ５’ are each alkyl; R ６ and R １１ are each independently —H or alkyl; R ７ is -Y-triazolyl-L; R Ｚ is C ８～３０ Fatty acid chain or -C(O)-C １６～３０ is a fatty acid chain; Y is alkylene; L is a fatty acid chain, -alkylene-C(O)-W, -alkylene-O-C(O)-W, -alkylene-N-(alkylene-C(O)-NR １１ -Alkylene-NR １１ -C(O)-W) ２ and -alkylene-N-(alkylene-C(O)-W) ２ selected from the group consisting of: W is a fatty acid chain, -O-alkylene-C(H)(OR ８ )-alkylene-OR ９ , a phospholipid, or a sterol; R ８ and R ９ are each independently R Ｘ or -C(O)-R Ｘ and R ２２ , R ３３ , R ３３’ , R ４４ , R ４４’ , R ５５ , and R ５５’ are each independently H or R Ａ and R Ｘ is a fatty acid chain; Each of the foregoing alkyl, alkylene, alkylene-aryl, aryl, and triazolyl groups may be selected from one or more R Ａ and optionally substituted with R Ａ is hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, —N(R Ｃ ) (R Ｄ ), -C(O)N(R Ｃ ) (R Ｄ ), -N(R Ｃ ) C(O)R Ｂ , —OC(O)NR Ｃ R Ｄ , -NR Ｃ C(O)OR Ｂ , -OC(O)R Ｂ , -C(O)OR Ｂ , -C(O)R Ｂ , -CO ２ H, -NO ２ , -SH,S(O) Ｘ R Ｂ (wherein X is 0, 1, or 2), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R Ｂ independently selected for each occurrence from the group consisting of: R Ｃ and R Ｄ is hydrogen, alkyl, haloalkyl-C(O)R Ｂ , and —C(O)OR Ｂ or R Ｃ and R Ｄ together with the nitrogen to which they are attached, form R Ａ forming an optionally substituted heterocycle; R Ｂ is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro).

2. The compound of formula (I) may be of formula (IA): 【Chemistry 2】 10. The compound of claim 1, wherein the compound is:

3. R ２ The compound of claim 1 , wherein is —H or benzyl.

4. R ２ The compound of claim 1 , wherein is —H.

5. R ２２ , R ３３ , R ３３’ , R ４４ , R ４４’ , R ５５ , and R ５５’ The compound of claim 1 , wherein each is —H.

6. R ４ The compound of claim 1 , wherein is alkyl.

7. R ４ The compound of claim 4, wherein is methyl.

8. R ３ and R ６ The compound of claim 1 , wherein

9. Y is -CH ２ - 2. The compound of claim 1, wherein:

10. The compound of formula (I) may be a compound of formula (II): 【Transformation 3】 or a pharmaceutically acceptable salt thereof (In the formula, X １ is -N-, and X ２ is —C—; or X １ is -C- and X ２ is -N-) 2. The compound of claim 1, wherein:

11. The compound of formula (II) may be of formula (IIA): 【Chemistry 4】 11. The compound of claim 10, wherein the compound is:

12. Y is C １～６ The compound of claim 10 which is an alkylene.

13. R Ａ The compound of claim 10, wherein is —H.

14. L is -CH ２ The compound of claim 1, which is -C(O)-W.

15. W is C ８～３０ The compound of claim 1 , wherein the compound is alkyl.

16. W is, 【Transformation 5】 (In the formula, R Ｘ and R Ｘ’ are each independently -C ８～３０ fatty acid chains) 2. The compound of claim 1, wherein:

17. R Ｘ and R Ｘ’ However, each independently -C ８～３０ 17. The compound of claim 16, wherein the compound is alkyl.

18. R Ｘ and R Ｘ’ But both are -(CH ２ CH ２ ) ８ -CH ３ 18. The compound of claim 17, wherein:

19. W is cholesterol: 【Transformation 6】 2. The compound of claim 1, wherein:

20. 2. The compound of claim 1, wherein W is a phospholipid.

21. W has the structure: 【Transformation 7】 Phospholipids having (In the formula, Y Ｑ１ , Y Ｑ２ , and Y Ｑ３ are each independently alkylene, and R Ｘ and R Ｘ’ are each independently a fatty acid chain having at least 15 carbons.

21. The compound of claim 20, wherein:

22. R Ｘ and R Ｘ’ However, each independently C １５～２０ Alkyl or C １５～２０ 22. The compound of claim 21, which is alkenyl.

23. W has the structure: 【Transformation 8】 or a pharmaceutically acceptable salt thereof. (In the formula, R Ｘ and R Ｘ’ are each independently C ８～３０ fatty acid chains) 22. The compound of claim 21, wherein:

24. R Ｘ and R Ｘ’ However, each independently C １２～１８ 24. The compound of claim 23, which is a fatty acid.

25. 24. The compound of claim 23, wherein the fatty acid is saturated.

26. R Ｘ and R Ｘ’ But both are -(CH ２ CH ２ ) ８ -CH ３ 24. The compound of claim 23, wherein: 【Request Item 27】 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 and pharmaceutically acceptable salts thereof, wherein Bn is a benzyl group.

28. 10. A nanobiological composition comprising high density lipoprotein (HDL)-derived nanoparticles, the nanoparticles comprising one or more phospholipids and the compound of claim 1.

29. 29. The nanobiological composition of claim 28, wherein said phospholipids are independently selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, sphingomyelin or other ceramides, phospholipid-containing oils, phosphatidylglycerol, phosphatidic acid, lysophosphatidylcholine, and combinations thereof.

30. 29. The nanobiological composition of claim 28, further comprising a phospholipid selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and a lysolipid selected from the group consisting of 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), and 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC).

31. 29. The nanobiological composition of claim 28, wherein said HDL-derived nanoparticles comprise apoA-I or a peptidomimetic of apoA-I.

32. 30. The nanobiological composition of claim 28, wherein said HDL-derived nanoparticles further comprise cholesterol.

33. 33. The nanobiological composition of claim 32, wherein said HDL-derived nanoparticles comprise one or more phospholipids and cholesterol in a molar ratio ranging from about 1:0.05 to about 1:0.

25.

34. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. 30. A composition for activating the NOD2 receptor, comprising a therapeutically effective amount of the nanobiological composition of claim 28.

36. The compound of formula (II) may be represented by formula (II-I): 【Chemistry 10】 11. The compound of claim 10, wherein the compound is:

37. The compound is 【Chemistry 11】 28. The compound of claim 27, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

38. The compound is 【Chemistry 12】 28. The compound of claim 27, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

39. The compound is 【Chemistry 13】 28. The compound of claim 27, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

40. The compound is 【Chemistry 14】 28. The compound of claim 27, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

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