Compositions containing amino lipid compounds and methods of making and using same - Patents.com

Abstract

Disclosed herein are compositions that include amino lipid compounds, as well as methods of making and using same.

Description

Detailed Description of the Invention

[0001] [Technical field] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 278,274, filed November 11, 2021, the entire contents of which are incorporated by reference herein. [Background technology] Efficient delivery of mRNA remains a critical step and challenge for mRNA therapeutics applicants. Despite promising data from ongoing clinical trials, the clinical use of mRNA requires the discovery and development of more efficient delivery systems.

[0002] The compositions and methods discussed herein address these and other needs. In accordance with the disclosed apparatus and method objectives embodied and broadly described herein, the disclosed subject matter relates to compositions that include amino lipid compounds, and methods of making and using same.

[0003] For example, disclosed herein are compositions comprising a compound defined by Formula I, or a pharma- ceutically acceptable salt thereof:

[0004] [ka] [In the formula, R 10 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 11 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 6 -C 20 is alkyl, However, R 10 Ga-C 5 H 10- and R 11 Ga-C 3 H 6 -If R 12 , R 13 , and R 14 All of

[0005] [ka] Instead, However, R 10 Ga-C 5 H 10 - and R 11 Ga-C 3 H 6 -If R 12 , R 13 , and R 14 All of

[0006] [ka] Instead, In some instances, R 11 is a substituted or unsubstituted C 2 -C 4 In some instances, R 11 is a substituted or unsubstituted C 3 In some instances, R 11 is unsubstituted C 2 -C 4 In some instances, R 11 is a substituted or unsubstituted C 3 It is an alkyl.

[0007] In some embodiments, the compound is a compound of formula IA:

[0008] [ka] or a pharma- ceutically acceptable salt thereof.

[0009] In some instances, R 10 is unsubstituted C 1 -C5 It is an alkyl. In some examples, the compound is defined by formula IB or a pharma- ceutically acceptable salt thereof:

[0010] [ka] [In the formula, n is an integer of 1 to 5].

[0011] Also disclosed herein are compositions comprising a compound defined by formula IA, or a pharma- ceutically acceptable salt thereof:

[0012] [ka] [In the formula, R 10 is a substitution C 1 -C 5 Alkyl or unsubstituted C 1 -C 4 is alkyl, R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 6 -C 20 alkyl].

[0013] In some instances, R 10 is unsubstituted C 1 -C 4 It is an alkyl. Also disclosed herein are compositions comprising a compound defined by formula IB, or a pharma- ceutically acceptable salt thereof:

[0014] [ka] [In the formula, n is an integer from 1 to 4; R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 6 -C20 alkyl].

[0015] In some instances, R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 10 -C 18 In some instances, R 12 , R 13 , and R 14 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some instances, R 12 , R 13 , and R 14 each independently represents a linear or branched substitution C 10 -C 18 In some instances, R 12 , R 13 , and R 14 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some instances, R 12 , R 13 , and R 14 are each independently

[0016] [ka] and pharma- ceutically acceptable salts thereof. In some examples, R 12 , R 13 , and R 14 are the same for each.

[0017] Also disclosed herein are compositions comprising a compound defined by formula IC, or a pharma- ceutically acceptable salt thereof:

[0018] [ka] [In the formula, n is an integer of 1 to 4].

[0019] Also disclosed herein are compositions comprising a compound defined by Formula II, or a pharma- ceutically acceptable salt thereof:

[0020] [ka] [In the formula, R 15 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 16 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 6 -C 20 is alkyl, However, R 15 Ga-C 5 H 10 - and R 16 Ga-C 3 H 6 -If R 17 , R 18 , and R 19 All of

[0021] [ka] Instead, However, R 15 Ga-C 5 H 10 - and R 16 Ga-C 3 H 6 -If R 17 , R 18 , and R 19 All of

[0022] [ka] isn't it].

[0023] In some instances, R 16 is a substituted or unsubstituted C 2 -C 4 In some instances, R 16 is a substituted or unsubstituted C 3 In some instances, R 16 is unsubstituted C 2 -C 4 In some instances, R 16 is a substituted or unsubstituted C 3 It is an alkyl.

[0024] In some embodiments, the compound has formula II-A:

[0025] [ka] or a pharma- ceutically acceptable salt thereof.

[0026] In some instances, R 15 is unsubstituted C 1 -C 5 It is an alkyl. In some examples, the compound is defined by formula II-B or a pharma- ceutically acceptable salt thereof:

[0027] [ka] [In the formula, m is an integer of 1 to 5].

[0028] Also disclosed herein are compositions comprising a compound defined by formula II-A, or a pharma- ceutically acceptable salt thereof:

[0029] [ka] [In the formula, R 15 is a substitution C 1-C 5 Alkyl or unsubstituted C 1 -C 4 is alkyl, R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 6 -C 20 alkyl].

[0030] In some instances, R 15 is unsubstituted C 1 -C 4 It is an alkyl. Also disclosed herein are compositions comprising a compound defined by formula II-B, or a pharma- ceutically acceptable salt thereof:

[0031] [ka] [In the formula, m is an integer from 1 to 4; R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 6 -C 20 alkyl].

[0032] In some instances, R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 10 -C 18 In some instances, R 17 , R 18 , and R 19 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some instances, R 17 , R 18 , and R 19 each independently represents a linear or branched substitution C 1 0 -C 18 In some instances, R17 , R 18 , and R 19 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some instances, R 17 , R 18 , and R 19 are each independently

[0033] [ka] and pharma- ceutically acceptable salts thereof. In some examples, R 17 , R 18 , and R 19 is the same.

[0034] Also disclosed herein are compositions comprising a compound defined by Formula III, or a pharma- ceutically acceptable salt thereof:

[0035] [ka] [In the formula, R 20 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 21 and R 22 each independently represents a substituted or unsubstituted C 6 -C 20 alkyl].

[0036] In some instances, R 20 is a substituted or unsubstituted C 2 -C 4 In some instances, R 20 is a substituted or unsubstituted C 3 In some instances, R 20 is unsubstituted C 2 -C 4In some instances, R 20 is a substituted or unsubstituted C 3 It is an alkyl.

[0037] In some embodiments, the compound has formula III-A:

[0038] [ka] or a pharma- ceutically acceptable salt thereof.

[0039] In some instances, R 21 and R 22 each independently represents a substituted or unsubstituted C 10 -C 18 In some instances, R 21 and R 22 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some instances, R 21 and R 22 each independently represents a linear or branched substitution C 10 -C 18 In some instances, R 21 and R 22 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some instances, R 21 and R 22 are each independently

[0040] [ka] and pharma- ceutically acceptable salts thereof. In some examples, R 21 and R 22 is the same.

[0041] Also disclosed herein are compositions comprising a compound selected from the group consisting of:

[0042] [ka]

[0043] [ka] A composition comprising a compound selected from the group consisting of pharma- ceutically acceptable salts thereof, and combinations thereof.

[0044] Also provided herein are methods of making any of the compounds or compositions disclosed herein. Also disclosed herein are lipid particles comprising any of the compounds or compositions disclosed herein. In some examples, the lipid particles are substantially spherical in shape. In some examples, the lipid particles have an average particle size of 30 nanometers (nm) to 800 nm. In some examples, the lipid particles have a polydispersity index of 0.5 or less. In some examples, the lipid particles further comprise additional components, such as additional lipids.

[0045] Also disclosed herein are pharmaceutical compositions comprising a therapeutic agent encapsulated in any of the lipid particles disclosed herein. In some examples, the therapeutic agent is encapsulated in the lipid particles with an encapsulation efficiency of 30% or more. In some examples, the therapeutic agent comprises an anti-cancer agent, an anti-inflammatory agent, an anti-microbial agent, or a combination thereof. In some examples, the therapeutic agent comprises a viral antigen, a tumor antigen, a gene editing component, a protein replacement component, an immunomodulatory agent, or a combination thereof. In some examples, the therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, or a combination thereof. In some examples, the therapeutic agent comprises a nucleic acid such as mRNA.

[0046] Also provided herein are methods of making any of the pharmaceutical compositions disclosed herein. Also disclosed herein is a method of treating a disease in a subject in need of such treatment, comprising administering to the subject an effective amount of any of the pharmaceutical compositions disclosed herein.

[0047] Also disclosed herein is a method of inhibiting the growth of a tumor in a subject, comprising contacting at least a portion of the tumor with a therapeutically effective amount of any of the pharmaceutical compositions disclosed herein.

[0048] Additional advantages of the disclosed compositions and methods will be set forth in part in the description which follows and in part will be apparent from the specification. The advantages of the disclosed compositions and methods will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosed compositions and methods as claimed.

[0049] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0050] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects of the present disclosure and, together with the description, serve to explain the principles of the disclosure. [Brief description of the drawings]

[0051] [Figure 1] Relative luminescence intensity of the novel substances in Hep3B cells. Data are normalized to Lipofectamine 3000 (Lipo3000). [Diagram 2] Relative luminescence intensity of the novel substances in vivo after intramuscular injection. Data are normalized to ALC-0315. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] The compositions and methods described herein may be understood more readily by reference to the following detailed description of certain aspects of the disclosed subject matter and the examples included therein. Before the present compositions and methods are disclosed and described, it is to be understood that the embodiments described below are not limited to particular synthetic methods or to particular reagents, which, as such, can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0053] Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this disclosed subject matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0054] General definition In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings.

[0055] Throughout the description and claims of this specification, the word "comprise" and other forms of that word, such as "comprising" and "comprises," mean "including but not limited to" and are not intended to exclude, for example, other appendants, components, integers, or steps.

[0056] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "composition" includes mixtures of two or more such compositions, reference to an "agent" includes mixtures of two or more such agents, reference to a "component" includes mixtures of two or more such components, etc.

[0057] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

[0058] Ranges are expressed herein as from "about" one particular value, and / or to "about" another particular value. and can be expressed as: "about" means within 5% of a value, for example, within 4, 3, 2, or 1% of a value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant in relation to the other endpoint, and independently of the other endpoint.

[0059] "Exemplary" means "an example of" and is not intended to convey an indication of a preferred or ideal embodiment. "Such as" is used for purposes of explanation rather than limitation.

[0060] Values ​​may be expressed herein as "average" values. "Average" generally refers to a statistical average value. "Substantially" means within 5%, for example, within 4%, 3%, 2%, or 1%.

[0061] It should be understood that throughout this specification, the identifiers "first" and "second" are used merely to facilitate distinguishing between various components and steps of the disclosed subject matter. The identifiers "first" and "second" are not intended to imply a particular order, quantity, priority, or importance to the components or steps modified by these terms.

[0062] Reference in this specification and in the concluding claims to parts by weight of a particular element or component in a composition indicates the weight relationship between that element or component and any other elements or components in the composition or article for which the parts by weight are expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0063] Weight percentage (wt %) of a component is based on the total weight of the formulation or composition in which the component is included, unless specified to the contrary. The term "or combinations thereof" as used herein refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, if order is important in a particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, combinations including repeats of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. Those skilled in the art will understand that there is typically no limit to the number of items or terms in any combination, unless otherwise clear from the context.

[0064] As used herein, "subject" refers to an individual. Thus, "subject" can include domestic animals (e.g., cats, dogs, etc.), livestock animals (e.g., cows, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mice, rabbits, rats, guinea pigs, etc.), and birds. "Subject" can also include mammals, such as primates or humans. Thus, a subject can be a human or animal patient. The term "patient" refers to a subject receiving the care of a clinician, such as a physician.

[0065] The term "inhibit" refers to a decrease in an activity, response, condition, disease, or other biological parameter. This can include, but is not limited to, the complete elimination of the activity, response, condition, or disease. It can also include, for example, a 10% decrease in the activity, response, condition, or disease compared to the native or control level. Thus, the decrease can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 190, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, It may be a reduction of 90, 100%, or any value in between.

[0066] "Reduce" or other forms of the word such as "reducing" or "reduction" means to decrease an event or characteristic (e.g., tumor growth). It is understood that this is usually relative to some standard or expected value, in other words, relative, but does not necessarily refer to a standard or relative value. For example, "reducing tumor growth" means to decrease the rate of tumor growth compared to a standard or control.

[0067] "Prevent" or other forms of the word, such as "preventing" or "prevention," means to stop a particular event or characteristic, to stabilize or delay the occurrence or progression of a particular event or characteristic, or to minimize the likelihood of a particular event or characteristic occurring. Prevent is usually absolute, as compared to, for example, reduce, and does not require a comparison to a control. As used herein, some things can be reduced but not prevented, and some things can be prevented by reducing them. Similarly, some things can be prevented but not reduced, and some things can be reduced by preventing them. When reduce or prevent is used, it is understood that the use of other words is also expressly disclosed unless specifically indicated otherwise. For example, the term "prevent" or "inhibit" can refer to a treatment that forestalls or delays the onset of a disease or condition, or reduces the severity of a disease or condition. Thus, where a treatment can treat a disease in a subject who has symptoms of the disease, it can also prevent or inhibit the disease in a subject who has not yet developed some or all of the symptoms.

[0068] The term "treatment" refers to the medical management of a patient with the goal of curing, ameliorating, stabilizing, or preventing a disease, pathological condition, or disorder. The term includes active treatment, i.e., treatment specifically aimed at ameliorating a disease, condition, or disorder, and also includes causal treatment, i.e., treatment aimed at eliminating the cause of an associated disease, condition, or disorder. In addition, the term includes palliative treatment, i.e., treatment aimed at reducing symptoms, but not curing, a disease, pathological condition, or disorder; preventive treatment, i.e., treatment aimed at minimizing or partially or completely inhibiting the onset of an associated disease, pathological condition, or disorder; and supportive treatment, i.e., treatment employed to complement another specific therapy aimed at ameliorating an associated disease, pathological condition, or disorder. By way of example, with respect to fibrotic conditions, "treating," "treat," and "treatment" as used herein refer to partially or completely inhibiting or reducing the fibrotic condition from which the subject suffers. In one embodiment, the term refers to actions taken while a patient is suffering from or diagnosed with a fibrotic condition to reduce the severity of the condition or to slow or delay the progression of the condition. Treatment need not result in a complete cure of the condition; partial inhibition or reduction of the fibrotic condition is encompassed by the term.

[0069] The term "therapeutically effective amount" refers to the amount of the composition used that is sufficient to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration requires only a reduction or alteration, not necessarily elimination.

[0070] The term "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the bounds of safe medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0071] The term "anticancer drug" refers to the ability to treat or control cell proliferation and / or tumor growth at any concentration. As used herein, unless otherwise specified, "molecular weight" means 1 Refers to number average molecular weight as measured by H NMR spectroscopy.

[0072] As used herein, the term "delivery" encompasses both local and systemic delivery. For example, delivery of mRNA includes a situation in which the mRNA is delivered to a target tissue and the encoded protein or peptide is expressed and retained in the target tissue (also referred to as "local distribution" or "local delivery"), and a situation in which the mRNA is delivered to a target tissue and the encoded protein or peptide is expressed, secreted into the patient's circulatory system (such as serum), and distributed systemically to other tissues for uptake (also referred to as "systemic distribution" or "systemic delivery").

[0073] As used herein, the term "encapsulation" or grammatical equivalents refer to the process of confining individual nucleic acid molecules within nanoparticles. As used herein, "expression" of mRNA refers to the translation of mRNA into a peptide (such as an antigen), polypeptide, or protein (such as an enzyme), and may also include post-translational modification of a peptide, polypeptide, or fully assembled protein (such as an enzyme), as indicated by the context. In this application, the terms "expression" and "production," and grammatically equivalent terms, are used interchangeably.

[0074] As used herein, the term "messenger RNA (mRNA)" refers to a polynucleotide that encodes at least one peptide, polypeptide, or protein. As used herein, mRNA includes both modified and unmodified RNA. mRNA can include one or more coding and non-coding regions. mRNA can be purified from natural sources or produced using recombinant expression systems, and can be purified as needed or chemically synthesized. Where appropriate, e.g., in the case of chemically synthesized molecules, mRNA can include nucleoside analogs, such as analogs having chemically modified bases or sugars, backbone modifications, and the like. mRNA sequences are represented in the 5' to 3' orientation unless otherwise noted. In some embodiments, the mRNA is designed to contain natural nucleosides (e.g., adenosine, guanosine, cytidine, uridine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolopyrimidine, 3-methyladenosine, 5-methylcytidine, C-5 propynylcytidine, C-5 propynyluridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyluridine, C5-propynylcytidine, C5-methylcyt ...bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bromouridine, C5-bro The base may be or contain a base selected from the group consisting of 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, 2-thiocytidine, pseudouridine, and 5-methylcytidine, chemically modified bases, biologically modified bases (e.g., methylated bases), intervening bases, modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, hexose), and / or modified phosphate groups (e.g., phosphorothioate and 5'-N-phosphoramidite linkages).

[0075] As used herein, the term "nucleic acid" in its broadest sense refers to any compound and / or substance that is or can be incorporated into a polynucleotide chain. In some embodiments, a nucleic acid is a compound and / or substance that is or can be incorporated into a polynucleotide chain via a phosphodiester bond. In some embodiments, "nucleic acid" refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, "nucleic acid" refers to a polynucleotide chain made up of individual nucleic acid residues. In some embodiments, "nucleic acid" refers to RNA as well as It also encompasses single-stranded and / or double-stranded DNA and / or cDNA. Furthermore, the terms "nucleic acid," "DNA," "RNA" and / or similar terms include nucleic acid analogs, i.e., analogs having other than a phosphodiester backbone.

[0076] chemical definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0077] The organic moieties referred to in defining variable positions within the general formulae described herein (e.g., the term "halogen") are generic to the individual substituents contained within the organic moiety. The prefix C before the group or moiety n -C m indicates in each case the possible number of carbon atoms in the following group or moiety.

[0078] As used herein, the term "ion" refers to any molecule, molecular part, molecular cluster, molecular complex, moiety, or atom that contains or can be made to contain a charge (positive, negative, or both simultaneously in one molecule, molecular cluster, molecular complex, or moiety (e.g., a zwitterion)). Methods for generating a charge in a molecule, molecular part, molecular cluster, molecular complex, moiety, or atom are disclosed herein and can be accomplished by methods known in the art, such as, for example, protonation, deprotonation, oxidation, reduction, alkylation, acetylation, esterification, deesterification, hydrolysis, and the like.

[0079] The term "anion" is a type of ion and is included within the meaning of the term "ion". An "anion" is any molecule, part of a molecule (e.g., a zwitterion), cluster of molecules, molecular complex, moiety, or atom that contains or can be made to contain a net negative charge. The term "anion precursor" is used herein specifically to refer to a molecule that can be converted to an anion via a chemical reaction (e.g., deprotonation).

[0080] The term "cation" is a type of ion and is included within the meaning of the term "ion." A "cation" is any molecule, part of a molecule (e.g., a zwitterion), cluster of molecules, molecular complex, moiety, or atom that contains or can be made to contain a net positive charge. The term "cation precursor" is used herein to specifically refer to a molecule that can be converted to a cation via a chemical reaction (e.g., protonation or alkylation).

[0081] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. The terms "substituted" or "substituted with" also include the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, as well as that the substitution results in a compound (e.g., a stable compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.).

[0082] "Z 1 ", "Z 2 ", "Z 3 " and "Z 4 " is used herein to refer to various specific substituents. These symbols can be any substituent, not limited to the substituents disclosed herein, and where in one instance they are defined as a particular substituent, they may be defined as some other substituent in another instance.

[0083] The term "aliphatic," as used herein, refers to non-aromatic hydrocarbon groups, and includes branched and unbranched alkyl, alkenyl, or alkynyl groups. As used herein, the term "alkyl" refers to a saturated, straight-chain or branched saturated hydrocarbon moiety. 1 -C 24 (For example, C 1 -C 22 , C 1 -C 20 , C1 -C 18 , C 1 -C 16 , C 1 -C 14 , C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 Alkyl groups are contemplated. Examples of alkyl groups include methyl, ethyl, propyl, 1-methyl-ethyl, butyl, 1-methyl-propyl, 2-methyl-propyl, 1,1-dimethyl-ethyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1,1-dimethyl-propyl, 1,2-dimethyl-propyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1,1-dimethyl -butyl, 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, 3,3-dimethyl-butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2-trimethyl-propyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. Alkyl substituents may be unsubstituted or substituted with one or more chemical moieties. Alkyl groups may be substituted with one or more groups, including but not limited to, hydroxyl, halogen, acetal, acyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, cyano, carboxylic acid, ester, ether, carbonate, carbamate, ketone, nitro, phosphonyl, silyl, sulfoxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below, provided that the substituents are sterically compatible and chemical bonding and strain energy rules are satisfied.

[0084] Throughout this specification, "alkyl" is used generally to refer to both unsubstituted and substituted alkyl groups, but herein, substituted alkyl groups are specifically referred to by identifying the specific substituent(s) on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halides (halogens; e.g., fluorine, chlorine, bromine, or iodine). The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "alkylamino" specifically refers to an alkyl group substituted with one or more amino groups, as described below. When "alkyl" is used in one instance and a specific term such as "alkylalcohol" is used in another instance, it is not intended that the term "alkyl" does not also mean the specific term such as "alkylalcohol".

[0085] This practice is also used for other groups described herein. That is, a term such as "cycloalkyl" refers to both unsubstituted and substituted cycloalkyl moieties, but the substituted moieties can be further specifically identified herein; for example, a specific substituted cycloalkyl can be specifically referred to as, for example, an "alkylcycloalkyl". Similarly, a substituted alkoxy can be specifically referred to as, for example, a "halogenated alkoxy", a specific substituted alkenyl can be, for example, an "alkenylalcohol", and the like. Again, the practice of using a general term such as "cycloalkyl" and a specific term such as "alkylcycloalkyl" is not intended to mean that the general term does not also include the specific term.

[0086] As used herein, the term "alkenyl" refers to an unsaturated, straight-chain or branched hydrocarbon moiety containing a double bond. 2 -C 24 (For example, C 2 -C 22 , C 2 -C 20 , C 2-W 18 ,W 2 -W 16 ,W 2 -W 14 ,W 2 -W 12 ,W 2 -W 10 ,W 2 -W 8 ,W 2 -W 6 、またはC 2 -W 4) alkenyl groups are contemplated. Alkenyl groups may contain multiple unsaturated bonds.Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-Methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl -3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethylyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl.The term "vinyl" refers to the structure -CH=CH. 2 and 1-propenyl refers to a group having the structure -CH=CH-CH 3 and 2-propenyl refers to a group having the structure -CH 2 -CH=CH 2 (Z 1 Z 2 )C=C(Z 3 Z 4 Asymmetric structures such as alkoxy, ...

[0087] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon moiety containing a triple bond. 2 -C 24 (For example, C 2 -C 24 , C 2 -C 20 , C 2 -C 18 , C 2 -C 16 , C 2 -C 14 , C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 , or C 2 -C 4) alkynyl groups are contemplated. The alkynyl group may contain multiple unsaturated bonds. Examples include C 2 -C 6 -alkynyl, for example ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 1-methyl-2-pentynyl, 4-methyl Alkynyl substituents include 1-ethyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, and 1-ethyl-1-methyl-2-propynyl. Alkynyl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acetal, acyl, aldehyde, amino, cyano, carboxylic acid, ester, ether, carbonate, carbamate, halide, hydroxyl, ketone, nitro, phosphonyl, silyl, sulfoxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0088] As used herein, the term "aryl" and derivative terms such as aryloxy refer to groups containing a monovalent aromatic carbocyclic group of 3 to 50 carbon atoms. An aryl group can contain a single ring or multiple fused rings. In some embodiments, an aryl group includes a C 6 -C 10The term "aryl" includes aryl groups. Examples of aryl groups include, but are not limited to, benzene, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, phenoxybenzene, and indanyl. The term "aryl" also includes "heteroaryl," which is defined as a group that contains an aromatic group with at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The term "non-heteroaryl," which is also included in the term "aryl," defines a group that contains an aromatic group that does not contain a heteroatom. Aryl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acetal, acyl, aldehyde, amino, cyano, carboxylic acid, ester, ether, carbonate, carbamate, halide, hydroxyl, ketone, nitro, phosphonyl, silyl, sulfoxo, sulfonyl, sulfone, sulfoxide, or thiol, as described herein. The term "biaryl" is a special type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups linked through a fused ring structure, as in naphthalene, or through one or more carbon-carbon bonds, as in biphenyl.

[0089] As used herein, the term "cycloalkyl" refers to a non-aromatic carbon-based ring of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "heterocycloalkyl" refers to a cycloalkyl group as defined above, in which at least one of the carbon atoms of the ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups may be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups include, but are not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acetal, acyl, aldehyde, amino, cyano, carboxylic acid, ester, ether, carbonate, carbamate, halide, hydroxyl, ketone, nitro, phosphonyl, silyl, sulfoxo, etc., as described herein. The alkyl group may be substituted with one or more groups including, for example, a sulfonyl, a sulfone, a sulfoxide, or a thiol.

[0090] As used herein, the term "cycloalkenyl" refers to a non-aromatic carbon-based ring consisting of at least three carbon atoms and having at least one double bond (i.e., C=C). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term "heterocycloalkenyl" is a type of cycloalkenyl group as defined above and is included within the meaning of the term "cycloalkenyl", in which at least one of the ring carbon atoms is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups may be substituted or unsubstituted. The cycloalkenyl and heterocycloalkenyl groups can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acetal, acyl, aldehyde, amino, cyano, carboxylic acid, ester, ether, carbonate, carbamate, halide, hydroxyl, ketone, nitro, phosphonyl, silyl, sulfoxo, sulfonyl, sulfone, sulfoxide, or thiol, as described herein.

[0091] The term "cyclic group" is used herein to refer to aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems (e.g., monocyclic, bicyclic, tricyclic, polycyclic, etc.) that can be substituted or unsubstituted. Cyclic groups can contain one or more aryl groups, one or more non-aryl groups, or one or more aryl groups and one or more non-aryl groups.

[0092] As used herein, the term "acyl" refers to a group having the formula -C(O)Z 1 In the formula, Z 1may be hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl groups as described above. As used herein, the term "acyl" may be used interchangeably with "carbonyl." Throughout this specification, "C(O)" or "CO" is an abbreviation for C=O.

[0093] As used herein, the term “acetal” refers to a compound of the formula (Z 1 Z 2 )C(=OZ 3 )(=OZ 4 ) wherein Z 1 , Z 2 , Z 3 , and Z 4 may be independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl groups as described above.

[0094] As used herein, the term "alkanol" refers to an alkanol having the formula Z 1 OH, wherein Z 1 may be an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0095] As used herein, the term "alkoxy" as used herein refers to an alkyl group attached through a single, terminal ether bond, i.e., an "alkoxy" group has the formula Z 1 -O-, where Z 1 is unsubstituted or substituted alkyl as defined above. Unless otherwise specified, Z 1 But, C 1 -C 24 (For example, C 1 -C 22 , C 1 -C 20, C 1 -C 18 , C 1 -C 16 , C 1 -C 14 , C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 ) an alkyl group Examples include methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1,1-dimethyl-ethoxy, pentoxy, 1-methyl-butyloxy, 2-methyl-butoxy, 3-methyl-butoxy, 2,2-dimethyl-propoxy, 1-ethyl-propoxy, hexoxy, 1,1-dimethyl-propoxy, 1,2-dimethyl-propoxy, 1-methyl-pentoxy, 2-methyl-pentoxy, 3- These include methyl-pentoxy, 4-methyl-penoxy, 1,1-dimethyl-butoxy, 1,2-dimethyl-butoxy, 1,3-dimethyl-butoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy, 3,3-dimethyl-butoxy, 1-ethyl-butoxy, 2-ethylbutoxy, 1,1,2-trimethyl-propoxy, 1,2,2-trimethyl-propoxy, 1-ethyl-1-methyl-propoxy, and 1-ethyl-2-methyl-propoxy.

[0096] The term "aldehyde" as used herein is represented by the formula -C(O)H. Throughout this specification, "C(O)" is a shorthand notation for C=O. As used herein, the term "amine" or "amino" refers to a group of the formula -NZ 1 Z 2 Z 3 In the formula, Z 1 , Z 2 , and Z 3may each be a substituent as described herein, for example, hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group.

[0097] As used herein, the term "amide" or "amido" refers to a compound of the formula -C(O)NZ 1 Z 2 In the formula, Z 1 and Z 2 may each be a substituent as described herein, for example, hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group.

[0098] As used herein, the term "anhydride" refers to a compound of formula Z 1 C(O)OC(O)Z 2 In the formula, Z 1 and Z 2 may independently be an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0099] As used herein, the term "cyclic anhydride" is represented by the formula:

[0100] [ka] In the formula, Z 1 may be an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0101] The term "azide" as used herein is represented by the formula -N=N=N. The term "carboxylic acid" as used herein is represented by the formula -C(O)OH. As used herein, a "carboxylate" or "carboxyl" group is represented by the formula -C(O)O-.

[0102] As used herein, a "carbonate" group has the formula Z 1 O.C.O.Z. 2 It is expressed as: The term "cyano" as used herein is represented by the formula --CN. As used herein, the term "ester" refers to an ester of the formula -OC(O)Z 1 or -C(O)OZ 1 In the formula, Z 1 may be an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0103] As used herein, the term "ether" refers to a group of the formula Z 1 OZ 2 In the formula, Z 1 and Z 2 may independently be an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0104] The term "epoxy" or "epoxide" as used herein refers to a cyclic ether having a three atom ring and can be represented by the following formula:

[0105] [ka] In the formula, Z 1 , Z 2 , Z 3 , and Z 4 may independently be an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0106] As used herein, the term "ketone" refers to a compound of the formula Z 1 C(O)Z 2 In the formula, Z 1 and Z 2 may independently be an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0107] The terms "halide" or "halogen" or "halo" as used herein refer to fluorine, chlorine, bromine, and iodine. The term "hydroxyl" as used herein is represented by the formula --OH.

[0108] As used herein, the term "nitro" refers to a group of the formula -NO 2 It is expressed as: The term "phosphonyl" as used herein refers to a group of the formula -P(O)(OZ 1 ) 2 is used to refer to a phospho-oxo group represented by the formula: 1 may be hydrogen, an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group.

[0109] As used herein, the term "silyl" refers to a group of the formula -SiZ 1 Z 2 Z 3 In the formula, Z 1 , Z 2 , and Z 3 may be independently hydrogen, an alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0110] The term "sulfonyl" or "sulfone" refers to a group of the formula -S(O) 2 Z 1 is used herein to refer to a sulfooxo group represented by the formula1 may be hydrogen, an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as defined above.

[0111] As used herein, the term "sulfide" includes groups of the formula -S-. The term "thiol" as used herein is represented by the formula --SH. As used herein, "R 1 ", "R 2 ", "R 3 ", "R n " etc., where n is any integer, may independently carry one or more of the above groups. For example, R 1 When is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be optionally replaced with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, etc. Depending on the group selected, the first group may be embedded within the second group, or alternatively, the first group may be pendant (i.e., attached) to the second group. For example, in the phrase "an alkyl group that includes an amino group," the amino group may be embedded within the backbone of the alkyl group. Alternatively, the amino group may be attached to the backbone of the alkyl group. The nature of the group(s) selected will determine whether the first group is embedded or attached to the second group.

[0112] Unless stated to the contrary, formulas containing chemical bonds shown only with solid lines, rather than wedges or dashed lines, contemplate each possible stereoisomer or mixture of stereoisomers (e.g., each enantiomer, each diastereomer, each meso compound, racemic mixture, or scalemic mixture).

[0113] compound Disclosed herein are compounds and methods of making and using them. For example, disclosed herein are compositions comprising a compound defined by Formula I, or a pharma- ceutically acceptable salt thereof:

[0114] [ka] [In the formula, R 10 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 11 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 6 -C 20 is alkyl, However, R 10 Ga-C 5 H 10 - and R 11 Ga-C 3 H 6 -If R 12 , R 13 , and R 14 All of

[0115] [ka] Instead, However, R 10 Ga-C 5 H 10 - and R 11 Ga-C 3 H 6 -If R 12 , R 13 , and R 14 All of

[0116] [ka] isn't it].

[0117] In some examples of Formula I, R 11 is a substituted or unsubstituted C 2 -C 4 In some examples of Formula I, R 11is a substituted or unsubstituted C 3 In some examples of Formula I, R 11 is unsubstituted C 2 -C 4 In some examples of Formula I, R 11 is a substituted or unsubstituted C 3 It is an alkyl.

[0118] In some examples of Formula I, R 10 is unsubstituted C 1 -C 5 In some examples of Formula I, R 10 is a substitution C 1 -C 5 Alkyl or unsubstituted C 1 -C 4 In some examples of Formula I, R 10 is unsubstituted C 1 -C 4 It is an alkyl.

[0119] In some examples of Formula I, R 11 is unsubstituted C 3 is alkyl, R 10 is unsubstituted C 1 -C 5 In some examples of Formula I, R 11 is unsubstituted C 3 is alkyl, R 10 is unsubstituted C 1 -C 4 It is an alkyl.

[0120] In some examples of Formula I, R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 10 -C 18 In some examples of Formula I, R 12 , R 13 , and R 14 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of Formula I, R 12 , R 13, and R 14 each independently represents a linear or branched substitution C 10 -C 18 In some examples of Formula I, R 12 , R 13 , and R 14 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of Formula I, R 12 , R 13 , and R 14 are each independently

[0121] [ka] and pharma- ceutically acceptable salts thereof. In some examples of Formula I, , R 12 , R 13 , and R 14 are the same for each.

[0122] In some examples of Formula I, R 11 is unsubstituted C 3 is alkyl, R 10 is unsubstituted C 1 -C 5 is alkyl, R 12 , R 13 , and R 14 C is a straight or branched chain substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates. 10 -C 18 In some examples of Formula I, R 11 is unsubstituted C 3 is alkyl, R 10 is unsubstituted C 1 -C 4 is alkyl, R 12 , R 13 , and R 14C is a straight or branched chain substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates. 10 -C 18 It is an alkyl.

[0123] In some examples, the compound is defined by formula IA or a pharma- ceutically acceptable salt thereof:

[0124] [ka] [In the formula, R 10 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 6 -C 20 is alkyl, However, R 10 Ga-C 5 H 10 -If R 12 , R 13 , and R 14 All of

[0125] [ka] Instead, However, R 10 Ga-C 5 H 10 -If R 12 , R 13 , and R 14 All of

[0126] [ka] isn't it].

[0127] In some examples of formula IA, R 10 is unsubstituted C1 -C 5 In some examples of formula IA, R 10 is a substitution C 1 -C 5 Alkyl or unsubstituted C 1 -C 4 In some examples of formula IA, R 10 is unsubstituted C 1 -C 4 It is an alkyl.

[0128] In some examples of formula IA, R 10 is unsubstituted C 1 In some examples of formula IA, R 10 is unsubstituted C 2 In some examples of formula IA, R 10 is unsubstituted C 3 In some examples of formula IA, R 10 is unsubstituted C 4 In some examples of formula IA, R 10 is unsubstituted C 5 It is an alkyl.

[0129] In some examples of formula IA, R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 10 -C 18 In some examples of formula IA, R 12 , R 13 , and R 14 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of formula IA, R 12 , R 13 , and R 14 each independently represents a linear or branched substitution C 10 -C 18 In some examples of formula IA, R 12 , R 13 , and R 14each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of formula IA, R 12 , R 13 , and R 14 are each independently

[0130] [ka] and pharma- ceutically acceptable salts thereof. In some examples of formula IA, R 12 , R 13 , and R 14 are the same for each.

[0131] In some examples of formula IA, R 10 is unsubstituted C 1 -C 5 is alkyl, R 12 , R 13 , and R 14 is a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of formula IA, R 10 is unsubstituted C 1 -C 4 is alkyl, R 12 , R 13 , and R 14 is a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 It is an alkyl.

[0132] In some examples, the compound is defined by formula IB or a pharma- ceutically acceptable salt thereof:

[0133] [ka] [In the formula, n is an integer from 1 to 5; R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 6 -C 20 is alkyl, However, if n is 5, then R 12 , R 13 , and R 14 All of

[0134] [ka] Instead, However, if n is 5, then R 12 , R 13 , and R 14 All of

[0135] [ka] isn't it].

[0136] In some examples of formula IB, n is an integer from 1 to 4. In some examples of formula IB, n is 1. In some examples of formula IB, n is 2. In some examples of formula IB, n is 3. In some examples of formula IB, n is 4. In some examples of formula IB, n is 5.

[0137] In some examples of formula IB, R 12 , R 13 , and R 14 each independently represents a substituted or unsubstituted C 10 -C 18 In some examples of formula IB, R 12 , R 13 , and R 14 each independently represents a straight or branched chain unsubstituted C 10 -C 18In some examples of formula IB, R 12 , R 13 , and R 14 each independently represents a linear or branched substitution C 10 -C 18 In some examples of formula IB, R 12 , R 13 , and R 14 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of formula IB, R 12 , R 13 , and R 14 are each independently

[0138] [ka] and pharma- ceutically acceptable salts thereof. In some examples of formula IB, R 12 , R 13 , and R 14 are the same for each.

[0139] In some examples, the compound is defined by formula IC or a pharma- ceutically acceptable salt thereof:

[0140] [ka] [In the formula, n is an integer of 1 to 4].

[0141] In some examples of formula IC, n is 1. In some examples of formula IC, n is 2. In some examples of formula IC, n is 3. In some examples of formula IC, n is 4.

[0142] In some embodiments, the compound is

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] [ka]

[0150] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0151] In some embodiments, the compound is

[0152] [ka]

[0153] [ka]

[0154] [ka]

[0155] [ka]

[0156] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0157] In some embodiments, the compound is

[0158] [ka]

[0159] [ka]

[0160] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0161] In some embodiments, the compound is

[0162] [ka]

[0163] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0164] In some embodiments, the compound is

[0165] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0166] Also disclosed herein are compositions comprising a compound defined by Formula II, or a pharma- ceutically acceptable salt thereof:

[0167] [ka] [In the formula, R 15 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 16 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 6 -C 20 is alkyl, However, R 15 Ga-C 5 H 10 - and R 16 Ga-C 3 H 6 -If R 17 , R 18 , and R 19 All of

[0168] [ka] Instead, However, R 15 Ga-C 5 H 10 - and R 16 Ga-C 3 H 6 -If R 17 , R18 , and R 19 All of

[0169] [ka] isn't it].

[0170] In some examples of Formula II, R 16 is a substituted or unsubstituted C 2 -C 4 In some examples of Formula II, R 16 is a substituted or unsubstituted C 3 In some examples of Formula II, R 16 is unsubstituted C 2 -C 4 In some examples of Formula II, R 16 is a substituted or unsubstituted C 3 It is an alkyl.

[0171] In some examples of Formula II, R 15 is unsubstituted C 1 -C 5 In some examples of Formula II, R 15 is a substitution C 1 -C 5 Alkyl or unsubstituted C 1 -C 4 In some examples of Formula II, R 15 is unsubstituted C 1 -C 4 It is an alkyl.

[0172] In some examples of Formula II, R 16 is unsubstituted C 3 is alkyl, R 15 is unsubstituted C 1 -C 5 In some examples of Formula II, R 16 is unsubstituted C 3 is alkyl, R 15 is unsubstituted C 1 -C 4 It is an alkyl.

[0173] In some examples of Formula II, R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 10 -C 18 In some examples of Formula II, R 17 , R 18 , and R 19 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of Formula II, R 17 , R 18 , and R 19 each independently represents a linear or branched substitution C 10 -C 18 In some examples of Formula II, R 17 , R 18 , and R 19 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of Formula II, R 17 , R 18 , and R 19 are each independently

[0174] [ka] and pharma- ceutically acceptable salts thereof. In some examples of Formula II, R 17 , R 18 , and R 19 is the same.

[0175] In some examples of Formula II, R 16 is unsubstituted C 3 is alkyl, R 15 is unsubstituted C 1 -C 5 is alkyl, R 17 , R 18 , and R 19each independently represents a straight or branched chain C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of Formula II, R 16 is unsubstituted C 3 is alkyl, R 15 is unsubstituted C 1 -C 4 is alkyl, R 17 , R 18 , and R 19 each independently represents a straight or branched chain C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 It is an alkyl.

[0176] In some examples, the compound is defined by formula II-A or a pharma- ceutically acceptable salt thereof:

[0177] [ka] [In the formula, R 15 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 6 -C 20 is alkyl, However, R 15 Ga-C 5 H 10 -If R 17 , R 18 , and R 19 All of

[0178] [ka] Instead, However, R15 Ga-C 5 H 10 -If R 17 , R 18 , and R 19 All of

[0179] [ka] isn't it].

[0180] In some examples of formula II-A, R 15 is unsubstituted C 1 -C 5 In some examples of formula II-A, R 15 is a substitution C 1 -C 5 Alkyl or unsubstituted C 1 -C 4 In some examples of formula II-A, R 15 is unsubstituted C 1 -C 4 It is an alkyl.

[0181] In some examples of formula II-A, R 15 is unsubstituted C 1 In some examples of formula II-A, R 15 is unsubstituted C 2 In some examples of formula II-A, R 15 is unsubstituted C 3 In some examples of formula II-A, R 15 is unsubstituted C 4 In some examples of formula II-A, R 15 is unsubstituted C 5 It is an alkyl.

[0182] In some examples of formula II-A, R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 10 -C 18 In some examples of formula II-A, R 17 , R18 , and R 19 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of formula II-A, R 17 , R 18 , and R 19 each independently represents a linear or branched substitution C 10 -C 18 In some examples of formula II-A, R 17 , R 18 , and R 19 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of formula II-A, R 17 , R 18 , and R 19 are each independently

[0183] [ka] and pharma- ceutically acceptable salts thereof. In some examples of Formula II-A, R 17 , R 18 , and R 19 is the same.

[0184] In some examples of formula II-A, R 15 is unsubstituted C 1 -C 5 is alkyl, R 17 , R 18 , and R 19 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of formula II-A, R 15 is unsubstituted C 1 -C 4 is alkyl, R 17, R 18 , and R 19 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 It is an alkyl.

[0185] In some examples, the compound is defined by formula II-B or a pharma- ceutically acceptable salt thereof:

[0186] [ka] [In the formula, m is an integer from 1 to 5; R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 6 -C 20 is alkyl, However, if m is 5, then R 17 , R 18 , and R 19 All of

[0187] [ka] Instead, However, if m is 5, then R 17 , R 18 , and R 19 All of

[0188] [ka] isn't it].

[0189] In some examples of formula II-B, m is an integer from 1 to 4. In some examples of Formula II-B, m is 1. In some examples of Formula II-B, m is 2. In some examples of Formula II-B, m is 3. In some examples of Formula II-B, m is 4. In some examples of Formula II-B, m is 5.

[0190] In some examples of formula II-B, R 17 , R 18 , and R 19 each independently represents a substituted or unsubstituted C 10 -C 18 In some examples of formula II-B, R 17 , R 18 , and R 19 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of formula II-B, R 17 , R 18 , and R 19 each independently represents a linear or branched substitution C 10 -C 18 In some examples of formula II-B, R 17 , R 18 , and R 19 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of formula II-B, R 17 , R 18 , and R 19 are each independently

[0191] [ka] and pharma- ceutically acceptable salts thereof. Some of the compounds of formula II-B are selected from the group consisting of: In the example, R 17 , R 18 , and R 19 is the same.

[0192] In some embodiments, the compound is

[0193] [ka]

[0194] [ka]

[0195] [ka]

[0196] [ka]

[0197] [ka]

[0198] [ka]

[0199] [ka]

[0200] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0201] In some embodiments, the compound is

[0202] [ka]

[0203] [ka]

[0204] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0205] In some embodiments, the compound is

[0206] [ka]

[0207] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0208] In some embodiments, the compound is

[0209] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0210] Also disclosed herein are compositions comprising a compound defined by Formula III, or a pharma- ceutically acceptable salt thereof:

[0211] [ka] [In the formula, R 20 is a substituted or unsubstituted C 1 -C 5 is alkyl, R 21 and R 22 each independently represents a substituted or unsubstituted C 6 -C20 alkyl].

[0212] In some examples of formula III, R 20 is a substituted or unsubstituted C 2 -C 4 In some examples of formula III, R 20 is a substituted or unsubstituted C 3 In some examples of formula III, R 20 is unsubstituted C 2 -C 4 In some examples of formula III, R 20 is a substituted or unsubstituted C 3 It is an alkyl.

[0213] In some examples of formula III, R 21 and R 22 each independently represents a substituted or unsubstituted C 10 -C 18 In some examples of formula III, R 21 and R 22 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of formula III, R 21 and R 22 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of formula III, R 21 and R 22 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of formula III, R 21 and R 22 are each independently

[0214] [ka] and pharma- ceutically acceptable salts thereof. In some examples of Formula III, R 21 and R 22 is the same.

[0215] In some examples of formula III, R 20 is unsubstituted C 3 is alkyl, R 21 and R 22 each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 It is an alkyl.

[0216] In some examples, the compound is defined by formula III-A or a pharma- ceutically acceptable salt thereof:

[0217] [ka] [In the formula, R 21 and R 22 each independently represents a substituted or unsubstituted C 6 -C 20 Alkyl [is].

[0218] In some examples of formula III-A, R 21 and R 22 each independently represents a substituted or unsubstituted C 10 -C 18 In some examples of formula III-A, R 21 and R 22 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of formula III-A, R 21 and R 22 each independently represents a straight or branched chain unsubstituted C 10 -C 18 In some examples of formula III-A, R 21 and R 22each independently represents a linear or branched C substituted with one or more substituents selected from the group consisting of esters, ethers, acetals, carbonates, and carbamates; 10 -C 18 In some examples of formula III-A, R 21 and R 22 are each independently

[0219] [ka] and pharma- ceutically acceptable salts thereof. In some examples of formula III-A, R 21 and R 22 is the same.

[0220] In some embodiments, the compound is

[0221] [ka]

[0222] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0223] In some embodiments, the compound is

[0224] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0225] Also disclosed herein are compositions comprising a compound selected from the group consisting of:

[0226] [ka]

[0227] [ka] and pharma- ceutically acceptable salts thereof, and combinations thereof.

[0228] lipid particles Also disclosed herein are lipid particles (eg, one or more lipid particles) comprising any of the compositions disclosed herein.

[0229] The lipid particles may be of any shape (e.g., spherical, rod-shaped, square, elliptical, triangular, polygonal, etc.). In some examples, the lipid particles can have a regular shape, an irregular shape, an isotropic shape, an anisotropic shape, or a combination thereof. In some examples, the lipid particles are substantially spherical in shape.

[0230] Lipid particles can have an average particle size. "Average particle size" and "mean particle size" are used interchangeably herein and generally refer to the statistical average particle size of particles in a particle population. For example, the average particle size of a plurality of particles having a substantially spherical shape can include the average diameter of a plurality of particles. For particles having a substantially spherical shape, the diameter of a particle can refer to, for example, the hydrodynamic diameter. As used herein, the hydrodynamic diameter of a particle refers to the maximum linear distance between two points on the surface of the particle. The average particle size can be measured using methods well known in the art, such as by scanning electron microscopy, transmission electron microscopy, and / or dynamic light scattering evaluation.

[0231] The lipid particles can be, for example, 30 nanometers (nm) or greater (e.g., 40 nm or greater, 50 nm or greater, 60 nm or greater, 70 nm or greater, 80 nm or greater, 90 nm or greater, 100 nm or greater, 110 nm or greater, 120 nm or greater, 130 nm or greater, 140 nm or greater, 150 nm or greater, 160 nm or greater, 170 nm or greater, 180 nm or greater, 190 nm or greater, 200 nm or greater, 210 nm or greater, 220 nm or greater, 230 nm or greater, 240 nm or greater, 250 nm or greater, 260 nm or greater, 270 nm or greater, 280 nm or greater, 290 nm or greater, 300 nm or greater, 310 nm or greater, 320 nm or greater, 33 nm or greater, 160 nm or greater, 170 nm or greater, 180 nm or greater, 190 nm or greater, 200 nm or greater, 225 nm or greater, 250 nm or greater, 275 nm or greater, 300 nm or greater, 325 nm or greater, 350 nm or greater, 375 nm or greater, 400 nm or greater, 425 nm or greater, 450 nm or greater, 475 nm or greater, 500 nm or greater, 550 nm or greater, 600 nm or greater, 650 nm or greater, 700 nm or greater, or 750 nm or greater). In some examples, the lipid particles can have an average particle size of 800 nm or less (e.g., 750 nm or less, 700 nm or less, 650 nm or less, 600 nm or less, 550 nm or less, 500 nm or less, 475 nm or less, 450 nm or less, 425 nm or less, 400 nm or less, 375 nm or less, 350 nm or less, 325 nm or less, 300 nm or less, 275 nm or less, 250 nm or less, 225 nm or less, 200 nm or less, 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 90 nm or less, 80 nm or less, 70 nm or less, 60 nm or less, 50 nm or less, or 40 nm or less). The average particle size of the lipid particles can range from any of the minimum values ​​above to any of the maximum values ​​above. For example, the lipid particles can have an average particle size of 30 nm to 800 nm (e.g., 30 nm to 425 nm, 425 nm to 800 nm, 30 nm to 200 nm, 200 nm to 400 nm, 400 nm to 600 nm, 600 nm to 800 nm, 50 nm to 800 nm, 30 nm to 750 nm, or 50 nm to 750 nm).

[0232] With regard to the characterization of particle size distribution, the parameter used to define the size range of lipid particles is called the "polydispersity index" (PDI). The term "polydispersity" (or "dispersity" as recommended by IUPAC) is used to describe the degree of heterogeneity of the particle size distribution. PDI essentially describes the distribution of particle size populations within a particular sample. The numerical value of PDI ranges from 0.0 (for a sample that is completely homogeneous in terms of particle size) to 1.0 (for a highly polydisperse sample with multiple particle size populations).

[0233] In some examples, the lipid particles have a molecular weight of 0.5 or less (e.g., 0.49 or less, 0.48 or less, 0.47 or less, 0.46 or less, 0.45 or less, 0.44 or less, 0.43 or less, 0.42 or less, 0.41 or less, 0.40 or less, 0.39 or less, 0.38 or less, 0.37 or less, 0.36 or less, 0.35 or less, 0.34 or less, 0.33 or less, 0.32 or less, 0.31 or less, 0.30 or less, 0.29 or less, 0.28 or less, 0.27 or less, 0.26 ...8 or less, 0.38 or less, 0.38 or less, 0.38 or less, 0.38 or less, 0.38 or less, 0.38 or less, 0.38 or less, 0.38 or less, 0.38 or less In some embodiments, the polydispersity index may be 0.25 or less, 0.24 or less, 0.23 or less, 0.22 or less, 0.21 or less, 0.20 or less, 0.19 or less, 0.18 or less, 0.17 or less, 0.16 or less, 0.15 or less, 0.14 or less, 0.13 or less, 0.12 or less, 0.11 or less, 0.10 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less.

[0234] In some instances, lipid particles may be substantially monodisperse. As used herein, "monodisperse" and "uniform particle size distribution" generally refer to a population of particles where all particles are the same or approximately the same particle size. As used herein, monodisperse distribution refers to a particle distribution where 80% of the distribution (e.g., 85% of the distribution, 90% of the distribution, or 95% of the distribution) is within 25% of the median particle size (e.g., within 20% of the median particle size, within 15% of the median particle size, within 10% of the median particle size, or within 5% of the median particle size).

[0235] In some examples, the lipid particles may further comprise additional components, such as additional lipids, hi some examples, the additional lipids may comprise phospholipids, sterols, or combinations thereof.

[0236] Pharmaceutical Compositions Provided herein are pharmaceutical compositions comprising any of the compounds or lipid particles disclosed herein. The object is also disclosed.

[0237] For example, also disclosed herein is a pharmaceutical composition comprising a therapeutic agent encapsulated in any of the lipid particles disclosed herein. For example, the therapeutic agent can be encapsulated in the lipid particles with an encapsulation efficiency of 30% or more (e.g., 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more).

[0238] Therapeutic agents can include, for example, anti-cancer agents, anti-inflammatory agents, anti-microbial agents, or combinations thereof. As used herein, anti-microbial agents include, for example, anti-bacterial agents, anti-fungal agents, and anti-viral agents.

[0239] Examples of antibacterial agents include, but are not limited to, alexidine, asphodelin A, atromentin, aurantin, austrocorthyrutein, austrocorthyrubin, azelidine, chlorubisan, chloroxine, sidex, cinoxacin, citreorosein, copper usnate, cupienine, curvularin, DBNPA, dehydrocurvularin, desoxyfructoserotonin, dichloroisocyanuric acid, elaiomycin, Holtfreter's solution, marettinin, naphthomycin, neutrolin, niphimycin, nitrocefin, oxadiazole, paenibacterin, proclin, litiomethane, ritipenem, silicone quaternary amines, stylysin, taurolidine, tirandamycin, trichloroisocyanuric acid, triclocarban, and combinations thereof.

[0240] Examples of antibacterial agents include, but are not limited to, acetoxycycloheximide, aciduliprofundum, actaplanin, actinorhodin, arazopeptin, albomycin, allicin, aristatin, allyl isothiocyanate, ambazone, aminocoumarin, aminoglycosides, 4-aminosalicylic acid, ampicillin, ansamycin, anthramycin, antimycin A, aphidicolin, aplasmomycin, archaeocin, arenicin, arsphenamine, arylomycin A2, ascofuranone, aspergillic acid, avena uramide, avibactam, azelaic acid, bafilomycin, bambermycin, beauvericin, benzoyl peroxide, blasticidin S, bothromycin, brilacidin, caprazamycin, carbomycin, cathelicidin, cephalosporin, ceragenin, chartreucin, chromomycin A3, cithromycin, clindamycin, clofazimine, clofoctol, clorobiocin, coprinol, coumermycin A1, cyclic lipopeptide, cycloheximide, cycloserine, dalfopristin, dapsone, daptomycin, debromomarin , 17-dimethylaminoethylamino-17-demethoxygeldanamycin, echinomycin, enediandric acid C, enediyne, enviomycin, eravacycline, erythromycin, esperamicin, ethambutol, ethionamide, (6S)-6-fluoroshikimic acid, fosfomycin, fosmidomycin, friulimicin, furazolidone, flonazide, fusidic acid, geldanamycin, gentamicin, gepotidacin, glycycycline, glycyrrhizole, gramicidin S, guanacastepene A, hachimycin, halocysamicin , hedamycin, herkinorin, herbimycin, hexamethylenetetramine, hitatimycin, hydramacin-1, isoniazid, kanamycin, katanosin, kedarcidin, kendomycin, ketapeptin, kidamycin, lacticin, lactocillin, landomycin, landmycinone, lasalocid, lenapenem, leptomycin, lincosamide, linopristin, lipiarmycin, macbecin, macrolide, macromomycin B, maduropeptin, mannopeptimycin glycopeptide, marinone, meclocycline, melafix,Methylenomycin A, Methylenomycin B, Monensin, Moromycin, Mupirocin, Mycosubtilin, Myriocin, Myxopyronine, Naphthomycin A, Narasin, Neocarzinostatin, Neopluramycin, Neosalvarsan, Neothramycin, Netropsin, Ni, Floxazid, nifluquinazole, nigericin, nitrofural, nitrofurantoin, nocathiacin I, novobiocin, omadacycline, oxacephem, oxazolidinone, penicillin, peptaibol, phytoalexin, plantazolicin, platensimycin, plectasin, pluramycin A, polymyxin, polyoxin, pristinamycin, pristinamycin IA, promin, prothionamide, pulvinone, puromycin, pyocyanase, pyocyanin, pirenosine, questhiomycin A, quinolone, quinupristin, la Moplanin, Raphanin, Resistome, Reuterin, Rifalazil, Rifamycin, Ristocetin, Rosefirin, Salinomycin, Salinosporamide A, Saptomycin, Saquayamycin, Serraticin, Sideromycin, Sodium Sulfacetamide, Solasulfone, Solithromycin, Sparasol, Spectinomycin, Staurosporine, Streptozolin, Streptogramin, Streptogramin B, Streptolydigin, Streptonigrin, Stierlin A, Sulfonamide, Surfactin, Slotomycin, Tachyplesin, Tak Sta, tanespimycin, telavancin, tetracycline, thioacetazone, thiocarperidone, thiolutin, thiostrepton, tobramycin, trichostatin A, triclosan, trimethoprim, trimethoprim, tunicamycin, tyrocidin, urautimicin, validamycin, viridicatumtoxin B, bulgamycin, xanthomycin A, xibornol, amikacin, amoxicillin, ampicillin, atovaquone, azithromycin, aztreonam, bacitracin, carbenicillin, cefadroxil, cefazolin, cefdinir, Cefditoren, cefepime, cefiderocol, cefoperazone, cefotetan, cefoxitin, cefotaxime, cefpodoxime, cefprozil, ceftaroline, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, chloramphenicol, colistimethate, cefuroxime, cephalexin, cephradine, cilastatin, cinoxacin, ciprofloxacin, clarithromycin, clindamycin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, doripenem, doxycycline,eravacycline, ertapenem, erythromycin, fidaxomicin, fosfomycin, gatifloxacin, gemifloxacin, gentamicin, imipenem, lefamulin, lincomycin, linezolid, lomefloxacin, loracarbef, meropenem, metronidazole, minocycline, moxifloxacin, nafcillin, nalidixic acid, neomycin, norfloxacin, ofloxacin, omadacycline, oritavancin, oxacillin, oxytocin tetracycline, paromomycin, penicillin, pentamidine, piperacillin, plazomycin, quinupristin, rifaximin, sarecycline, secnidazole, sparfloxacin, spectinomycin, sulfamethoxazole, sulfisoxazole, tedizolid, telavancin, telithromycin, ticarcillin, tigecycline, tobramycin, trimethoprim, trovafloxacin, vancomycin, and combinations thereof.

[0241] Examples of antifungal agents include, but are not limited to, abafungin, acibenzolar, acibenzolar-S-methyl, acrisorcin, allicin, aminocandin, amorolfine, amphotericin B, anidulafungin, azoxystrobin, bacillomycin, Bacillus pumilus, barium borate, benomyl, binapacryl, boric acid, bromine monochloride, bromochlorosalicylanilide, bupirimate, butenafine, candicidin, caprylic acid, captafol, captan, carbendazim, caspofungin, cerulenin, chloranil, chlormidazole, chloramphenicol ... Rolofetanol, chlorothalonil, chloroxylenol, copper chromate arsenate, ciclopirox, cilofungin, cinnamaldehyde, clioquinol, copper(I) cyanide, copper(II) arsenate, cluenthalen, cycloheximide, davicil, dehydroacetic acid, dicarboximide fungicides, dichlofluanid, dimazole, diphenylamine, echinocandin, echinocandin B, epoxiconazole, ethnam, falcarindiol, falcarinol, famoxadone, fenamidone, fenarimol, fenpropimorph, fentin acetate, fentichlor, fentin Ilipin, fluazinam, fluopicolide, flusilazole, fluxapyroxad, fuberidazole, griseofulvin, halicylindramide, haloprogin, hamycin, hexachlorobenzene, hexachlorocyclohexa-2,5-dien-1-one, 5-hydroxy-2(5H)-furanone, iprodione, lime sulfur, mancozeb, maneb, melafix, metalaxyl, metam sodium, methylisothiazolone, methylparaben, micafungin, mi Lutefosine, sodium methylarsenate, mycobacillin, myclobutanil, natamycin, β-nitrostyrene, nystatin, paclobutrazol, papulacandin B, parietin, paecilosin, pencycuron, pentamidine, pentachloronitrobenzene, pentachlorophenol, perimycin, 2-phenylphenol, polyene antifungals, propamocarb, propiconazole, pterulon, ptilomycalin A, pyrazophos, pyrimethanil, pyrrolnitrin, Selenium disulfide, sparasole, strobilurin, sulventin, tavaborol, tebuconazole, terbinafine, theonelamid F, thymol, thiabendazole, cyclaton, tolcyclate, tolnaftate, triadimefon, triamiphos, tribromometacresol, 2,4,6-tribromophenol, tributyltin oxide, triclocarban, triclosan, tridemorph, trimetrexate, undecylenic acid, validamycin, venturicidin, These include vinclozolin, vinyldithiin, buthione, xanthene, zinc borate, zinc pyrithione, zineb, ziram, voriconazole, itraconazole, posaconazole, fluconazole, ketoconazole, clotrimazole, isavuconazonium, miconazole, caspofungin, anidulafungin, micafungin, griseofulvin, terbinafine, flucytosine, terbinafine, nystatin, amphotericin B, and combinations thereof.

[0242] Examples of antiviral drugs include, but are not limited to, afovirsen, alisporivir, angustific acid, angustifodilactone, alovudine, beclavuvir, 2,3-Bis(acetylmercaptomethyl)quinoxaline, brincidofovir, dasabuvir, docosanol, fialuridine, ibasitabine, imiquimod, inosine, inosine pranobex, interferon, methisazone, miltefosine, neocadoslanine, neotripterifolidine, ombitasvir, oragen, oseltamivir, peginterferon, podophyllotoxin, ladarbuvir, semapimod, tecobirimat, telbivudine, theaflavin, tilorone, tryptofilidine C-2, variecrol, ZMapp, abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, baravir, baloxavir Marboxil, boceprevir, cidofovir, cobicistat, daclatasvir, darunavir, delavirdine, didanosine, docasanol, dolutegravir, doravirine, ecolever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, forscarnet, fosnonet, famciclovir, favipravir, fomivirsen, foscavir, ganciclovir, ibasitabine, idoxuridine, indinavir, inosine, inosine pranobex, type I interferon, type II interferon, type III interferon, lamivudine, letermovir, letermovir, lopinavir, loviride, maraviro , methisazone, moroxydine, nelfinavir, nevirapine, nitazoxanide, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesevir, ribavirin, rilpivirine, rimantadine, lintatolimod, ritonavir, saquinavir, simeprevir, sovosbuvir, stavudine, talabivirine, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, umifenovir, valacyclovir, valganciclovir, vidarabine, zalcitabine, zanamivir, zidovudine, and the like, A combination of the following is included.

[0243] In some examples, the therapeutic agent comprises a viral antigen, a tumor antigen, a gene editing component, a protein replacement component, an immunomodulatory agent, or a combination thereof. In some embodiments, the therapeutic agent comprises an anti-cancer agent, hi some examples, the therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, or a combination thereof.

[0244] In some embodiments, the therapeutic agent is a chemotherapeutic agent. Chemotherapy is the treatment of cancer with one or more cytotoxic antitumor agents (e.g., chemotherapeutic agents) as part of a standardized regimen. Chemotherapy may be performed with the intent of cure or with the intent of prolonging life or palliating symptoms. In some cases, chemotherapy may be used in conjunction with other cancer treatments, such as radiation therapy, surgery, hyperthermia, or a combination thereof. Examples of chemotherapeutic agents include, but are not limited to, 13-cis-retinoic acid, 2-amino-6-mercaptopurine, 2-CdA, 2-chlorodeoxyadenosine, 5-fluorouracil, 6-thioguanine, 6-mercaptopurine, Accutane, actinomycin-D, Adriamycin, Adrsil, Agrylin, Alaquat, Aldesleukin, Alemtuzumab, Alitretinoin, Alcaban-AQ, Alkeran, All-Trans Retinoic Acid, Alpha Interferon, Altretamine, Amethopterin, Amifostine, Aminoglutethimide, Anagrelide, Anandrone, Anastrozole, Arabinosylcytosine, Aranesp, Aredia, Arimidex, Aromasin, Arsenic Trioxide, Asparaginase, ATRA, Avastin, BC G, BCNU, bevacizumab, bexarotene, bicalutamide, BiCNU, blenoxane, bleomycin, bortezomib, busulfan, busulfex, C225, calcium leucovorin, campas, camptosar, camptothecin-11, capecitabine, carac, carboplatin, carmustine, carmustine wafer, casodex, CCNU, CDDP, CeeNU, cerbidine, cetuximab, chlorambucil, cisplatin, citrovorum factor, cladribine, cortisone, cosmegen, CPT-11, cyclophosphamide, cytadren, cytarabine, cytarabine liposome, cytosar-U, cytoxan, dacarbazine, dactinomycin, darbepoetin alfa, daunomycin, daunorubicin, daunorubicin hydrochloride, daunorubicinLiposome, Daunoxome, Decadron, Deltacortef, Deltasone, Denileukin diftitox, Depocyte, Dexamethasone, Dexamethasone acetate, Dexamethasone sodium phosphate, Dexasone, Dexrazoxane, DHAD, DIC, Geodex, Docetaxel, Doxil, Doxorubicin, Doxorubicin liposome, Droxia, DTIC, DTIC-Dome, Duralon, Efdex, Eligard, Elence, Eloxatin, Elspar, Emcyt, Epirubicin, Epoetin alfa, Erbitux, Erwinia L-asparaginase, estramustine, ethyol, etopophos, etoposide, etoposide phosphate, eurexin, evista, exemestane, fareston, faslodex, femara, filgrastim, floxuridine, fludara, fludarabine, fluoroplex, fluorouracil, fluorouracil (cream), fluoxymesterone, flutamide, folic acid, FUDR, fulvestrant, G-CSF, gefitinib, gemcitabine, gemtuzumab ozogamicin, gemzar, glivec, lupron, lupron depot, matulane, maxidex, mechlorethamine, mechlorethamine hydrochloride, medralone, medoraone rol, Megased, megestrol, megestrol acetate, melphalan, mercaptopurine, mesna, mesnex, methotrexate, methotrexate sodium, methylprednisolone, Mirocel, letrozole, Neosar, Neulasta, Neumega, Neupogen, Nilandrone, Nilutamide, Nitrogen Mustard, Novaldex, Novantrone, octreotide, octreotide acetate, Oncospar, Oncovin, Ontac, Onxal, Oplevukin, Olapred, Orazone, oxaliplatin, paclitaxel, pamidronate, panretin, paraplatin, pediapred, PEG interferon , pegaspargase, pegfilgrastim, pegIntron, PEG-L-asparaginase, phenylalanine mustard, Platinol, Platinol-AQ, prednisolone, prednisone, Prelon, procarbazine, PROCRIT, Proleukin, ProLife Prospan 20 in combination with carmustine implant, Prinesol, raloxifene, Rheumatrex, Rituxan, Rituximab, Loberon-A (interferon alfa-2a), Rubex, rubidomycin hydrochloride, Sandostatin, Sandostatin LAR, Sargramostim, Sol-Cortef, Sol-Medrol, STI-571, Streptozocin, Tamoxifen, Targretin, Taxol, Taxotere, Temodar, Temozolomide, Teniposide, TESPA, Thalidomide, Thalomide, Therasys, Thioguanine, Thioguanine Tabloid, Thiophosphoamide, Thioplex, Thiotepa, TICE, Toposar, Topotecan, Toremifene, Trastuzumab Bu, tretinoin, Trexol, Trisenox, TSPA, VCR, Velban, Velcade, Bepesid, Vesanoid, Viadur, Vinblastine, Vinblastine sulfate, Vincasar Pfs, Vincristine, Vinorelbine, Vinorelbine tartrate, VLB, VP-16, Bumon, Xeloda, Zanosar, Zevalin, Zincard, Zoladex, Zoledronic acid, Zometa, Gliadel wafer, Gleevec, GM- CSF, goserelin, granulocyte colony-stimulating factor, halotestin, herceptin, hexadrol, hexalen, hexamethylmelamine, HMM, hycamtin, hydrea, hydrocort acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocort phosphate, hydroxyurea, ibritumomab, ibritumomab tiuxetan, idamycin, idarubicin, ifex, IFN-α, ifosfamide, IL-2, IL-11, imatinib mesylate, imidazole carboxamide, interferon α, interferon α-2b (PEG conjugate), interleukin 2, interleukin-11, intron A (interferon α-2b), leucovorin, leukelan, leukin, leuprolide, leurocristin, leustatin, liposomal Ara-C, liquidPred, lomustine, L-PAM, L-sarcolysin, methycortene, mitomycin, mitomycin-C, mitoxantrone, M-prednisole, MTC, MTX, mastergen, mustine, mutamycin, myleran, Iressa, irinotecan, isotretinoin, quidrolase, lanacort, L-asparaginase, LCR, FAM-HYD-1, marizomib (NPI-0052), lenalidomide, carfilzomib, panobinostat, xinostat, selinexol, oprozomib, and combinations thereof. Anticancer drugs can also include biopharmaceuticals, such as antibodies.

[0245] Examples of suitable immunotherapeutic agents include, but are not limited to, alemtuzumab, cetuximab (Erbitux), gemtuzumab, iodine-131 tositumomab, rituximab, trastuzumab (Herceptin), and combinations thereof.

[0246] In some examples, the therapeutic agent may include an anti-inflammatory drug, such as a steroidal anti-inflammatory drug and / or a non-steroidal anti-inflammatory drug. Examples of steroidal anti-inflammatory drugs include, but are not limited to, hydrocortisone, dexamethasone, prednisolone, prednisone, triamcinolone, methylprednisolone, budesonide, betamethasone, cortisone, and deflazacort. Examples of non-steroidal anti-inflammatory drugs include acetaminophen, aspirin, ibuprofen, naproxen, celebrex, ketoprofen, tolmetin, etodolac, fenoprofen, flurbiprofen, diclofenac, piroxicam, indomethacin, sulindax, meloxicam, nabumetone, oxaprozin, mefenamic acid, and diflunisal.

[0247] In some examples, the therapeutic agent comprises a nucleic acid. Examples of specific nucleic acids include, but are not limited to, oligonucleotides, miRNA, shRNA, siRNA, DNA, RNA, mRNA, cDNA, double-stranded nucleic acids, single-stranded nucleic acids, and the like. Specific examples In some instances, the nucleic acid may be an mRNA. In some instances, the mRNA encodes a protein or peptide of therapeutic use.

[0248] In some examples, a pharmaceutical composition is administered. In some examples, the subject is a mammal. In some examples, the subject is a primate. In some examples, the mammal is a human. In some examples, the human is a patient.

[0249] In some examples, the disclosed compositions comprise a disclosed compound (including pharma- ceutically acceptable salts thereof) as an active ingredient, a pharma- ceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route of administration in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is to be administered. The compositions can be provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art.

[0250] Manufacturing method Also provided herein is a method of making any of the compounds or compositions disclosed herein.Also provided herein is a method of making any of the lipid particles disclosed herein.Also provided herein is a method of making any of the pharmaceutical compositions disclosed herein.

[0251] The compounds described herein can be prepared by a variety of methods well known to those skilled in the art of organic synthesis, or variations thereon that will be recognized by those skilled in the art. The compounds described herein can be prepared from readily available starting materials. Optimum reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by those skilled in the art.

[0252] Variations of the compounds described herein include the addition, deletion, or movement of various components described for each compound. Similarly, the chirality of the molecule can be altered if there is one or more chiral centers in the molecule. Furthermore, the synthesis of the compounds can involve the protection and deprotection of various chemical groups. The use of protection and deprotection, and the selection of suitable protecting groups, can be determined by those skilled in the art. The chemistry of protecting groups is described, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, which is incorporated herein by reference in its entirety.

[0253] Starting materials and reagents used in preparing the disclosed compounds and compositions may be purchased from Katchem (Prague, Czech Republic), Aldrich Chemical Co., (Milwaukee, WI), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, PA), Sigma (St. Louis, MO), Pfizer (New York, NY), GlaxoSmithKline (Raleigh, NC), Merck (Whitehouse Station, NJ), Johnson & Johnson (New Brunswick, NJ), Aventis (Bridgewater, NJ), AstraZeneca (Wilmington, DE), Novartis (Basel, Switzerland), Wyeth (Madison, NJ), Bristol-Myers-Squibb (New York, NY), Roche (Basel, Switzerland), Lilly (Indianapolis, IN), Abbott (Abbott Park, IL), Schering Plough (Kenilworth, NJ), or Boehringer Ingelheim (In These reagents are available from manufacturers such as Sigmalheim, Germany, or are prepared by methods known to those skilled in the art according to procedures described in references such as Fieser and R. Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Other materials, such as pharmaceutical excipients, disclosed herein can be obtained from commercial sources.

[0254] The reactions to produce the compounds described herein can be carried out in a solvent that can be selected by one skilled in the art of organic synthesis. The solvent can be substantially non-reactive to the starting materials (reactants), intermediates, or products under the conditions (i.e., temperature and pressure) at which the reaction is carried out. The reaction can be carried out in one solvent or a mixture of multiple solvents. The formation of the product or intermediate can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be monitored by infrared spectroscopy, spectrophotometry (eg, UV-visible), or mass spectrometry, or chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0255] How to use Also provided herein are methods of using any of the compounds or compositions disclosed herein.

[0256] For example, also disclosed herein are methods of treating, preventing, or ameliorating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of any of the pharmaceutical compositions disclosed herein.

[0257] For example, also disclosed herein is a method of treating a disease or disorder in a subject in need of such treatment, comprising administering to the subject an effective amount of any of the pharmaceutical compositions disclosed herein.

[0258] Examples of diseases or disorders include, but are not limited to, cancer. In some examples, the disease includes cancer. For example, the compounds and compositions described herein, or pharma- ceutically acceptable salts thereof, are useful for the treatment of cancer in humans (e.g., pediatric and geriatric populations), as well as in animals (e.g., veterinary applications). The disclosed methods can optionally include identifying a patient who is in need of, or may be in need of, cancer treatment. Examples of types of cancer treatable by the compounds and compositions described herein include bladder cancer, brain cancer, breast cancer, colon cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, and testicular cancer. Further examples include cancers and / or tumors of the anus, bile duct, bone, bone marrow, intestine (including colon and rectum), eye, gallbladder, kidney, mouth, larynx, esophagus, stomach, testes, cervix, mesothelioma, neuroendocrine, penis, skin, spinal cord, thyroid, vagina, vulva, uterus, liver, muscle, and blood cells (including lymphocytes and other immune system cells). Further examples of cancers treatable by the compounds and compositions described herein include carcinoma, Kaposi's sarcoma, melanoma, mesothelioma, soft tissue sarcoma, pancreatic cancer, lung cancer, leukemia (acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and the like). These include lymphomas (Hodgkin's lymphoma and non-Hodgkin's lymphoma), and multiple myeloma.

[0259] The methods of treating or preventing cancer described herein may, in some instances, further include treatment with one or more additional agents (e.g., anti-cancer agents or ionizing radiation). For example, the compounds or compositions described herein, or pharma- ceutically acceptable salts thereof, may be formulated in a pharmaceutical composition with additional anti-cancer agents. The additional anti-cancer agents may also include biopharmaceuticals, such as antibodies. Many tumors and cancers have viral genomes present in the tumor or cancer cells. For example, Epstein-Barr Virus (EBV) is associated with many mammalian malignancies. The compounds disclosed herein may also be used alone or in combination with anti-cancer or anti-viral agents, such as ganciclovir, azidothymidine (AZT), lamivudine (3TC), to treat patients infected with viruses that may cause cellular transformation and / or to treat patients with tumors or cancers associated with the presence of viral genomes in cells. The compounds disclosed herein may also be used in combination with virus-based treatments of neoplastic diseases.

[0260] Also disclosed herein is a method of inhibiting tumor growth in a subject. The method includes contacting at least a portion of the tumor with a therapeutically effective amount of any of the compounds or compositions described herein. In some examples, the method further includes irradiating at least a portion of the tumor with a therapeutically effective amount of ionizing radiation. As used herein, the term ionizing radiation refers to radiation that includes particles or photons that have or can generate sufficient energy to cause ionization by nuclear interaction. An example of ionizing radiation includes X-rays. A therapeutically effective amount of ionizing radiation refers to a dose of ionizing radiation that, when administered in combination with a compound described herein, results in increased cell damage or cell death. Ionizing radiation can be delivered according to methods well known in the art, including administration of radiolabeled antibodies and radioisotopes.

[0261] The methods of treating a disease or disorder described herein may further include treatment with one or more additional agents. One or more additional agents and compounds as well as compositions or pharma- ceutically acceptable salts thereof as described herein may be administered in any order, including simultaneous administration and administration with a time interval of up to several days. These methods may also include multiple administrations of one or more additional agents and / or compounds as described herein and compositions or pharma- ceutically acceptable salts thereof. The administration of one or more additional agents and compounds as described herein and compositions or pharma- ceutically acceptable salts thereof may be by the same route or different routes. When treating with one or more additional agents, the compounds as described herein and compositions or pharma- ceutically acceptable salts thereof may be combined with a pharmaceutical composition comprising one or more additional agents.

[0262] In some examples, the compound or composition is administered to a subject at a dose of 1 μg per kilogram (kg) of the subject's body weight per day (μg / kg / day) or more (e.g., 2 μg / kg / day or more, 3 μg / kg / day or more, 4 μg / kg / day or more, 5 μg / kg / day or more, 10 μg / kg / day or more, 15 μg / kg / day or more, 20 μg / kg / day or more, 25 μg / kg / day or more, 30 μg / kg / day or more, 35 μg / kg / day or more, 40 μg / kg / day or more, 45 μg / kg / day or more, 50 μg / kg / day or more, 60 μg / kg / day or more, 70 μg / kg / day or more, kg / day, 80μg / kg / day or more, 90μg / kg / day or more, 100μg / kg / day or more, 125μg / kg / day or more, 150μg / kg / day or more, 175μg / kg / day or more, 200μg / kg / day or more, 225μg / kg / day or more, 250μg / kg / day or more Above, 300μg / kg / day or more, 350μg / kg / day or more, 400μg / kg / day or more, 450μg / kg / day or more, 500μg / kg / day or more, 600μg / kg / day or more, 700μg / kg / day or more, 800μg / kg / day or more, 900μg / kg / day or more, 1 The drug can be administered in an amount of (milligrams (mg) / kg / day or more, 2 mg / kg / day or more, 3 mg / kg / day or more, 4 mg / kg / day or more, 5 mg / kg / day or more, 6 mg / kg / day or more, 7 mg / kg / day or more, 8 mg / kg / day or more, or 9 mg / kg / day or more). In some examples, the compound or composition is administered to a subject at a dose of 10 mg per kilogram (kg) of the subject's body weight per day (mg / kg / day) or less (e.g., 9 mg / kg / day or less, 8 mg / kg / day or less, 7 mg / kg / day or less, 6 mg / kg / day or less, 5 mg / kg / day or less, 4 mg / kg / day or less, 3 mg / kg / day or less, 2 mg / kg / day or less, 1 mg / kg / day or less, 900 μg / kg / day or less, 800 μg / kg / day or less, 700 μg / kg / day or less, 600 μg / kg / day or less, 500 μg / kg / day or less, 450 μg / kg / day or less, 400 μg / kg / day or less, 350 μg / kg / day or less, 300 μg / kg / day or less, 250 μg / kg / day or less). 5 μg / kg / day or less, 225 μg / kg / day or less, 200 μg / kg / day or less, 175 μg / kg / day or less, 150 μg / kg / day or less, 125 μg / kg / day or less, 100 μg / kg / day or less, 90 μg / kg / day or less, 80 μg / kg / day or less, 70 μg / kg / day or less, 60 μg / kg / day or less, 50 μg / kg / day or less, 45 μg / kg / day or less, 40 μg / kg / day or less, 35 μg / kg / day or less, 30 μg / kg / day or less, 25 μg / kg / day or less, 20 μg / kg / day or less, 15 μg / kg / day or less, 10 μg / kg / day or less, 5 μg / kg / day or less, 4 μg / kg / day or less, 3 μg / kg / day or less, or 2 μg / kg / day or less.

[0263] The amount of the compound or composition administered to the subject can range from any of the minimum values ​​above to any of the maximum values ​​above. For example, the compound or composition can be administered to the subject in an amount of 1 microgram (μg) to 10 milligrams (mg) per kilogram (kg) of the subject's body weight per day (e.g., 1 μg / kg / day to 100 μg / kg / day, 100 μg / kg / day to 10 mg / kg / day, 1 μg / kg / day to 10 μg / kg / day, 10 μg / kg / day to 100 μg / kg / day, 100 μg / kg / day to 1 mg / kg / day, 1 mg / kg / day to 10 mg / kg / day, 5 μg / kg / day to 10 mg / kg / day, 1 μg / kg / day to 5 mg / kg / day, or 5 to 5 mg / kg / day).

[0264] However, it is understood that the specific dose level for a particular subject will depend on a variety of factors. Such factors include the age, weight, general health, sex, and diet of the subject. Other factors include the time and route of administration, rate of excretion, drug combinations, and the type and severity of the particular disease or disorder.

[0265] The methods, compounds, and compositions described herein are useful for both prophylactic and therapeutic treatments. The term therapy or treatment as used herein includes prevention; delaying onset; reducing, eradicating, or delaying the worsening of signs or symptoms after onset; and preventing recurrence. For prophylactic use, a therapeutically effective amount of the compounds and compositions described herein, or a pharma- ceutically acceptable salt thereof, is administered to a subject before onset (e.g., before overt signs of a disease or disorder), during early onset (e.g., upon early signs and symptoms of a disease or disorder), or after established onset of a disease or disorder. Prophylactic administration can occur days to years before the appearance of symptoms of a disease or disorder. Therapeutic treatment includes administering a therapeutically effective amount of the compounds and compositions described herein, or a pharma- ceutically acceptable salt thereof, to a subject after a disease or disorder has been diagnosed.

[0266] In certain embodiments, it may be desirable to target the nanoparticles using targeting moieties that are specific to a cell type and / or tissue type. In some embodiments, targeting moieties can be used to target the nanoparticles to specific cells, tissues, and / or organs. Exemplary, non-limiting targeting moieties include ligands, cell surface receptors, glycoproteins, vitamins (e.g., riboflavin), and antibodies (e.g., full-length antibodies, antibody fragments (e.g., Examples of targeting moieties include Fv fragments, single chain Fv (scFv) fragments, Fab' fragments, or F(ab')2 fragments), single domain antibodies, camelid antibodies and fragments thereof, human antibodies and fragments thereof, monoclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies). In some embodiments, the targeting moiety may be a polypeptide. The targeting moiety may include an entire polypeptide (e.g., a peptide or protein) or a fragment thereof. The targeting moiety is typically disposed on the outer surface of the nanoparticle in a manner that makes it available for interaction with the targeting moiety, e.g., a cell surface receptor. A variety of different targeting moieties and methods are known and available in the art, including, for example, those described in Sapra et al., Prog. Lipid Res. 42(5):439-62, 2003 and Abra et al., J. Liposome Res. 12:1-3, 2002.

[0267] The targeting moiety can target any known cell type, including, but not limited to, hepatocytes, colon cells, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, lung cells, bone cells, stem cells, mesenchymal cells, neural cells, cardiac cells, adipocytes, vascular smooth muscle cells, cardiac muscle cells, skeletal muscle cells, beta cells, pituitary cells, synovial lining cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, granulocytes, and tumor cells (including primary tumor cells and metastatic tumor cells). In certain embodiments, the targeting moiety targets the lipid nanoparticles to hepatocytes. In other embodiments, the targeting moiety targets the lipid nanoparticles to colon cells. In some embodiments, the targeting moiety targets the lipid nanoparticles to liver cancer cells (e.g., hepatocellular carcinoma cells) or colon cancer cells (e.g., primary tumors or metastases).

[0268] Compositions, formulations, methods of administration, and kits The in vivo application of the disclosed compounds and compositions containing them can be achieved by any suitable method and technique known to those skilled in the art now or in the future. For example, the disclosed compounds can be formulated in a physiologically or pharma-ceutically acceptable form and administered by any suitable route known in the art, including, for example, oral, nasal, rectal, topical, and parenteral routes of administration. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. The administration of the disclosed compounds or compositions can be a single dose, or continuous or at different intervals, as can be easily determined by those skilled in the art.

[0269] The compounds disclosed herein and compositions containing them can also be administered using liposome technology, sustained release capsules, implantable pumps, and biodegradable containers.These delivery methods can advantageously provide a uniform dosage over a long period of time.The compounds can also be administered in their salt derivative form or crystalline form.

[0270] The compounds disclosed herein can be formulated according to known methods for preparing pharma- ceutically acceptable compositions. Formulations are well known to those skilled in the art and are described in detail in many sources readily available. For example, Remington's Pharmaceutical Science (1995) by EW Martin describes formulations that can be used in connection with the disclosed methods. In general, the compounds disclosed herein can be formulated so that an effective amount of the compound is combined with a suitable excipient to facilitate effective administration of the compound. The compositions used can also be in various forms. These include solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, suppositories, injection and infusion solutions, and sprays. The preferred form depends on the intended mode of administration and application. The compositions can also include conventional pharma- ceutically acceptable carriers and diluents well known to those skilled in the art.

[0271] Examples of carriers or diluents for use with the compounds include ethanol, dimethylsulfate, ethyl acetate ... Examples of suitable carriers and diluents include sulfoxide, glycerol, alumina, starch, saline, and equivalent carriers and diluents. To provide for administration of such dosage amounts for the desired use, the compositions disclosed herein can contain from about 0.1% to 100% by weight of one or more of the subject compounds in total, based on the total weight of the composition including the carrier or diluent.

[0272] The pharmaceutical carrier used can be, for example, solid, liquid or gas.The examples of solid carrier include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.The examples of liquid carrier include sugar syrup, peanut oil, olive oil and water.The examples of gaseous carrier include carbon dioxide and nitrogen.

[0273] Preparations suitable for administration include aqueous sterile injection solutions that may contain, for example, antioxidants, buffers, bacteriostatic agents, and solutes that render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, which requires only the preparation of a sterile liquid carrier, for example water, prior to use for injection. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, tablets, and the like. It should be understood that in addition to the excipients specifically mentioned above, the compositions disclosed herein may contain other agents conventional in the art, taking into account the type of preparation in question.

[0274] The compounds disclosed herein, and compositions containing them, can be delivered to cells by direct contact with the cells or via a carrier means. Carrier means for delivering compounds and compositions to cells are known in the art.

[0275] For the treatment of neoplastic disorders, the compounds or compositions disclosed herein can be administered to a patient in need of treatment in combination with other antitumor or anticancer substances, and / or with radiation therapy and / or photodynamic therapy, and / or with surgical treatment to remove the tumor. These other substances or treatments can be given at the same time as the compounds or compositions disclosed herein, or at different times. For example, the compounds or compositions disclosed herein can be combined with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cyclophosamide or ifosfamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, antiangiogenic agents such as etoposide or camptothecin, angiostatin, antiestrogens such as tamoxifen, and / or other anticancer agents or antibodies, for example, GLEEVEC (Novartis Pharmaceuticals Corporation) and HERCEPTIN (Genentech, Inc.), respectively, or with immunotherapies such as ipilimumab and bortezomib.

[0276] In certain examples, the compounds and compositions disclosed herein can be administered locally to one or more anatomical sites, e.g., the site of unwanted cell proliferation (e.g., injected or applied topically to a tumor site or benign skin tumor, e.g., a tumor or skin tumor), optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent. The compounds and compositions disclosed herein can be administered systemically, such as intravenously or orally, optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent, or an assimilable edible carrier for oral delivery. They can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the active compounds can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, aerosol sprays, and the like.

[0277] Tablets, troches, pills, capsules, etc. may contain the following: binders such as gum tragacanth, acacia, cornstarch, or gelatin; diluents such as dicalcium phosphate; disintegrating agents such as cornstarch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, oil of wintergreen, cherry flavoring, etc. If the unit dosage form is a capsule, in addition to the above types of materials, liquid carriers such as vegetable oils or polyethylene glycols may be included. Various other materials may be present as coatings or to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, or the like. Syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methyl and propylparabens as preservatives, a dye, and flavorings such as cherry or orange flavoring. Of course, any material used in preparing any unit dosage form should be pharma- ceutically acceptable and substantially non-toxic in the amounts employed.Furthermore, the active compounds can be incorporated into sustained-release preparations and devices.

[0278] The compounds and compositions disclosed herein, including pharma- ceutically acceptable salts, can be administered intravenously, intramuscularly, or intraperitoneally by infusion or injection.The solution of the active agent or its salt can be prepared in water, optionally mixed with a non-toxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, as well as in oil.These preparations can contain preservatives to prevent the growth of microorganisms under normal storage and use conditions.

[0279] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient, which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, and may be encapsulated in liposomes. The final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be, for example, a solvent or liquid dispersion medium, including water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by forming liposomes, by maintaining the required particle size in the case of dispersions, or by using surfactants. Optionally, the action of microorganisms can be suppressed by various other antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.

[0280] The pharmaceutical compositions disclosed herein suitable for injectable use include sterile aqueous solutions or dispersions. Moreover, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some instances, the final injectable form can be sterile and effectively fluid to facilitate injectability. In some instances, the pharmaceutical composition can be stable under the conditions of manufacture and storage, and thus can be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0281] Sterile injectable solutions can be prepared by incorporating the compounds and / or agents disclosed herein in the required amount in an appropriate solvent with various of the other ingredients enumerated above, as required. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient combined with any additional desired ingredient present in a previously sterile-filtered solution thereof.

[0282] The pharmaceutical compositions disclosed herein can be in a form suitable for topical use, such as, for example, aerosols, creams, ointments, lotions, dusting powders, mouthwashes, gargles, solutions, tinctures, etc. In some instances, the compositions can be in a form suitable for use in transdermal devices. In some instances, it may be desirable to administer them topically to the skin as a composition in combination with a dermatologically acceptable carrier, which may be solid or liquid. The compounds, agents, and compositions disclosed herein can be applied topically to the skin of a subject. These formulations can be prepared via conventional processing methods utilizing any of the compounds disclosed herein or their pharma-ceutically acceptable salts.

[0283] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohol or glycol, or water-alcohol / glycol mixtures, optionally with the aid of non-toxic surfactants, to dissolve or disperse the compound at effective levels. Adjuvants such as fragrances and additional antibacterial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied from absorbent pads, impregnated into bandages and other dressings, or sprayed onto the affected area using pump or aerosol sprayers.

[0284] Thickening agents such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified mineral materials may also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like for application directly to the user's skin.

[0285] The pharmaceutical composition disclosed herein can be in a suitable form for rectal administration, where the carrier is solid.In some embodiments, the mixture forms a unit dose suppository.Suitable carriers include cocoa butter and other materials commonly used in the art.The suppository can be conveniently formed by first mixing the composition with the softened or melted carrier, followed by cooling and shaping.

[0286] In addition to the above carrier components, the above pharmaceutical formulations may optionally include one or more additional carrier components such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants). In addition, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions comprising any of the compounds disclosed herein and / or their pharma-ceutically acceptable salts may also be prepared in powder or liquid concentrate form.

[0287] Useful dosages of the compounds and agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art.

[0288] The dosage range for administering the composition is sufficient to produce the desired effect that the symptom or disorder is affected.The dosage should not be so large as to cause harmful side effects such as undesirable cross-reactions, anaphylactic reactions, etc. Generally, dosage varies according to the age, condition, sex, and degree of disease of the patient, and can be determined by those skilled in the art.The dosage can be adjusted by individual physicians if there are any counter indications. Dosage may vary, for example, by one or more doses administered daily over one or several days.

[0289] Also disclosed are kits comprising a compound disclosed herein in one or more containers. The disclosed kits may optionally comprise a pharma- ceutically acceptable carrier and / or diluent. In one embodiment, the kit comprises one or more other components, adjuvants, or supplements described herein. In one embodiment, the kit comprises instructions or packaging materials that describe how to administer the compound or composition of the kit. The containers of the kit may be of any suitable material, e.g., glass, plastic, metal, and any suitable size, shape, or configuration. In one embodiment, the compound and / or agent disclosed herein is provided in the kit as a solid, such as a tablet, pill, or powder form. In another embodiment, the compound and / or agent disclosed herein is provided in the kit as a liquid or solution. In one embodiment, the kit comprises an ampoule or syringe containing the compound and / or agent disclosed herein in liquid or solution form.

[0290] In some instances, the kit further comprises at least one agent, and the compound and agent are formulated together. In some instances, the compound and the agent are packaged together.

[0291] The kits can also include compounds and / or products that are packaged together, formulated together, and / or delivered together with other components. For example, a drug manufacturer, drug reseller, physician, compounding house, or pharmacist can provide a kit that includes a disclosed compound and / or product and another component for delivery to a patient.

[0292] It is contemplated that the disclosed kits can be used in connection with the disclosed methods of making the disclosed compositions, the disclosed methods of using the disclosed compositions, and / or the disclosed compositions.

[0293] Numerous embodiments of the invention have been described. Of course, it is understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0294] The following examples are intended to further illustrate certain aspects of the systems and methods described herein, and are not intended to limit the scope of the claims. EXAMPLES

[0295] The following examples are provided below to illustrate the methods and results of the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention that are apparent to those skilled in the art.

[0296] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless otherwise noted, parts are parts by weight, temperature is °C or is ambient temperature, and pressure is at or near atmospheric. There are many variations and combinations of measurement conditions, such as, for example, component concentrations, temperatures, pressures, and other measurement ranges and conditions that can be used to optimize the described processes.

[0297] Example 1 Efficient delivery of mRNA remains a critical step and challenge for mRNA therapeutics applicants. Despite promising data from ongoing clinical trials, the clinical use of mRNA requires the discovery and development of more efficient delivery systems.

[0298] Disclosed herein are functionalized amino lipid nanoparticles and applications thereof. For example, disclosed herein are three classes of functionalized amino lipids and their formulations that can be used, for example, in gene therapy and drug delivery applications.

[0299] The synthetic routes and properties of the compounds and compositions disclosed herein are provided below. The relative luminescence intensities of certain compounds in Hep3B cells are shown in FIG. The relative luminescence intensities of certain compounds in vivo after intramuscular injection are shown in FIG.

[0300] [ka]

[0301] [ka] Aldehyde synthesis example

[0302] [ka]

[0303] To a suspension of paraformaldehyde (1.5 g, 50 mmol) in TMSCl (25 mL, 197 mmol) was added 1-hexanol 10 (5.1 g, 50 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h. The clear solution was concentrated under reduced pressure to give 1-chloromethoxy-hexane 11 as a colorless oil, which was used directly without further purification.

[0304] The above chloromethyl ether was reacted with 1,6-hexanediol 12 (11.8 g, 100 mmol) and i-Pr 2 CH of NEt (17.45 mL, 100 mmol) 2 Cl 2 (150 mL). The reaction mixture was stirred at room temperature for 24 h, followed by NH 4 The reaction was quenched by adding a saturated solution of Cl (80 mL). 2 Cl 2 The combined organic layer was washed with water (30 mL) and saturated saline (30 mL), and then extracted with Na 2 SO 4The organic phase was filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (20% EtOAc in hexanes) to give 6.74 g of 13 as a colorless oil (yield 58.0%). 1 H NMR (300 Mhz, chloroform-d) δ 4.65 (s, 2H), 3.63 (q, J = 6.4 Hz, 2H), 3.51 (td, J = 6.6, 2.9 Hz, 4H), 1.57 (dq, J = 13.5, 6.8 Hz, 6H), 1.50-1.21 (m, 10H), 0.94-0.82 (m, 3H).MS (m / z): [M+Na] + C 13 H 28 N a O 3 Calculated value for: 255.1931; Measured value: 255.1941.

[0305] [ka]

[0306] (Diacetoxyiodo)benzene (0.79 g, 2.45 mmol) was dissolved in 14 (518 mg, 2.23 mmol), TEMPO (34.9 mg, 0.22 mmol) and NaHCO 3 (412 mg, 4.9 mmol) was added to a suspension of 14 (10 mL) in dry DCM at room temperature. The reaction mixture was stirred for 3 h, at which time TLC showed that 14 was completely consumed. The mixture was then diluted with Na 2 S 2 O 3 (30 mL) and extracted with DCM (3×20 mL). The DCM layers were combined and NaHCO 3 Wash with aqueous solution (20 ml) and saturated saline (20 ml), and add anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes). 510 mg of 15 was obtained as a colorless oil (quantitative). 1H NMR (300 MHz, chloroform-d) δ 9.76 (s, 1H), 4.64 (s, 2H), 3.51 (q, J = 5.9 Hz, 4H), 2.43 (t, J = 7.4 Hz, 2H), 1.60 (ddt, J = 17.8, 12.9, 7.3 Hz, 6H), 1.46-1.23 (m, 8H), 0.95-0.81 (m, 3H).MS (m / z): [M+Na] + C 13 H 26 N a O 3 Calculated value for: 253.1774; Measured value: 255.1941.

[0307] [ka]

[0308] To a solution of 16 (5.0 g, 30.4 mmol) in DCM (30 mL), a solution of 1,5-hexanediol 12 and TEA (16.9 mL, 121 mmol) in DCM (100 mL) was added dropwise over 30 min at 0° C. After stirring for 3 h, the reaction was quenched with 50 mL of water and extracted with DCM (50 mL × 3), after which the combined organic phase was washed with water and purified by N a 2SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc in hexanes) to give 3.2 g of 17 as a colorless oil (45.3% yield). 1 H NMR (300 Mhz, chloroform-d) δ 4.11 (td, J = 6.7, 2.6 Hz, 4H), 3.62 (td, J = 6.5, 3.1 Hz, 3H), 1.65 (p, J = 7.0 Hz, 4H), 1.56 (dq, J = MS (m / z): [M+Na] + C 13 H26 N a O 4 Calculated value for: 269.1723; Measured value: 269.1735.

[0309] [ka]

[0310] BAIB (1.41 g, 4.38 mmol) was dissolved in 17 (0.98 g, 3.98 mmol), TEMPO (62.2 mg, 0.4 mmol) and NaHCO 3 (736 mg, 8.6 mmol) in 20 mL of DCM. The reaction mixture was stirred for 3 h until TLC showed complete consumption of A. The mixture was diluted with saturated Na 2 S 2 O 3 (30 mL) and extracted with DCM (3×20 mL). The DCM layers were combined and NaHCO 3 Wash with aqueous solution (20 ml) and saturated saline (20 ml), and add anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (10% EtOAc in hexanes). 0.78 g of 18 was obtained as a pale yellow oil (yield 80.2%). 1 H NMR (300 Mhz, chloroform-d) δ 9.77 (q, J = 1.6 Hz, 1H), 4.13 (td, J = 6.6, 2.6 Hz, 5H), 2.45 (td, J = 7.2, 1.7 Hz, 2H), 1.78-1.59 (m, 7H), 1.49-1.24 (m, 10H), 0.95-0.84 (m, 4H).

[0311] [ka]

[0312] To a solution of acetaldehyde (1.76 g, 40 mmol) in TMSCl (20 mL, 157 mmol) was added 1-hexanol 10 (5.1 g, 50 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h. The clear solution was concentrated under reduced pressure to give 19 as a colorless oil, which was used directly without further purification.

[0313] The above chloromethyl ether was reacted with 1,6-hexanediol 12 (9.44 g, 80 mmol) and i-Pr 2 CH of NEt (13.96 mL, 80 mmol) 2 Cl 2 (150 mL). The reaction mixture was stirred at room temperature for 24 h, and then NH 4 The reaction was quenched by adding a saturated solution of Cl (80 mL). 2 Cl 2 The combined organic layer was washed with water (30 mL) and saturated saline (30 mL), and then extracted with Na 2 SO 4 The organic phase was filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (20% EtOAc in hexanes). 3.45 g of 20 was obtained as a colorless oil (yield 35.0%). 1 H NMR (300 Mhz, chloroform-d) δ 4.64 (q, J = 5.3 Hz, 1H), 3.66-3.47 (m, MS (m / z): [M+Na] + C 14 H 30 N a O 3 Calculated value for: 269.2087; Measured value: 269.2075.

[0314] [ka]

[0315] BAIB (1.77 g, 5.5 mmol) was dissolved in 20 (1.23 g, 5.0 mmol), TEMPO (78.2 mg, 0.5 mmol) and NaHCO 3 (924 mg, 11.0 mmol) in 20 mL of DCM. The reaction mixture was stirred for 3 h until TLC showed complete consumption of A. The mixture was diluted with saturated Na 2 S 2 O 3 (30 mL) and extracted with DCM (3×20 mL). The DCM layers were combined and NaHCO 3 Wash with aqueous solution (20 ml) and saturated saline (20 ml), and add anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (10% EtOAc in hexanes) to give 1.0 g of 21 as a pale yellow oil (yield 81.8%). 1 H NMR (300 Mhz, chloroform-d) δ 9.78 (s, 1H), 4.66 (q, J = 5.3 Hz, 1H), 3.57 (dq, J = 9.2, 6.8 Hz, 2H), 3.41 (dtd, J = 9.7, 6.5, 3.3 Hz, 2H), 2.45 (td, J = 7.3, 1.7 Hz, 2H), 1.73-1.51 (m, 6H), 1.48-1.25 (m, 11H), 0.95-0.82 (m, 3H).MS (m / z): [M+Na] + C 13 H 28 N a O 3 Calculated value: 255.1931; Measured value: 255.1941.

[0316] [ka]

[0317] 1H NMR (400 Mhz, chloroform-d) δ 9.78 (t, J = 1.7 Hz, 1H), 4.65 (q, J = 5.3 Hz, 1H), 3.62 (dt, J = 9.4, 6.1 Hz, 1H), 3.54 (dt, J = 9.3, 6.7 Hz, 1H), 3.49-3.32 (m, 2H), 2.53 (td, J = 7.1, 1.6 Hz, 2H), 2.03-1.84 (m, 2H), 1.67-1.43 (m, 2H), 1.28 (q, J = 4.7, 3.6 Hz, 13H), 0.98-0.80 (m, 3H). General procedure for the synthesis of alcohols 3-n To a solution of 1,3-propyldiamine 1 (2.22 g, 30.0 mmol) and 2-n (10 mmol) in n-butanol (10 mL) was added potassium iodide (84 mg, 0.5 mmol) and potassium carbonate (0.69 g, 5.0 mmol). The resulting mixture was refluxed for 24 h. The mixture was then cooled slowly to room temperature, filtered, and concentrated in vacuo. The resulting mixture was dissolved in 10 mL of MeOH and added with Boc HCl at room temperature. 2 2H (8.3 g, 60 mmol) for 30 min. MeOH was removed under reduced pressure. The residue was purified on a CombiFlash system (hexane / ethyl acetate=1:1) to give the desired product.

[0318] [ka]

[0319] 1 H NMR (300 Mhz, chloroform-d) δ 3.67-3.47 (m, 2H), 3.42-3.30 (m, 2H), 3.28-3.16 (m, 2H), 3.16-3.04 (m, 2H), 1.73-1.64 (m, 4H), 1.47 (s, 9H), 1.44 (s, 9H).

[0320] [ka]

[0321] 1 1H NMR (300 MHz, chloroform-d) δ 4.00 (t, J = 6.0 Hz, 2H), 3.59 (t, J = 6.9 Hz, 2H), 3.52 (d, J = 7.2 Hz, 2H), 3.44 (t, J = 6.6 Hz, 2H), 2.13 (br s, 1H), 2.05 - 1.84 (m, 6H), 1.80 (s, 9H), 1.78 (s, 9H).

[0322]

Chem.

[0323] 1 1H NMR (300 MHz, chloroform-d) δ 3.67 - 3.61 (m, 2H), 3.27 - 2.95 (m, 6H), 1.73 - 1.47 (m, 8H), 1.47 - 1.27 (m, 18H).

[0324]

Chem.

[0325] 1 1H NMR (400 MHz, chloroform-d) δ 3.64 (t, J = 6. 6 Hz, 2H), 3.33 - 3.21 (m, 2H), 3.20 - 3.04 (m, 4H), 1.89 - 1.75 (m, 1H), 1.71 - 1.62 (m, 2H), 1.60 - 1.50 m, 4H), 1.47 (s, 9H), 1.44 (s, 9H), 1.39 (q, J = 7.6 Hz, 2H), 1.34 - 1.28 (m, 2H). MS (m / z): [M+Na] + C 14 H 30 N a O 3 Calculated value for: 275.2; Measured value: 275.3. General procedure for the synthesis of alcohol 6-m Amine 4 (2.61 g, 15.0 mmol) was dissolved in 20 mL of dry MeCN. Potassium carbonate (1.59 g, 15.0 mmol) was added to this solution. A solution of 5-m (10.0 mmol) in 10 mL of dry MeCN was added dropwise to the above solution over 1 h at room temperature. The reaction was then stirred at room temperature for 24 h. Solid Na 2 CO 3 The residue was purified by silica gel chromatography.

[0326] [ka]

[0327] 1 H NMR (300 Mhz, chloroform-d) δ 3.28 (s, 2H), 3.20 (q, J = 6.6 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H), 1.67 (q, J = 6.6 Hz, 2H), 1.46 (s, 9H), 1.43 (s, 9H).

[0328] [ka]

[0329] 1 H NMR (300 Mhz, chloroform-d) δ 5.05 (s, 1H), 3.20 (q, J = 6.3 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.69 (t, J = 6.6 Hz, 2H), 2.44 (t, J = 6.6 Hz, 2H), 1.98 (br s, 1H), 1.67 (p, J = 6.6 Hz, 2H), 1.45 (s, 9H), 1.44 (s, 9H).

[0330] [ka]

[0331] 1 H NMR (300 Mhz, chloroform-d) δ 5.25 (s, 1H), 3.27-3.15 (m, 2H), 2.68 (dt, J = 14.4, 6.9 Hz, 4H), 2.59 (br s, 1H), 2.28 (t, J = 7.5 Hz, 2H), 1.81 (p, J = 7.2 Hz, 2H), 1.75-1.63 (m, 2H), 1.43 (s, 18H).

[0332] [ka]

[0333] 1 H NMR (400 Mhz, chloroform-d) δ 5.18 (br s, 1H), 3.63 (s, 1H), 3.21-3.12 (m, 2H), 2.65 (t, J = 6.4 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.21 (t, J = 7.2 Hz, 2H), 1.66-1.57 (m, 5H), 1.50 (q, J = 7.4 Hz, 2H), 1.45-1.40 (m, 18H). General Procedure for the Synthesis of Amino Alcohol Lipids and Amino Acid Lipids 3-n or 6-m (0.1 mmol) in CH 2 Cl 2 (0.46 mL) was added trifluoroacetic acid (TFA, 0.46 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred at room temperature for 3-4 h and monitored by thin layer chromatography. Upon completion of the reaction, the solvent was evaporated and the residue was dissolved in MeOH and concentrated. The residue was dissolved in 2 mL of THF and TEA (0.028 mL, 0.2 mmol) was added and stirred at room temperature for 10 min. The aldehyde (0.4 mmol) was then added followed by NaBH(OAc) 3(95.4 mg, 0.45 mmol) was added. The resulting solution was stirred at room temperature for 48 h. The reaction was quenched with saturated aqueous NaHCO3, the THF was removed under reduced pressure, the aqueous phase was extracted with DCM (10 mL x 3), the organic phases were combined and diluted with anhydrous Na 2 SO 4 After drying at 40° C., the solution was filtered and concentrated, and the residue was purified by silica gel chromatography to give the desired product.

[0334] [ka]

[0335] 1 H NMR (300 MHz, chloroform-d) δ 3.55 (t, J = 5.1 Hz, 2H), 2.57-2.39 (m, 12H), 1.65-1.55 (m, 2H), 1.52-1.36 (m, 6H), 1.32-1.22 (m, 54H), 0.87 (t, J = 6.6 Hz, 9H).

[0336] [ka]

[0337] 1 H NMR (300 MHz, chloroform-d) δ 4.80 (p, J = 6.3 Hz, 3H), 3.52 (t, J = 5.1 Hz, 2H), 2.61-2.32 (m, 12H), 2.27 (t, J = 7.4 Hz, 6H), 1.67-1.35 (m, 26H), 1.32-1.17 (m, 42H), 0.92-0.80 (m, 18H).

[0338] [ka]

[0339] 1H NMR (300 MHz, クロロホルム-d) δ 4.12 (td, J = 6.6, 4.5 Hz, 12H), 3.54 (t, J = 5.1 Hz, 2H), 2.56 (t, J = 5.1 Hz, 2H), 2.53-2.27 (m, 10H), 1.72-1.42 (m, 20H), 1.39-1.21 (m, 30H), 0.94-0.81 (m, 9H).

[0340]

change

[0341] 1 H NMR (300 MHz, クロロホルム-d) δ 4.65 (q, J = 5.4 Hz, 3H), 3.54 (dt, J = 9.6, 6.6 Hz, 9H), 3. 38 (dtd, J = 9.6, 6.3, 3.3 Hz, 6H), 2.54 (t, J = 5.1 Hz, 2H), 2.51-2.33 (m, 10H), 1.59-1.44 (m, 20H), 1.34-1.16 (m, 40H), 0.93-0.79 (m, 9H).

[0342]

change

[0343] 1 H NMR (400 MHz, クロロホルム-d) δ 4.65 (s, 6H), 3.53-3.49 (m, 14H), 2.55 (d, J = 5.0 Hz, 2H), 2.52-2.28 (m, 10H), 1.61-1.53 (m, 14H), 1.46-1.40 (t, J = 7.2 Hz, 6H), 1.41-1.25 (m, 30H), 0.93-0.82 (m, 9H).

[0344]

change

[0345] 1 H NMR (300 MHz, クロロホルム-d) δ 3.80-3.77 (m, 2H), 2.65-2.34 (m, 12H), 1.71-1.63 (m, 4H), 1.54-1.35 (m, 6H), 1.35-1.17 (m, 54H), 0.95-0.82 (m, 9H).

[0346]

change

[0347] 1 H NMR (300 MHz, クロロホルム-d) δ 4.80 (p, J = 6.3 Hz, 3H), 3.78 (t, J = 5.1 Hz, 2H), 2.63 (t, J = 5.4 Hz, 2H), 2.58-2.31 (m, 10H), 2.28 (t, J = 7.5 Hz, 6H), 1.73-1.36 (m, 28H), 1.32-1.20 (m, 42H), 0.91-0.82 (m, 18H).

[0348]

change

[0349] 1 H NMR (300 MHz, クロロホルム-d) δ 4.89-4.74 (m, 3H), 3.55 (t, J = 4.0 Hz, 2H), 2.77-2.31 (m, 12H), 2.28 (t, J = 7.5 Hz, 6H), 1.68-1.40 (m, 28H), 1.36-1.17 (m, 44H), 0.93-0.81 (m, 18H).

[0350]

change

[0351] 1 H NMR (300 MHz, クロロホルム-d) δ 4.68 (s, 6H), 3.66-3.58 (m, 2H), 3.54 (t, J = 6.6 Hz, 12H), 2.98-2.34 (m, 12H), 1.79-1.48 (m, 24H), 1.47-1.26 (m, 30H), 0.97-0.85 (m, 9H).

[0352]

change

[0353] 1 H NMR (300 MHz, クロロホルム-d) δ 4.80 (p, J = 6.3 Hz, 3H), 3.62 (t, J = 6.6 Hz, 2H), 2.43-2.35 (m, 12H), 2.27 (t, J = 7.5 Hz, 6H), 1.67-1.37 (m, 30H), 1.35-1.20 (m, 44H), 0.93-0.79 (m, 18H).

[0354]

change

[0355] 1 H NMR (400 MHz, クロロホルム-d) δ 4.66 (q, J = 5.4 Hz, 3H), 3.70-3.47 (m, 8H), 3.43-3.34 (m, 6H), 2.66-2.24 (m, 12H), 1.60-1.45 (q, J = 18.5, 12.9 Hz, 20H), 1.39-1.21 m, 39H), 0.88 (t, J = 6.8 Hz, 9H).

[0356]

change

[0357] 1 H NMR (300 MHz, chloroform-d) δ 3.62 (t, J = 6.3 Hz, 2H), 2.64 - 2.48 (m, 12H), 1.76-1.67 (m, 2H), 1.60-1.41 (m, 10H), 1.40-1.24 (m, 56H), 0.87 (t, J = 6.6 Hz, 9H). MS (m / z): [M+Na] + C 14 H 30 N a O 3 Calculated value: 679.7; Measured value: 679.9.

[0358] [ka]

[0359] 1 H NMR (300 Mhz, chloroform-d) δ 4.81 (p, J = 6.3 Hz, 3H), 3.63 (t, J = 6.6 Hz, 2H), 2.43-2.25 (m, 12H), 2.28 (t, J= 7.5 Hz, 6H), 1.64-1.47 (m, 22H), 1.45-1.37 (m, 8H), 1.35-1.16 (m, 46H), 0.92-0.80 (m, 18H). MS (m / z): [M+Na] + C 14 H 30 N a O 3 Calculated value: 979.9; Measured value: 979.9.

[0360] [ka]

[0361] 11H NMR (300 Mhz, chloroform-d) δ 4.29 - 3.98 (m, 12H), 3.63 (td, J = 6.6, 2.4 Hz, 2H), 3.49 - 3.43 (m, 1H), 2.70 - 2.23 (m, 12H), 1.74 - 1.62 (m, 12H), 1.60 - 1.41 (m, 12H), 1.40 - 1.22 (m, 34H), 0.97 - 0.79 (m, 9H).

[0362]

Chem.

[0363] 1 1H NMR (300 Mhz, chloroform-d) δ 4.11 (t, J = 6.6 Hz, 12H), 3.63 (t, J = 6.6 Hz, 2H), 2.51 - 2.18 (m, 12H), 1.67 (h, J = 6.9 Hz, 12H), 1.59 - 1.52 (m, 4H), 1.44 - 1.26 (m, 60H), 0.94 - 0.79 (m, 9H). MS (m / z): [M+Na] + C 14 H 30 N a O 3 Calculated value for: 985.8; Measured value: 985.9.

[0364]

Chem.

[0365] 11H NMR (300 Mhz, chloroform-d) δ 4.11 (t, J = 6.6 Hz, 12H), 3.63 (t, J = 6.6 Hz, 2H), 2.37 (t, J = 7.1 Hz, 12H), 1.72 - 1.62 (m, 12H), 1.59 - 1.52 (m, 4H), 1.46 - 1.21 (m, 66H), 0.94 - 0.80 (m, 9H). MS (m / z): [M+Na] + C 14 H 30 N a O 3 Calculated value for: 1027.9; Measured value: 1027.9.

[0366]

Chemical Structure

[0367] 1 1H NMR (300 Mhz, chloroform-d) δ 4.65 (q, J = 5.4 Hz, 3H), 3.64 - 3.51 (m, 8H), 3.43 - 3.34 (m, 6H), 2.51 - 2.29 (m, 12H), 1.60 - 1.39 (m, 24H), 1.37 - 1.19 (m, 44H), 0.87 (t, J = 6.6 Hz, 9H).

[0368]

Chemical Structure

[0369] 1 1H NMR (300 Mhz, chloroform-d) δ 4.66 (q, J = 5.4 Hz, 3H), 3.68 - 3.49 (m, 8H), 3.39 (dt, J = 9.3, 6.6 Hz, 6H), 2.46 - 2.27 (m, 12H), 1.64 - 1.49 (m, 16H), 1.49 - 1.16 (m, 52H), 0.95 - 0.79 (m, 9H). MS (m / z): [M+Na] + C14 H 30 N a O 3 Calculated value for: 859.8; Measured value: 859.9.

[0370]

Chem.

[0371] 1 H NMR (300 Mhz, chloroform-d) δ 4.65 (s, 6H), 3.61 (t, J = 6.6 Hz, 2H), 3.51 (t, J = 6.6 Hz, 12H), 2.45 - 2.30 (m, 12H), 1.63 - 1.49 (m, 16H ), 1.62 - 1.42 (m, 42H), 0.93 - 0.81 (m, 9H). MS (m / z): [M+Na] + C 14 H 30 N a O 3 Calculated value for: 817.8; Measured value: 817.9.

[0372]

Chem.

[0373] 1 H NMR (400 MHz, chloroform-d) δ 3.17 (s, 2H), 2.97 (q, J = 7.4, 6.8 Hz, 2H), 2.94 - 2.79 (m, 4H), 2.63 (t, J = 6.0 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.85 - 1.73 (m, 2H), 1.73 - 1.56 (m, 4H), 1.47 (t, J = 7.6 Hz, 2H), 1.31 - 1.19 (m, 54H), 0.88 (t, J = 6.8 Hz, 9H).

[0374]

Chem.

[0375] 1 H NMR (400 MHz, クロロホルム-d) δ 4.80 (p, J = 6.4 Hz, 3H), 3.15 (s, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.92-2.80 (m, 4H), 2.59 (d, J = 6.0 Hz, 2H), 2.41 (t, J = 8.0 Hz, 2H), 2.27 (t, J = 7.6 Hz, 6H), 1.78 (t, J = 6.4 Hz, 2H), 1.71-1.37 (m, 24H), 1.35-1.18 (m, 42H), 0.86 (t, J = 7.6 Hz, 18H).

[0376]

change

[0377] 1 H NMR (400 MHz, クロロホルム-d) δ 4.11 (t, J = 6.8 Hz, 12H), 3.16 (s, 2H), 2.95 (t, J = 5.6 Hz, 2H), 2.92-2.79 (m, 4H), 2.60 (br. s, 2H), 2.43 (br s, 2H), 1.83-1.73 (m, 2H), 1.71-1.62 (m, 16H), 1.54-1.17 (m, 56H), 0.87 (t, J = 6.8 Hz, 9H).

[0378]

change

[0379] 1H NMR (400 MHz, クロロホルム-d) δ 4.66 (q, J = 5.2 Hz, 3H), 3.65-3.47 (m, 6H), 3.43-3.35 (m, 6H), 3.16 (s, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.92-2.75 (m, 4H), 2.60 (t, J = 5.6 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H), 1.77 (q, J = 6.0 Hz, 2H), 1.73-1.61 (m, 4H), 1.60-1.53 ​​(m, 12H), 1.51-1.17 (m, 41H), 0.89 (t, J = 6.8 Hz, 9H).

[0380]

change

[0381] 1 H NMR (300 MHz, クロロホルム-d) δ 4.65 (s, 6H), 3.51 (t, J = 6.3 Hz, 12H), 3.16 (s, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.91-2.86 (m, 4H), 2.62 (br s, 2H), 2.44 (t, J = 6.0 H, 2H), 1.84-1. 74 (m, 2H), 1.72-1.52 (m, 16H), 1.51-1.18 (m, 32H), 0.98-0.81 (m, 9H).

[0382]

change

[0383] 1H NMR (400 MHz, クロロホルム-d) δ 4.83 (p, J = 6.0 Hz, 3H), 2.88 (t, J = 6.4 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.71-2.64 (m, 2H), 2.63-2.41 (m, 6H), 2.31 (t, J = 7.6 Hz, 6H), 1.82 (br s, 2H), 1.71-1.43 (m, 22H), 1.39-1.05 (m, 44H), 0.91-0.87 m, 18H).

[0384]

change

[0385] 1 H NMR (400 MHz, クロロホルム-d) δ 4.14 (t, J = 6.8 Hz, 12H), 2.87 (t, J = 6.4 Hz, 2H), 2.76-2.61 (m, 4H), 2.54-2.46 (m, 8H), 1.79-1.55 (m, 16H), 1.54-1.17 (m, 60H), 0.90 (t, J = 6.8 Hz, 9H).

[0386]

change

[0387] 1 H NMR (400 MHz, クロロホルム-d) δ 4.65 (q, J = 5.6 Hz, 3H), 3.57-3.49 (m, 6H), 3.41-3.53 (m, 6H), 2.84 (t, J = 6.4 Hz, 2H), 2.70-2.61 m, 4H), 2.51-2.40 (m, 8H), 1.70 (t, J = 7.8 Hz, 2H), 1.57-1.51 (m, 14H), 1.47-1.24 (m, 43H), 0.87 (t, J = 6.8 Hz, 9H).

[0388]

change

[0389] 1 H NMR (300 MHz, クロロホルム-d) δ 2.80-2.73 (m, 4H), 2.71-2.62 (m, 2H), 2.62-2.38 (m, 8H), 1.89-1.82 (m, 4H), 1.60 (dt, J = 13.8, 9.0 Hz, 2H), 1.53-1.36 (m, 4H), 1.32-1.17 (m, 54H), 0.88 (t, J = 6.6 Hz, 9H).

[0390]

change

[0391] 1 H NMR (300 MHz, クロロホルム-d) δ 4.80 (p, J = 6.3 Hz, 3H), 2.78-2.71 (m, 4H), 2.70-2.61 (m, 2H), 2.61-2.35 (m, 8H), 2.28 (t, J = 7.5 Hz, 6H), 1.86-1.70 (m, 4H), 1.66-1.36 (m, 24H), 1.36-1.18 (m, 42H), 0.95-0.78 (m, 18H).

[0392]

change

[0393] 1 H NMR (400 MHz, クロロホルム-d) δ 2.91-2.64 (m, 6H), 2.59-2.38 (m, 6H), 2.25 (t, J = 6.0 Hz, 2H), 1.80 - 1.69 (m, 2H), 1.69 - 1.58 (m, 4H), 1.58 - 1.49 (m, 2H), 1.47 - 1.39 (m, 4H), 1.33 - 1.17 (m, 54H), 0.89 (t, J = 6.8 Hz, 9H).

[0394]

Chem.

[0395] 1 1H NMR (400 MHz, chloroform - d) δ 4.81 (p, J = 6.4 Hz, 3H), 2.84 - 2.64 m, 6H), 2.58 - 2.41 (m, 6H), 2.31 - 2.20 (m, 8H), 1.80 - 1.69 (m, 2H), 1.69 - 1.36 (m, 28H), 1.36 - 1.08 (m, 42H), 0.88 - 0.84 (m, 18H).

[0396]

Chem.

[0397] 1 1H NMR (400 MHz, chloroform - d) δ 4.81 (ddd, J = 12.4, 6.8, 5.5 Hz, 3H), 2.72 (d, J = 8.6 Hz, 6H), 2.45 (q, J = 9.5, 7.8 Hz, 6H), 2.28 (t, J = 7.5 Hz, 6H), 2.21 (t, J = 6.6 Hz, 2H), 1.72 (t, J = 7.8 Hz, 2H), 1.68 - 1.42 (m, 26H), 1.42 - 1.16 (m, 46H), 0.93 - 0.80 (m, 18H). MS (m / z): [M + H] + C 60 H 117 N 2 O 8 Calculated value for C, H, N, O: 993.8805; Measured value: 993.8782.

[0398]

change

[0399] 1 H NMR (400 Mhz, クロロホルム-d) δ 4.10 (t, J = 6.8 Hz, 12H), 2.78-2.58 (m, 6H), 2.49 (p, J = 6.8 Hz, 6H), 2.20 (t, J = 6.8 Hz, 2H), 1.76-1.56 (m, J = 8.5, 7.7 Hz, 16H), 1.55-1.46 (m, 6H), 1.45-1.22 (m, 56H), 0.87 (t, J = 6.8 Hz, 9H).

[0400]

change

[0401] 1 H NMR (400 Mhz, クロロホルム-d) δ 4.65 (q, J = 5.6 Hz, 3H), 3.62-3.49 (m, 6H), 3.45-3.31 (m, 6H), 2.79-2.56 (m, 6H), 2.51-2.36 (m, 6H), 2.20 (t, J = 6.8 Hz, 2H), 1.71 (br s, 2H), 1.66-1.40 (m, 22H), 1.40-1.17 (m, 41H), 0.88 (t, J = 6.4 Hz, 9H).

[0402]

change

[0403] 1H NMR (400 Mhz, chloroform-d) δ 4.64 (s, 6H), 3.50 (t, J = 6.8 Hz, 12H), 2.70-2.58 (m, 6H), 2.58-2.39 (m, 6H), 2.20 (t, J = 6.8 Hz, 2H), 1.71 (t, J = 7.8 Hz, 2H), 1.65-1.41 (m, 22H), 1.39-1.24 (m, 32H), 0.89-0.86 (m, 9H). General procedure for the synthesis of 9-R A solution of amine 8 (24.3 mg, 0.15 mmol, 1.0 equiv) and aldehyde (0.39 mmol, 2.6 equiv) in THF was treated with NaBH(OAc) 3 was added in one portion. The resulting mixture was stirred at room temperature for 12 h. THF was removed by rotary evaporation under reduced pressure. The residue was dissolved in 20 mL of DCM and washed twice with 10 mL of saturated aqueous NaHCO3. The organic layer was washed with anhydrous Na 2 SO 4 It was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (0% to 100% Ultra in dichloromethane) to give the corresponding product as a yellow oil.

[0404] [ka]

[0405] 1 H NMR (400 MHz, chloroform-d) δ 3.60 (t, J = 5.2 Hz, 4H), 2.65-2.48 (m, 6H), 2.52-2.48 (m, 2H), 2.41-2.37 (m, 4H), 1.61 (t, J = 6.4 Hz, 2H), 1.51-1.34 (m, 4H), 1.40 -1.19 (m, 36H), 0.87 (t, J = 6.8 Hz, 6H).

[0406] [ka]

[0407] 1 H NMR (300 MHz, クロロホルム-d) δ 4.80 (p, J = 6.3 Hz, 2H), 3.60 (t, J = 5.1 Hz, 4H), 2.60 (q, J = 6.0, 5.1 Hz, 6H), 2.51 (q, J = 5.8, 4.9 Hz, 2H), 2.47-2.34 (m, 4H), 2.27 (t, J = 7.5 Hz, 4H), 1.65-1.37 (m, 18H), 1.32-1.20 (m, 28H), 0.89-0.83 (m, 12H).

[0408]

change

[0409] 1 H NMR (400 MHz, クロロホルム-d) δ 4.13 (t, J = 6.8 Hz, 8H), 3.64 (t, J = 5.2 Hz, 4H), 2.70-2.61 (m, 6H), 2.58-2.52 (m, 2H), 2.51-2.39 (m, 4H), 1.72-1.62 (m, 10H), 1.53-1.24 (m, 40H), 0.90 (t, J = 6.8 Hz, 6H).

[0410]

change

[0411] 1 H NMR (300 MHz, クロロホルム-d) δ 4.66 (q, J = 5.4 Hz, 2H), 3.68-3.52 (m, 8H), 3.44-3.36 (m, 4H), 2.78-2.39 (m, 12H), 1.67 (t, J = 6.6 Hz, 2H), 1.64-1.49 (m, 12H), 1.40-1.27 (m, 26H), 0.96-0.83 (m, 6H).

[0412] [ka]

[0413] 1 H NMR (400 MHz, chloroform-d) δ 4.65 (s, 4H), 3.60 (t, J = 5.2 Hz, 4H), 3.51 (t, J = 6.8 Hz, 8H), 2.67-2.55 (m, 6H), 2.52 (t, J = 6.2 Hz, 2H), 2.44-2.40 (m, 4H), 1.64-1.53 ​​(m, 10H), 1.50-1.41 (m, 4H), 1.40-1.23 (m, 20H), 0.88 (t, J = 6.8 Hz, 6H). Other advantages which are obvious and inherent to the present invention will be apparent to those skilled in the art. It will be understood that certain characteristics and subcombinations are advantageous and may be used without reference to other characteristics and subcombinations. It will be understood that all matters herein described or shown in the accompanying drawings are to be interpreted in an illustrative and not limiting sense, since many possible embodiments of the invention contemplated by and within the scope of the claims may be practiced without departing from the scope thereof.

[0414] The methods of the appended claims are not limited in scope by the specific methods described herein, which are intended to be illustrative of some aspects of the claims, and any methods that are functionally equivalent are intended to be within the scope of the claims. Various modifications of the methods in addition to those shown and described herein are intended to be within the scope of the appended claims. Furthermore, although only certain representative method steps disclosed herein have been specifically described, other combinations of method steps are also intended to be within the scope of the appended claims, even if not specifically recited. Thus, although a combination of steps, elements, components, or elements may be explicitly referred to herein, other combinations of steps, elements, components, and elements are included even if not explicitly stated.

Claims

1. A composition comprising a compound defined by Formula I, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, R １０ is a substituted or unsubstituted C １ -C ５ is alkyl, R １１ is a substituted or unsubstituted C １ -C ５ is alkyl, R １２ , R １３ , and R １４ are each independently substituted or unsubstituted C ６ -C ２０ is alkyl, However, R １０ Ga-C ５ H １０ - and R １１ Ga-C ３ H ６ -, then R １２ , R １３ , and R １４ is everything 【Chemistry 2】 Instead, However, R １０ Ga-C ５ H １０ - and R １１ Ga-C ３ H ６ -, then R １２ , R １３ , and R １４ is everything 【Transformation 3】 isn't it].

2. The compound has formula IA: 【Chemistry 4】 10. The composition of claim 1, wherein the compound is defined by:

3. 10. The composition of claim 1, wherein the compound is defined by formula I-B or a pharmaceutically acceptable salt thereof: 【Transformation 5】 [wherein n is an integer from 1 to 5].

4. R １２ , R １３ , and R １４ are each independently substituted or unsubstituted C １０ -C １８ The composition of claim 1 wherein the alkyl is alkyl.

5. The composition of claim 1, wherein the compound is defined by Formula I-C or a pharmaceutically acceptable salt thereof: 【Transformation 6】 [wherein n is an integer from 1 to 4].

6. The compound is 【Chemistry 7-1】 【Chemistry 7-2】 【Transformation 7-3】 【Chemistry 7-4】 【Transformation 7-5】 【Transformation 7-6】 【Transformation 7-7】 [Transformation 7-8] 10. The composition of claim 1, wherein the compound is selected from the group consisting of pharmaceutically acceptable salts thereof, and combinations thereof.

7. The compound is 【Transformation 8】 10. The composition of claim 1, wherein the compound is selected from the group consisting of pharmaceutically acceptable salts thereof, and combinations thereof.

8. A composition comprising a compound defined by Formula II, or a pharmaceutically acceptable salt thereof: 【Chemistry 9】 [In the formula, R １５ is a substituted or unsubstituted C １ -C ５ is alkyl, R １６ is a substituted or unsubstituted C １ -C ５ is alkyl, R １７ , R １８ , and R １９ are each independently substituted or unsubstituted C ６ -C ２０ is alkyl, However, R １５ Ga-C ５ H １０ - and R １６ Ga-C ３ H ６ -, then R １７ , R １８ , and R １９ is everything 【Chemistry 10】 Instead, However, R １５ Ga-C ５ H １０ - and R １６ Ga-C ３ H ６ -, then R １７ , R １８ , and R １９ is everything 【Chemistry 11】 isn't it].

9. The compound has formula II-A: 【Chemistry 12】 9. The composition of claim 8, wherein the compound is defined by:

10. The composition of claim 8, wherein the compound is defined by Formula II-B or a pharmaceutically acceptable salt thereof: 【Chemistry 13】 [wherein m is an integer of 1 to 5].

11. R １７ , R １８ , and R １９ are each independently substituted or unsubstituted C １０ -C １８ The composition of claim 8 wherein the alkyl is alkyl.

12. The compound is 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 【Chemistry 14-6】 【Chemistry 14-7】 【Chemistry 14-8】 9. The composition of claim 8, wherein the compound is selected from the group consisting of pharmaceutically acceptable salts thereof, and combinations thereof.

13. The compound is 【Chemistry 15】 9. The composition of claim 8, wherein the compound is selected from the group consisting of pharmaceutically acceptable salts thereof, and combinations thereof.

14. A composition comprising a compound defined by Formula III, or a pharmaceutically acceptable salt thereof: 【Chemistry 16】 [In the formula, R ２０ is a substituted or unsubstituted C １ -C ５ is alkyl, R ２１ and R ２２ are each independently substituted or unsubstituted C ６ -C ２０ alkyl].

15. The compound has the formula III-A: 【Chemistry 17】 15. The composition of claim 14, wherein the compound is defined by:

16. R ２１ and R ２２ are each independently substituted or unsubstituted C １０ -C １８ The composition of claim 14, wherein the alkyl is alkyl.

17. The compound is 【Chemistry 18-1】 【Chemistry 18-2】 15. The composition of claim 14, wherein the compound is selected from the group consisting of pharmaceutically acceptable salts thereof, and combinations thereof.

18. The compound is 【Chemistry 19-1】 【Chemistry 19-2】 15. The composition of claim 14, wherein the compound is selected from the group consisting of pharmaceutically acceptable salts thereof, and combinations thereof.

19. A lipid particle comprising the composition of any one of claims 1 to 18.

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