Fentanyl haptens for use as antigens in vaccines

Abstract

The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. The compound of Formula (I) is used as hapten and is useful as an antigen in a vaccine for a disease, (e.g., opioid addiction). Also provided in the present disclosure are vaccines, pharmaceutical compositions, kits, methods, and uses including or using compounds of Formula (I) and compositions comprising compounds of Formula (I).

Description

[0001] FENTANYL HAPTENS FOR USE AS ANTIGENS IN VACCINES RELATEDAPPLICATIONThis application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N.63 / 685,537, filed August 21, 2024, which is incorporated herein by reference in its entirety. FEDERALLY SPONSORED RESEARCH This invention was made with government support under Contract Number 75N93020C00038 awarded by the National Institutes of Health. The Government has certain rights in the invention. BACKGROUND Illicit drug use is taking a major toll on public health with >100 Americans dying of opioid overdose per day, especially due to fentanyl (FEN) overdose. There is an unmet need for biomedical interventions that prevent FEN overdose deaths. Haptens are small molecules that elicit an immune response when attached to a carrier such as a protein. The immune response includes the production of hapten-specific antibodies which can cross-react with a target molecule and / or its metabolites. SUMMARY The present disclosure stems from identification of an approach to address the opioid crisis by development of opioid vaccines that induce antibodies which block the ability of fentanyl to cross the blood brain barrier where it suppresses respiration and leads to death. To this end, the present disclosure describes the systematic creation and evaluation of fentanyl analogs that are effective in hapten-protein carrier conjugation, reduce agonist / antagonist binding of the Mu opioid receptor, and impart vaccine immunogenicity. In particular, the disclosed haptens are coupled with a carrier protein to induce and / or elicit an enhanced immune response in a subject. The immune response includes the production of hapten-specific antibodies which can cross-react with fentanyl, fentanyl analogs, metabolites of fentanyl, and / or fentanyl analog metabolites. Accordingly, provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein: X is halogen, –ORA, –N(RA)2, –SRA, or a carrier protein; L is substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted alkyl-(heterocyclyl)-alkylene; each instance of R1is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA; each instance of R2is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA; each instance of R3is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; m is an integer from 0-5; n is an integer from 0-9; and p is an integer from 0-5. In another aspect, provided are pharmaceutical compositions including compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, a pharmaceutical composition described herein includes a therapeutically or prophylactically effective amount of a compound of Formula (I). In certain embodiments, a pharmaceutical composition described herein further comprises an additional pharmaceutical agent. In another aspect, provided are vaccine compositions comprising an adjuvant and a compound of Formula (I). In another aspect, provided are kits including a compound or composition described herein and instructions for use. In another aspect, the present disclosure provides methods of inducing an immune response against an opioid in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a composition described herein. In another aspect, the present disclosure provides methods of enhancing an immune response against an opioid in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a composition described herein. In another aspect, the present disclosure provides methods of preventing or treating opioid addiction in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a composition described herein. In another aspect, the present disclosure provides methods of enhancing the cessation rate or reducing the relapse rate, or both, for a subject with opioid use disorder (OUD), the methods comprising administering to the subject an effective amount of a composition described herein. In another aspect, provided are methods of vaccinating a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or composition described herein. In yet another aspect, the present disclosure provides compounds, compositions, and / or vaccines described herein for use in a method of the disclosure (e.g., inducing an immune response, a method of treating and / or preventing a disease (e.g., opioid addiction). DEFINITIONS Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein. Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw– Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6. The term “aliphatic” includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term “alkyl” includes straight, branched and cyclic alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl”, and the like. Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the like encompass both substituted and unsubstituted groups. In certain embodiments, “lower alkyl” is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, vinyl, allyl, n-butyl, sec- butyl, isobutyl, tert-butyl, cyclobutyl, -CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert- pentyl, cyclopentyl, -CH2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH2-cyclohexyl moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1- yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl (propargyl), 1-propynyl, and the like. The term “alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n–propyl, isopropyl), butyl (C4) (e.g., n–butyl, tert–butyl, sec–butyl, iso–butyl), pentyl (C5) (e.g., n–pentyl, 3–pentanyl, amyl, neopentyl, 3–methyl–2–butanyl, tertiary amyl), and hexyl (C6) (e.g., n–hexyl). Additional examples of alkyl groups include n–heptyl (C7), n– octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–10 alkyl (such as unsubstituted C1-6 alkyl, e.g., –CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–10 alkyl (such as substituted C1-6alkyl, e.g., –CF3, Bn). “Alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds, and no triple bonds (“C2–20 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2–4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is unsubstituted C2–10 alkenyl. In certain embodiments, the alkenyl group is substituted C2–10alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., –CH=CHCH3 ) may be an (E)- or (Z)- double bond. “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds, and optionally one or more double bonds (“C2–20alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2–10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–4alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is unsubstituted C2–10alkynyl. In certain embodiments, the alkynyl group is substituted C2–10 alkynyl. “Carbocyclyl” or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3–10carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3–8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5–10carbocyclyl”). Exemplary C3–6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3–8carbocyclyl groups include, without limitation, the aforementioned C3–6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3–10carbocyclyl groups include, without limitation, the aforementioned C3–8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3–10carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3–10carbocyclyl. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3–10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3–8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5–6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5–10cycloalkyl”). Examples of C5–6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3–6 cycloalkyl groups include the aforementioned C5–6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3–8cycloalkyl groups include the aforementioned C3–6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3–10cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3–10 cycloalkyl. “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non– aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3–10 membered heterocyclyl. In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7– membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5- membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6–14 aryl. In certain embodiments, the aryl group is substituted C6–14 aryl. “Aralkyl” is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, the aralkyl is optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl. “Heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5– indolyl). In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5–14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5–14 membered heteroaryl. Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6– bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. “Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group. “Unsaturated” or “partially unsaturated” refers to a group that includes at least one double or triple bond. A “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups). Likewise, “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds. Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups, are further referred to using the suffix –ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene. An atom, moiety, or group described herein may be unsubstituted or substituted, as valency permits, unless otherwise provided expressly. The term “optionally substituted” refers to substituted or unsubstituted. A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent. Exemplary carbon atom substituents include, but are not limited to, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1-6alkyl, −ON(C1-6alkyl)2, −N(C1-6alkyl)2, −N(C1-6alkyl)3+X−, −NH(C1-6alkyl)2+X−, −NH2(C1-6 alkyl)+X−, −NH3+X−, −N(OC1-6 alkyl)(C1-6 alkyl), −N(OH)(C1-6 alkyl), −NH(OH), −SH, −SC1-6 alkyl, −SS(C1-6 alkyl), −C(=O)(C1-6 alkyl), −CO2H, −CO2(C1-6 alkyl), −OC(=O)(C1-6alkyl), −OCO2(C1-6alkyl), −C(=O)NH2, −C(=O)N(C1-6alkyl)2, −OC(=O)NH(C1-6alkyl), −NHC(=O)( C1-6alkyl), −N(C1-6alkyl)C(=O)( C1-6alkyl), −NHCO2(C1-6 alkyl), −NHC(=O)N(C1-6 alkyl)2, −NHC(=O)NH(C1-6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6 alkyl), −OC(=NH)(C1-6 alkyl), −OC(=NH)OC1-6 alkyl, −C(=NH)N(C1-6 alkyl)2, −C(=NH)NH(C1-6alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6alkyl)2, −OC(NH)NH(C1-6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1-6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1-6 alkyl), −SO2N(C1-6 alkyl)2, −SO2NH(C1-6 alkyl), −SO2NH2, −SO2C1-6 alkyl, −SO2OC1-6 alkyl, −OSO2C1-6alkyl, −SOC1-6alkyl, −Si(C1-6alkyl)3, −OSi(C1-6alkyl)3−C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, −C(=O)S(C1-6 alkyl), −C(=S)SC1-6 alkyl, −SC(=S)SC1-6 alkyl, −P(=O)(OC1-6 alkyl)2, −P(=O)(C1-6 alkyl)2, −OP(=O)(C1-6 alkyl)2, −OP(=O)(OC1-6 alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion. A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO − 3 , HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−,B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. “Halo” or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I). “Acyl” refers to a moiety selected from the group consisting of –C(=O)Raa, –CHO, – Rbbare as defined herein. Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1-10alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. For example, nitrogen protecting groups such as amide groups (e.g., −C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide. Nitrogen protecting groups such as carbamate groups (e.g., −C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1- methylethyl carbamate (t-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3- dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m- chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. Nitrogen protecting groups such as sulfonamide groups (e.g., −S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N’-p-toluenesulfonylaminoacyl derivative, N’-phenylaminothioacyl derivative, N- benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2- one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl- 4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N- 2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2- picolylamino N’-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N,N’- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. As used herein, a “leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups OC OP(=O)2Raa, –OP(=O)(Raa)2, –OP(=O)(ORcc)2, –OP(=O)2N(Rbb)2, and –OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein). A “hydrocarbon chain” refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) one or more chains of carbon atoms immediately between the two radicals of the hydrocarbon chain; (2) optionally one or more hydrogen atoms on the chain(s) of carbon atoms; and (3) optionally one or more substituents (“non-chain substituents,” which are not hydrogen) on the chain(s) of carbon atoms. A chain of carbon atoms consists of consecutively connected carbon atoms (“chain atoms”) and does not include hydrogen atoms or heteroatoms. However, a non-chain substituent of a hydrocarbon chain may include any atoms, including hydrogen atoms, carbon atoms, and heteroatoms. For example, hydrocarbon chain –CAH(CBH2CCH3)– includes one chain atom CA, one hydrogen atom on CA, and non-chain substituent –(CBH2CCH3). The term “Cx hydrocarbon chain,” wherein x is a positive integer, refers to a hydrocarbon chain that includes x number of chain atom(s) between the two radicals of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used for the definition of the hydrocarbon chain. For example, –CH(C2H5)– is a C1 hydrocarbon chain, and is a C3 hydrocarbon chain. When a range of values is used, the meaning of the range is as described herein. For example, a C3-10hydrocarbon chain refers to a hydrocarbon chain where the number of chain atoms of the shortest chain of carbon atoms immediately between the two radicals of the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbon chain may be saturated (e.g., –(CH2)4–). A hydrocarbon chain may also be unsaturated and include one or more C=C and / or C≡C bonds anywhere in the hydrocarbon chain. For instance, –CH=CH–(CH2)2–, –CH2–C≡C–CH2–, and –C≡C–CH=CH– are all examples of an unsubstituted and unsaturated hydrocarbon chain. In certain embodiments, the hydrocarbon chain is unsubstituted (e.g., –C≡C– or –(CH2)4–). In certain embodiments, the hydrocarbon chain is substituted (e.g., –CH(C2H5)– and –CF2–). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring. For instance, herein. When a chain atom of a Cx hydrocarbon chain is replaced with a heteroatom, the resulting group is referred to as a Cxhydrocarbon chain wherein a chain atom is replaced with a heteroatom, as opposed to a Cx-1 hydrocarbon chain. For example, is a C3 hydrocarbon chain wherein one chain atom is replaced with an oxygen atom. The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R⋅0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H2O) and hexahydrates (R⋅6 H2O)). The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations. It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. In some embodiments, a stereoisomer may be an atropisomer (stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers). The term “polymorphs” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. The term “small molecule” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g / mol, not more than about 900 g / mol, not more than about 800 g / mol, not more than about 700 g / mol, not more than about 600 g / mol, not more than about 500 g / mol, not more than about 400 g / mol, not more than about 300 g / mol, not more than about 200 g / mol, or not more than about 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention. The terms “composition” and “formulation” are used interchangeably. A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., neonate, infant, child, or adolescent) or adult subject (e.g., young adult, middle–aged adult, or older adult)) or non–human animal or plant. In certain embodiments, the non–human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. A “patient” refers to a human subject in need of treatment of a disease or disorder. The subject may also be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a non-vascular land plant. In certain embodiments, the plant is a vascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant is a tree or shrub. The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. The terms “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject. The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., considering a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of relapse of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of relapse of the disease than an average healthy member of a population. The terms “condition,” “disease,” and “disorder” are used interchangeably. An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. When an effective amount of a composition is referred herein, it means the amount is prophylactically and / or therapeutically effective, depending on the subject and / or the disease to be treated. Determining the effective amount or dosage is within the abilities of one skilled in the art. A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. A “prophylactically effective amount” of a compound described herein is an amount effective to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. An “adjuvant” refers to a pharmacological or immunological agent that modifies the effect of other agents, for example, of an antigen in a vaccine. Adjuvants are typically included in vaccines to enhance the recipient subject’s immune response to an antigen. The use of adjuvants enables induction of a greater immune response in a subject with the same dose of antigen, or the induction of a similar level of immune response with a lower dose of injected antigen (aka “antigen dose sparing”). Adjuvants that are known to those of skill in the art, include, without limitation: aluminum salts, liposomes, monophosphoryl lipid A (MPLA), molecular cages for antigen, components of bacterial cell walls, endocytosed nucleic acids such as double-stranded RNA (dsRNA), single-stranded DNA (ssDNA), and unmethylated CpG dinucleotide-containing DNA. Adjuvants function in several ways, for example, but not limited to, increasing the surface area of antigen, prolonging the retention of the antigen in the body thus allowing time for the lymphoid system to have access to the antigen, slowing the release of antigen, targeting antigen to antigen-presenting cells, engaging innate immune pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) to activate leukocytes such as antigen-presenting cells (e.g., monocytes, macrophages, and / or dendritic cells), enhancing T cell responses, either directly or indirectly via innate immune modulation, or otherwise eliciting broad activation of the cells of the immune system. See, e.g., H. S. Warren et al, Annu. Rev. Immunol., 4:369 (1986) and B. Pulendran, et al., Nat. Rev. Drug Discov.20, 454–475 (2021), both of which are incorporated herein by reference. The ability of an adjuvant to induce and increase a specific type of immune response and the identification of that ability is thus a key factor in the selection of particular adjuvants for vaccine use against a particular pathogen. Adjuvants that are known to those of skill in the art, include, without limitation: aluminum salts (referred to herein as “alum”), liposomes, lipopolysaccharide (LPS) or its derivatives such as monophosphoryl lipid A (MPLA), molecular cages for antigen, components of bacterial cell walls, endocytosed nucleic acids such as double-stranded RNA (dsRNA), single stranded RNA (ssRNA), single-stranded DNA (ssDNA), and unmethylated CpG dinucleotide-containing DNA. Typical adjuvants include oil-in-water emulsions, e.g., Freund's adjuvant and MF59, and chemical compounds such as aluminum hydroxide or alum. At present, currently licensed vaccines in the United States contain only a limited number of adjuvants, such as alum that enhances production of T helper 2 (Th2) cells and MPLA which activates innte immunity via Toll-like receptor 4 (TLR4). Many of the most effective adjuvants include bacteria or their products, e.g., self- adjuvanted microorganisms such as the live attenuated strain of Mycobacterium bovis named Bacillus Calmette-Guérin (BCG) vaccine and microorganism components, e.g., alum- precipitated diphtheria toxoid and derivatives of bacterial lipopolysaccharide and endotoxins such as MPLA. A “hapten” refers to a small molecule which elicits a detectable immune response when attached to a carrier moiety (e.g., carrier protein). When constructed as an immunoconjugate, the hapten is characterized as the specificity-determining portion of the immunoconjugate. A “carrier protein” as used herein, refers to a protein that is a conjugation partner capable of enhancing the immunogenicity of the hapten. BRIEFDESCRIPTION OF THEDRAWINGSThe accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. In the drawings: FIGs.1A-B Depict Fentanyl Haptens for use as Antigens in Addiction Vaccines. FIG. 1A: overview of rational hapten design strategy. The systematic creation and evaluation of FEN analogs for useful hapten-protein carrier conjugation, reduced agonist / antagonist binding of the Mu opioid receptor and vaccine immunogenicity. FIG.1B: Details of Oxeth, Oxeth2, MADD, AADD, PDD, and CDDD, including rationale for specific R group modification, and confirmed physicochemical properties, including molecular weight, partition coefficient (clogP) and topological polar surface area (t-PSA). FIGs.2A-B Depict in vitro analysis of hapten activity to the human μ-receptor. FIG. 2A: Six novel haptens were tested for activity against the human μ-receptor by Eurofins using CHO-K1 vitro assays. Haptens were considered agonists to the μ-receptor if cAMP levels in exposed CHO-K1 cells expressing the human μ-receptor increased by more than 50% when compared to a known agonist compared to hapten binding of the known μ-receptor, DAMGO (([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), a synthetic opioid peptide with high μ-opioid receptor specificity (i.e., 100% agonist activity set at 3.90nM DAMGO). FIG.2B: Compound were tested for their ability to inhibit binding to the μ-receptor by co-incubating the compound with 3nM [3H]Morphine for 1 hour (i.e., 100% agonist activity). Haptens which inhibited at least 50% of [3H]Morphine’s ability to bind to the μ-receptor were considered capable of binding to the μ-receptor binding site. In all, no novel hapten reached the cutoff threshold for either agonist activity or receptor binding. Any activity that was observed was below the 50% threshold and was lost when tittered to lower concentrations. FIGs.3A-B show that the novel haptens do not impact nociception in mice. Female Balb / c mice were immunized with one of six novel haptens or saline and monitored for 10 weeks. At 10 weeks mice were given either 100 μg / kg or 1000 μg / kg fentanyl and their responses to external stimuli measured to determine the effectiveness of the fentanyl analgesic using either a tail flick assay (FIG.3A) or hotplate assay (FIG.3B). Saline control mice showed no reduction in mean percentage maximum possible effect (%MPE) to the administered fentanyl in either assay. All mice immunized with one of the experimental haptens demonstrated a meaningful reduction in %MPE indicating a protective effect of vaccination to fentanyl by the haptens. FIGs.4A-D show that adjuvanticity boosts antibody response to FEN-hapten antigens. In vivo evaluation of novel haptens conjugated to CRM197 for anti-fentanyl antibodies with and without TLR7 / 8 adjuvant. FIG.4A: Groups of Balb / c (N=5-10 mice) immunized IM with saline, CRM197-FEN (CRM-Fen), CRM-Fen+Alum::UM-3003, or one of six novel haptens + / - Alum:UM-3003 on weeks 0, 3, and 6 and bled for immunological analysis on weeks 4, 6, 8, and 10. FIG.4B: Week 8 total anti-fentanyl IgG by immunization group demonstrated differences in mean IgG between saline control and adjuvated Oxeth conjugated to CRM197 (x = 3455 ng / mL, SD = 5325, n = 10, p = 0.0370) and adjuvanted Oxeth2 conjugated to CRM197 (x = 8497 ng / mL, SD = 21,906, n = 10, p = 0.0298). FIG.4C: At week 10 anti-fentanyl IgG2a levels were elevated in the Oxeth2 test groups, however, not noticeably different to saline nor between adjuvanted and non-adjuvanted test groups. FIG. 4D: The ratio of IgG2a to IgG1 due to TLR7 / 8 adjuvantation. No distinct differences in mean IgG2a / IgG1 ratio were seen at week 10 between groups. However, CRM-FEN had the highest mean ratio (x = 13.16, SD=20.91, n=5, p=>0.999). All graphs show mean ± SEM. *p<0.05 **p<0.01, ***p<0.001, ****p<0.0001 determined by Kruskal-Wallis Test for multiple comparisons. FIGs.5A-B show mouse immunogenicity to fentanyl following immunization with Oxeth2 conjugated to CRM197 and adjuvanted with TLR7 / 8 adjuvant plus alum. Balb / c mice were immunized with 5 μg of Oxeth2 adjuvanted with or without TLR7 / 8 adjuvant UM-3003 adsorbed to alum and monitored for 8 weeks. FIG.5A: Mice vaccinated with the adjuvanted Oxeth2 demonstrated significantly higher IgG concentrations at weeks 4 -10 (10-100-fold increase in anti-fentanyl IgG compared to saline control). N = 5-10 per group. FIG.5B: Mice vaccinated with the adjuvanted Oxeth2 demonstrated significantly higher IgG2a concentrations at weeks 4, 6, and 8. Serum was tested via indirect ELISA against BSA-FEN. Results are shown as mean, *p<0.05 **p<0.01, of adjuvanted group by week vs non- adjuvanted group of same week as determined by Mann-Whitney Test. Weeks post primary immunization are indicated on the X axis . Booster immunizations given at weeks 4 and 6. N = 5-10 per group. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Described herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof. The disclosed compounds are haptens and, in certain embodiments, include a carrier protein to form an immunoconjugate. The compounds have little or no agonist / antagonist binding of the Mu opioid receptor. The immunoconjugates induce and / or elicit an enhanced immune response in a subject and are useful in vaccines against opioids such as fentanyl, fentanyl analogs and / or their metabolites. Compounds In one aspect, the present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: X is halogen, –ORA, –N(RA)2, –SRA, or a carrier protein; L is substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted alkyl-(heterocyclyl)-alkylene; each instance of R1is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA; each instance of R2is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA; each instance of R3is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; m is an integer from 0-5; n is an integer from 0-9; and p is an integer from 0-5. X As described herein, X is halogen, –ORA, –N(RA)2, –SRA, or a carrier protein. In certain embodiments, X is –ORA. In certain embodiments, wherein X is –ORA, and RAis hydrogen, or substituted or unsubstituted alkyl. In certain embodiments, X is –OH, -OCH3, - OCH2Ph, or -OC(CH3)3. In certain embodiments, X is –OH. In certain embodiments, X is - OCH3. In certain embodiments, X is -OCH2Ph. In certain embodiments, X is -OC(CH3)3. In certain embodiments, X is a carrier protein. In certain embodiments, X the carrier protein is a pharmaceutically acceptable protein that enables a safe and effective hapten approach. In certain embodiments, X is a tetanus toxoid (TT), diphtheria toxoid (DT), cross- reacting material (CRM), a non-toxic variant of Clostridium diphtheriae toxin (CRM197), meningococcal outer membrane protein complex (OMPC), Haemophilus influenzae protein D (HiD), or another suitable non-toxic microbial protein. In certain embodiments, X is a tetanus toxoid (TT), diphtheria toxoid (DT), cross-reacting material (CRM), a non-toxic variant of Clostridium diphtheriae toxin (CRM197), meningococcal outer membrane protein complex (OMPC), or Haemophilus influenzae protein D (HiD), or other pharmaceutically acceptable protein that enables a safe and effective hapten approach. In certain embodiments, X is a tetanus toxoid (TT), diphtheria toxoid (DT), cross-reacting material (CRM), a non-toxic variant of Clostridium diphtheriae toxin (CRM197), meningococcal outer membrane protein complex (OMPC), or Haemophilus influenzae protein D (HiD). In certain embodiments, X is a cross-reacting material (CRM). In certain embodiments, X is CRM197. L As described herein, L is substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted alkyl-(heterocyclyl)-alkylene. In certain embodiments, L is substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted alkyl-(heterocyclyl)-alkylene. In certain embodiments, L is substituted or unsubstituted C2-10heteroalkylene, substituted or unsubstituted C3-6cycloalkylene, or substituted or unsubstituted alkyl-(4-6-membered heterocyclyl)-alkylene. In certain embodiments, L comprises at least one instance of oxygen. In certain embodiments, L comprises at least two instances of oxygen. In certain embodiments, L comprises at least one instance of nitrogen. In certain embodiments, L is substituted or unsubstituted heteroalkylene. In certain embodiments, L is substituted or unsubstituted C2-10 heteroalkylene. In certain embodiments, L is substituted or unsubstituted C2-8heteroalkylene. In certain embodiments, L is substituted or unsubstituted C2-6 heteroalkylene. In certain embodiments, L is substituted or unsubstituted C3-6 heteroalkylene. In certain embodiments, L is unsubstituted C3-6 heteroalkylene. In certain embodiments, L is substituted or unsubstituted C2-4heteroalkylene. In certain embodiments, L is unsubstituted C2-4 heteroalkylene. In certain embodiments, L is , . In certain embodiments, L is certain embodiments, L is . In certain embodiments, L is , or . In certain embodiments, L is . In certain embodiments, L is . In certain embodiments, L is substituted or unsubstituted carbocyclylene. In certain embodiments, L is unsubstituted carbocyclylene. In certain embodiments, L is substituted or unsubstituted cycloalkylene. In certain embodiments, L is unsubstituted cycloalkylene. In certain embodiments, L is substituted or unsubstituted C3-6cycloalkylene. In certain embodiments, L is unsubstituted C3-6 cycloalkylene. In certain embodiments, L is substituted or unsubstituted cyclopropylene. In certain embodiments, L is unsubstituted cyclopropylene. In certain embodiments, L is . In certain embodiments, L is unsubstituted cyclopropylene. In certain embodiments, L is . In certain embodiments, L is . In certain embodiments, L is unsubstituted cyclopropylene. In certain embodiments, L is . In certain embodiments, L is . In certain embodiments, L is substituted or unsubstituted alkyl-(heterocyclyl)- alkylene. In certain embodiments, L is substituted or unsubstituted alkyl-(4-6-membered heterocyclyl)-alkylene. In certain embodiments, L is unsubstituted alkyl-(4-6-membered heterocyclyl)-alkylene. In certain embodiments, L is unsubstituted C1-2alkyl-(4-6-membered heterocyclyl)-C1-2 alkylene. In certain embodiments, L is unsubstituted C1-2 alkyl-(5-6- membered heterocyclyl)-C1-2 alkylene. In certain embodiments, L is unsubstituted C1-2 alkyl- (6-membered heterocyclyl)-C1-2alkylene, wherein the 6-membered heterocyclyl has at least one nitrogen atom in the ring. In certain embodiments, L is unsubstituted C1-2alkyl-(6- membered heterocyclyl)-C1-2 alkylene, wherein the 6-membered heterocyclyl has at least two nitrogen atoms in the ring. In certain embodiments, L is . R1and m As described herein, each instance of R1is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA. In certain embodiments, each instance of R1is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, each instance of R1is independently halogen, substituted or unsubstituted alkyl. In certain embodiments, each instance of R1is independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, each instance of R1is independently substituted or unsubstituted C1-4 alkyl. In certain embodiments, each instance of R1is independently substituted or unsubstituted C1-3alkyl. In certain embodiments, each instance of R1is independently substituted or unsubstituted C1-2 alkyl. In certain embodiments, each instance of R1is independently halogen (e.g., -F). In certain embodiments, m is an integer from 0-4. In certain embodiments, m is an integer from 0-3. In certain embodiments, m is an integer from 0-2. In certain embodiments, m is 0 or 1. In certain embodiments, m is 0. R2and n As described herein, each instance of R2is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA. In certain embodiments, each instance of R2is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, each instance of R2is independently halogen, substituted or unsubstituted alkyl. In certain embodiments, each instance of R2is independently substituted or unsubstituted C1-6alkyl. In certain embodiments, each instance of R2is independently substituted or unsubstituted C1-4 alkyl. In certain embodiments, each instance of R2is independently substituted or unsubstituted C1-3 alkyl. In certain embodiments, each instance of R2is independently substituted or unsubstituted C1-2alkyl. In certain embodiments, each instance of R2is independently halogen (e.g., -F). In certain embodiments, n is an integer from 0-8. In certain embodiments, n is an integer from 0-7. In certain embodiments, n is an integer from 0-6. In certain embodiments, n is an integer from 0-5. In certain embodiments, n is an integer from 0-4. In certain embodiments, n is an integer from 0-3. In certain embodiments, n is an integer from 0-2. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0. R3and p As described herein, each instance of R3is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA. In certain embodiments, each instance of R3is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, each instance of R3is independently halogen, substituted or unsubstituted alkyl. In certain embodiments, each instance of R3is independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, each instance of R3is independently substituted or unsubstituted C1-4 alkyl. In certain embodiments, each instance of R3is independently substituted or unsubstituted C1-3alkyl. In certain embodiments, each instance of R3is independently substituted or unsubstituted C1-2alkyl. In certain embodiments, each instance of R3is independently halogen (e.g., -F). In certain embodiments, p is an integer from 0-4. In certain embodiments, p is an integer from 0-3. In certain embodiments, p is an integer from 0-2. In certain embodiments, p is 0 or 1. In certain embodiments, p is 0. Embodiments of Formula (I)

[0002] In certain embodiments, the compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X, L, R1, and m are as defined herein. In certain embodiments, the compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X, L, R2, and n are as defined herein. In certain embodiments, the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X, L, R3, and p are as defined herein. In certain embodiments, the compound of Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X and L are as defined herein. In certain embodiments, X is a carrier protein. In certain embodiments, X is CRM197. In certain embodiments, the compound of Formula (I) is of Formula (I-e): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RAand L are as defined herein. In certain embodiments, the compound of Formula (I) is of Formula (I-f): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein L is as defined herein. In certain embodiments, the compound of Formula (I) is of Formula (I-g): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X is as defined herein. In certain embodiments, X is a carrier protein. In certain embodiments, X is CRM197. In certain embodiments, the compound of Formula (I) is of Formula (I-h): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RAis as defined herein. In certain embodiments, the compound of Formula (I) is of formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is of formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is of formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X is as defined herein. In certain embodiments, X is CRM197. In certain embodiments, the compound of Formula (I) is of formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X is as defined herein. In certain embodiments, X is CRM197. Compositions, Kits, and Administration The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative, and optionally a pharmaceutically acceptable excipient. In certain embodiments, a compound of Formula (I) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, a therapeutically effective amount is an amount effective for treating a disease (e.g., addiction, risk of drug overdose). In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, a therapeutically effective amount is an amount effective for inducing an immune response. In certain embodiments, a therapeutically effective amount is an amount effective for inducing an immune response against an opioid. In certain embodiments, a therapeutically effective amount is an amount effective for inducing an immune response against fentanyl, a fentanyl analog, and / or a fentanyl metabolite. In certain embodiments, a therapeutically effective amount is an amount effective for enhancing an immune response. In certain embodiments, a therapeutically effective amount is an amount effective for enhancing an immune response against an opioid. In certain embodiments, a therapeutically effective amount is an amount effective for enhancing an immune response against fentanyl, a fentanyl analog, and / or a fentanyl metabolite. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, a prophylactically effective amount is an amount effective for preventing a disease (e.g., addiction, risk of drug overdose). In certain embodiments, a prophylactically effective amount is an amount effective for inducing an immune response. In certain embodiments, a prophylactically effective amount is an amount effective for inducing an immune response against an opioid. In certain embodiments, a prophylactically effective amount is an amount effective for inducing an immune response against fentanyl, a fentanyl analog, and / or a fentanyl metabolite. In certain embodiments, a prophylactically effective amount is an amount effective for enhancing an immune response. In certain embodiments, a prophylactically effective amount is an amount effective for enhancing an immune response against an opioid. In certain embodiments, a prophylactically effective amount is an amount effective for enhancing an immune response against fentanyl, a fentanyl analog, and / or a fentanyl metabolite. The present disclosure also provides vaccine compositions comprising an adjuvant and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof. In certain embodiments, a compound of Formula (I) is provided in an effective amount in the vaccine composition. A “vaccine composition” is a composition that induces or enhances a subject’s immune response to an antigen after the composition is administered to the subject. The terms "vaccine composition" and “vaccine” are used interchangeably herein. In some embodiments, a vaccine stimulates the subject’s immune system to recognize the antigen as foreign and enhances the subject’s immune response if the subject is later exposed to the pathogen, whether attenuated, inactivated, killed, or not. Vaccines may be prophylactic, for example, preventing or ameliorating a detrimental effect of a future exposure to a pathogen, or therapeutic, for example, activating the subject’s immune response to a pathogen after the subject has been exposed to the pathogen. In some embodiments, a vaccine composition is used to protect or treat an organism against a disease (e.g., addiction, risk of drug overdose). In some embodiments, the vaccine is a subunit vaccine (e.g., a recombinant subunit vaccine), an attenuated vaccine (e.g., containing an attenuated pathogen such as a bacterial cell or a viral genome), a live vaccine (e.g., containing a live attenuated pathogen such as a bacterium or virus), a conjugated vaccine (e.g., a vaccine containing an antigen that is not very immunogenic covalently attached to an antigen that is more immunogenic) or an mRNA vaccine. One non-limiting example of a conjugated vaccine is a pneumococcal conjugate vaccine in which pneumoccal polysacchraides are attached to a protein antigen. Compositions described herein are immunogenic. Being “immunogenic” means that the composition elicits immune response when administered to a subject (e.g., a mammalian subject such as a human). As used herein, an “immune response” refers to a response by a cell of the immune system, such as an antigen-presenting cell, dendritic cell, monocyte, macrophage, NKT cell, NK cell, basophil, eosinophil, or neutrophil, B cell, T cell (CD4 or CD8), regulatory T cell, antigen-presenting cell, dendritic cell, monocyte, macrophage, NKT cell, NK cell, basophil, eosinophil, or neutrophil, to a stimulus (e.g., to an antigen or an adjuvant). In some embodiments, the immune response elicited by the compositions described herein is specific for a particular antigen (an "antigen-specific response" or “adaptive immune response”) and refers to a response by a CD4+T cell, CD8+T cell, or B cell via their antigen- specific receptor. In some embodiments, an immune response is a T cell response, such as a CD4+response or a CD8+response. Such responses by these cells can include, for example, cytotoxicity, proliferation, cytokine or chemokine production, trafficking, or phagocytosis, and can be dependent on the nature of the immune cell undergoing the response. In some embodiments, an antigen-specific immune response includes both a humoral and / or a cell-mediated immune response to the antigen. A "humoral immune response" is an antibody-mediated immune response and involves the induction and generation of antibodies that recognize and bind with some affinity for the antigen in the immunogenic composition of the invention, while a "cell-mediated immune response" is one mediated by T-cells and / or other white blood cells. A "cell-mediated immune response" is elicited by the presentation of antigenic epitopes in association with Class I or Class II molecules of the major histocompatibility complex (MHC), CD1 or other non-classical MHC-like molecules. This activates antigen-specific CD4+ T helper cells or CD8+ cytotoxic lymphocyte cells ("CTLs"). CTLs have specificity for peptide antigens that are presented in association with proteins encoded by classical or non-classical MHCs and expressed on the surfaces of cells. CTLs help induce and promote the intracellular destruction of intracellular microbes, or the lysis of cells infected with such microbes. Another aspect of cellular immunity involves an antigen- specific response by helper T-cells. Helper T-cells act to help stimulate the function, and focus the activity of, nonspecific effector cells against cells displaying peptide or other antigens in association with classical or non-classical MHC molecules on their surface. A "cell-mediated immune response" also refers to the production of cytokines, chemokines, and other such molecules produced by activated T-cells and / or other white blood cells, including those derived from CD4+ and CD8+ T-cells. The ability of a particular antigen or composition to stimulate a cell-mediated immunological response may be determined by various assays, such as by lymphoproliferation (lymphocyte activation) assays, CTL cytotoxic cell assays, by assaying for T-lymphocytes specific for the antigen in a sensitized subject, or by measurement of cytokine production by T cells in response to re-stimulation with antigen. Such assays are well known in the art. See, e.g., Erickson et al. (1993) J. Immunol.151:4189-4199; and Doe et al. (1994) Eur. J. Immunol.24:2369-2376. In some embodiments, the immune response elicited by a composition described herein is an innate immune response. An “innate immune response” refers to the response by the innate immune system. The innate immune system uses a set of germline-encoded receptors (“pattern recognition receptor” or “PRR”) for the recognition of conserved molecular patterns present in microorganisms. These molecular patterns occur in certain constituents of microorganisms including lipopolysaccharides, peptidoglycans, lipoteichoic acids, phosphatidyl cholines, bacteria-specific proteins, including lipoproteins, bacterial DNAs, viral single and double-stranded RNAs, unmethylated CpG-DNAs, mannans, and a variety of other bacterial and fungal cell wall components. Such molecular patterns can also occur in other molecules such as plant alkaloids. These targets of innate immune recognition are called Pathogen Associated Molecular Patterns (PAMPs) since they are produced by microorganisms and not by the infected host organism. In some embodiments, the innate immune response elicited by the composition described herein confers heterologous (“non- specific”) immunity to a broad range of pathogenic microbes by enhancing innate immune responses to subsequent stimuli, a phenomenon known as “trained immunity”, a form of innate memory, e.g., as described in Netea et al. (Trained Immunity: An Ancient Way of Remembering. Cell Host Microbe.2017 Mar 8;21(3):297-300, incorporated herein by reference). The receptors of the innate immune system that recognize PAMPs are called Pattern Recognition Receptors (PRRs). (Janeway et al. (1989) Cold Spring Harb. Symp. Quant. Biol. 54: 1-13; Medzhitov et al. (1997) Curr. Opin. Immunol.94: 4-9, incorporated herein by reference). PRRs vary in structure and belong to several different protein families. Some of these receptors recognize PAMPs directly (e.g., CD14, DEC205, collectins), while others (e.g., complement receptors) recognize the products generated by PAMP recognition. Members of these receptor families can, generally, be divided into three types: 1) humoral receptors circulating in the plasma; 2) endocytic receptors expressed on immune-cell surfaces, and 3) signaling receptors that can be expressed either on the cell surface or intracellularly. (Medzhitov et al. (1997) Curr. Opin. Immunol.94: 4-9; Fearon et al. (1996) Science 272: 50-3, incorporated herein by reference). Non-limiting examples of PRRs include: Toll-like receptors (e.g., TLR2), NOD1 / 2, RIG-1 / MDA-5, C-type lectins, and STING. Cellular PRRs are expressed on effector cells of the innate immune system, including cells that function as professional antigen-presenting cells (APC) in adaptive immunity. Such effector cells include, but are not limited to, macrophages, dendritic cells, B lymphocytes and surface epithelia. This expression profile allows PRRs to directly induce innate effect or mechanisms, and to alert the host organism to the presence of infectious agents by inducing the expression of a set of endogenous signals, such as inflammatory cytokines and chemokines, including, without limitation: chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors. This latter function allows efficient mobilization of effector forces to combat the invaders. Any known adjuvant may be used in the compositions described herein. In some embodiments, the adjuvant enhances antigen-presenting cell activity. In some embodiments, the adjuvant activates B cell immunity. In some embodiments, the adjuvant is an agonist of Pattern Recognition Receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptor, C-type Lectin receptors (CLRs), and stimulator of interferon genes (STING). An “agonist” is a chemical that binds to a receptor and activates the receptor to produce a biological response. Agonists of the PPRs enhance immune responses (e.g., innate or adaptive immune response). Agonists of PPRs are known to those skilled in the art. For example, various TLR and NLR agonists are described in Kaur et al., Curr. Opin. Chem. Biol.2022, 70, 102172; Kaczanowska et al, J Leukoc Biol.2013 Jun; 93(6): 847–863; Higgins et al., Curr Infect Dis Rep.2010 Jan;12(1):4-12; and Maisonneuve et al., Proc Natl Acad Sci U S A.2014 Aug 26; 111(34): 12294–12299, incorporated herein by reference. RIG-I-like receptor agonists are described in Bourquin, et al., Pharmacological Research, 2020, 154, 104192; Ranjith-Kumar et al., J Biol Chem.2009 Jan 9; 284(2): 1155– 1165; and Goulet et al., PLOS Pathogens 9(8): 10, incorporated herein by reference. CLR agonists are described in Lamb et al., Biochemistry.2002 Dec 3;41(48):14340-7; and Yan et al., Front Immunol.2015; 6: 408, incorporated herein by reference. STING agonists are described in Amouzegar, et al., Cancers 2021, 13, 2695; Fu et al., Sci Transl Med.2015 Apr 15; 7(283): 283ra52; and Foote et al., Cancer Immunology Research, DOI: 10.1158 / 2326- 6066.CIR-16-0284, incorporated herein by reference. The PPR agonists described herein are also commercially available, e.g., from InvivoGen (California, USA). In some embodiments, the adjuvant is bound to or adsorbed to alum. In some embodiments, the adjuvant is alum. In some embodiments, the adjuvant includes an oil-in-water emulsion. In some embodiments, the vaccine composition described herein comprises two or more adjuvants (also referred to as an “adjuvant system”). Any known adjuvant may be used as the second adjuvant (e.g., any adjuvant described herein). In some embodiments, the second adjuvant is bound to or adsorbed to alum. In some embodiments, the second adjuvant is alum. In certain embodiments, the effective amount of the compound and / or composition is an amount effective for enhancing an immune response by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In certain embodiments, the effective amount of the compound and / or composition is an amount effective for enhancing an immune response by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. The use of the compounds described herein in veterinary vaccine is also within the scope of the present disclosure. “A companion animal,” as used herein, refers to pets and other domestic animals. Non-limiting examples of companion animals include dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat, guinea pig, and hamster), dog, pig, rabbit, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile. Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit. In some embodiments, the vaccine composition is formulated or administered in combination with one or more pharmaceutically acceptable excipients. In some embodiments, vaccine compositions comprise at least one additional active substance such as, for example, a therapeutically-active substance, a prophylactically-active substance, or a combination of both. Vaccine compositions may be sterile, pyrogen-free or both sterile and pyrogen-free. General considerations in the formulation and / or manufacture of pharmaceutical agents, such as vaccine compositions, may be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference in its entirety). Formulations of the vaccine compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the compound of Formula (I) and / or the adjuvant into association with an excipient (e.g., pharmaceutically acceptable excipient) and / or one or more other accessory ingredients, and then, if necessary and / or desirable, dividing, shaping and / or packaging the product into a desired single- or multi-dose unit. Relative amounts of the compound of Formula (I), the adjuvant, the pharmaceutically acceptable excipient, and / or any additional ingredients in a vaccine composition in accordance with the disclosure will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w / w) active ingredient. The disclosed compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage. In some embodiments, the disclosed compositions described herein are formulated for administration to a subject. Although the descriptions of compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of compositions suitable for administration to humans to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation. The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical, mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are intramuscular, oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or composition is administered intradermally, intramuscularly, intravaginally, intravenously, intranasally, orally, subcutaneously, transdermally, topically, and / or sublingually. In certain embodiments, the compound or composition is administered via intramuscular, intradermal, oral, intravenous, topical, transdermal, intranasal, intravaginal, or sublingual administration. In certain embodiments, the administration of the compound or composition is prophylactic. In certain embodiments, the administration of the compound or composition is therapeutic. In certain embodiments, the compound or composition is administered as a combination therapy with another immunomodulatory agent, an immunomodulating antibody, an immunomodulating biologic, or an inhibitor of molecular pathways that limits immune responses. In certain embodiments, the immunomodulatory agent is a pattern recognition receptor agonist (e.g., an alum, or a Toll-like receptor (TLR) Agonist). In certain embodiments, the immunomodulating antibody or immunomodulating biologic is a cytokine, chemokine or colony stimulating factor. A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compound or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in enhancing an immune response (e.g., innate and / or adaptive immune response) in a subject, biological sample, tissue, or cell), serving as an adjuvant in a vaccine for a disease (e.g., addiction, risk of drug overdose), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject, biological sample, tissue, or cell, or as stand alone anti-infective or immune response modifying agents. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compounds and the additional pharmaceutical agent, but not both. The compound or composition can be administered concurrently with, prior to, or after one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., addiction, risk of drug overdose). Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound or composition described herein. In certain embodiments, the kits are useful as inducers, enhancers and / or modifiers of an immune response in a subject, biological sample, tissue, or cell. In certain embodiments, a kit described herein further includes instructions for using the compound or composition included in the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., addiction, risk of drug overdose) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., addiction, risk of drug overdose) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inducing an immune response in a subject, biological sample, tissue, or cell. In certain embodiments, the kits and instructions provide for enhancing of an immune response in a subject, biological sample, tissue, or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Uses The present disclosure provides methods of inducing an immune response (e.g., innate and / or adaptive immune response) in a subject, biological sample, tissue, or cell. The present disclosure also provides methods of enhancing an immune response (e.g., innate and / or adaptive immune response) in a subject, biological sample, tissue, or cell. In another aspect, the present disclosure provides methods of inducing an immune response (e.g., innate and / or adaptive immune response) in a subject in need thereof, the methods comprising administering to the subject an effective amount of a composition described herein. In certain embodiments, production of opioid-specific antibodies is increased, compared to when the compound of Formula (I) is administered alone. In certain embodiments, the opioid is fentanyl, a fentanyl analogue, a fentanyl metabolite, or a fentanyl analogue metabolite. In certain embodiments, the opioid is fentanyl. In certain embodiments, the opioid is a fentanyl analogue. In certain embodiments, the opioid is a fentanyl metabolite. In certain embodiments, the opioid is a fentanyl analogue metabolite. In certain embodiments, the subject has or is at risk of opioid overdose and / or developing opioid use disorder. In another aspect, the present disclosure provides methods of enhancing an immune response (e.g., innate and / or adaptive immune response) in a subject in need thereof, the methods comprising administering to the subject an effective amount of a composition described herein. In certain embodiments, production of opioid-specific antibodies is increased, compared to when the compound of Formula (I) is administered alone. In certain embodiments, the opioid is fentanyl, a fentanyl analogue, a fentanyl metabolite, or a fentanyl analogue metabolite. In certain embodiments, the opioid is fentanyl. In certain embodiments, the opioid is a fentanyl analogue. In certain embodiments, the opioid is a fentanyl metabolite. In certain embodiments, the opioid is a fentanyl analogue metabolite. In certain embodiments, the subject has or is at risk of opioid overdose and / or developing opioid use disorder. In another aspect, the present disclosure provides methods of precenting or treating addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed composition. In another aspect, the present disclosure provides methods of treating addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed composition. In another aspect, the present disclosure provides methods of preventing addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed composition. In certain embodiments, the addiction is opioid addiction (e.g., addiction to an opioid such as fentanyl). In certain embodiments, the subject has or is at risk of opioid overdose (e.g., overdose of an opioid such as fentanyl) and / or developing opioid use disorder. In certain embodiments, the subject has opioid use disorder (e.g., the subject meets clinical criteria for OUD). In certain embodiments, the subject is at higher than average risk of opioid overdose and / or developing opioid use disorder (e.g., the subject may have a family member with OUD, or the subject may have a marijuana use disorder). In certain embodiments, the subject is in normal health. In an embodiment, the present disclosure provides methods for compounds of Formula (I) as antigens in a vaccine for treatment of disease. In certain embodiments, the disease is addiction (e.g., addiction to an opioid such as fentanyl). In certain embodiments, the disease is risk of overdose (e.g., overdose of an opioid such as fentanyl). In certain embodiments, the opioid is fentanyl, a fentanyl analogue, a fentanyl metabolite, or a fentanyl analogue metabolite. In certain embodiments, the opioid is fentanyl. In certain embodiments, the opioid is a fentanyl analogue. In certain embodiments, the opioid is a fentanyl metabolite. In certain embodiments, the opioid is a fentanyl analogue metabolite. In another aspect, the present disclosure provides methods of enhancing the cessation rate or reducing the relapse rate, or both, for a subject with opioid use disorder, the method comprising administering to the subject an effective amount of a disclosed composition. In certain embodiments, the present disclosure provides methods of enhancing the cessation rate for a subject with opioid use disorder, the method comprising administering to the subject an effective amount of a disclosed composition. In certain embodiments, the present disclosure provides methods of reducing the relapse rate for a subject with opioid use disorder, the method comprising administering to the subject an effective amount of a disclosed composition. In certain embodiments, the present disclosure provides methods of enhancing the cessation rate and reducing the relapse rate for a subject with opioid use disorder, the method comprising administering to the subject an effective amount of a disclosed composition. As used herein, “cessation rate” refers to the process of discontinuing opioid use by a subject. As used herein, “relapse rate” refers to a return to opioid use after a period of non-use by a subject. In certain embodiments, the opioid is fentanyl, a fentanyl analogue, a fentanyl metabolite, or a fentanyl analogue metabolite. In certain embodiments, the opioid is fentanyl. In certain embodiments, the opioid is a fentanyl analogue. In certain embodiments, the opioid is a fentanyl metabolite. In certain embodiments, the opioid is a fentanyl analogue metabolite. In another aspect, the present disclosure provides methods of inducing an immune response (e.g., innate and / or adaptive immune response) in a biological sample, tissue, or cell, the methods comprising contacting the biological sample, tissue, or cell with an effective amount of a composition described herein. In certain embodiments, the present disclosure provides a method of inducing an immune response against an opioid in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition. In certain embodiments, the opioid is fentanyl, a fentanyl analogue, a fentanyl metabolite, or a fentanyl analogue metabolite. In certain embodiments, the opioid is fentanyl. In certain embodiments, the opioid is a fentanyl analogue. In certain embodiments, the opioid is a fentanyl metabolite. In certain embodiments, the opioid is a fentanyl analogue metabolite. In another aspect, the present disclosure provides methods of enhancing an immune response (e.g., innate and / or adaptive immune response) in a biological sample, tissue, or cell, the methods comprising contacting the biological sample, tissue, or cell with an effective amount of a composition described herein. In certain embodiments, the present disclosure provides a method of enhancing an immune response against an opioid in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition. In certain embodiments, the opioid is fentanyl, a fentanyl analogue, a fentanyl metabolite, or a fentanyl analogue metabolite. In certain embodiments, the opioid is fentanyl. In certain embodiments, the opioid is a fentanyl analogue. In certain embodiments, the opioid is a fentanyl metabolite. In certain embodiments, the opioid is a fentanyl analogue metabolite. In certain embodiments, the immune response (e.g., innate and / or adaptive immune response) is enhanced by a compound, pharmaceutical composition, kit, use, or method described herein by at least 1%, at least 3%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In certain embodiments, the immune response (e.g., innate and / or adaptive immune response) in a subject, biological sample, tissue, or cell is enhanced by a compound, pharmaceutical composition, kit, use, or method described herein by not more than 1%, not more than 3%, not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, or not more than 90%. In certain embodiments, the compound of Formula (I) is an immunogen in the composition being administered or contacted. In certain embodiments, the compound of Formula (I) is an antigen in the composition being administered or contacted. In some embodiments, a compound of Formula (I) is administered separately from the adjuvant. In some embodiments, a compound of Formula (I) is administered prior to administering the adjuvant. In some embodiments, a compound of Formula (I) is administered after administering the adjuvant. In some embodiments, a compound of Formula (I) and the adjuvant are administered simultaneously. In some embodiments, a compound of Formula (I) and the adjuvant are administered as an admixture. In certain embodiments, the compositions described herein are used in methods of vaccinating a subject by prophylactically administering to the subject an effective amount of a composition described herein. “Vaccinating a subject” refers to a process of administering an immunogen, typically an antigen formulated into a vaccine, to the subject in an amount effective to increase or activate an immune response against the antigen and, thus, against a pathogen displaying the antigen. In some embodiments, the terms do not require the creation of complete immunity against the pathogen. In some embodiments, the terms encompass a clinically favorable enhancement of an immune response toward the antigen or pathogen. Methods for immunization, including formulation of a vaccine composition and selection of doses, routes of administration and the schedule of administration (e.g., primary dose and one or more booster doses), are well known in the art. In some embodiments, vaccinating a subject reduces the risk of developing a disease (e.g., addiction) in a subject. In certain embodiments, the compound or composition is administered repeatedly to the subject. In certain embodiments, the subject is a human. In some embodiments, the human subject is a pediatric human of up to 18 years of age. In certain embodiments, the subject is an adult human (i.e., 18 years of age or older). In certain embodiments, the subject is an older adult human. In certain embodiments, the subject is 65 years of age or older. In certain embodiments, the subject is more than 65 years of age. EXAMPLESIn order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Preparation of the compounds described herein Compounds of Formula (I) were prepared following the synthetic schemes and procedures described in detail below. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Compounds of the disclosure that are not explicitly described in the following procedures may be prepared by analogous methods. Those having ordinary skill in the art would understand how to make such compounds from the disclosure provided herein and by means known in the art of organic synthesis. For example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof are representative and instructive. Methods for optimizing reaction conditions, if necessary, minimizing competing by products, are known in the art. All reactions involving air-sensitive reagents were carried out with magnetic stirring and oven-dried glassware with rubber septa under argon unless otherwise stated. All commercially available chemicals and reagent grade solvents were used directly without further purification, unless otherwise specified. Reactions were monitored by thin-layer chromatography (TLC) on Baker-flex® silica gel plates (IB2-F) using UV-light (254 and 365 nm) detection or visualizing agents (e.g., iodine, ninhydrin or phosphomolybdic acid stain). Flash chromatography was conducted on a silica gel (230-400 mesh) using a Teledyne ISCO Combiflash® Rf. NMR spectra were recorded at room temperature using a JEOL ECA-600 instrument (1H NMR at 600 MHz and13C NMR at 151 MHz) with tetramethyl silane (TMS) as an internal standard. Chemical shifts (δ) are given in parts per million (ppm) with reference to solvent signals [1H-NMR: CDCl3 (7.26 ppm), CD3OD (3.30 ppm), DMSO-d6 (2.50 ppm);13C-NMR: CDCl3(77.0 ppm), MeOH-d4(49.0 ppm), DMSO-d6(39.5 ppm)]. Signal patterns are reported as s (singlet), d (doublet), t (triplet), q (quartet), qu (quintet), m (multiplet) and brs (broad singlet). Coupling constants (J) are given in Hz. Rotamers (*) were obtained for a few compounds and all values were reported. High-resolution mass spectra (HRMS) were obtained by the University of Texas, Austin mass spectral facility using a Star Elite-ESI and reported as m / z (relative intensity) for the molecular ion [M]. 2-(2-(2-Oxo-2-((1-phenethylpiperidin-4-yl)(phenyl)amino)ethoxy)ethoxy)acetic acid (2; Oxeth2) Scheme 1. Reagents and conditions: a) K2CO3, CH3CN, 80 °C, 5 h; b) Aniline, Na(OAc)3BH, AcOH, CH2Cl2, 0 °C-rt, 16 h; c) benzyl bromide, Et3N, Acetone, 0 °C-rt, 16 h; d) SOCl2, reflux, 60oC, 16 h; e) py, CH2Cl2, 0 °C-rt, 16 h; f) H2, Pd / C, MeOH, rt, 2 h. To a solution of 4-piperidone monohydrate hydrochloride A (2.0 g, 14.8 mmol) was dissolved in acetonitrile (40 mL) was added K2CO3 (6.1 g, 44.1 mmol) and (2- bromoethyl)benzene (2.5 g, 13.3 mmol) at ambient temperature. The resulting suspension was refluxed at 80oC for 5 h. The reaction mixture was monitored by TLC (50% ethyl acetate in hexane). Upon completion of the reaction, it was allowed to cool to room temperature, filtered through a small Celite pad and concentrated. The material was purified byflash column chromatography (0-30% ethyl acetate in hexane) to afford B (1.7 g, 57%) as an off-white solid; mp.57-59 °C.1H NMR (500 MHz, CDCl3): δ 7.32 - 7.26 (m, 2H), 7.23 - 7.20 (m, 3H), 2.86 - 2.82 (m, 6H), 2.75 - 2.71 (m, 2H), 2.48 (t, J = 6.0 Hz, 4H);13C NMR (125 MHz, CDCl3): δ 209.1, 139.9, 128.6, 128.4, 126.1, 59.3, 53.0, 41.2, 34.1. To a solution of aniline (90 μL, 0.98 mmol) in dichloromethane (3 mL) was added acetic acid (56 μL, 0.98 mmol) drop wise at 0oC. Subsequently, N-phenylethylpiperidin-4- one B (200 mg, 0.98 mmol, dissolved in 1 mL dichloromethane) was added drop wise, followed by addition of sodium triacetoxyborohydride (313 mg, 1.5 mmol) in 3 portions at 12 min intervals. The reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction, methanol (3 mL) was added to the reaction mixture and partitioned between dichloromethane and sat. NaHCO3. The organic phase was separated and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The material was purified by flash column chromatography (0-50% ethyl acetate in hexane) to obtain C as an off-white solid (211 mg, 76%). mp.96-98oC.1H NMR (500 MHz, CDCl3): δ 7.28 - 7.27 (m, 2H), 7.21 - 7.15 (m, 5H), 6.68 (t, J = 7.0 Hz, 1H), 6.60 (d, J = 8.0 Hz, 2H), 3.52 (brs, 1H), 3.36 - 3.28 (m, 1H), 2.98 - 2.95 (m, 2H), 2.83 - 2.80 (m, 2H), 2.63 - 2.59 (m, 2H), 2.21 (t, J = 11.0, 2H), 2.10 - 2.07 (m, 2H), 1.53 - 1.47 (m, 2H);13C NMR (125 MHz, CDCl3): δ 147.1, 140.3, 129.3, 128.7, 128.4, 126.0, 117.2, 113.2, 60.6, 52.4, 49.8, 33.8, 32.5. To a solution of an acid D (0.5 g, 2.8 mmol) in acetone (7.0 mL) was added Et3N (0.3 mL, 5.96 mmol) at 0oC. Then benzylbromide (0.3 mL, 2.8 mmol) was added slowly dropwise. The resulting mixture was stirred at room temperature overnight. The reaction mixture was monitored by TLC (50% ethyl acetate in hexane). Upon completion of the reaction, the precipitate was filtered, and the filtrate was concentrated under reduced pressure. The crude material was dissolved in sat. NaHCO3 solution (6.0 mL) and acidified the aqueous solution with 3N HCl to pH 3-2. The organic compound was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine solution and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified byflash column chromatography (0-30% ethyl acetate in hexane and then increased to 100% ethyl acetate) to afford E (220 mg, 30%) as a colorless viscous liquid.1H NMR (600 MHz, CDCl3): δ 7.36 (m, 5H), 5.22 (s, 2H), 4.21 (s, 2H), 4.18 (s, 2H), 3.78 (s, 4H);13C NMR (151 MHz, CDCl3): δ 172.5, 170.1, 135.2, 128.7, 128.6, 128.5, 71.2, 70.6, 68.5, 68.5, 66.8. Thionyl chloride (0.8 mL, 11.0 mmol) was added to an acid E (220 mg, 0.8 mmol) in a round bottom flask, and heated at 60oC overnight. After completion of reaction, SOCl2 was distilled off and toluene (1.0 mL) was added and concentrated under reduced pressure. The crude acid halide F was used for the next step without purification. To a solution of C (125 mg, 0.45 mmol) in anhydrous dichloromethane (3 mL) was added pyridine (0.17 mL, 2.3 mmol) and benzyl 2-(2-(2-chloro-2-oxoethoxy)ethoxy)acetate F (255 mg, 0.89 mmol, dissolved in 1 mL dichloromethane) dropwise at 0oC. The reaction mixture was stirred for 5-10 min at 0oC. The reaction mixture was allowed to warm to room temperature and then stir for 16 h. Reaction progress was monitored by TLC (5% methanol in dichloromethane). Upon completion of reaction, it was quenched with sat. NaHCO3 solution. The organic layer was separated, and the aqueous layer was washed with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by flash column chromatography (0-2% methanol in dichloromethane) to obtain G as a colorless viscous liquid (153 mg, 65%).1H NMR (600 MHz, CDCl3): δ 7.40 - 7.30 (m, 8H), 7.27 - 7.25 (m, 2H), 7.19 - 7.13 (dd, J = 6.5Hz, 19.3 Hz m, 3H), 7.08 (d, J = 3.4 Hz, 2H), 5.16 (s, 2H), 4.69 - 4.63 (m, 1H), 4.16 (s, 2H), 3.75 (s, 2H), 3.71 (s, 2H), 3.66 (s, 2H), 3.01 (d, J = 10.3 Hz, 2H), 2.73 (d, J = 7.9 Hz, 2H), 2.55 (t, J = 5.7 Hz m, 2H), 2.20 - 2.15 (m, 2H), 1.81 (d, J = 11.7 Hz , 2H), 1.45 (q, J = 12.1 Hz, 2H);13C NMR (151 MHz, CDCl3): δ 170.3, 168.8, 140.0, 136.8, 135.4, 130.2, 129.5, 128.8, 128.6, 128.5, 128.4, 128.3, 126.1, 71.0, 70.8, 69.8, 68.6, 66.4, 60.2, 52.8, 52.2, 33.5, 30.0. To a solution of G (150 mg, 0.28 mmol) in anhydrous methanol (5 mL) was added Pd / C (50 mg). The mixture was stirred under a hydrogen atmosphere for 2 h. Reaction progress was monitored by TLC (10% methanol in dichloromethane). Upon completion of the reaction, it was filtered through a small Celite pad. The volatiles were removed under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-10% methanol in dichloromethane) to obtain 2 (Oxeth2) as a while solid (111 mg, 89%); mp 83-85 °C.1H NMR (600 MHz, MeOH-d4): δ 7.53 - 7.48 (m, 3H), 7.30 - 7.28 (m, 4H), 7.23 - 7.20 (m, 3H), 4.76 - 4.70 (m, 1H), 3.84 (s, 2H), 3.79 (s, 2H), 3.60 - 3.55 (m, 4H), 3.49 (d, J = 11.7 Hz, 2H), 3.08 - 3.04 (m, 2H), 2.93 - 2.87 (m, 4H), 2.06 (d, J = 12.9 Hz, 2H), 1.70 – 1.63 (m, 2H);13C NMR (151 MHz, MeOH-d4): δ 177.4, 171.3, 138.7, 137.6, 131.4, 131.1, 130.6, 129.8, 129.8, 127.9, 71.3, 71.2, 70.8, 70.4, 59.4, 53.2, 52.4, 32.2, 29.2. HRMS (ESI): m / z [M + Na]+ calcd for C25H32N2NaO5: 463.2199; found: 463.2198. Purity was determined to be 99% by analytical high-performance liquid chromatography (WATERS HPLC) using binary pump Kinetex 5 µm C18100A column (250 x 4.6 mm). UV absorption was monitored at λ = 254 nm. The injection volume was 15 µL. The gradient of acetonitrile / water (both containing 0.1% trifluoroacetic acid) was 2:98 to 98:2 over a total run time of 30 min and a flow rate of 1 mL / min. tR= 17.75. rel-(1S,2S)-2-((1-phenethylpiperidin-4-yl)(phenyl)carbamoyl)cyclopropane-1-carboxylic acid (6, CPDD)

[0003] Scheme 2. Reagents and conditions: a) (COCl)2, CH2Cl2, DMF, 0 °C-rt, 3 h; b), py, CH2Cl2, 0 °C-rt, 16 h; c) LiOH•H2O, MeOH, rt, 2 h. To a solution of H (0.2 g, 1.40 mmol) in anhydrous dichloromethane (8.0 mL) was added oxalyl chloride (0.4 mL, 4.0 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 3 h. After completion of reaction, oxalyl chloride was distilled off and toluene (1.0 mL) was added and concentrated under reduced pressure. The crude acid halide I (180 mg) was used for the next step without purification. To a solution of C (200 mg, 0.71 mmol) in anhydrous dichloromethane (7 mL) was added pyridine (0.1 mL, 1.43 mmol) and methyl rel-(1S,2S)-2- (chlorocarbonyl)cyclopropane-1-carboxylate I (180 mg, 1.10 mmol) at 0oC. The reaction mixture was stirred for 5-10 min at 0oC, allowed to warm to room temperature and stir for 16 h. Reaction progress was monitored by TLC (5% methanol in dichloromethane). Upon completion of reaction, it was quenched with sat. NaHCO3solution. The organic layer was separated, and the aqueous layer was washed with dichloromethane (2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-2% methanol in dichloromethane) to obtain J as a colorless viscous liquid (172 mg, 59%).1H NMR (600 MHz, CDCl3): δ 7.41 - 7.35 (m, 3H), 7.28 - 7.25 (m, 2H), 7.19 - 7.13 (m, 5H), 4.65 - 4.58 (tt, J = 3.8 Hz, 12.2 Hz, 1H), 3.59 (s, 3H), 3.0 (d, J = 11.7 Hz, 2H), 2.75 - 2.70 (m, 2H), 2.55 - 2.51 (m, 2H), 2.18 - 2.11 (m, 3H), 1.80 (d, J = 12.1 Hz, 2H), 1.68 - 1.63 (m, 1H), 1.51 - 1.42 (m, 3H), 1.19 - 1.14 (m, 1H) ;13C NMR (151 MHz, CDCl3): δ 172.8, 169.8, 140.1, 138.0., 130.4, 129.4, 129.3, 128.6, 128.3, 126.0, 60.4, 53.0, 52.8, 51.9, 33.8, 30.4, 23.3, 22.3, 15.5. To a solution of J (110 mg, 0.27 mmol) in 2 mL of methanol was added 0.6 mL of 1.0 M LiOH•H2O solution. The reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC (10% methanol in dichloromethane). Upon completion of reaction, the solution was acidified with 3N HCl solution to pH 3-2. Upon addition of 10 mL of dichloromethane, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-10% methanol in dichloromethane) to obtain 6 (CPDD) as a white solid (68 mg, 64%). mp 117-120oC.1H NMR (600 MHz, MeOH-d4): δ 7.55 - 7.44 (m, 3H), 7.33 - 7.22 (m, 7H), 4.74 - 4.68 (tt, J = 3.8 Hz, 12.2 Hz, 1H), 3.58 - 3.51 (m, 2H), 3.17 - 3.13 (m, 2H), 3.02 (t, J = 12.5 Hz, 2H), 2.95 - 2.91 (m, 2H), 2.10 - 2.02 (m, 2H), 1.96 - 1.93 (m, 1H), 1.73 - 1.64 (m, 2H), 1.62 - 1.59 (m, 1H), 1.32 - 1.28 (m, 1H), 1.09 - 1.06 (m, 1H);13C NMR (151 MHz, MeOH-d4, (*)): δ 177.6, 173.1, 139.2, 138.0, 131.5, 131.0, 130.3, 129.9, 129.8, 128.2, 58.9, 53.2, 53.1, 52.1, 31.7, 29.1, 29.0, 25.6, 23.7, 15.8. HRMS (ESI): m / z [M + H]+ calcd for C24H28N2O3: 393.2173; found: 393.2180. Purity was determined to be 95% by analytical high-performance liquid chromatography (WATERS HPLC) using binary pump Kinetex 5 µm C18100A column (250 x 4.6 mm). UV absorption was monitored at λ = 254 nm. The injection volume was 15 µL. The gradient of acetonitrile / water (both containing 0.1% trifluoroacetic acid) was 2:98 to 98:2 over a total run time of 30 min and a flow rate of 1 mL / min. tR = 17.740. 2-(2-Oxo-2-((1-phenethylpiperidin-4-yl)(phenyl)amino)ethoxy)acetic acid (1, Oxeth); N- methyl-N-(2-oxo-2-((1-phenethylpiperidin-4-yl)(phenyl)amino)ethyl)glycine (3, MADD) Scheme 3. Reagents and conditions: a) AcOH, CH2Cl2,80 °C, 16 h. To a solution of C (100 mg, 0.36 mmol) in anhydrous dichloromethane (4 mL) in a sealable tube was added acetic acid (0.3 mL) and 1,4-dioxane-2,6-dione K (62 mg, 0.53 mmol) at room temperature. The sealed tube was heated at reflux (80oC) for 16 h. Reaction progress was monitored by TLC (10% methanol in dichloromethane). Upon completion of reaction, all volatiles were removed under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-10% methanol in dichloromethane) to obtain 1 (Oxeth) as a white solid (126 mg, 89%). mp.58-60 °C.1H NMR (600 MHz, MeOH-d4): δ 7.51 - 7.47 (m, 3H), 7.31 - 7.27 (m, 4H), 7.24 - 7.22 (m, 3H), 4.75 - 4.70 (tt, J = 3.8 Hz, 12.2 Hz, 1H), 3.83 (d, J = 3.6 Hz, 4H), 3.53 (d, J = 12.2 Hz, 2H), 3.14 - 3.10 (m, 2H), 3.01 - 2.91 (m, 4H), 2.08 (d, J = 13.4 Hz, 2H), 1.72 - 1.64 (qd, J = 3.6 Hz, 13.4 Hz, 2H);13C NMR (151 MHz, MeOH-d4): δ 176.8, 171.2, 138.2, 137.7, 131.3, 131.1, 130.6, 129.9, 129.8, 128.1, 70.9, 69.9, 58.9, 53.1, 52.1, 31.7, 28.8. HRMS (ESI): m / z [M + H]+ calcd for C23H28N2O4: 397.2122; found: 397.2122. Purity was determined to be 99% by analytical high-performance liquid chromatography (WATERS HPLC) using binary pump Kinetex 5 µm C18100A column (250 x 4.6 mm). UV absorption was monitored at λ = 254 nm. The injection volume was 15 µL. The gradient of acetonitrile / water (both containing 0.1% trifluoroacetic acid) was 2:98 to 98:2 over a total run time of 30 min and a flow rate of 1 mL / min. tR = 17.57. To a solution C (150 mg, 0.54 mmol) in anhydrous dichloromethane (3 mL) in a sealable tube was added acetic acid (0.2 mL) and 4-methylmorpholine-2,6-dione L (103 mg, 0.80 mmol) at room temperature. The sealable tube was heated at reflux (80oC) for 16 h. Reaction progress was monitored by TLC (20% methanol in dichloromethane). Upon completion of reaction, all volatiles were removed under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-15% methanol in dichloromethane) to obtain the desired compound 3 (MADD) as a white solid (110 mg, 50%). mp.65-67 °C.1H NMR (600 MHz, MeOH-d4): δ 7.57 - 7.50 (m, 3H), 7.31 (d, J = 6.7 Hz, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.20 - 7.15 (m, 3H), 4.70 - 4.63 (m, 1H), 3.58 - 3.34 (m, 4H), 3.23 (d, J = 11.5 Hz, 2H), 2.84 - 2.60 (m, 7H), 2.47 (t, J = 11.9 Hz, 2H), 1.97 (d, J = 12.4 Hz, 2H), 1.60 - 1.51 (m, 2H);13C NMR (151 MHz, MeOH-d4): δ 171.8, 167.6, 140.1, 137.4, 131.4, 131.2, 130.8, 129.7, 129.6, 127.5, 60.7, 60.6, 59.0, 54.0, 53.6, 43.5, 33.4, 30.2; HRMS (ESI): m / z [M + H]+ calcd for C24H31N3O3: 410.2438 ; found: 410.2435. Purity was determined to be 99% by analytical high-performance liquid chromatography (WATERS HPLC) using binary pump Kinetex 5 µm C18100A column (250 x 4.6 mm). UV absorption was monitored at λ = 254 nm. The injection volume was 15 µL. The gradient of acetonitrile / water (both containing 0.1% trifluoroacetic acid) was 2:98 to 98:2 over a total run time of 30 min and a flow rate of 1 mL / min. tR= 15.0. 2-(4-(2-Oxo-2-((1-phenethylpiperidin-4-yl)(phenyl)amino)ethyl)piperazin-1-yl)acetic acid (5, PDD) Scheme 4. Reagents and conditions: a) 2-chloroacetyl chloride, CH2Cl2,0 °C-rt, 16 h; b) tert- butyl 2-bromoacetate, CH3CN, rt, 5-6 h; c) K2CO3, CH3CN, 80 °C, 16 h; d) 4M HCl in dioxane, CH2Cl2,rt, 5-6 h. To a solution C (2.5 g, 8.92 mmol) in anhydrous dichloromethane (15 mL) was added 2-chloroacetyl chloride (1.1 g, 9.83 mmol) at 0oC. The reaction mixture was slowly brought to room temperature and then stirred for 16 h. Reaction progress was monitored by TLC (10% methanol in dichloromethane). Upon completion of the reaction, water (10 mL) was added to quench the reaction and the organic layer was separated. The aqueous layer was washed with dichloromethane (2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-3% methanol in dichloromethane) to obtain M as a while solid (1.8 g, 56%) NMR (600 MHz, MeOH-d4): δ 7.58 - 7.53 (m, 3H), 7.37 - 7.31 (m, 4H), 7.28 - 7.24 (m, 3H), 4.83 - 4.76 (m, 1H), 3.85 (s, 2H), 3.67 (d, J = 12.2 Hz, 2H), 3.30 - 3.27 (m, 2H), 3.20 (t, J = 12.5 Hz, 2H), 3.02 -2.99 (m, 2H), 2.20 - 2.15 (m, 2H), 1.80 - 1.71 (m, 2H);13C NMR (151 MHz, MeOH- d4): δ 168.5, 138.1, 137.5, 131.4, 131.2, 130.9, 130.0, 129.8, 128.3, 58.9, 53.1, 52.3, 43.3, 31.4, 28.6. To a solution of N (1.0 g, 11.61 mmol) in anhydrous acetonitrile (20 mL) was added tert-butyl 2-bromoacetate (0.9 mL, 5.79 mmol dissolved in 5.0 mL of acetonitrile) dropwise at room temperature. The mixture was stirred at room temperature for 5-6 h. The precipitate was filtered and the filtrate was evaporated under reduced pressure. The crude compound was dissolved in water (20 mL). The organic compound was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine solution and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified byflash column chromatography (0-10% dichloromethane in methanol) to afford O (0.5 g, 21%) as a viscous liquid and then slowly turned to an off-white solid.1H NMR (600 MHz, CDCl3): δ 3.10 (s, 2H), 2.95 - 2.93 (m, 4H), 2.55 (brs, 4H), 1.47 (s, 9H);13C NMR (151 MHz, CDCl3): δ 169.5, 81.0, 60.5, 53.9, 45.8, 28.1. To a solution of M (215 mg, 0.60 mmol) and tert-butyl 2-(piperazin-1-yl)acetate O (180 mg, 0.90 mmol) in anhydrous acetonitrile (15 mL) was added K2CO3 (250 mg, 1.81 mmol). The reaction mixture was refluxed at 80oC for 16 h. Reaction progress was monitored by TLC (5% methanol in dichloromethane). Upon completion of reaction, water (10 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-3% methanol in dichloromethane) to obtain P as a colorless viscous liquid (215 mg, 68%).1H NMR (600 MHz, MeOH-d4): δ 7.50 - 7.45 (m, 3H), 7.24 - 7.22 (m, 4H), 7.16 - 7.14 (m, 3H), 4.61 - 4.56 (tt, J = 4.0 Hz, 12.2 Hz, 1H), 3.08 - 3.06 (m, 4H), 2.81 (s, 2H), 2.74-2.72 (m, 2H), 2.56-2.40 (m, 10H), 2.23 (t, J = 11.7 Hz, 2H), 1.85 (d, J = 12.2 Hz, 2H), 1.48 - 1.42 (m, 11H);13C NMR (151 MHz, MeOH- d4): δ 170.8, 170.6, 141.0, 138.9, 131.7, 130.7, 130.1, 129.6, 129.5, 127.2, 82.4, 61.3, 61.2, 60.5, 53.9, 53.8, 53.7, 53.4, 34.0, 30.9, 28.3. To a solution of ester P (150 mg, 0.29 mmol) in dichloromethane (2 mL) was added 1.5 mL of 4.0 M HCl in dioxane. The reaction mixture was stirred for 5-6 h at room temperature. Progress of the reaction was monitored by TLC (10% methanol in dichloromethane). Upon completion of reaction, all volatiles were removed under reduced pressure provided the crude compound, which was washed multiple time with diethyl ether to obtain 5 (PDD) as an off-white solid (130 mg, 97%). mp 113-118oC.1H NMR (600 MHz, MeOH-d4): δ 7.59 - 7.55 (m, 3H), 7.34 - 7.30 (m, 4H), 7.26 - 7.23 (m, 3H), 4.87 - 4.82 (tt, J = 3.8 Hz, 12.2 Hz, 1H), 3.68 (d, J = 12.7 Hz , 2H), 3.58 (s, 2H), 3.48 (s, 2H), 3.28 - 3.26 (m, 2H), 3.21 - 2.96 (m, 12H), 2.17 (d, J = 13.6 Hz, 2H), 1.75 - 1.68 (m, 2H);13C NMR (151 MHz, MeOH-d4): δ 169.4, 165.1, 161.1 (q, trifluoroacetic acid from HPLC), 135.3, 135.1, 129.5, 129.4, 129.1, 128.0, 127.7, 126.4, 116.9 and 114.9 (trifluoroacetic acid from HPLC), 57.0, 56.8, 55.6, 51.1, 50.6, 49.8, 49.4, 29.4, 26.7. HRMS (ESI): m / z [M + H]+ calcd for C27H36N4O3: 465.2860; found: 465.2861. Purity was determined to be 100% by analytical high-performance liquid chromatography (WATERS HPLC) using binary pump Kinetex 5 µm C18100A column (250 x 4.6 mm). UV absorption was monitored at λ = 254 nm. The injection volume was 15 µL. The gradient of acetonitrile / water (both containing 0.1% trifluoroacetic acid) was 2:98 to 98:2 over a total run time of 30 min and a flow rate of 1 mL / min. tR= 14.376. N-acetyl-N-(2-oxo-2-((1-phenethylpiperidin-4-yl)(phenyl)amino)ethyl)glycine (4, AADD) Scheme 5. Reagents and conditions: a) methyl glycinate hydrochloride, K2CO3, KI, DMF, 80 °C, 16 h; b) Ac2O, Et3N, CH2Cl2, 0 °C-rt, 16 h; c) LiOH•H2O, MeOH, 2 h. A solution of M (520 mg, 1.45 mmol), methyl glycinate hydrochloride (790 mg, 5.78 mmol), K2CO3 (910 mg, 7.22 mmol), KI (960 mg, 5.78 mmol) in anhydrous dimethylformamide (20 mL) was refluxed at 80oC in a sealed tube. Reaction progress was monitored by TLC (5% methanol in dichloromethane). Upon completion of the reaction, water (20 mL) was added to quench the reaction mixture and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-3% methanol in dichloromethane) to obtain Q as a colorless liquid (370 mg, 62%).1H NMR (600 MHz, MeOH-d4): δ 7.51 - 7.46 (m, 3H), 7.25 - 7.22 (m, 4H), 7.16 - 7.14 (m, 3H), 4.61 - 4.56 (tt, J = 4.0 Hz, 12.2 Hz, 1H), 3.66 (s, 3H), 3.34 - 3.32 (m, 2H), 3.09 - 2.99 (m, 4H), 2.75 - 2.72 (m, 2H), 2.56 - 2.54 (m, 2H), 2.25 - 2.20 (td, J = 1.6 Hz, 12.1 Hz, 2H), 1.87 (d, J = 10.8 Hz, 2H), 1.50 - 1.42 (qd, J = 3.8 Hz, 12.6 Hz, 2H);13C NMR (151 MHz, MeOH-d4): δ 173.4, 171.6, 141.0, 138.5, 131.5, 130.8, 130.3, 129.6, 129.5, 127.2, 61.3, 54.0, 53.9, 52.2, 51.5, 50.1, 34.0, 30.9. To a solution of Q (350 mg, 0.86 mmol) in anhydrous dichloromethane (10 mL) was added triethyl amine (0.5 mL, 3.42 mmol) at 0oC. Then acetic anhydride (0.12 mL, 1.28 mmol) was added dropwise, and the mixture was slowly warmed to room temperature. Stirring was continued for 16 h. Reaction progress was monitored by TLC (5% methanol in dichloromethane). Upon completion of reaction, all volatiles were removed under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-3% methanol in dichloromethane) to obtain R as a pale-yellow viscous liquid (305 mg, 79%).1H NMR (600 MHz, CDCl3, (*)): δ 7.47 – 7.37 (m, 3H), 7.28 – 7.24 (m, 2H), 7.20 – 7.11 (m, 5H), 4.66 – 4.57 (m, 1H), 4.18 (d, J = 10.8 Hz, 2H), 3.76 – 3.67 (m, 5H), 3.01 (t, J = 10.7 Hz, 2H), 2.74 – 2.70 (td, J = 2.6 Hz, 7.9 Hz, 2H), 2.56 – 2.51 (m, 2H), 2.13 (q, J = 12.9 Hz, 2H), 2.06 (s, 1.5 H), 1.94 (s, 1.5 H), 1.84 – 1.73 (m, 2H), 1.50 – 1.41 (m, 2H);13C NMR (151 MHz, CDCl3, (*)): δ 171.2, 171.0, 170.2, 169.8, 167.8, 167.1, 140.1, 140.1, 137.1, 136.8, 130.2, 130.0, 129.9, 129.6, 129.3, 128.9, 128.6, 128.6, 128.4, 128.3, 126.1, 126.0, 60.4, 60.4, 53.1, 52.9, 52.8, 52.8, 52.3, 52.0, 51.8, 51.1, 48.9, 47.9, 33.8, 33.8, 30.3, 30.3, 21.1, 20.8. To a solution of R (260 mg, 0.58 mmol) in 5 mL of methanol was added 2.5 mL of 1.0 M LiOH•H2O solution. The reaction mixture was stirred for 3 – 4 h at room temperature. Reaction progress was monitored by TLC (10% methanol in dichloromethane). Upon completion of the reaction, the solution was acidified with 3N HCl solution to pH 3-2. Dichloromethane (10.0 mL) was added. The organic layer was separated and washed with brine solution dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was washed with diethyl ether multiple times to obtain 4 (AADD) as an off-white solid (230 mg, 81%). mp 115-117oC.1H NMR (600 MHz, MeOH-d4, (*)): δ 7.57 – 7.48 (m, 3H), 7.37 - 7.30 (m, 4H), 7.26 – 7.23 (m, 3H), 4.82 – 4.76 (m, 1H), 3.99 – 3.97 (d, 2H), 3.87 (s, 0.5H), 3.78 (s, 1.5H), 3.63 (d, J = 11.7 Hz, 2H), 3.26 – 3.23 (m, 2H), 3.18 – 3.12 (m, 2H), 3.00 – 2.96 (m, 2H), 2.19 – 2.12 (m, 2H), 2.04 (s, 2H), 1.97 (s, 1H), 1.78 – 1.68 (m, 2H);13C NMR (151 MHz, MeOH-d4, (*)): δ 176.4, 175.7, 174.2, 174.1, 170.1, 169.6, 141.2, 138.5, 138.3, 131.6, 131.4, 131.1, 130.8, , 130.2, 129.6, 129.4, 127.1, 61.4, 55.0, 54.3, 53.9, 53.8, 51.1, 34.2, 31.0, 21.3, 21.2. HRMS (ESI): m / z [M + H]+ calcd for C25H32N3O4: 438.2384; found: 438.2384. Purity was determined to be 97% by analytical high-performance liquid chromatography (WATERS HPLC) using binary pump Kinetex 5 µm C18100A column (250 x 4.6 mm). UV absorption was monitored at λ = 254 nm. The injection volume was 15 µL. The gradient of acetonitrile / water (both containing 0.1% trifluoroacetic acid) was 2:98 to 98:2 over a total run time of 30 min and a flow rate of 1 mL / min. tR = 17.31. Hapten-CRM Conjugation Procedures Oxeth2-CRM conjugation: To a mixture of Oxeth2 (2) (0.09 mg, 40 equiv, 2.1 x 10-4mmol), EDC (0.04 mg, 40 equiv, 2.1 x 10-4mmol) and NHS (0.03 mg, 40 equiv, 2.1 x 10-4mmol) in 45 μL DMSO was added. The reaction mixture was stirred at room temperature for 2 h. Then the resulting reaction mixture was added drop wise to the solution of EcoCRM (0.3 mg, 1 equiv, 5.1 x 10-6mmol, dissolved in 300 μL water) and then stirred overnight. Next, a dialysis column (Thermo Scientific) was prepared by adding approximately 14.5 mL of sterile 1X PBS into the bottom reservoir. The top reservoir was then rinsed with 500 μL of 1X PBS and placed into the bottom and a reaction mixture was transferred and added 100 μL of IX PBS to wash the vial. The column was then sealed and placed onto an orbital shaker (180 rpm) for 2 hours. After agitation, the mixture was removed and placed into Eppendorf tubes and volume recorded. The mixture is then loaded into a 5 mL syringe and sterilized by filtering it through a 0.2 μm HT Tuffryn membrane (Acrodisk syringe filter, Pall Corporation, Ann Arbor, MI). The hapten ratio (1.93) was measured by using Maldi mass spec. CPDD-CRM conjugation: To a mixture of CPDD (6) (0.08 mg, 40 equiv, 2.1 x 10-4mmol), EDC (0.04 mg, 40 equiv, 2.1 x 10-4mmol) and NHS (0.03 mg, 40 equiv, 2.1 x 10-4mmol) in 45 μL DMSO was added. The reaction mixture was stirred at room temperature for 2 h. Then the resulting reaction mixture was added drop wise to the solution of EcoCRM (0.3 mg, 1 equiv, 5.1 x 10-6mmol, dissolved in 300 μL water) and then stirred overnight. Next, a dialysis column (Thermo Scientific) was prepared by adding approximately 14.5 mL of sterile 1X PBS into the bottom reservoir. The top reservoir was then rinsed with 500 μL of 1X PBS and placed into the bottom and a reaction mixture was transferred and added 100 μL of IX PBS to wash the vial. The column was then sealed and placed onto an orbital shaker (180 rpm) for 2 hours. After agitation, the mixture was removed and placed into Eppendorf tubes and volume recorded. The mixture is then loaded into a 5 mL syringe and sterilized by filtering it through a 0.2 μm HT Tuffryn membrane (Acrodisk syringe filter, Pall Corporation, Ann Arbor, MI). Oxeth-CRM conjugation: To a mixture of Oxeth (1) (0.08 mg, 40 equiv, 2.1 x 10-4mmol), EDC (0.04 mg, 40 equiv, 2.1 x 10-4mmol) and NHS (0.03 mg, 40 equiv, 2.1 x 10-4mmol) in 45 μL DMSO was added. The reaction mixture was stirred at room temperature for 2 h. Then the resulting reaction mixture was added drop wise to the solution of EcoCRM (0.3 mg, 1 equiv, 5.1 x 10-6mmol, dissolved in 300 μL water) and then stirred overnight. Next, a dialysis column (Thermo Scientific) was prepared by adding approximately 14.5 mL of sterile 1X PBS into the bottom reservoir. The top reservoir was then rinsed with 500 μL of 1X PBS and placed into the bottom and a reaction mixture was transferred and added 100 μL of IX PBS to wash the vial. The column was then sealed and placed onto an orbital shaker (180 rpm) for 2 hours. After agitation, the mixture was removed and placed into Eppendorf tubes and volume recorded. The mixture is then loaded into a 5 mL syringe and sterilized by filtering it through a 0.2 μm HT Tuffryn membrane (Acrodisk syringe filter, Pall Corporation, Ann Arbor, MI). The hapten ratio (0.98) was measured by using Maldi mass spec. MADD-CRM conjugation: To a mixture of MADD (3) (0.08 mg, 40 equiv, 2.1 x 10-4mmol), EDC (0.04 mg, 40 equiv, 2.1 x 10-4mmol) and NHS (0.02 mg, 40 equiv, 2.1 x 10-4mmol) in 45 μL DMSO was added. The reaction mixture was stirred at room temperature for 2 h. Then the resulting reaction mixture was added drop wise to the solution of EcoCRM (0.3 mg, 1 equiv, 5.1 x 10-6mmol, dissolved in 300 μL water) and then stirred overnight. Next, a dialysis column (Thermo Scientific) was prepared by adding approximately 14.5 mL of sterile 1X PBS into the bottom reservoir. The top reservoir was then rinsed with 500 μL of 1X PBS and placed into the bottom and a reaction mixture was transferred and added 100 μL of IX PBS to wash the vial. The column was then sealed and placed onto an orbital shaker (180 rpm) for 2 hours. After agitation, the mixture was removed and placed into Eppendorf tubes and volume recorded. The mixture is then loaded into a 5 mL syringe and sterilized by filtering it through a 0.2 μm HT Tuffryn membrane (Acrodisk syringe filter, Pall Corporation, Ann Arbor, MI). The hapten ratio (4.42) was measured by using Maldi mass spec. PDD-CRM conjugation: To a mixture of PDD (5) (0.09 mg, 40 equiv, 2.1 x 10-4mmol), EDC (0.04 mg, 40 equiv, 2.1 x 10-4mmol) and NHS (0.03 mg, 40 equiv, 2.1 x 10-4mmol) in 45 μL DMSO was added. The reaction mixture was stirred at room temperature for 2 h. Then the resulting reaction mixture was added drop wise to the solution of EcoCRM (0.3 mg, 1 equiv, 5.1 x 10-6mmol, dissolved in 300 μL water) and then stirred overnight. Next, a dialysis column (Thermo Scientific) was prepared by adding approximately 14.5 mL of sterile 1X PBS into the bottom reservoir. The top reservoir was then rinsed with 500 μL of 1X PBS and placed into the bottom and a reaction mixture was transferred and added 100 μL of IX PBS to wash the vial. The column was then sealed and placed onto an orbital shaker (180 rpm) for 2 hours. After agitation, the mixture was removed and placed into Eppendorf tubes and volume recorded. The mixture is then loaded into a 5 mL syringe and sterilized by filtering it through a 0.2 μm HT Tuffryn membrane (Acrodisk syringe filter, Pall Corporation, Ann Arbor, MI). The hapten ratio (1.43) was measured by using Maldi mass spec. AADD-CRM conjugation: To a mixture of AADD (4) (0.09 mg, 40 equiv, 2.1 x 10-4mmol), EDC (0.04 mg, 40 equiv, 2.1 x 10-4mmol) and NHS (0.03 mg, 40 equiv, 2.1 x 10-4mmol) in 45 μL DMSO was added. The reaction mixture was stirred at room temperature for 2 h. Then the resulting reaction mixture was added drop wise to the solution of EcoCRM (0.3 mg, 1 equiv, 5.1 x 10-6mmol, dissolved in 300 μL water) and then stirred overnight. Next, a dialysis column (Thermo Scientific) was prepared by adding approximately 14.5 mL of sterile 1X PBS into the bottom reservoir. The top reservoir was then rinsed with 500 μL of 1X PBS and placed into the bottom and a reaction mixture was transferred and added 100 μL of IX PBS to wash the vial. The column was then sealed and placed onto an orbital shaker (180 rpm) for 2 hours. After agitation, the mixture was removed and placed into Eppendorf tubes and volume recorded. The mixture is then loaded into a 5 mL syringe and sterilized by filtering it through a 0.2 μm HT Tuffryn membrane (Acrodisk syringe filter, Pall Corporation, Ann Arbor, MI). The hapten ratio (4.22) was measured by using Maldi mass spec. Human μ–receptor activity Compounds 1-6 were tested for agonist activity and inhibition activity against the human μ–receptor in vitro expressed on CHO-K1 cells (Eurofins, Taiwan). DAMGO, a known μ–receptor agonist, was used as a control as was fentanyl certified reference material. Syn Intermediate, an intermediary product of hapten synthesis, was included for analysis to assure safety during production. Table 1 shows the results. Tested haptens are rank ordered by median agonist activity from left (highest) to right (lowest) starting with fentanyl reference. Haptens with agonist activity greater than 50% are considered to have activated the μ–receptor. No hapten, nor the syn intermediate, had a median agonist activity greater than 50%, although AADD did have one test point above 50%. Further testing was done to determine antagonist activity to the μ–receptor by measuring the inhibition of [3H]Morphine binding to the μ–receptor. As with agonist activity, antagonist activity was determined by an inhibition of [3H]Morphine percentage greater than 50%. Only the syn intermediate registered as a μ–receptor antagonist amongst the test compounds. * indicates Oxeth2 as the lead hapten candidate for further vaccine development. < LoD = below lower limit of detection. Table 1. EQUIVALENTS ANDSCOPEIn the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: X is halogen, –ORA, –N(RA)2, –SRA, or a carrier protein; L is substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted alkyl-(heterocyclyl)-alkylene; each instance of R1is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA; each instance of R2is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA;each instance of R3is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, –CN, – SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, – C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, – NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, – OS(O)2RA, or –S(O)2RA; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; m is an integer from 0-5; n is an integer from 0-9; and p is an integer from 0-5.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is –ORA.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is –ORA, and RAis hydrogen, or substituted or unsubstituted alkyl.

4. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X is –OH, -OCH3, -OCH2Ph, or -OC(CH3)3.

5. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X is –OH.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a carrier protein.

7. The compound of claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein X is a tetanus toxoid (TT), diphtheria toxoid (DT), cross-reacting material (CRM), a non- toxic variant of Clostridium diphtheriae toxin (CRM197), meningococcal outer membrane protein complex (OMPC), or Haemophilus influenzae protein D (HiD).

8. The compound of any one of claims 1, 6, or 7, or a pharmaceutically acceptable salt thereof, wherein X is CRM197.

9. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L is substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted alkyl-(heterocyclyl)-alkylene.

10. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L is substituted or unsubstituted C2-10 heteroalkylene, substituted or unsubstituted C3-6 cycloalkylene, or substituted or unsubstituted alkyl-(4-6-membered heterocyclyl)-alkylene.

11. The compound of any of the preceding claims, or a pharmaceutically acceptable salt12. The compound of any of the preceding claims, or a pharmaceutically acceptable salt13. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein14. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 0.

15. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0.

16. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 0.

17. The compound of claim 1, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is of Formula (I-b):or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is of Formula (I-c):or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is of Formula (I-d):or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is of Formula (I-e):or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound is of Formula (I-f):or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound is of Formula (I-g):or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound is of Formula (I-h):or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof. 5 26. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein X is CRM197.

27. A pharmaceutical composition comprising the compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptableexcipient.

28. The pharmaceutical composition of claim 27 further comprising one or more pharmaceutical agents.

29. A vaccine composition comprising the compound of any of the preceding claims and a pharmaceutically acceptable excipient.

30. The vaccine composition of claim 29 further comprising an adjuvant.

31. The vaccine composition of claim 30, wherein the adjuvant is bound to or adsorbed to alum.

32. The vaccine composition of any one of claims 29-31 further comprising a second adjuvant.

33. The vaccine composition of claim 32, wherein the second adjuvant is bound to or adsorbed to alum.

34. The vaccine composition of claim 32, wherein the second adjuvant is alum.

35. A method of inducing an immune response against an opioid in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any of claims 27-34.

36. A method of enhancing an immune response against an opioid in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any of claims 27-34.

37. The method of claim 36, wherein production of opioid-specific antibodies is increased, compared to when the compound is administered alone.

38. A method of preventing or treating opioid addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any of claims 27-34.

39. The method of any one of claims 35-38, wherein the subject has or is at risk of opioid overdose and / or developing opioid use disorder.

40. The method of any one of claims 35-38, wherein the subject has a higher than average risk of opioid overdose and / or developing opioid use disorder.

41. The method of any one of claims 35-38, wherein the subject is in normal health.

42. A method of enhancing the cessation rate or reducing the relapse rate, or both, for a subject with opioid use disorder, the method comprising administering to the subject an effective amount of the composition of any of claims 27-34.

43. The method of any of claims 35-42, wherein the opioid is fentanyl, a fentanyl analogue, a fentanyl metabolite, or a fentanyl analogue metabolite.

44. The method of any of claims 35-43, wherein the composition is administered once to the subject.

45. The method of any of claims 35-44, wherein the composition is administered repeatedly to the subject.

46. The method of any one of claims 35-45, wherein the administration is systemic or local.

47. The method of any one of claims 35-46, wherein the administration is intramuscular, intradermal, oral, intravenous, topical, transdermal, intranasal, intravaginal, or sublingual.

48. The method of any one of claims 35-47, wherein the administration is prophylactic.

49. The method of any one of claims 35-47, wherein the administration is therapeutic.

50. The method of any one of claims 35-49, wherein the subject is a human.

51. A kit comprising the compound of any one of claims 1-26, or the composition of any one of claims 27-34; and instructions for use.

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