Functionalized imidazopyrimidine compounds and uses thereof

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 an enhancer and / or modifier of an immune response (e.g., innate and / or adaptive immune response), and is useful in treating and / or preventing a disease, as an adjuvant in a vaccine for a disease, (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose), or as stand alone anti-infective or immune response modifying agents. Also provided in the present disclosure are vaccines, pharmaceutical compositions, kits, methods, and uses including or using compounds of Formula (I).

Description

[0001] FUNCTIONALIZED IMIDAZOPYRIMIDINE COMPOUNDS AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional

[0004] Application, U.S.S.N. 63 / 619,707, filed January 10, 2024, which is incorporated herein by reference in its entirety.

[0005] FEDERALLY SPONSORED RESEARCH

[0006] 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.

[0007] BACKGROUND

[0008] Vaccination remains one of the most cost-effective health interventions available, significantly reducing morbidity, and preventing ~4-5 million deaths every year from vaccine-preventable infectious diseases (VPID) including diphtheria, tetanus, pertussis, measles, influenza, and SARS-CoV-2. In addition, vaccines can be employed for additional indications such as prevention of cancer (e.g., human papilloma virus vaccine and hepatitis B vaccine) and on-going discovery and development of vaccines for addiction such as those designed to prevent drug (e.g., opioid) overdose. Contemporary vaccine strategies generally moved away from live attenuated vaccines with a greater focus on target defined antigens, employing a broad set of platforms, including purified recombinant proteins and genetic delivery. Although this approach has lowered reactogenicity of many clinically licensed formulations, vaccine efficacy and durability of protection may lag, especially in vulnerable populaitons such as the very young and older adults with distinct and generally weaker immunity, due to insufficient innate immune stimulation important to enhancing the magnitude, breadth and durability of vaccine immunogenicity. Adjuvants can enhance vaccine responses by activating pattern-recognition receptors (PRRs) and / or by modulating antigen pharmacokinetics. Indeed, many first-generation 20thcentury vaccines, consisting of live attenuated or inactivated vaccines, expressed immune-stimulating components that activate PRRs and therefore are “self-adjuvanted”. Multi-disciplinary investigations of innate immunity and systems vaccinology have further informed discovery and development of novel adjuvants, which may also have utility in developing adjuvanted vaccines against i SARS-CoV-2 and future pandemics. Thus, there is a need to identify compounds capable of modifying human immune responses that may act as therapeutics on their own and / or as adjuvants.

[0009] SUMMARY

[0010] Although Toll-like receptor 7 and 8 (TLR7 / 8) agonists have a history of efficacy as stand alone immunomodulatory compounds and as vaccine adjuvants in pre-clinical and clinical settings, the present disclosure stems from the recognition that known small molecule TLR7 / 8 agonists such as the imidazoquinoline R848 (resiquimod) have limited adjuvanticity potential and inherent systemic reactogenicity, as they have uncontrolled biodistribution, limiting their use in development of new adjuvanted vaccines. Thus, novel TLR7 / 8 agonists that activate innate and adaptive immunity while promoting targeted delivery and averting systemic inflammation are desirable. Novel small molecule adjuvants also offer significant advantages such as targeted activation of antigen presenting cells (APCs), increased stability of small molecules for longer duration, potential dose-sparing effects, improved reactogenicity profiles, long-term safety, and efficacy.

[0011] Some aspects of the present disclosure are based on the discovery that certain functionalized imidazopyrimidine compounds (e.g., having a lipid or anionic group) possesses surprisingly exceptional properties that render the compounds useful as both single-agent therapeutics and as adjuvants in vaccines. For example, such compounds demonstrate high levels of immunogenic enhancement for multiple protein antigens.

[0012] 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:

[0013] R1Ais substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted 6-membered heteroaryl;

[0014] Z is -CN, substituted or unsubstituted heteroalkyl comprising at least one nitrogen atom, substituted heteroarylalkyl comprising at least one nitrogen atom, or a lipid group, wherein Z is not -CHoNFT or -OCH3; R1is hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, -ORa, or -N(Ralh; each instance of RAis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; each instance of RBis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; 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; each instance of Ralis 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, or two instances of Ralare joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; and q is 1 or 2.

[0015] Compounds of Formula (I) are useful in enhancing and / or modifying human immune responses, including innate and adaptive immune responses. In some embodiments, compounds of Formula (I) are used as an adjuvant in vaccines to prevent diseases (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft- versus-host disease, chronic disease, addiction or risk of drug overdose), or as a stand alone anti-infective or immune response modifying agent (e.g., single agent), in a subject in need thereof. In some aspects, using compounds of Formula (I) as a vaccine adjuvant enables effective immunization in vulnerable populations (e.g., neonates, infants, older adults, those with chronic disease and / or co-morbid condition, or immunocompromised individuals).

[0016] In another aspect, provided are pharmaceutical compositions including compounds of Formula (I) and optionally 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. The pharmaceutical compositions may be useful as enhancers and / or modifiers of an immune response (e.g., innate and / or adaptive immune response), and / or adjuvants in a vaccine to prevent a disease, (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose), or as stand alone anti-infective or immune response modifying agents.

[0017] In another aspect, provided are compositions comprising an antigen and a compound of Formula (I). In some embodiments, the composition is a vaccine composition. In some embodiments, the compound of Formula (I) is an adjuvant. In another aspect, provided are vaccines comprising an antigen and a compound of Formula (I).

[0018] In another aspect, provided are kits including a container with a compound, composition, or vaccine described herein. A kit described herein may include a single dose or multiple doses of the compound, compositions, or vaccines. The described kits may be useful in enhancing an immune response (e.g., innate and / or adaptive immune response) in a subject, biological sample, tissue, or cell, in treating a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject in need thereof, and / or in preventing a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject in need thereof. In certain embodiments, a kit described herein further includes instructions for using the compound, compositions, or vaccines included in the kit.

[0019] 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 a therapeutically effective amount of a compound, composition, or vaccine described herein.

[0020] In another aspect, the present disclosure provides methods of enhancing an immune response (e.g., innate and / or adaptive immune response) to an antigen in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound, composition, or vaccine described herein.

[0021] In another aspect, the present disclosure provides methods of treating a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft- versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound, composition, or vaccine described herein. In another aspect, the present disclosure provides methods of preventing a disease in a subject in need thereof, the methods comprising administering to the subject a prophylactically effective amount of a compound, composition, or vaccine described herein.

[0022] 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, composition, or vaccine described herein.

[0023] In yet another aspect, the present disclosure provides a compound, compositions, and / or vaccines described herein for use in a method of the disclosure (e.g., enhancing an immune response (e.g., innate and / or adaptive immune response), a method of treating and / or preventing a disease (e.g., a proliferative disease).

[0024] DEFINITIONS

[0025] 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, 3rd Edition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein.

[0026] 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.

[0027] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example “Ci-6” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, Ci-5, CM, CI-3, Ci-2, C2 6, C2-5, C2 4, C2-3, C3-6, C3-5, C34, C46, C4-5, and C5^.

[0028] 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.

[0029] 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, -Cth-cyclopropyl, vinyl, allyl, n-butyl, secbutyl, isobutyl, tert-butyl, cyclobutyl, -Cth-cyclobutyl, n-pentyl, sec -pentyl, isopentyl, tertpentyl, cyclopentyl, -Cth-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -ClU-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, l-methyl-2-buten-l- yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl (propargyl), 1-propynyl, and the like.

[0030] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“Ci-io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). 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 (“CM alkyl”). 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 (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), 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 (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (Cs), 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 Ci-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 (z-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 (z-Bu)). In certain embodiments, the alkyl group is a substituted Ci-10 alkyl (such as substituted C1-6 alkyl, 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 (“C2-9 alkenyl”). 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 (“C2-6 alkenyl”). 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 (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon 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 C2-6 alkenyl groups include the aforementioned C2 4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), 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 C2-10alkenyl. 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 or )may be an (£)- or (Z)- double bond.

[0031] “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 (“C2-20 alkynyl”). 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 (“C2-6 alkynyl”). 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 (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2 4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), 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 C2-10alkynyl.

[0032] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). 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 (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / / -indeny 1 (C9), decahydronaphthalenyl (C10), spiro [4.5] dec any 1 (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 C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-10 carbocyclyl.

[0033] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). 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 (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl 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 C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). 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 C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10 cycloalkyl.

[0034] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered nonaromatic 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.

[0035] 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.

[0036] 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 Ce aryl 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.

[0037] “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 (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cu 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 Ce-14 aryl. In certain embodiments, the aryl group is substituted Ce-14 aryl.

[0038] “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.

[0039] “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).

[0040] 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.

[0041] 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.

[0042] “Hetero aralkyl” is a subset of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0043] “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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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)NRbbS02Raa, -NRbbS02Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -0S(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -0P(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X“, -P(ORCC)3+X“, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -0P(RCC)3+X“, -OP(ORCC)2, -0P(ORCC)3+X“, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORCC), C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 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 Ci-io alkyl, Ci-io perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroCi-10 alkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroCi-ioalkyl, heteroC2-1alkenyl, heteroC2-ioalkynyl, C3-10carbocyclyl, 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, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -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, Ci-6alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-ealkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io 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 Ci-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io 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, C2-6 alkenyl, C2-6 alkynyl, heteroCi-ealkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl 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, -OC1-6 alkyl, -ON(CI-6alkyl)2, -N(CI-6alkyl)2, -N(CI-6alkyl)3+X-, -NH(CI-6alkyl)2+X-, -NH2(CI-6alkyl)+X“, -NH3+X“, -N(OCI-6alkyl)(Ci-6alkyl), -N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6alkyl), -OC(=O)(Ci-6alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6alkyl), -NHC(=O)( C1-6 alkyl), -N(CI-6alkyl)C(=O)( C1-6 alkyl), -NHCO2(CI-6alkyl), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=O)NH2, -C(=NH)O(CI-6alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(CI-6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(NH)NH(Ci- 6 alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2C1-6 alkyl, -SO2OC1-6 alkyl, -OSO2C1-6 alkyl, -SOC1-6 alkyl, -Si(Ci-6alkyl)3, -OSi(Ci-6alkyl)3-C(=S)N(CI-6alkyl)2, C(=S)NH(CI-6alkyl), C(=S)NH2, -C(=O)S(Ci-6alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi-6alkyl, -P(=O)(OCi-6alkyl)2, -P(=O)(Ci-6alkyl)2, -OP(=O)(Ci-6alkyl)2, -OP(=O)(OCi-6alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-ealkyl, heteroC2- ealkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, Ce-io aryl, 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.

[0048] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order 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 bivalent. Exemplary counterions include halide ions (e.g., F , Cl", Br , I"), NO3 , CIO4 , OH , H2PO4 , HCOa-, 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-, PFe", AsF6. SbF6. B [ 3,5-(CF32C6H3]41 , B(C6F5)4“, BPI14 , A1(OC(CF3)3)4", and carborane anions (e.g., CB11H12" or (HCB1Me5Br6) ). 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.

[0049] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0050] “Acyl” refers to a moiety selected from the group consisting of -C(=O)Raa, -CHO, - CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, - C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2, -C(=O)SRaa, or -C(=S)SRaa, wherein Raaand Rbbare as defined herein.

[0051] 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(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)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, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, Ci-10 alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroCi-ioalkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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.

[0052] In certain embodiments, the substituent present on the nitrogen atom is an 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, Ci-io alkyl (e.g., aralkyl, heteroaralkyl), C2-10alkenyl, C2-10alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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.

[0053] 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-nitrophenoxy acetamide, 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.

[0054] 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), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l- 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-(l,3- dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl 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, l-methyl-l-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1 -phenylethyl carbamate, 1 -methyl- l-(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.

[0055] 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), P- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0056] 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-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,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-(l-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 (Fem), 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-l-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), dimethylthiopho sphinamide (Mpt), diphenylthiopho sphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3 -nitropyridinesulf enamide (Npys).

[0057] 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, -R^, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=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.

[0058] 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- methoxy tetrahydropyranyl (MTHP), 4-methoxy tetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1 - [(2-chloro-4-methyl)phenyl] -4- methoxypiperidin-4-yl (CTMP), l,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 -ethoxy ethyl, 1- (2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 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, a- 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-l-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, l,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-l-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, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0059] 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 are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SCER^, -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 R^, 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.

[0060] 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 (e.g., -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, - OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2R^, -OP(RCC)2, -OP(RCC)3, - OP(=O)2Raa, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -OP(=O)2N(Rbb)2, and -OP(=O)(NRbb)2, wherein R^, Rbb, and Rccare as defined herein).

[0061] 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 “Cxhydrocarbon 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(C2Hs)- is a Ci 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 C3-10 hydrocarbon 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(C2Hs)- 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, d herein. When a chain atom of a Cxhydrocarbon 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-i hydrocarbon chain. For example, is a C3 hydrocarbon chain wherein one chain atom is replaced with an oxygen atom.

[0062] 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+(Ci - alky 1)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.

[0063] 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.

[0064] 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 O.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0065] 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.

[0066] 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”.

[0067] 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 manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (z.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).

[0068] 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.

[0069] 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 (z.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.

[0070] The terms “composition” and “formulation” are used interchangeably.

[0071] A “subject” to which administration is contemplated refers to a human (z.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, com, 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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, lipopolysaccharide (LPS), 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 are thought to 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.

[0081] 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-Guerin (BCG) vaccine and microorganism components, e.g., alum- precipitated diphtheria toxoid, bacterial lipopolysaccharide and endotoxins or their derivatives such as MPLA.

[0082] The term “infectious disease” refers to an illness caused by a pathogenic biological agent that results from transmission from an infected person, animal, or reservoir to a susceptible host, either directly or indirectly, through an intermediate plant or animal host, vector, or inanimate environment. See Last J M. ed. A dictionary of epidemiology. 4th ed., New York: Oxford University Press, 1988. Infectious disease is also known as transmissible disease or communicable disease. In certain embodiments, infectious diseases may be asymptomatic for much or even all their course in a given host. Infectious pathogens include some viruses, bacteria, fungi, protozoa, multicellular parasites, and aberrant proteins known as prions. A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g.. collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (z.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0083] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g.. VEGF). “Pathological angiogenesis” refers to abnormal (e.g.. excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0084] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis”, “metastatic”, or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0085] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and can infiltrate and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, hematological malignancies such as leukemia and lymphoma. Additional exemplary cancers include, but are not limited to, lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); kidney cancer (e.g., nephroblastoma, a.k.a. Wilms’ tumor, renal cell carcinoma); acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); sarcoma of the spleen; thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva). In some embodiments, the cancer treated using the composition and methods of the present disclosure is a skin cancer. In some embodiments, the cancer treated using the composition and methods of the present disclosure is melanoma.

[0086] The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0087] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0088] A “chronic disease” refers to a disease lasting for three or more months. Exemplary chronic diseases include, but are not limited to, arthritis, cardiovascular disease such as heart disease, stroke, cancer (e.g., breast cancer or colon cancer), chronic respiratory diseases, diabetes, epilepsy, seizures, obesity, and oral health problems.

[0089] BRIEF DESCRIPTION OF THE DRAWINGS

[0090] The 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:

[0091] FIG. 1. depicts that several exemplary compounds demonstrate robust TNF induction activity towards human adult PBMCs. Human adult PBMCs (100,000 cells / well, N = 4) were stimulated with compounds in singlet, with each compound titrated at 4 concentrations between 3.7 and 100 pM. TNF induction by each compound is depicted at 33 pM only. Following a ~24 hour incubation at 37°C and 5% CO2, supernatant were harvested and TNF cytokine levels were quantified by ELISAs. For statistical comparisons, * p < 0.05, for each compound vs. RMPI alone by Mann- Whitney test. NS indicates not significant.

[0092] FIG. 2. is a graph showing that compounds of the disclosure enhance adjuvanticity. 6- 8 weeks old C57BL / 6 adult mice were injected IM prime Day 0 with saline, rHA admixed with 10 nmol / mouse of each compound. Ab titers for rHA- specific the IgG subtype were measured by ELISA at Day 28. Data is presented as Box and whiskers plot with individual data points of 5-20 mice / group. For statistical comparisons, * p < 0.05, ** p < 0.01, *** p < 0.001 for each compound vs. rHA alone by Mann- Whitney test. Dotted line indicates median rHA induced IgG response. NS indicates not significant. FIG. 3. is a graph showing that compounds of the disclosure enhance Type 1 immune polarization. 6-8 weeks old C57BL / 6 adult mice were injected IM prime (Day 0) / boost (Day 28) with saline, rHA admixed with 100 nmol / mouse of each compound. Ab titers for rHA- specific IgG subtypes were measured by ELISA at Day 28 or 42. Data is presented as Box and whiskers plot with individual data points of 5-20 mice / group. As compared to rHA alone, all rHA+compound (except 11, and 5) induced significantly enhanced IgG2c Ab response (*** p < 0.001 by repeated measure one-way ANOVA of Log-transformed data). Dotted line indicates median rHA alone-induced IgG2c response.

[0093] FIG. 4. shows that compounds of the disclosure display robust adjuvant activity after a single dose. 6-8 week old C57BL / 6 adult mice were injected IM prime on Day 0 with rHA alone or rHA admixed with 10 nmol of 2, 12, 14 or 18. Antibody titers for rHA-specific IgG isotypes were measured by ELISA at day 28 or 42. N = 5 mice per group. * p < 0.0332, ** p

[0094] < 0.0021, *** p < 0.0002, **** p < 0.0001 for compound vs. rHA alone by Kruskal- Wallis test of Log-transformed data.

[0095] FIG. 5. shows that exemplary compound 14 is an adjuvant that markedly enhances single shot seasonal flu vaccination. 6-8 week old C57BL / 6 adult mice were injected IM prime (Day 0) / boost (Day 28) with saline, rHA admixed with 100 nmol / mouse of each 14. Ab titers for rHA-specific IgG subtypes were measured by ELISA at day 28. Data is depicted as Box and whiskers plots with individual data points (N = 10 - 30 mice / group). As compared to rHA alone, rHA + 14 induced significantly enhanced total IgG and IgG2c Ab responses (*** p <0.001 by RM 1-way ANOVA of Log-transformed data).

[0096] FIG. 6. is a series of graphs showing that exemplary compound 14 demonstrates robust adjuvanticity of rHA immunization after one and two doses. 6-8 weeks old (young) or 52-week-old (aged) C57BL / 6 adult mice were injected IM prime on Day O / boost on Day 28 with rHA alone or rHA admixed with 14. Antibody titers for rHA-specific IgG and IgG isotypes were measured by ELISA at day 28 or 42. N = 5 mice per group. * p < 0.0332, ** p

[0097] < 0.0021, *** p < 0.0002, **** p < 0.0001 for compound 14 + rHA vs. rHA alone by Kruskal-Wallis test of Log-transformed data.

[0098] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0099] Described herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof. The compounds described herein possess surprisingly exceptional properties (e.g., robust immunomodulatory activity) rendering them useful single-agent therapeutics and as vaccine adjuvants. Thus, the compounds described herein are enhancers and / or modifiers of an immune response (e.g., innate and / or adaptive immune response), and / or adjuvants in a vaccine for a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose), or as a stand alone (e.g., single agent) anti-infective or immune response modifying agent. The compounds are useful in treating or preventing a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject in need thereof. Also provided are pharmaceutical compositions, vaccines, kits, and uses including a compound described herein.

[0100] Compounds

[0101] 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:

[0102] R1Ais substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted 6-membered heteroaryl;

[0103] Z is -CN, substituted or unsubstituted heteroalkyl comprising at least one nitrogen atom, substituted heteroarylalkyl comprising at least one nitrogen atom, or a lipid group, wherein Z is not -CHoNHo or -OCH3;

[0104] R1is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -ORa, or -N(Ralh; each instance of RAis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; each instance of RBis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; 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; each instance of Ralis 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, or two instances of Ralare joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; and q is 1 or 2.

[0105] In certain embodiments, q is 1. In certain embodiments, q is 2.

[0106] R1

[0107] As described herein, R1is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, - ORa, or -N(Ral)2. In certain embodiments, R1is hydrogen. In certain embodiments, R1is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R1is substituted or unsubstituted C1-6 alkyl (e.g., substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In certain embodiments, R1is methyl. In certain embodiments, R1is ethyl. In certain embodiments, R1is -ORa(e.g., -OH, -O(substituted or unsubstituted C1-6 alkyl) (e.g., -OMe, -OEt, -OPr, -OBu, or -OBn). In certain embodiments, R1is -N(Ral)2(e.g., -NH2, - NH(substituted or unsubstituted Ci-6 alkyl) (e.g., -NHMe), or -N(substituted or unsubstituted Ci-6 alkyl)-(substituted or unsubstituted Ci-6 alkyl) (e.g., -NMe2)).

[0108] R1A& R1A-Z

[0109] As described herein, R1Ais substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted 6-membered heteroaryl. In certain embodiments, R1Ais substituted or unsubstituted phenyl. In certain embodiments, R1Ais substituted phenyl.

[0110] In certain embodiments, R1A-Z is of the formula: , wherein each instance of Rcis 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(Ralh, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, - C(=O)N(Ral)2, or -NO2; and c is 0, 1, 2, 3, 4, or 5. In certain embodiments, c is 0, 1, 2, 3, or 4. In certain embodiments, c is 0, 1, 2, or 3. In certain embodiments, c is 0, 1, or 2. In certain embodiments, c is 0 or 1. In certain embodiments, c is 1 or 2. In certain embodiments, c is 0. In certain embodiments, c is 1. In certain embodiments, c is 2. In certain embodiments, at least one instance of Rcis halogen. In certain embodiments, at least one instance of Rcis F. In certain embodiments, at least one instance of Rcis Br. In certain embodiments, at least one instance of Rcis Cl. In certain embodiments, at least one instance of Rcis I. In certain embodiments, at least one instance of Rcis substituted or unsubstituted alkyl (e.g., C1-6 alkyl). In certain embodiments, at least one instance of Rcis substituted or unsubstituted methyl. In certain embodiments, at least one instance of Rcis methyl. In certain embodiments, at least one instance of Rcis substituted methyl (e.g., -CF3 or Bn). In certain embodiments, at least one instance of Rcis haloalkyl (e.g., C1-6 haloalkyl). In certain embodiments, at least one instance of Rcis C1-6 haloalkyl. In certain embodiments, at least one instance of Rcis C1-4 haloalkyl. In certain embodiments, at least one instance of Rcis Ci- 3 haloalkyl. In certain embodiments, at least one instance of Rcis C1-2 haloalkyl. In certain embodiments, at least one instance of Rcis -CF3. In certain embodiments, at least one instance of Rcis substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of Rcis substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of Rcis substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of Rcis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of Rcis substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of Rcis substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of Rcis -ORa(e. g., -OH or -O(substituted or unsubstituted C1-6 alkyl) (e.g., -OMe)). In certain embodiments, at least one instance of Rcis -OMe. In certain embodiments, at least one instance of Rcis -N(Ralh (e.g., -NH2, -NH(substituted or unsubstituted C1-6 alkyl) (e.g., - NHMe), or -NMe2). In certain embodiments, at least one instance of Rcis -SRa(e.g., -SH, - S(substituted or unsubstituted C1-6 alkyl) (e.g., -SMe, -SEt, -SPr, -SBu, or -SBn), or - S(substituted or unsubstituted phenyl) (e.g., -SPh)). In certain embodiments, at least one instance of Rcis -CN. In certain embodiments, at least one instance of RAis -C(=O)Ra(e.g., -C(=O)(substituted or unsubstituted alkyl) or -C(=O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of Rcis -C(=O)ORa(e.g., -C(=O)OH, - C(=O)O(substituted or unsubstituted alkyl) (e.g., -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of Rcis -C(=O)N(Ral)2(e.g., -C(=O)NH2, -C(=O)NH(substituted or unsubstituted alkyl), -C(=O)NH(substituted or unsubstituted phenyl), -C(=O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or -C(=O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of Rcis -NO2. In certain embodiments, R1A-Z is of the formula: of the formula: certain embodiments, R1A-Z is of the formula: embodiments, R1A-Z is of the formula: certain embodiments, R1A-Z is of the formula:

[0111] In certain embodiments, R1Ais substituted or unsubstituted benzyl. In certain embodiments, R1A-Z is of the formula: Z?wherein each instance of R2is independently hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, -ORa, or -N(Ralh; each instance of Rcis 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(Ralh, -SRa, -CN, -C(=O)Ra, -C(=O)ORa, - C(=O)N(Ral)2, or -NO2; and c is 0, 1, 2, 3, 4, or 5. In certain embodiments, c is 0, 1, 2, 3, or

[0112] 4. In certain embodiments, c is 0, 1, 2, or 3. In certain embodiments, c is 0, 1, or 2. In certain embodiments, c is 0 or 1. In certain embodiments, c is 1 or 2. In certain embodiments, c is 0.

[0113] In certain embodiments, c is 1. In certain embodiments, c is 2. In certain embodiments, R1Ais of the formula: Z , wherein R2is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -ORa, or -N(Ral)2; each instance of Rcis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; and c is 0, 1, 2, 3, 4, or 5. In certain embodiments, R1Ais of the formula:

[0114] In certain embodiments, at least one instance of R2is hydrogen. In certain embodiments, at least one instance of R2is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R2is substituted or unsubstituted C1-6 alkyl (e.g., substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In certain embodiments, at least one instance of R2is methyl. In certain embodiments, at least one instance of R2is substituted or unsubstituted methyl. In certain embodiments, R2is -CH2OH. In certain embodiments, at least one instance of R2is Et. In certain embodiments, at least one instance of R2is -ORa(e.g., -OH, -O(substituted or unsubstituted C1-6 alkyl) (e.g., -OMe, - OEt, -OPr, -OBu, or -OBn). In certain embodiments, at least one instance of R2is -N(Ral)2(e.g., -NH2, -NH(substituted or unsubstituted C1-6 alkyl) (e.g., -NHMe), or -N(substituted or unsubstituted C1-6 alkyl)-(substituted or unsubstituted C1-6 alkyl) (e.g., -NMe2)). In certain embodiments, R1Ais of the formula:

[0115] In certain embodiments, R1Ais substituted or unsubstituted 6-membered heteroaryl.

[0116] In certain embodiments, R1Ais substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, or substituted or unsubstituted pyrazine.

[0117] RA

[0118] As described herein, each instance of RAis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2. When Formula (I) includes two or more instances of RA, any two instances of RAmay be the same or different from each other. In certain embodiments, a is 0. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, at least one instance of RAis halogen. In certain embodiments, at least one instance of RAis F. In certain embodiments, at least one instance of RAis Br, Cl, or I. In certain embodiments, at least one instance of RAis substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl). In certain embodiments, at least one instance of RAis methyl. In certain embodiments, RAis methyl and a is 1. In certain embodiments, at least one instance of RAis substituted methyl (e.g., -CF3 or Bn). In certain embodiments, at least one instance of RAis ethyl. In certain embodiments, at least one instance of RAis substituted ethyl. In certain embodiments, at least one instance of RAis n-Pr. In certain embodiments, at least one instance of RAis z-Pr. In certain embodiments, at least one instance of RAis substituted propyl (e.g., perfluoropropyl). In certain embodiments, at least one instance of RAis Me, Et, or 77-Pr. In certain embodiments, at least one instance of RAis substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of RAis substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of RAis substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of RAis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of RAis substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of RAis substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of RAis -ORa(e.g. , -OH or -O(substituted or unsubstituted Ci-6 alkyl) (e.g. , - OMe)). In certain embodiments, at least one instance of RAis -OMe. In certain embodiments, at least one instance of RAis -N(Ral)2(e.g., -NH2, -NH(substituted or unsubstituted C1-6 alkyl) (e.g., -NHMe), or -NMe2). In certain embodiments, at least one instance of RAis - SRa(e.g., -SH, -S(substituted or unsubstituted C1-6 alkyl) (e.g., -SMe, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh)). In certain embodiments, at least one instance of RAis -CN. In certain embodiments, at least one instance of RAis - C(=O)Ra(e.g., -C(=O)(substituted or unsubstituted alkyl) or -C(=O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of RAis -C(=O)ORa(e.g., -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (e.g., -C(=O)OMe), or - C(=O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of RAis -C(=O)N(Ral)2(e.g., -C(=O)NH2, -C(=O)NH(substituted or unsubstituted alkyl), - C(=O)NH(substituted or unsubstituted phenyl), -C(=O)N(substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -C(=O)N(substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of RAis - NO2.

[0119] RB

[0120] As described herein, each instance of RBis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2. When Formula (I) includes two or more instances of RB, any two instances of RBmay be the same or different from each other. In certain embodiments, b is 0. In certain embodiments, b is 1. In certain embodiments, b is 2. In certain embodiments, b is 3. In certain embodiments, at least one instance of RBis halogen. In certain embodiments, at least one instance of RBis F. In certain embodiments, at least one instance of RBis Br, Cl, or I. In certain embodiments, at least one instance of RBis substituted or unsubstituted alkyl (e.g., substituted or unsubstituted Ci-6 alkyl). In certain embodiments, at least one instance of RBis methyl. In certain embodiments, at least one instance of RBis substituted methyl (e.g., -CF3 or Bn). In certain embodiments, at least one instance of RBis ethyl. In certain embodiments, at least one instance of RBis substituted ethyl. In certain embodiments, at least one instance of RBis 77-Pr. In certain embodiments, at least one instance of RBis z-Pr. In certain embodiments, at least one instance of RBis substituted propyl (e.g., perfluoropropyl). In certain embodiments, at least one instance of RBis methyl, ethyl, or zz-propyl. In certain embodiments, at least one instance of RBis substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of RBis substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of RBis substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7- membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of RBis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of RBis substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of RBis substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of RBis -ORa(e.g., -OH or -O(substituted or unsubstituted C1-6 alkyl) (e.g., -OMe)). In certain embodiments, at least one instance of RBis -OMe. In certain embodiments, at least one instance of RBis -N(Ral)2(e.g., -NH2, -NH(substituted or unsubstituted C1-6 alkyl) (e.g., - NHMe), or -NMe2). In certain embodiments, at least one instance of RBis -SRa(e.g., -SH, - S(substituted or unsubstituted C1-6 alkyl) (e.g., -SMe, -SEt, -SPr, -SBu, or -SBn), or - S(substituted or unsubstituted phenyl) (e.g., -SPh)). In certain embodiments, at least one instance of RBis -CN. In certain embodiments, at least one instance of RBis -C(=O)Ra(e.g., -C(=O)(substituted or unsubstituted alkyl) or -C(=O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of RBis -C(=O)ORa(e.g., -C(=O)OH, - C(=O)O(substituted or unsubstituted alkyl) (e.g., -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of RBis -C(=O)N(Ral)2(e.g., -C(=O)NH2, -C(=O)NH(substituted or unsubstituted alkyl), -C(=O)NH(substituted or unsubstituted phenyl), -C(=O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or -C(=O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of RBis -NO2.

[0121] Ra

[0122] As described herein, 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. In certain embodiments, Rais hydrogen. In certain embodiments, Rais substituted or unsubstituted acyl (e.g., -C(=O)Me). In certain embodiments, Rais substituted or unsubstituted alkyl (e.g., C1-6 alkyl). In certain embodiments, Rais substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, Rais substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, Rais substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, Rais substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10- membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, Rais substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, Rais substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, Rais a nitrogen protecting group when attached to a nitrogen atom (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, Rais an oxygen protecting group when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, Rais a sulfur protecting group when attached to a sulfur atom.

[0123] Ral

[0124] As described herein, each instance of Ralis 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, or two instances of Ralare joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring. In certain embodiments, Ralis hydrogen. In certain embodiments, Ralis substituted or unsubstituted acyl (e.g., -C(=O)Me). In certain embodiments, Ralis substituted or unsubstituted alkyl (e.g., Ci-6 alkyl). In certain embodiments, Ralis substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2- 6 alkenyl). In certain embodiments, Ralis substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, Ralis substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, Ralis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, Ralis substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, Ralis substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, Ralis a nitrogen protecting group when attached to a nitrogen atom (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, two instances of Ralare joined to form a substituted or unsubstituted, heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, two instances of Ralare joined to form a substituted or unsubstituted, heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

[0125] Z

[0126] As described herein, Z is -CN, substituted or unsubstituted heteroalkyl comprising at least one nitrogen atom, substituted heteroarylalkyl comprising at least one nitrogen atom, or a lipid group, wherein Z is not -CH2NH2 or -OCH3.

[0127] In certain embodiments, Z is -CN.

[0128] In certain embodiments, Z is substituted or unsubstituted heteroalkyl comprising at least one nitrogen atom, or substituted heteroarylalkyl comprising at least one nitrogen atom. In certain embodiments, Z is substituted or unsubstituted heteroalkyl comprising at least one nitrogen atom. In certain embodiments, Z is substituted or unsubstituted C1-8 heteroalkyl comprising at least one nitrogen atom.

[0129] In certain embodiments, Z is of formula: wherein: L1is substituted or unsubstituted alkylene; R10is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, -SO2Ra, or -C(=O)Ra; and R20is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, -SO2Ra, or -C(=O)Ra.

[0130] In certain embodiments, Z is of formula:

[0131] each L5is independently substituted or unsubstituted Ci-is alkyl, or substituted or unsubstituted -C(=O)-C1-18alkyl; each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl.

[0132] In certain embodiments, R10is hydrogen or -CH2CH2OH; and R20is -CH2CH2OH , each L5is independently substituted or unsubstituted C1-18 alkyl, or substituted or unsubstituted -C(=O)-C1-18alkyl; each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl. each L5is independently substituted or unsubstituted Ci-is alkyl, or substituted or unsubstituted -C(=O)-C1-18alkyl; each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl. In certain embodiments, R10is hydrogen; each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2.

[0133] In certain embodiments, Z is of formula: each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl.

[0134] each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl. In certain embodiments, Z is of formula: each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2.

[0135] In certain embodiments, Z is of formula:

[0136] In certain embodiments, Z is substituted heteroarylalkyl comprising at least one nitrogen atom. In certain embodiments, Z is substituted 5-membered heteroarylalkyl comprising at least one nitrogen atom.

[0137] In certain embodiments, Z is of formula: wherein: L1is substituted or unsubstituted alkylene; R30is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R40is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0138] In certain embodiments, Z is of formula:

[0139] each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl.

[0140] each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl. o p

[0141] In certain embodiments, R30is hydrogen or 0H; and R40is each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2.

[0142] In certain embodiments, R30is hydrogen; and R40is each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl.

[0143] In certain embodiments, Z is of formula:

[0144] each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl.

[0145] each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl.

[0146] In certain embodiments, Z is of formula:

[0147] In certain embodiments, Z is of formula: each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2.

[0148] In certain embodiments, Z is of formula:

[0149] each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl. In certain embodiments, Z is of formula: each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2; and each Ralis 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, or substituted or unsubstituted heteroaryl.

[0150] In certain embodiments, Z is a lipid group. A lipid group is a moiety that is soluble in organic solvents and includes, but is not limited to, oils, fats, sterols, triglycerides, fatty acids, and phospholipids. In certain embodiments, the lipid group comprises a lipid selected from the group consisting of sterol lipids, fatty acids, fatty alcohols, glycerolipids (e.g., monoglycerides, diglycerides, and triglycerides), phospholipids, glycerophospholipids, sphingolipids, prenol lipids, saccharolipids, polyketides, and any combination thereof. In certain embodiments, the lipid group comprises more than one lipid. In certain embodiments, the lipid group comprises additional functional groups such as polyethylene glycol chains. In certain embodiments, the lipid group comprises a saturated long-chain fatty acid. In certain embodiment, the lipid group comprises a phospholipid. In certain embodiments, the lipid group comprises a polyunsaturated fatty acid or alcohol.

[0151] In certain embodiments, Z is of formula: , wherein: L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; X1is a bond, , -NRa1-, or -O-; L2is a bond or substituted or unsubstituted alkylene; X2is a bond, -C(O)-, bond, substituted or unsubstituted alkylene, -

[0152] NRalCH2-, or -NRa1-; R10is hydrogen or -Y-(CH2)m-CH3; each Y is independently -O-, -

[0153] C(=O)O-, -O(O=)C-, -CH2O(O=)C-, -NRa1-, -C(=O)NRa1-, -NRal(O=)C-, or -CH2-; X3is hydrogen or -ORa; n is 0-10; m is 8-30; and t is 8-30. In certain embodiments, n is 2-4; m is 10-20; and t is 10-20. In certain embodiments, n is 3-4; m is 12-18; and t is 12-18. In certain embodiments, n is 3; m is 12-18; and t is 12-18. In certain embodiments, n is 3; m is 12-15; and t is 12-15. In certain embodiments, n is 0-6; m is 14; and t is 14. In certain embodiments, n is 1-6; m is 14; and t is 14. In certain embodiments, n is 2-6; m is 14; and t is 14. In certain embodiments, n is 3-6; m is 14; and t is 14. In certain embodiments, n is 2-5; m is 14; and t is 14. In certain embodiments, n is 2-4; m is 14; and t is 14. In certain embodiments, n is 3-5; m is 14; and t is 14. In certain embodiments, n is 3-4; m is 14; and t is 14. In certain embodiments, n is 4-6; m is 14; and t is 14. In certain embodiments, n is 0; m is 14; and t is 14. In certain embodiments, n is 1; m is 14; and t is 14. In certain embodiments, n is 2; m is 14; and t is 14. In certain embodiments, n is 3; m is 14; and t is 14. In certain embodiments, n is 4; m is 14; and t is 14. In certain embodiments, n is 5; m is 14; and t is 14. In certain embodiments, n is 6; m is 14; and t is 14.

[0154] In certain embodiments, Zis of formula: or certain embodiments, Z is of formula:

[0155] In certain embodiments, Z is of formula:

[0156] In certain embodiments, Zis of formula:

[0157] In certain embodiments, Zis of formula:

[0158] In certain embodiments, Zis of formula:

[0159] In certain embodiments, Zis of formula: In certain embodiments, Zis of formula:

[0160] In certain embodiments, Zis of formula:

[0161] In certain embodiments, Z is of formula: " * , wherein

[0162] L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; X1is -NRal- or -O-; L2is a bond or substituted or unsubstituted alkylene; X2 bond, substituted or unsubstituted alkylene, or

[0163] -NRa1-; R10is hydrogen or -Y-(CH2)m-CH3; each Y is independently -0-, -C(0)0-, -0(0)C-,

[0164] - NRa1-, -C(0)NRa1-, - NRal(0)C-, or -CH2-; n is 0-10; m is 8-30; and t is 8-30. In certain embodiments, each Y is independently -O(O)C- or -CH2-. In certain embodiments, X2is - . In certain embodiments, X2is -C(O)-. In certain embodiments, X2is . in embodiments, n is 0-6; m is 8-20; and t is 8-20. In certain embodiments, n is 0-4; m is 10-20; and t is 8-20. In certain embodiments, n is 0-4; m is 12- 18; and t is 10-18. In certain embodiments, n is 0-4; m is 12-18; and t is 10-18. In certain embodiments, n is 0-4; m is 12-15; and t is 10-15.

[0165] In certain embodiments, Zis of formula: , wherein

[0166] L2is a bond or substituted or unsubstituted alkylene; X2is -C(O)- or ; L3is a bond or substituted or unsubstituted alkylene; R10is hydrogen or -Y-(CH2)m-CH3; each Y is independently -O-, -C(O)O-, -O(O)C-, - NRa1-, -C(O) NRa1-, - NRal(O)C-, or -CH2-; n is 0- 10; m is 8-30; and t is 8-30. In certain embodiments, each Y is independently -O(O)C- or - CH2-.

[0167] In certain embodiments, Zis of formula: wherein L2is a bond or substituted or unsubstituted alkylene; X2is -C(O)- or ; L3is a bond or substituted or unsubstituted alkylene; R10is hydrogen or -Y-(CH2)m-CH3; each Y is independently -O-, -C(O)O-, -O(O)C-, - NRa1-, -C(O) NRa1-, - NRal(O)C-, or -CH2- ; n is 0-10; m is 8-30; and t is 8-30. In certain embodiments, each Y is independently -O(O)C- or -CH2-. In certain embodiments, each Y is -O(O)C-.

[0168] In certain embodiments, Zis of formula: wherein: L2is a bond or substituted or unsubstituted alkylene; X2is -C(O)- or L3is a bond or substituted or unsubstituted alkylene; n is 0-6; m is 8-20; and t is 8-20.

[0169] In certain embodiments, Zis of formula wherein n is 0-6; m is 8-20; and t is 8-20. In certain embodiments, n is 2-4; m is 10-20; and t is 10-20. In certain embodiments, n is 3-4; m is 12-18; and t is 12-18. In certain embodiments, n is 3; m is 12-18; and t is 12-18. In certain embodiments, n is 3; m is 12-15; and t is 12-15. In certain embodiments, n is 0-6; m is 14; and t is 14. In certain embodiments, n is 1-6; m is 14; and t is 14. In certain embodiments, n is 2-6; m is 14; and t is 14. In certain embodiments, n is 3-6; m is 14; and t is 14. In certain embodiments, n is 2-5; m is 14; and t is 14. In certain embodiments, n is 2-4; m is 14; and t is 14. In certain embodiments, n is 3-5; m is 14; and t is 14. In certain embodiments, n is 3-4; m is 14; and t is 14. In certain embodiments, n is 4-6; m is 14; and t is 14. In certain embodiments, n is 0; m is 14; and t is 14. In certain embodiments, n is 1; m is 14; and t is 14. In certain embodiments, n is 2; m is 14; and t is 14. In certain embodiments, n is 3; m is 14; and t is 14. In certain embodiments, n is 4; m is 14; and t is 14. In certain embodiments, n is 5; m is 14; and t is 14. In certain embodiments, n is 6; m is 14; and t is 14.

[0170] In certain embodiments, Zis of formula:

[0171] In certain embodiments, Zis of formula:

[0172] In certain embodiments, Z is of formula , wherein n is 1-6; m is 8-20; and t is 8-20. In certain embodiments, n is 2-4; m is 10-20; and t is 10-20. In certain embodiments, n is 3-4; m is 12-18; and t is 12-18. In certain embodiments, n is 4; m is 12-18; and t is 12-18. In certain embodiments, n is 4; m is 12-15; and t is 12-15. In certain embodiments, n is 0-6; m is 14; and t is 14. In certain embodiments, n is 1-6; m is 14; and t is 14. In certain embodiments, n is 2-6; m is 14; and t is 14. In certain embodiments, n is 3-6; m is 14; and t is 14. In certain embodiments, n is 2-5; m is 14; and t is 14. In certain embodiments, n is 2-4; m is 14; and t is 14. In certain embodiments, n is 3-5; m is 14; and t is 14. In certain embodiments, n is 3-4; m is 14; and t is 14. In certain embodiments, n is 4-6; m is 14; and t is 14. In certain embodiments, n is 0; m is 14; and t is 14. In certain embodiments, n is 1; m is 14; and t is 14. In certain embodiments, n is 2; m is 14; and t is 14. In certain embodiments, n is 3; m is 14; and t is 14. In certain embodiments, n is 4; m is 14; and t is 14. In certain embodiments, n is 5; m is 14; and t is 14. In certain embodiments, n is 6; m is 14; and t is 14.

[0173] In certain embodiments, Zis of formula In certain embodiments, Zis of formula

[0174] In certain embodiments, Zis of formula wherein t is 8-20. In certain embodiments, t is 10-20. In certain embodiments, t is 8-18. In certain embodiments, t is 10-18. In certain embodiments, t is 10-15. In certain embodiments, t is 10-12. In certain embodiments, t is 9-12. In certain embodiments, t is 11.

[0175] In certain embodiments, Zis of formula , wherein t is 8-20. In certain embodiments, t is 10-20. In certain embodiments, t is 12-18. In certain embodiments, t is 12-

[0176] 15. In certain embodiments, t is 14.

[0177] In certain embodiments, Zis of formula

[0178] In certain embodiments, Zis of formula

[0179] O

[0180] In certain embodiments, Z is of formula , In certain embodiments, Zis of formula wherein n is 0-6; m is 8-20; and t is 8-20. In certain embodiments, n is 2-4; m is 10-20; and t is 10-20. In certain embodiments, n is 3-4; m is 12-18; and t is 12-18. In certain embodiments, n is 3; m is 12-18; and t is 12-18. In certain embodiments, n is 3; m is 12-15; and t is 12-15. In certain embodiments, n is 3; m is 14; and t is 14. In certain embodiments, n is 4; m is 12-18; and t is 12-18. In certain embodiments, n is 4; m is 12-15; and t is 12-15. In certain embodiments, n is 0-6; m is 14; and t is 14. In certain embodiments, n is 1-6; m is 14; and t is 14. In certain embodiments, n is 2-6; m is 14; and t is 14. In certain embodiments, n is 3-6; m is 14; and t is 14. In certain embodiments, n is 2-5; m is 14; and t is 14. In certain embodiments, n is 2-4; m is 14; and t is 14. In certain embodiments, n is 3-5; m is 14; and t is 14. In certain embodiments, n is 3-4; m is 14; and t is 14. In certain embodiments, n is 4-6; m is 14; and t is 14. In certain embodiments, n is 0; m is 14; and t is 14. In certain embodiments, n is 1; m is 14; and t is 14. In certain embodiments, n is 2; m is 14; and t is 14. In certain embodiments, n is 3; m is 14; and t is 14. In certain embodiments, n is 4; m is 14; and t is 14. In certain embodiments, n is 5; m is 14; and t is 14. In certain embodiments, n is 6; m is 14; and t is 14.

[0181] In certain embodiments, Zis of formula:

[0182] each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2.

[0183] In certain embodiments, Zis of formula:

[0184] In certain embodiments, Zis of formula: In certain embodiments, Z is of formula:

[0185] each W is independently -SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2.

[0186] In certain embodiments, Zis of formula

[0187] In certain embodiments, Zis of formula

[0188] In certain embodiments, Zis of formula

[0189] In certain embodiments, Zis of formula

[0190] In certain embodiments, Z is of formula 0

[0191] In certain embodiments, Zis of formula 0 ; and W is -SO2(OH), -

[0192] PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2.

[0193] In certain embodiments, Zis of formula

[0194] O

[0195] In certain embodiments, Zis of formula

[0196] In certain embodiments, Zis of formula

[0197] SO2(OH), -PO(OH)2, -CH2PO(OH)2, or -CF2PO(OH)2.

[0198] In certain embodiments, Zis of formula

[0199] In certain embodiments, Zis of formula

[0200] In certain embodiments, Zis of formula

[0201] In certain embodiments, Zis of formula

[0202]

[0203] In certain embodiments, Zis of formula: wherein: each L1is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; L2is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; each R20is independently hydrogen, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and each R30is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0204] In certain embodiments, Zis of formula:

[0205] In certain embodiments, Zis of formula:

[0206] In certain embodiments, Zis of formula: wherein:

[0207] In certain embodiments, Zis of formula:

[0208] In certain embodiments, Zis of formula: In certain embodiments, Zis of formula: certain embodiments, Z is

[0209] Embodiments of Formula (I)

[0210] 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 RA, RB, R1, R1A, Z, a, and b are as defined herein.

[0211] 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 RA, RB, Rc, R1, Z, a, b, and c are as defined herein.

[0212] In certain embodiments, the compound of Formula (I) is of Formula (I-b-1): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, RB, Rc, R1, Z, a, b, and c are as defined herein.

[0213] 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 RA, Rc, R1, Z, a, and c are as defined herein.

[0214] In certain embodiments, the compound of Formula (I) is of Formula (I-c-1): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, Rc, R1, Z, a, and c 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 RA, Rc, R1, Z, and c are as defined herein.

[0215] In certain embodiments, the compound of Formula (I) is of Formula (I-d-1): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, Rc, R1, Z, and c are as defined herein.

[0216] 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 RA, Rc, Z, and c are as defined herein.

[0217] In certain embodiments, the compound of Formula (I) is of Formula (I-e-1): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, Rc, Z, and c are as defined herein.

[0218] 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 RA, Rc, and Z are as defined herein.

[0219] In certain embodiments, the compound of Formula (I) is of Formula (I-f-1): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, Rc, and Z are 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 Rcand Z are as defined herein.

[0220] In certain embodiments, the compound of Formula (I) is of Formula (I-g-1): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rcand Z are as defined herein.

[0221] 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 Z is as defined herein.

[0222] In certain embodiments, the compound of Formula (I) is of Formula (I-i): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Z is as defined herein.

[0223] In certain embodiments, the compound of Formula (I) is of Formula (I-j): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, RB, Rc, R1, R2, Z, a, b, and c are as defined herein.

[0224] In certain embodiments, the compound of Formula (I) is of Formula (Il-a): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, RB, R1, R1A, Z, a, and b are as defined herein.

[0225] In certain embodiments, the compound of Formula (I) is of Formula (Il-b): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, RB, Rc, R1, Z, a, b, and c are as defined herein.

[0226] In certain embodiments, the compound of Formula (I) is of Formula (II-c): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, Rc, R1, Z, a, and c are as defined herein.

[0227] In certain embodiments, the compound of Formula (I) is of Formula (Il-d): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, Rc, R1, Z, and c are as defined herein. In certain embodiments, the compound of Formula (I) is of Formula (Il-e): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, Rc, Z, and c are as defined herein.

[0228] In certain embodiments, the compound of Formula (I) is of Formula (Il-f): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein RA, Rc, and Z are as defined herein.

[0229] In certain embodiments, the compound of Formula (I) is of Formula (Il-g) : or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Rcand Z are 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, wherein Z is as defined herein.

[0230] In certain embodiments, the compound of Formula (I) is of Formula (Il-i): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Z is as defined herein.

[0231] In certain embodiments, the compound of Formula (I) is of the formula:

[0232]

[0233]

[0234] 5 stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0235] In certain embodiments, the compound of Formula (I) is of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0236] Pharmaceutical Compositions, Kits, and. Administration

[0237] 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.

[0238] 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, the effective amount is a prophy tactically effective amount. In certain embodiments, a therapeutically effective amount is an amount effective for enhancing an immune response (e.g., innate and / or adaptive immune response). In certain embodiments, a therapeutically effective amount is an amount effective for treating a disease (e.g., proliferative disease). In certain embodiments, a therapeutically effective amount is an amount effective for serving as an adjuvant in a vaccine for a disease, (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose), or as stand alone anti-infective or immune response modifying agents. In certain embodiments, a prophylactically effective amount is an amount effective for preventing a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose). In certain embodiments, a prophylactically effective amount is an amount effective for enhancing an immune response (e.g., innate and / or adaptive immune response), and preventing a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft- versus-host disease, chronic disease, addiction, or risk of drug overdose).

[0239] In certain embodiments, the effective amount is an amount effective for enhancing an immune response (e.g., innate and / or adaptive 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 is an amount effective for enhancing an immune response (e.g., innate and / or adaptive 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%.

[0240] 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.

[0241] In certain embodiments, the cell is present in vitro. In certain embodiments, the cell is present in vivo.

[0242] 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 (z.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. Pharmaceutical 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.

[0243] Although the descriptions of pharmaceutical 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 pharmaceutical 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.

[0244] 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 as a prophylactic. 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 Tolllike 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., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or 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.

[0245] 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., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or 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.

[0246] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent (e.g., anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR- U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase Erwinia Chrysanthemi), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an antilymphoma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP- ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCAS AR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine ), VID AZA (azacitidine ), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin ), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), A VASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EV ACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI , FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotec an hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VID AZA (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XT ANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv- aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), ENMD-2076, PCI- 32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP- 11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF- 4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,, aminopterin, and hexamethyl melamine, or a combination thereof. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of an HMT (e.g., EZH1, EZH2, DOTI). In certain embodiments, the additional pharmaceutical agent is a protein kinase inhibitor (e.g., tyrosine protein kinase inhibitor). In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HD AC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0247] 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.

[0248] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject in need thereof. In certain embodiments, the kits are useful as enhancers and / or modifiers of an immune response (e.g., innate and / or adaptive immune response), and / or adjuvants in a vaccine for a disease, (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject, biological sample, tissue, or cell, or as stand alone anti-infective or immune response modifying agents.

[0249] In certain embodiments, a kit described herein further includes instructions for using the compound or pharmaceutical 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., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject in need thereof. In certain embodiments, the kits and instructions provide for enhancing of an immune response (e.g., innate and / or adaptive immune response) in a subject, biological sample, tissue, or cell. In certain embodiments, the kits and instructions provide for use of the compound as an adjuvant in a vaccine for a disease, (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose) in a subject, biological sample, tissue, or cell, or as stand alone anti-infective or immune response modifying agents. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0250] Antigens

[0251] The present disclosure also provides compositions comprising an antigen and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative. An “antigen” refers to an entity that is bound by an antibody or receptor, or an entity that induces the production of the antibody. In some embodiments, an antigen increases the production of antibodies that specifically bind the antigen. In some embodiments, an antigen comprises a protein or polypeptide. Such protein or peptide are referred to herein as “immunogenic polypeptide.” In some embodiments, the term “antigen” encompasses nucleic acids (e.g., DNA or RNA molecules) that encode immunogenic polypeptides. In some embodiments, the antigen is from a microbial pathogen. For example, the antigen may comprise parts (coats, capsules, cell walls, flagella, fimbriae, and toxins) of bacteria, viruses, fungi, and other microorganisms. In some embodiments, the antigen is a cancer-specific antigen. In some embodiments, the antigen is a psychoactive substance or its hapten derivative (e.g., an opioidspecific antigen). In some embodiments, the antigen is a hapten.

[0252] In some embodiments, a protein or polypeptide antigen is a wild type protein or polypeptide. In some embodiments, a protein or polypeptide antigen is a polypeptide variant to a wild type protein or polypeptide. The term “polypeptide variant” refers to molecules which differ in their amino acid sequence from a native or reference sequence. The amino acid sequence variants may possess substitutions, deletions, and / or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence. In some embodiments, polypeptide variants possess at least 50% identity to a native or reference sequence. In some embodiments, variants share at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identity with a native or reference sequence.

[0253] In some embodiments, a polypeptide variant comprises substitutions, insertions, deletions. In some embodiments, a polypeptide variant encompasses covalent variants and derivatives. The term “derivative” is used synonymously with the term “variant” but generally refers to a molecule that has been modified and / or changed in any way relative to a reference molecule or starting molecule.

[0254] In some embodiments, sequence tags or amino acids, such as one or more lysines, can be added to peptide sequences (e.g., at the N-terminal or C-terminal ends). Sequence tags can be used for peptide detection, purification or localization. Lysines can be used to increase peptide solubility or to allow for biotinylation. Alternatively, amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences. Certain amino acids (e.g., C- terminal or N-terminal residues) may alternatively be deleted depending on the use of the sequence, as for example, expression of the sequence as part of a larger sequence which is soluble or linked to a solid support.

[0255] In some embodiments, the polypeptide variant comprises at least one amino acid residue in a native or starting sequence removed and a different amino acid inserted in its place at the same position. Substitutions may be single, where only one amino acid in the molecule has been substituted, or they may be multiple, where two or more amino acids have been substituted in the same molecule. In some embodiments, the antigen is a polypeptide that includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more substitutions compared to a reference protein.

[0256] In some embodiments, the substitution is a conservative amino acid substitution. The term “conservative amino acid substitution” refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity. Examples of conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine, and leucine for another non-polar residue. Likewise, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. Additionally, the substitution of a basic residue such as lysine, arginine or histidine for another, or the substitution of one acidic residue such as aspartic acid or glutamic acid for another acidic residue are additional examples of conservative substitutions. Examples of non-conservative substitutions include the substitution of a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and / or a polar residue for a non-polar residue.

[0257] In some embodiments, protein fragments, functional protein domains, and homologous proteins are used as antigens in accordance with the present disclosure. For example, an antigen may comprise any protein fragment (meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical) of a reference protein 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or greater than 100 amino acids in length. In another example, any protein that includes a stretch of 20, 30, 40, 50, or 100 amino acids which are 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% identical to a reference protein (e.g., a protein from a microbial pathogen) herein can be utilized in accordance with the disclosure.

[0258] In some embodiments, the antigen comprises more than one immunogenic protein or polypeptide (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more). In some embodiments, the more than one immunogenic protein or polypeptide are derived from one protein (e.g., different fragments or one protein). In some embodiments, the more than one immunogenic protein or polypeptide are derived from multiple proteins (e.g., from 2, 3, 4, 5, 6, 7, 8, 9, 10, or more proteins).

[0259] In some embodiments, the antigen comprises a nucleic acid encoding an immunogenic protein or polypeptide. In some embodiments, the antigen comprises an immunogenic protein or polypeptide and a nucleic acid encoding the immunogenic protein or polypeptide. The term “nucleic acid” or “polynucleotide,” in its broadest sense, includes any compound and / or substance that comprises a polymer of nucleotides. Nucleic acids encoding immunogenic proteins or polypeptides typically comprise an open reading frame (ORF), and one or more regulatory sequences. Nucleic acids (also referred to as polynucleotides) may be or may include, for example, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a P- D-ribo configuration, a-LNA having an a-L-ribo configuration (a diastereomer of LNA), 2'-amino-LNA having a 2'-amino functionalization, and 2'-amino- a-LNA having a 2'-amino functionalization), ethylene nucleic acids (ENA), cyclohexenyl nucleic acids (CeNA) or chimeras or combinations thereof.

[0260] In some embodiments, the nucleic acid encoding the immunogenic polypeptide is a DNA (e.g., an expression vector for an immunogenic protein or polypeptide). In some embodiments, the nucleic acid encoding the immunogenic polypeptide is an RNA (e.g., a messenger RNA). A “messenger RNA” (mRNA) refers to any polynucleotide that encodes a (at least one) polypeptide (a naturally-occurring, non-naturally-occurring, or modified polymer of amino acids) and can be translated to produce the encoded polypeptide in vitro, in vivo, in situ, or ex vivo. The basic components of an mRNA molecule typically include at least one coding region, a 5' untranslated region (UTR), a 3' UTR, a 5' cap and a poly-A tail.

[0261] In some embodiments, the coding region of the nucleic acid (e.g., DNA or RNA) encoding an immunogenic polypeptide is codon optimized. Codon optimization methods are known in the art and may be used as provided herein. Codon optimization, in some embodiments, may be used to match codon frequencies in target and host organisms to ensure proper folding; bias GC content to increase mRNA stability or reduce secondary structures; minimize tandem repeat codons or base runs that may impair gene construction or expression; customize transcriptional and translational control regions; insert or remove protein trafficking sequences; remove / add post translation modification sites in encoded protein (e.g. glycosylation sites); add, remove or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust translational rates to allow the various domains of the protein to fold properly; or to reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art - non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park CA) and / or proprietary methods. In some embodiments, the open reading frame (ORF) sequence is optimized using optimization algorithms.

[0262] In some embodiments, a codon optimized sequence shares less than 95% sequence identity to a naturally occurring or wild-type sequence (e.g., a naturally occurring or wildtype mRNA sequence encoding an immunogenic protein or polypeptide). In some embodiments, a codon optimized sequence shares less than 90% sequence identity to a naturally occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide). In some embodiments, a codon optimized sequence shares less than 85% sequence identity to a naturally occurring or wildtype sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide). In some embodiments, a codon optimized sequence shares less than 80% sequence identity to a naturally occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide). In some embodiments, a codon optimized sequence shares less than 75% sequence identity to a naturally occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide).

[0263] In some embodiments, the nucleic acid encoding an immunogenic protein or polypeptide comprises one or more chemical modifications. The terms “chemical modification” and “chemically modified” refer to modification with respect to adenosine (A), guanosine (G), uridine (U), thymidine (T) or cytidine (C) ribonucleosides or deoxyribnucleosides in at least one of their position, pattern, percent or population.

[0264] In some embodiments, the nucleic acids (e.g., DNA or RNA) comprise various (more than one) different modifications. In some embodiments, a particular region of a nucleic acid (e.g., DNA or RNA) contains one, two or more (optionally different) nucleoside or nucleotide modifications. In some embodiments, a modified nucleic acid (e.g., DNA or RNA), introduced to a cell or organism, exhibits reduced degradation in the cell or organism, respectively, relative to an unmodified nucleic acid. In some embodiments, a modified nucleic acid (e.g., DNA or RNA), introduced into a cell or organism, may exhibit reduced immunogenicity in the cell or organism, respectively (e.g., a reduced innate response).

[0265] Modified nucleic acid (e.g., DNA or RNA) may comprise modifications that are naturally occurring, non-naturally-occurring or the polynucleotide may comprise a combination of naturally-occurring and non-naturally-occurring modifications. Polynucleotides may include any useful modification, for example, of a sugar, a nucleobase, or an internucleoside linkage (e.g., to a linking phosphate, to a phosphodiester linkage or to the phosphodiester backbone). Modified nucleic acid (e.g., DNA or RNA), in some embodiments, comprise non-natural modified nucleotides that are introduced during synthesis or post-synthesis of the polynucleotides to achieve desired functions or properties. The modifications may be present on an internucleotide linkages, purine or pyrimidine bases, or sugars. The modification may be introduced with chemical synthesis or with a polymerase enzyme at the terminal of a chain or anywhere else in the chain. Any of the regions of a nucleic acid may be chemically modified.

[0266] In some embodiments, a chemically modified nucleic acid comprises one or more modified nucleosides. A “nucleoside” refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”). A nucleotide” refers to a nucleoside, including a phosphate group. Modified nucleotides may by synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non-natural nucleosides. Polynucleotides may comprise a region or regions of linked nucleosides. Such regions may have variable backbone linkages. The linkages may be standard phosphodiester linkages, in which case the polynucleotides would comprise regions of nucleotides.

[0267] In some embodiments, a modified nucleobase is a modified uridine. Exemplary nucleobases and nucleosides having a modified cytosine include N4-acetyl-cytidine (ac4C), 5-methyl-cytidine (m5C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm5C), 1-methyl-pseudoisocytidine, 2-thio-cytidine (s2C), and 2-thio-5-methyl-cytidine.

[0268] In some embodiments, a modified nucleobase is a modified uridine. In some embodiments, a modified nucleobase is a modified cytosine nucleosides having a modified uridine include 5-cyano uridine, and 4’ -thiouridine.

[0269] In some embodiments, a modified nucleobase is a modified adenine. Exemplary nucleobases and nucleosides having a modified adenine include 7-deaza- adenine, 1 -methyladenosine (mlA), 2-methyl-adenine (m2A), and N6-methyl-adenosine (m6A).

[0270] In some embodiments, a modified nucleobase is a modified guanine. Exemplary nucleobases and nucleosides having a modified guanine include inosine (I), 1-methyl-inosine (mil), wyosine (imG), methylwyosine (mimG), 7-deaza- guanosine, 7-cyano-7-deaza- guanosine (preQO), 7-aminomethyl-7-deaza-guanosine (preQi), 7-methyl-guanosine (m7G), 1-methyl-guanosine (mlG), 8-oxo-guanosine, 7-methyl-8-oxo-guanosine.

[0271] In some embodiments, the antigen of the present disclosure is from a microbial pathogen, e.g., from a bacterium, mycobacterium, fungus, a virus, parasite, or prion. For example, the antigen may comprise a protein or polypeptide, or a nucleic acid encoding the protein or polypeptide from the microbial pathogen. In some embodiments, the antigen may comprise a microbial pathogen (e.g., a bacterial cell, a viral particle, or a fungus cell). In some embodiments, the microbial pathogen cell is live or killed. In some embodiments, the live microbial pathogen is attenuated with respect to its pathogenicity. An attenuated microbial pathogen may elicit immune response but does not cause the disease that a wildtype microbial pathogen would cause.

[0272] Exemplary, non-limiting bacterial taxa, species, and strains, suitable for use in some embodiments of this disclosure include: Escherichia spp., Enterobacter spp. (e.g., Enterobacter cloacae), Salmonella spp. (e.g., Salmonella enteritidis, Salmonella typhi), Shigella spp., Pseudomonas spp. (e.g., Pseudomonas aeruginosa, Pseudomonas pachastr ellae, Pseudomonas stutzeri), Moraxella spp. (e.g., Moraxella catarrhalis), Neisseria spp. (e.g., Neisseria gonorrhoeae, Neisseria meningitidis), Helicobacter spp.. (e.g.. Helicobacter pylori) Stenotrophomonas spp., Vibrio spp. (e.g., Vibrio cholerae), Legionella spp. (Legionella pneumophila), Hemophilus spp. (e.g., Hemophilus influenzae), Klebsiella spp. (e.g., Klebsiella pneumoniae), Proteus spp. (e.g., Proteus mirabilis), Serratia spp. (Ser ratio marcescens), Streptococcus spp., Staphylococcus spp., Corynebacterium spp., Listeria spp., Bacillus spp. (e.g., Bacillus anthracis) Bordetella spp. (e.g., Bordetella pertussis); Borrelia spp. (e.g., Borrelia burgdorferi); Brucella spp. (e.g., Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis); Campylobacter spp. (e.g., Campylobacter jejuni); Chlamydia spp. and Chlamydophila spp. (e.g., Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci); Clostridium spp. (e.g., Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani); Corynebacterium spp. (e.g., Corynebacterium diphtheriae); Enterococcus spp. (e.g., Enterococcus faecalis, Enterococcus faecium); Escherichia spp. (e.g., Escherichia coli, Enterotoxic E. coli, enteropathogenic E. coli; E. coli O157:H7); Francisella spp. (e.g., Francisella tularensis); Haemophilus spp. (e.g., Haemophilus influenzae); Helicobacter spp. (e.g., Helicobacter pylori); Legionella spp. (e.g., Legionella pneumophila); Leptospira spp. (e.g., Leptospira interrogans); Listeria spp. (e.g., Listeria monocytogenes); Mycobacterium spp. (e.g., Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans); Mycoplasma spp. (e.g., Mycoplasma pneumoniae); Neisseria spp. (e.g., Neisseria gonorrhoeae, Neisseria meningitidis); Pseudomonas spp. (e.g., Pseudomonas aeruginosa); Rickettsia spp. (e.g., Rickettsia rickettsii); Salmonella spp. (e.g., Salmonella typhi, Salmonella typhimurium); Shigella spp. (e.g., Shigella sonnei); Staphylococcus spp. (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus); Streptococcus spp. (e.g., Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes); Treponema spp. (e.g., Treponema pallidum); Pseudodiomarina spp.( e.g., P. maritima); Marinobacter spp. (e.g., Marinobacter hydrocarbonoclasticus, Marinobacter vinifirmus) Alcanivorax spp. (e.g., alcanivorax dieselolei);Acetinobacter spp. (e.g., A. venetianus); Halomonas spp. (e.g., H. shengliensis); Labrenzia spp.; Microbulifer spp. (e.g., M. schleiferi); Shewanella spp. (e.g., S. algae); Vibrio spp. (e.g., Vibrio cholerae, Vibrio alginolyticus, Vibrio hepatarius); and Yersinia spp. (e.g., Yersinia pestis).

[0273] In some embodiments, the bacterium is Bacillus anthracis (causing anthrax), Bordetella pertussis (causing whooping cough), Corynebacterium diphtheriae (causing diphtheria), Clostridium tetani (causing tetanus), Haemophilus influenzae type b, pneumococcus (causing pneumococcal infections), Staphylococci spp. (including Group A or B streptococci), Mycobacterium tuberculosis, Neiserria meningitidis (causing meningococcal disease), Salmonella typhi (causing typhoid), Vibrio cholerae (causing Cholera), or Yersinia pestis (causing plague).

[0274] In some embodiments, the antigen is derived from a Gram-negative bacterium. In some embodiments, the antigen is a lipopolysaccharide endotoxin (LPS) from a Gramnegative bacterium. Non-limiting examples of Gram-negative bacterial species include: Neisseria species including Neisseria, gonorrhoeae and Neisseria meningitidis, Branhamella species including Branhamella catarrhalis, Escherichia species including Escherichia coll, Enterobacter species, Proteus species including Proteus mirabilis, Pseudomonas species including Pseudomonas aeruginosa, Pseudomonas mallei, and Pseudomonas pseudomallei, Klebsiella, species including Klebsiella pneumoniae, Salmonella species, Shigella species, Serratia. species, Acinetobacter species; Haemophilus s pecies including Haemophilus influenzae and Haemophilus ducreyi;

[0275] Brucella species, Yersinia species including Yersinia pestis and Yersinia enterocolitica, Francisella species including Francisella tularensis, Pasturella species including Pasteurella multocida, Vibrio cholerae, Flavobacterium species, meningosepticum,

[0276] Campylobacter species including Campylobacter jejuni, Bacteroides species (oral, pharyngeal) including Bacteroides fragilis, Fusobacterium species including Fusobacterium. nucleatum, Calymmatobacterium granulomatis, Streptobacillus species including Streptobacillus moniliformis, Legionella species including Legionella pneumophila.

[0277] In some embodiments, the antigen is derived from a Gram-positive bacterium. Exemplary Gram-positive bacteria include, but are not limited to, Staphylococcus spp., Streptococcus spp., Micrococcus spp., Peptococcus spp., Peptostreptococcus spp.. Enterococcus spp., Bacillus spp., Clostridium spp.. I xictobacillus spp., Listeria spp., Erysipelothrix spp., Propionibacterium spp., Eubacterium spp., Corynebacterium spp., Capnocytophaga spp., and Bifidobacterium, spp., In some embodiments, the Gram-positive bacteria is a bacteria of the phylum Firmicutes. In some embodiments, the Gram-positive bacteria is Streptococcus.

[0278] Other types of bacteria include acid-fast bacilli, spirochetes, and actinomycetes. Examples of acid-fast bacilli include Mycobacterium species including Mycobacterium tuberculosis and Mycobacterium leprae. Examples of spirochetes include Treponema species including Treponema pallidum. Treponema pertenue, Borrelia species including Borrelia burgdorferi (Lyme disease), and Borrelia recurrentis, and Leptospira, species. Examples of actinomycetes include: Actinomyces species including Actinomyces israelii, and Nocardia species including Nocardia asteroides.

[0279] Examples of viruses include but are not limited to: Retroviruses, human immunodeficiency viruses including HIV-1, HDTV-III, LAVE, HTLV-III / LAV, HIV-III, HIV-LP, Cytomegaloviruses (CMV), Picornaviruses, polio viruses, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, Calciviruses, Togaviruses, equine encephalitis viruses, rubella viruses, Flaviruses, dengue viruses, encephalitis viruses, yellow fever viruses, Coronaviruses (e.g., SARS-CoV-2), Rhabdoviruses, vesicular stomatitis viruses, rabies viruses, Filoviruses, ebola virus, Paramyxoviruses, parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus (RSV), Orthomyxoviruses, influenza viruses, Bungaviruses, Hantaan viruses, phleboviruses and Nairo viruses, Arena viruses, hemorrhagic fever viruses, reoviruses, orbiviruses, rotaviruses, Bimaviruses, Hepadnaviruses, Hepatitis B virus, parvoviruses, Papovaviridae, papilloma viruses, polyoma viruses, Adenoviruses, herpes viruses (e.g., herpes simplex virus 1, herpes simplex virus 2, human herpesvirus 6, human herpesvirus 8), varicella zoster virus, Poxviruses, variola viruses, vaccinia viruses, Irido viruses, African swine fever virus, delta hepatitis virus, non-A, non-B hepatitis virus, Hepatitis C, Norwalk viruses, astroviruses, and unclassified viruses. In some embodiments, the virus is adenovirus, enterovirus such as polio virus, Eastern Equine Encephalitis virus, Ebola virus, cytomegalovirus and varicella-zoster (chickenpox and shingles), measles, mumps, rubella, hepatitis- A, -B, or-C, human papilloma virus, Influenza virus, parainfluenza virus, rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), smallpox, monkeypox, yellow fever, or Zika Virus. In some embodiments, the virus is influenza or a coronavirus (e.g., SARS-CoV-2).

[0280] In some embodiments, the antigen comprises a viral protein and / or a nucleic acid encoding a viral protein (e.g., a viral structural or non-structural protein). In some embodiments, the antigen comprises a nucleic acid encoding the viral genome. In some embodiments, the viral genome is modified to produce a modified virus that is attenuated.

[0281] Examples of fungus include, but are not limited to: Cryptococcus species including Crytococcus neoformans, Histoplasma species including Histoplasma capsulatum, Coccidioid.es species including Coccidiodes immitis, Paracoccidioides species including Paracoccidioides brasiliensis, Blastomyces species including Blastomyces dermatitidis, Chlamydia species including Chlamydia trachomatis, Candida species including Candida albicans and Candida auris, Sporothrix species including Sporothrix schenckii, Aspergillus species, and fungi of mucormycosis. In some embodiments, the fungus is Candida spp., Aspergillus spp., Cryptococcus spp., Fusarium spp, Mucormycete, Blastomyces dermatitidis (causing blastomycosis), or endemic mycosis causing fungus such as Histoplasma capsulatum (causing histoplasmosis), or Sporothrix schenckii (causing sporotrichosis).

[0282] Other infectious organisms include, without limitation: parasites. Parasites include Plasmodium species, such as Plasmodium speci es including Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax and Toxoplasma gondii. Blood-borne and / or tissues parasites include Plasmodium species, Babesia species including Babesia microti and Babesia divergens, Leishmania species including Leishmania tropica, Leishmania species, Leishmania braziliensis, Leishmania donovani, Trypanosoma species including Trypanosoma gambiense, Trypanosoma rhodeslense (African sleeping sickness), and Trypanosoma cruzi (Chagas' disease). In some embodiments, the parasite is Plasmodium spp., Leishmania, or a helminth.

[0283] Other medically relevant microorganisms have been described extensively in the literature, e.g., see C. G, A Thomas, Medical Microbiology , Bailliere Tindall, Great Britain 1983, incorporated herein by reference.

[0284] In some embodiments, the antigen of the present disclosure comprises a cancerspecific antigen and / or a nucleic acid encoding such. A “cancer- specific antigen” refers to a protein that is specifically expressed or upregulated in a cancer cell, as compared to non- cancerous cells of the same origin. A cancer- specific antigen, or epitopes derived therefrom, can be recognized by the immune system to induce an immune response against the cancer. Classes of proteins that may be cancer-specific antigen include, without limitation: enzymes, receptors, and transcription factors.

[0285] Many proteins that specifically express in cancer cells or are upregulated in cancer cells have been identified (Hassane et al., Holland-Frei Cancer Medicine. 6th edition, incorporated herein by reference). The known tumor specific antigens are classified into different classes: cancer-testis antigens (e.g., MAGE family members or NY-ESO-1), differentiation antigens (e.g., tyrosinase and Melan-A / MART-1 for melanoma, and PSA for prostate cancer), overexpressed cancer- specific antigens (e.g., Her-2 / neu, Survivin, Telomerase and WT1), cancer- specific antigens arising from mutations of normal genes (e.g., mutated P-catenin or CDK4), cancer-specific antigens arising from abnormal post- translational modifications (e.g., altered glycosylation patterns) that lead to novel epitopes in tumors (e.g., MUC1), and oncoviral proteins (e.g., human papilloma type 16 virus proteins, E6 and E7). In some embodiments, the tumor- specific antigen is expressed in a broad range of different types of cancers. In some embodiments, the tumor- specific antigen is expressed only in one or a few types of cancers.

[0286] In some embodiments, the antigen comprises a fragment or an epitope derived from a cancer-specific antigen and / or a nucleic acid encoding such. For example, the fragment or an epitope derived from a cancer- specific antigen may be 5-40 amino acids long. In some embodiments, the fragment or an epitope derived from a cancer- specific antigen is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids long.

[0287] In some embodiments, the fragment or epitope derived from a cancer- specific antigen is a heteroclitic epitope. A “heteroclitic epitope” refers to an altered version of an endogenous peptide sequence (i.e., an analog) from a cancer-specific antigen engineered to elicit potent immune reactions. Heteroclitic epitopes have increased stimulatory capacity or potency for a specific T cell, as measured by increased responses to a given dose, or by a requirement of lesser amounts to achieve the same response and therefore provide benefit as vaccine components since these epitopes induce T cell responses stronger than those induced by the native epitope.

[0288] In some embodiments, the heteroclitic epitope comprises modifications, e.g., amino acid substitutions, as compared to the native sequence in the cancer-specific antigen. In some embodiments, the heteroclitic epitope comprises more than one amino acid substitutions (e.g., 2, 3, 4, 5, or more) compared to the native sequence of the cancer- specific antigen it is derived from. In some embodiments, a heteroclitic epitope is at least 60%, at least 70%, at least 80%, at least 90%, at least 98%, or at least 99% identical to the native sequence that it is derived from. In some embodiments, a heteroclitic epitope is 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the native sequence that it is derived from.

[0289] In some embodiments, a heteroclitic epitope is more immunogenic than a peptide of its native sequence. For example, a heteroclitic epitope may be at least 30% more immunogenic (i.e., induces a stronger immune response) than its corresponding native peptide. In some embodiments, a heteroclitic epitope may be at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or more immunogenic than its corresponding native peptide.

[0290] In some embodiments, the fragment or epitope derived from a cancer- specific antigen is a cryptic epitope. A “cryptic epitope” refers to an epitope derived from a cancer- specific antigen that does not necessarily undergo antigen processing / presentation and are ‘hidden’ from immune recognition. Cryptic epitopes usually appear in very low concentration on APC and do not delete auto-reactive T cells. Cryptic epitopes are not presented for recognition by T cells unless they are produced in unusually large concentrations or unless they are freed from the configuration of their native antigen. Cryptic epitopes derived from cancer- specific antigens may be used to break the tolerance of T cells to the tumor and induce potent immune response against the tumor. Such principles have been described in Pardoll, et al., PNAS, Vol. 96, pp. 5340-5342 (1999), the entire contents of which are incorporated herein by reference.

[0291] In some embodiments, the cryptic epitope is generated from translation of a noncoding region of the cancer- specific antigen gene or translation of a different reading frame of a coding region of the cancer- specific antigen. A cryptic epitope may be more immunogenic (i.e., induces a stronger immune response) than any native peptide derived from the cancer- specific antigen. For example, a cryptic epitope may be at least 30% more immunogenic than any native peptide derived from the cancer-specific antigen. In some embodiments, a cryptic epitope is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 3-fold, at least 4- fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10- fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or more immunogenic than any native peptide derived from the cancer-specific antigen. One skilled in the art is familiar with how to assess the immune response induced by an antigen, e.g., measuring antibody titers.

[0292] In some embodiments, the cancer- specific antigen is a neoantigen. A “neoantigen” refers to an antigen generated via random somatic mutations occurring in cancer cells and are thus specific to the lineage of cancer cells it is derived from. Neoantigens are regarded in the art to be responsible for the immunogenicity of tumors ((Srivastava et al., 1993, Duan et al., 2009; van der Bruggen et al., 2013, incorporated herein by reference), and mathematic modeling has predicted the existence of tens to hundreds of neoepitopes (epitopes derived from neoantigens) in individual human tumors (Srivastava 2009, incorporated herein by reference). The recent revolution in high-throughput DNA sequencing and accompanying bioinformatics approaches has finally made it possible to accurately identify the individually specific neoepitopes in individual cancers.

[0293] In some embodiments, the antigen described herein is an antigen designed to provide broad heterologous protection against a range of pathogens. Heterologous immunity refers to the phenomenon whereby a history of an immune response against a stimulus or pathogen can provide a level of immunity to a second unrelated stimulus or pathogen (e.g., as described in Chen et al., Virology 2015 482: 89-97, incorporated herein by reference). For example, an antigen that induces cross -reactive memory CD8+ T cells against multiple unrelated viruses such as influenza A and Epstein-Barr Virus (EBV), as described in Watkin et al., J Allerg Clin Immunol 2017 Oct; 140(4) 1206-1210, incorporated herein by reference. In some embodiments, a compound of Formula (I) induces and / or enhances the heterologous protection.

[0294] Polypeptide or polynucleotide molecules of the present disclosure may share a certain degree of sequence similarity or identity with reference molecules (e.g., reference polypeptides or reference polynucleotides), for example, wild-type molecules. The term “identity” as known in the art and described below, refers to a relationship between the sequences of two or more polypeptides or polynucleotides, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between them as determined by the number of matches between strings of two or more amino acid residues or nucleic acid residues. Identity measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (e.g., “algorithms”). Identity of related peptides can be readily calculated by known methods. “% identity” as it applies to polypeptide or polynucleotide sequences is defined as the percentage of residues (amino acid residues or nucleic acid residues) in the candidate amino acid or nucleic acid sequence that are identical with the residues in the amino acid sequence or nucleic acid sequence of a second sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity. Methods and computer programs for the alignment are well known in the art. It is understood that identity depends on a calculation of percent identity but may differ in value due to gaps and penalties introduced in the calculation. Generally, variants of a particular polynucleotide or polypeptide have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% but less than 100% sequence identity to that particular reference polynucleotide or polypeptide as determined by sequence alignment programs and parameters described herein and known to those skilled in the art. Such tools for alignment include those of the BLAST suite (Stephen F. Altschul, et al (1997), "Gapped BLAST and PSLBLAST: a new generation of protein database search programs", Nucleic Acids Res. 25:3389-3402). Another popular local alignment technique is based on the Smith-Waterman algorithm (Smith, T.F. & Waterman, M.S. (1981) “Identification of common molecular subsequences.” J. Mol. Biol. 147:195- 197.) A general global alignment technique based on dynamic programming is the Needleman-Wunsch algorithm (Needleman, S.B. & Wunsch, C.D. (1970) “A general method applicable to the search for similarities in the amino acid sequences of two proteins.” J. Mol. Biol. 48:443-453.). More recently a Fast Optimal Global Sequence Alignment Algorithm (FOGSAA) has been developed that purportedly produces global alignment of nucleotide and protein sequences faster than other optimal global alignment methods, including the Needleman-Wunsch algorithm. Other tools are described herein, specifically in the definition of “identity” below.

[0295] As used herein, the term “homology” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. Polymeric molecules (e.g., nucleic acid molecules (e.g. DNA molecules and / or RNA molecules) and / or polypeptide molecules) that share a threshold level of similarity or identity determined by alignment of matching residues are termed homologous. Homology is a qualitative term that describes a relationship between molecules and can be based upon the quantitative similarity or identity. Similarity or identity is a quantitative term that defines the degree of sequence match between two compared sequences. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical or similar. The term “homologous” necessarily refers to a comparison between at least two sequences (polynucleotide or polypeptide sequences). Two polynucleotide sequences are considered homologous if the polypeptides they encode are at least 50%, 60%, 70%, 80%, 90%, 95%, or even 99% for at least one stretch of at least 20 amino acids. In some embodiments, homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4- 5 uniquely specified amino acids. Two protein sequences are considered homologous if the proteins are at least 50%, 60%, 70%, 80%, or 90% identical for at least one stretch of at least 20 amino acids.

[0296] Homology implies that the compared sequences diverged in evolution from a common origin. The term “homolog” refers to a first amino acid sequence or nucleic acid sequence (e.g., gene (DNA or RNA) or protein sequence) that is related to a second amino acid sequence or nucleic acid sequence by descent from a common ancestral sequence. The term “homolog” may apply to the relationship between genes and / or proteins separated by the event of speciation or to the relationship between genes and / or proteins separated by the event of genetic duplication. “Orthologs” are genes (or proteins) in different species that evolved from a common ancestral gene (or protein) by speciation. Typically, orthologs retain the same function in the course of evolution. “Paralogs” are genes (or proteins) related by duplication within a genome. Orthologs retain the same function in the course of evolution, whereas paralogs evolve new functions, even if these are related to the original one. The term “identity” refers to the overall relatedness between polymeric molecules, for example, between polynucleotide molecules (e.g. DNA molecules and / or RNA molecules) and / or between polypeptide molecules. Calculation of the percent identity of two polynucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In some embodiments, the length of a sequence aligned for comparison purposes is 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 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, considering the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleic acid sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleic acid sequences can be determined using the algorithm of Meyers and Miller (CAB IOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleic acid sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H., and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990)).

[0297] Compositions and Vaccines

[0298] As described herein, the present disclosure provides compositions comprising an antigen and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof. In some embodiments, a compound of Formula (I) is conjugated to the antigen. In some embodiments, a compound of Formula (I) is not conjugated to the antigen.

[0299] Methods of conjugating a compound to another molecule (e.g., a protein or a nucleic acid) is known to those skilled in the art. For example, in some embodiments, conjugation may be achieved via reactive chemical groups by incorporating one of a pair of reactive chemical groups that react with each other to each of the two molecules to be conjugated. A “reactive chemical group” or “functional chemical group” refers to specific groups (moieties) of atoms or bonds within molecules that are responsible for the characteristic chemical reactions of those molecules. These terms are used interchangeably herein. One example of such reactive group is a “click chemistry handle.” Click chemistry is a chemical approach introduced by Sharpless in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together. See, e.g., Kolb, Finn, and Sharpless Angewandte Chemie International Edition (2001) 40: 2004-2021; Evans, Australian Journal of Chemistry (2007) 60: 384-395). Exemplary coupling reactions (some of which may be classified as “Click chemistry”) include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azide-alkyne Huisgon cycloaddition; thiol-yne addition; imine formation; and Michael additions (e.g., maleimide addition). Non-limiting examples of a click chemistry handle include an azide handle, an alkyne handle, or an aziridine handle. Azide is the anion with the formula N3-. It is the conjugate base of hydrazoic acid (HN3). N3- is a linear anion that is isoelectronic with CO2, NCO-, N2O, NO2+and NCF. Azide can be described by several resonance structures, an important one being -N=N+=N". An alkyne is an unsaturated hydrocarbon containing at least one carbon — carbon triple bond. The simplest acyclic alkynes with only one triple bond and no other functional groups form a homologous series with the general chemical formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature. Like other hydrocarbons, alkynes are generally hydrophobic but tend to be more reactive. Aziridines are organic compounds containing the aziridine functional group, a three-membered heterocycle with one amine group (-NH-) and two methylene bridges (-CH2-). The parent compound is aziridine (or ethylene imine), with molecular formula C2H5N.

[0300] Other non-limiting, exemplary reactive groups include: acetals, ketals, hemiacetals, and hemiketals, carboxylic acids, strong non-oxidizing acids, strong oxidizing acids, weak acids, acrylates and acrylic acids, acyl halides, sulfonyl halides, chloroformates, alcohols and polyols, aldehydes, alkynes with or without acetylenic hydrogen amides and imides, amines, aromatic, amines, phosphines, pyridines, anhydrides, aryl halides, azo, diazo, azido, hydrazine, and azide compounds, strong bases, weak bases, carbamates, carbonate salts, chlorosilanes, conjugated dienes, cyanides, inorganic, diazonium salts, epoxides, esters, sulfate esters, phosphate esters, thiophosphate esters borate esters, ethers, soluble fluoride salts, fluorinated organic compounds, halogenated organic compounds, halogenating agents, aliphatic saturated hydrocarbons, aliphatic unsaturated hydrocarbons, hydrocarbons, aromatic, insufficient information for classification, isocyanates and isothiocyanates, ketones, metal hydrides, metal alkyls, metal aryls, and silanes, alkali metals, nitrate and nitrite compounds, inorganic, nitrides, phosphides, carbides, and silicides, nitriles, nitro, nitroso, nitrate, nitrite compounds, organic, non-redox- active inorganic compounds, organometallic s, oximes, peroxides, organic, phenolic salts, phenols and cresols, polymerizable compounds, quaternary ammonium and phosphonium salts, strong reducing agents, weak reducing agents, acidic salts, basic salts, siloxanes, inorganic sulfides, organic sulfides, sulfite and thiosulfate salts, sulfonates, phosphonates, organic thiophosphonates, thiocarbamate esters and salts, and dithiocarbamate esters and salts. In some embodiments, the reactive group is a carboxylic acid group.

[0301] Compositions comprising an antigen and a compound of Formula (I) 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).

[0302] In some embodiments, the immune response elicited by the composition 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 antigenspecific 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.

[0303] 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 antigenspecific 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.

[0304] 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 (“nonspecific”) 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).

[0305] 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), NOD 1 / 2, RIG- 1 / MD A-5, C-type lectins, and STING.

[0306] 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.

[0307] In some embodiments, the composition comprising an antigen and a compound of Formula (I) is a vaccine composition. A “vaccine composition” is a composition that activates or enhances a subject’s immune response to an antigen after the vaccine is administered to the subject. 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., an infectious disease or cancer). 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 comprises a LPS attached to a strong protein antigen. The terms "vaccine composition" and “vaccine” are used interchangeably herein.

[0308] Vaccines that contain cancer- specific antigens are termed herein as “cancer vaccines.” Cancer vaccines induce cancer- specific immune responses against a cancer or a cancerspecific antigen. Such immunoresponse is effective in inhibiting cancer growth and / or preventing reoccurrence of tumor. Cancer vaccines may be used for cancer immunotherapy, which is a type of cancer treatment designed to boost the body's natural defenses to fight the cancer. It uses substances either made by the body or in a laboratory to improve or restore immune system function.

[0309] In some embodiments, a compound of Formula (I) is used as an adjuvant in a vaccine composition (e.g., to enhance an immune response in a subject). A compound of Formula (I) alone may induce cytokine (e.g., proinflammatory cytokines such as TNF, IL-12, IL-6, or IL- 1 P) and / or chemokine (e.g., CXCL8) production by human peripheral blood mononuclear cells (PBMCs) in vitro and enhance antigen- specific immune response against influenza hemagglutinin antigen in vivo.

[0310] In some embodiments, the vaccine composition described herein comprises two or more adjuvants (also referred to as an “adjuvant system”). The adjuvant system comprises a compound of Formula (I) and one or more other adjuvants described herein. In some embodiments, the vaccine composition described herein further comprises a second adjuvant in addition to a compound of Formula (I) (as the first adjuvant). Any known adjuvants may be used as the second adjuvant in the composition described herein. In some embodiments, a compound of Formula (I) and / or the second adjuvant enhance antigen-presenting cell activity. In some embodiments, a compound of Formula (I) and / or the second adjuvant activates B cell immunity.

[0311] In some embodiments, the second adjuvant is an agonist of Pattern Recognition Receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-L 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(l):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 second adjuvant is alum. In some embodiments, the second adjuvant includes an oil-in-water emulsion.

[0312] In some embodiments, the vaccine compositions described herein are formulated for administration to a subject. 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).

[0313] 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 antigen and / or the adjuvant (e.g., a compound of Formula (I)) 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.

[0314] Relative amounts of the antigen, 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.

[0315] The antigen, compound of Formula (I), and / or optionally the second adjuvant may be formulated using any of the methods described herein or known in the art separately or together.

[0316] Methods of Treatment and Uses

[0317] A compound of Formula (I) can enhance an immune response (e.g., innate and / or adaptive immune response). The present disclosure thus also provides methods of enhancing an immune response (e.g., innate and / or adaptive immune response) in a subject, biological sample, tissue, or cell. The present disclosure further provides methods for compounds of Formula (I) as adjuvants in a vaccine for treatment of a wide range of diseases, such as proliferative diseases, inflammatory diseases, autoimmune diseases, infectious diseases, addiction, and chronic diseases in a subject in need thereof, or as stand alone or immune response modifying agents.

[0318] In another aspect, the present disclosure provides methods of enhancing an immune response (e.g., innate and / or adaptive immune response), the methods comprising administering to the subject an effective amount of a compound of Formula (I) or pharmaceutical composition described herein.

[0319] 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 compound of Formula (I) or pharmaceutical composition described herein.

[0320] 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 some embodiments, the methods comprise administering to the subject an effective amount of a compound of Formula (I) (e.g., for enhancing an innate immune response, including induction of heterologous or trained immunity or innate memory).

[0321] Another aspect of the present disclosure relates to methods of using a compound of Formula (I) as an adjuvant in a vaccine for treating a disease in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition described herein. In some embodiments, the methods comprising administering to the subject an effective amount of a compound of Formula (I) and an effective amount of an antigen (e.g., for enhancing an antigen- specific immune response). In some embodiments, a compound of Formula (I) is administered separately from the antigen. In some embodiments, a compound of Formula (I) is administered prior to administering the antigen. In some embodiments, a compound of Formula (I) is administered after administering the antigen. In some embodiments, a compound of Formula (I) and the antigen are administered simultaneously. In some embodiments, a compound of Formula (I) and the antigen are administered as an admixture.

[0322] The antigen and / or a compound of Formula (I) (e.g., the antigen alone, a compound of Formula (I) alone, or the antigen and a compound of Formula (I) together) described herein elicits an immune response in the subject. In some embodiments, the antigen and / or a compound of Formula (I) activates cytokine and / or chemokine (e.g., CXCL-8) production. In some embodiments, the immune response is an innate immune response. In some embodiments, the immune response is an adaptive immune response specific to the antigen in the composition or vaccine. In some embodiments, the antigen and / or compound of Formula (I) activates B cell immunity. In some embodiments, the antigen and / or compound of Formula (I) elicits antibody production. In some embodiments, the composition and / or the vaccine activates cytotoxic T cells specific to the antigen.

[0323] In some embodiments, a compound of Formula (I), whether administered alone or in an admixture with an antigen, enhances the innate immune response, compared to without a compound of Formula (I) or when the antigen is administered alone. In some embodiments, a compound of Formula (I) activates peripheral blood mononuclear cells (PBMCs). In some embodiments, the number of PBMCs that are activated is increased by at least 10% in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone. For example, the number of PBMCs that are activated may be increased by 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 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, or at least 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone. In some embodiments, the number of PBMCs that are activated is increased by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone. In some embodiments, a compound of Formula (I) enhances response in PBMCs. In some embodiments, a compound of Formula (I) increases response in PBMCs by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone.

[0324] In some embodiments, a compound of Formula (I) activates a pattern recognition receptor (PRR). In some embodiments, a compound of Formula (I) activates one or more pattern recognition receptors (PRRs). In some embodiments, the PRR is selected from the group consisting of toll-like receptors (e.g., TLR2), NOD 1 / 2, RIG- 1 / MD A-5, C-type lectins, and STING. In some embodiments, the Toll-like receptor is TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR9, and / or TLR10. In some embodiments, the Toll-like receptor is TLR7 and / or TLR8. In some embodiments, the Toll-like receptor is TLR7. In some embodiments, the number of PRRs that are activated is increased by at least 20% in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone. For example, the number of PRRs that are activated may be increased by 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 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, or at least 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone. In some embodiments, the number of PRRs that are activated is increased by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone.

[0325] In some embodiments, a compound of Formula (I) induces the production of immunomodulatory cytokines and / or chemokines in the subject. In some embodiments, the immunomodulatory cytokines and / or chemokines are proinflammatory cytokines and / or chemokines. In some embodiments, the cytokines and chemokines include TNF, IL- 12, IL-6, IL-l-P, or CXCL-8. In some embodiments, the level of immunomodulatory cytokines and / or chemokines (e.g., CXCL-8) is increased by at least 20% in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone. For example, the level of immunomodulatory cytokines and / or chemokines (e.g., CXCL8) may be increased by 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 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, or at least 1000-fold or more, in the presence of a compound of Formula (I), compared to a compound of Formula (I) or when the antigen is administered alone. In some embodiments, the level of immunomodulatory cytokines and / or chemokines (e.g., CXCL8) is increased by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone.

[0326] In some embodiments, a compound of Formula (I) enhances innate immune memory (also referred to as trained immunity). “Innate immune memory” confers heterologous immunity that provides broad protection against a range of pathogens. In some embodiments, the innate immune memory is increased by at least 20% in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone. For example, the innate immune memory may be increased by 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 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, or at least 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone. In some embodiments, the innate immune memory is increased by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) or when the antigen is administered alone.

[0327] In some embodiments, a compound of Formula (I), when administered as an admixture with an antigen (e.g., the vaccine composition described herein), enhances the antigen- specific immune response against the antigen or against the invading agent where the antigen is derived from e.g., a microbial pathogen or cancer, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). In some embodiments, a compound of Formula (I) enhances the production of antigen- specific antibody titer (e.g., by at least 20%) in the subject, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). For example, a compound of Formula (I) may enhance the production of antigen- specific antibody titer by 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 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, or at least 1000- fold or more, in the subject, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). In some embodiments, a compound of Formula (I) enhances the production of antigen-specific antibody titer by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, or 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). One skilled in the art is familiar with how to evaluate the level of an antibody titer, e.g., by ELISA.

[0328] In some embodiments, a compound of Formula (I) enhances the activation of cytotoxic T-cells (e.g., by at least 20%) in the subject, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). For example, a compound of Formula (I) may enhance activation of cytotoxic T-cells by 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 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, or at least 1000-fold or more, in the subject, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). In some embodiments, a compound of Formula (I) enhances the activation of cytotoxic T-cells by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2- fold, 5-fold, 10-fold, 100-fold, or 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) (i.e., when the antigen is administered alone).

[0329] In some embodiments, a compound of Formula (I) polarizes the innate and adaptive immune response by shaping the pattern of cytokine and / or chemokine responses toward T helper 1 (Thl) immunity, which is important for host defense against intracellular pathogens. In some embodiments, a compound of Formula (I) polarizes the innate immune response toward T helper 2 (Th2) immunity, which is important for humoral immunity including antibody production. In some embodiments, humoral responses polarize the innate immune response toward T helper 17 (Thl7) immunity, which is important for mucosal immunity. In some embodiments, a compound of Formula (I) polarizes the innate immune response toward T follicular helper (Tfh) cell immunity.

[0330] The innate immune system plays a crucial role in the control of initiation of the adaptive immune response and in the induction of appropriate cell effector responses. (Fearon et al. (1996) Science 272: 50-3; Medzhitov et al. (1997) Cell 91: 295-8, incorporated herein by reference). As such, in some embodiments, a compound of Formula (I) enhances the innate immune response in a subject (e.g., when administered alone or in an admixture with an antigen), which in turn enhances the immunogenicity of a given antigen. This is particularly useful in subjects that have an underdeveloped (e.g., in a neonatal infant), weak (e.g., in older adults), compromised immune system (e.g., in a patient with primary immunodeficiency or acquired immunodeficiency secondary to HIV patient infection, a patient with cancer receiving chemotherapy and / or radiation therapy, or a transplant patient receiving immunosuppressive medications) or in those with a distinct immune system (e.g., in a subject with history of substance use disorder etc.).

[0331] In some embodiments, a compound of Formula (I) prolongs the durability of protection of a vaccine (e.g., by at least 20%) in the subject, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). For example, a compound of Formula (I) may prolong the effect of a vaccine by 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 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, or at least 1000-fold or more, in the subject, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). In some embodiments, a compound of Formula (I) prolongs the effect of a vaccine by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, or 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) (i.e., when the antigen is administered alone).

[0332] In some embodiments, a compound of Formula (I) increases rate of (accelerates) an immune response, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). For example, a compound of Formula (I) may increase the rate of an immune response by 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 100%, at least 2-fold, at least 5-fold, at least 10- fold, at least 100-fold, or at least 1000-fold or more, in the subject, compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). In some embodiments, a compound of Formula (I) increases the rate of an immune response by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). “Increase the rate of immune response” means that in the presence of the compound it takes less time for the immune system of a subject to react to an invading agent (e.g., a microbial pathogen). In some embodiments, the presence of a compound of Formula (I) enables antigen dose sparing- i.e., enables a given antigen to induce the same immunogenicity at a lower antigen dose compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). In some embodiments, the amount of antigen needed to produce the same level of immune response is reduced by at least 20% in the presence of a compound of Formula (I), compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). For example, the amount of antigen needed to produce the same level of immune response may be reduced by 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%, at least 99% or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) (i.e., when the antigen is administered alone). In some embodiments, the amount of antigen needed to produce the same level of immune response is reduced by at 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, in the presence of a compound of Formula (I), compared to without a compound of Formula (I) (i.e., when the antigen is administered alone).

[0333] The prophylactic or therapeutic use of a compound of Formula (I), or a composition or vaccine composition described herein is also within the scope of the present disclosure. In some embodiments, the composition or vaccine composition described herein are used in methods of vaccinating a subject by prophylactically administering to the subject an effective amount of the composition or vaccine 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., an infectious disease or cancer) in a subject.

[0334] In certain embodiments, the present disclosure provides methods of treating a disease. In certain embodiments, the disease is a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, or graft-versus-host disease. In certain embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. Vaccine compositions comprising cancer- specific antigens and a compound of Formula (I) may be used in cancer immunotherapy by eliciting cancer-specific immune response against the cancer. In certain embodiments, the disease is hyperplasia (e.g., germinal center (GC) hyperplasia). In certain embodiments, the cancer is skin cancer, brain cancer, breast cancer, or prostate cancer. In some embodiments, the cancer is a skin cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the cancer is melanoma, basal cell carcinoma, squamous cell carcinoma, or Merkel cell carcinoma. In some embodiments, the cancer is colorectal cancer, lung cancer, bladder cancer, breast cancer, kidney cancer, anal cancer, or salivary gland cancer. In some embodiments, the cancer is a lymphoma or leukemia.

[0335] In certain embodiments, the disease is a benign neoplasm. In certain embodiments, the disease is or is associated with pathological angiogenesis.

[0336] In some embodiments, additional anti-cancer agents may be administered in combination with the compound, composition or vaccine composition described herein. In some embodiments, the anti-cancer agent is selected from the group consisting of small molecules, oligonucleotides, polypeptides, and combinations thereof. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: Actinomycin, All-trans retinoic acid, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Irinotecan, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Topotecan, Valrubicin, Vinblastine, Vincristine, Vindesine, and Vinorelbine. In some embodiments, the chemotherapeutic agent is Doxorubicin.

[0337] In some embodiments, the anti-cancer agent is an immune checkpoint inhibitor. An “immune checkpoint” is a protein in the immune system that either enhances an immune response signal (co-stimulatory molecules) or reduces an immune response signal. Many cancers protect themselves from the immune system by exploiting the inhibitory immune checkpoint proteins to inhibit the T cell signal. Exemplary inhibitory checkpoint proteins include, without limitation, Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4), Programmed Death 1 receptor (PD-1), T-cell Immunoglobulin domain and Mucin domain 3 (TIM3), Lymphocyte Activation Gene-3 (LAG3), V-set domain-containing T-cell activation inhibitor 1 (VTVN1 or B7-H4), Cluster of Differentiation 276 (CD276 or B7-H3), B and T Lymphocyte Attenuator (BTLA), Galectin-9 (GAL9), Checkpoint kinase 1 (Chkl), Adenosine A2A receptor (A2aR), Indoleamine 2,3-dioxygenase (IDO), Killer-cell Immunoglobulin-like Receptor (KIR), Lymphocyte Activation Gene-3 (LAG3), and V- domain Ig suppressor of T cell activation (VISTA).

[0338] Some of these immune checkpoint proteins need their cognate binding partners, or ligands, for their immune inhibitory activity. For example, A2AR is the receptor of adenosine A2A and binding of A2A to A2AR activates a negative immune feedback loop. As another example, PD-1 associates with its two ligands, PD-L1 and PD-L2, to down regulate the immune system by preventing the activation of T-cells. PD-1 promotes the programmed cell death of antigen specific T-cells in lymph nodes and simultaneously reduces programmed cell death of suppressor T cells, thus achieving its immune inhibitory function. As yet another example, CTLA4 is present on the surface of T cells, and when bound to its binding partner CD80 or CD86 on the surface of antigen-present cells (APCs), it transmits an inhibitory signal to T cells, thereby reducing the immune response.

[0339] An “immune checkpoint inhibitor” is a molecule that prevents or weakens the activity of an immune checkpoint protein, for example, an immune checkpoint inhibitor may inhibit the binding of the immune checkpoint protein to its cognate binding partner, e.g., PD-1, CTLA-4, or A2aR. In some embodiments, the immune checkpoint inhibitor is a small molecule. In some embodiments, the immune checkpoint inhibitor is a nucleic acid aptamer (e.g., a siRNA targeting any one of the immune checkpoint proteins). In some embodiments, the immune checkpoint inhibitor is a recombinant protein. In some embodiments, the immune checkpoint inhibitor is an antibody. In some embodiments, the antibody comprises an anti- CTLA-4, anti-PD-1, anti-PD-Ll, anti-TIM3, anti-LAG3, anti-B7-H3, anti-B7-H4, anti- BTLA, anti-GAL9, anti-Chk, anti-A2aR, anti-IDO, anti-KIR, anti-LAG3, anti- VISTA antibody, or a combination of any two or more of the foregoing antibodies. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody. In some embodiments, the immune checkpoint inhibitor comprises anti-PDl, anti-PD-Ll, anti-CTLA- 4, or a combination of any two or more of the foregoing antibodies. For example, the anti- PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®) and the anti-CTLA- 4 antibody is ipilimumab (Yervoy®). Thus, in some embodiments, the immune checkpoint inhibitor comprises pembrolizumab, nivolumab, ipilimumab, or any combination of two or more of the foregoing antibodies. The examples described herein are not meant to be limiting and that any immune checkpoint inhibitors known in the art and any combinations thereof may be used in accordance with the present disclosure.

[0340] Additional exemplary agents that may be used in combination with the compound and compositions described herein include, but are not limited to, anti-proliferative agents, anticancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof. In some embodiments, the additional agent is an anti-proliferative agent (e.g., anti-cancer agent). In some embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In some embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase Erwinia Chrysanthemi), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE- AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCAS AR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In some embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In some embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-AB V, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alfa- 2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In some embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine ), VIDAZA (azacitidine ), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin ), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In some embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EV ACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI , FOLFIRI- BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE- AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL (cisplatin), PLATINOL- AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VID AZA (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), ENMD- 2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF- 4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,, aminopterin, and hexamethyl melamine, or a combination thereof. In some embodiments, the additional pharmaceutical agent is a binder or inhibitor of an HMT (e.g., EZH1, EZH2, DOTI). In some embodiments, the additional agent is a protein kinase inhibitor (e.g., tyrosine protein kinase inhibitor). In some embodiments, the additional agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HD AC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation.

[0341] In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is an autoimmune disease. In certain embodiments, the disease is an allergic or atopic disease.

[0342] In certain embodiments, the disease is an infectious disease. In certain embodiments, the disease is a viral infectious disease, sepsis, a pediatric infectious disease, a bacterial infectious disease, a mycobacterial infectious disease, a parasitic infectious disease, or a fungal infectious disease. In certain embodiments, the disease is an infection by a microbial pathogen (e.g., from a mycobacterium, bacterium, fungus, a virus, parasite, or prion). In certain embodiments, a disease described herein is a microbial infectious disease. In certain embodiments, the infectious disease is a viral infectious disease. In certain embodiments, the viral infectious disease being treated or prevented is an infection caused by influenza. In certain embodiments, the viral infectious disease being treated or prevented is an infection caused by a coronavirus. In certain embodiments, the viral infectious disease being treated or prevented is an infection caused by SARS-CoV-2. In certain embodiments, the infectious disease is sepsis. In certain embodiments, the infectious disease is bacterial, fungal or viral sepsis. In certain embodiments, the infectious disease is a pediatric infectious disease. In certain embodiments, the infectious disease is a disease of newborns, infants and / or school age children.

[0343] In some embodiments, the infectious disease is caused by Plasmodium malariae (malaria), Bacillus anthracis (anthrax), Bordetella pertussis (whooping cough), Corynebacterium diphtheriae (diphtheria), Clostridium tetani (tetanus), Haemophilus influenzae type b, pneumococcus (pneumococcal infections), Staphylococci spp., Group A or B streptococci, Mycobacterium tuberculosis, Neiserria meningitidis (meningococcal disease), Salmonella typhi (typhoid), Vibrio cholerae (Cholera), or Yersinia pestis (plague). In some embodiments, the infectious disease is caused by adenovirus, enterovirus such as polio virus, Ebola virus, herpes viruses (e.g., herpes simplex virus 1, herpes simplex virus 2, human herpesvirus 6, human herpesvirus 8), cytomegalovirus and varicella- zoster (chickenpox and shingles), measles, mumps, rubella, hepatitis-A, -B, or-C, human papilloma virus, Influenza virus, parainfluenza virus, a coronavirus (e.g., SARS-CoV-2), rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), smallpox, monkeypox, yellow fever, or Zika Virus. In some embodiments, the infectious disease is caused by malaria, Leishmania, or a helminth. In some embodiments, the infectious disease is caused by Candida spp., Aspergillus spp., Cryptococcus spp., Mucormycete, Blastomyces dermatitidis, Histoplasma capsulatum, or Sporothrix schenckii. In some embodiments, the infectious disease is caused by prion.

[0344] In certain embodiments, the infectious disease is a bacterial infectious disease. In certain embodiments, the bacterial infectious disease being treated or prevented is caused by an infection with a Gram-positive bacteria including, but not limited to, Staphylococcus spp., Streptococcus spp., Micrococcus spp., Peptococcus spp., Peptostreptococcus spp., Enterococcus spp., Bacillus spp., Clostridium spp., Lactobacillus spp., Listeria spp., Erysipelothrix spp., Propionibacterium spp., Eubacterium spp., Corynebacterium spp., Capnocytophaga spp., Bifidobacterium spp., and Gardnerella spp. In certain embodiments, the Gram-positive bacteria is a bacterium of the phylum Firmicutes. In certain embodiments, the Gram-positive bacteria is Streptococcus.

[0345] In certain embodiments, the bacterial infection being treated or prevented is an infection caused by a Gram-negative bacteria including, but not limited to, Escherichia, Citrobacter, Enterobacter, Klebsiella, Proteus, Serratia, Shigella, Salmonella, Morganella, Providencia, Edwardsiella, Erwinia, Hafnia, Yersinia, Acinetobacter, Vibrio, Aeromonas, Pseudomonas, Haemophilus, Pasteurella, Campylobacter, Helicobacter, Branhamella, Moraxella, Neisseria, Veillonella, Fusobacterium, Bacteroides, Actinobacillus, Aggregatibacter, Agrobacterium, Porphyromonas , Prevotella, Ruminobacter, Roseburia, Caulobacter, Francisella, Borrelia, Treponema, Brucella, Bordetella, and Rickettsia. In some embodiments, the bacterial infectious agent is Bacillus anthracis (causing anthrax), Bordetella pertussis (causing whooping cough), Corynebacterium diphtheriae (causing diphtheria), Clostridium tetani (causing tetanus), Haemophilus influenzae type b, pneumococcus (causing pneumococcal infections), Staphylococci spp. (including Group A or B streptococci), Mycobacterium tuberculosis, Neiserria meningitidis (causing meningococcal disease), Salmonella typhi (causing typhoid), Vibrio cholerae (causing Cholera), or Yersinia pestis (causing plague). In some embodiments, the bacterial infectious agent is anthrax, diphtheria, tetanus, Bordetella spp., Escherichia coli, Haemophilus influenzae type b, Klebsiella spp., Neiserria spp., Pseudomonas spp, Vibrio spp., cholera, Yersinia spp., Staphylococci spp., Streptococci spp., or Salmonella spp. In some embodiments, the bacterial infectious agent is Bordetella spp., Escherichia coli, Haemophilus influenzae type b, Klebsiella spp., Neiserria spp., Pseudomonas spp, Vibrio spp., cholera, Yersinia spp., Staphylococci spp., Streptococci spp., or Salmonella spp. In some embodiments, the bacterial infectious agent is Bacillus spp., Bordetella spp., Corynebacterium spp, Clostridium spp, Escherichia coli, Haemophilus spp., Klebsiella spp, Pseudomonas spp., Streptococcus spp, Staphylococci spp., Mycobacterium spp., Neiserria spp., Salmonella spp., Vibrio spp., or Yersinia spp. In some embodiments, the bacterial infectious disease is anthrax, diphtheria, tetanus, pertussis, Haemophilus influenzae type b, pneumococcal infection, meningococcal disease, cholera, plague, Staphylococcal disease, Group A or B streptococcal or pneumococcal infection, or typhoid. In certain embodiments, the Gram-negative bacteria is Bordetella pertussis. In certain embodiments, the bacterial infectious disease is pertussis. In some embodiments, the antigen is a lipopolysaccharide endotoxin (LPS) from a Gram-negative bacterium. Non-limiting examples of Gram-negative bacterial species include: Neisseria species including Neisseria gonorrhoeae and Neisseria meningitidis, Branhamella species including Branhamella catarrhalis, Escherichia species including Escherichia coli, Enterobacter species, Proteus species including Proteus mirabilis, Pseudomonas species including Pseudomonas aeruginosa, Pseudomonas mallei, and Pseudomonas pseudomallei, Klebsiella species including Klebsiella pneumoniae, Salmonella species, Shigella species, Serratia species, Acinetobacter species: Haemophilus species including Haemophilus influenzae and Haemophilus ducreyi; Brucella species, Yersinia species including Yersinia pestis and Yersinia enterocolilica, Francisella species including Francisella tularensis, Pasturella species including Pasteurella multocida. Vibrio cholerae, Flavobacterium species, meningoseplicum, Campylobacter species including Campylobacter jejuni, Bacteroides species (oral, pharyngeal) including Bacteroides fragilis, Fusobacterium species including Fusobacterium nucleatum, Calymmatobacterium granulomatis, Streptobacillus species including Streptobacillus moniliformis, Legionella species including Legionella pneumophila.

[0346] In certain embodiments, the bacteria are acid-fast bacilli, spirochetes, or acdnomycetes. Examples of acid-fast bacilli include Mycobacterium species including Mycobacterium tuberculosis and Mycobacterium leprae. Examples of spirochetes include Treponema species including Treponema pallidum. Treponema pertenue, Borrelia species including Borrelia burgdorferi (Lyme disease), and Borrelia recurrentis, and Leptospira species. Examples of actinomycetes include: Actinomyces species including Actinomyces israelii, and Nocardia species including Nocardia asteroides.

[0347] In certain embodiments, the bacteria is Escherichia spp., Enterobacter spp. (e.g., Enterobacter cloacae), Salmonella spp. (e.g., Salmonella enteritidis, Salmonella typhi), Shigella spp., Pseudomonas spp. (e.g., Pseudomonas aeruginosa, Pseudomonas pachastr ellae, Pseudomonas stutzeri), Moraxella spp. (e.g., Moraxella catarrhalis), Neisseria spp. (e.g., Neisseria gonorrhoeae, Neisseria meningitidis), Helicobacter spp.. (e.g.. Helicobacter pylori) Stenotrophomonas spp., Vibrio spp. (e.g., Vibrio cholerae), Legionella spp. (Legionella pneumophila), Hemophilus spp. (e.g., Hemophilus influenzae), Klebsiella spp. (e.g., Klebsiella pneumoniae), Proteus spp. (e.g., Proteus mirabilis), Serratia spp. (Serratia marcescens), Streptococcus spp., Staphylococcus spp., Corynebacterium spp., Listeria spp., Bacillus spp. (e.g., Bacillus anthracis) Bordetella spp. (e.g., Bordetella pertussis); Borrelia spp. (e.g., Borrelia burgdorferi); Brucella spp. (e.g., Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis); Campylobacter spp. (e.g., Campylobacter jejuni); Chlamydia spp. and Chlamydophila spp. (e.g., Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci); Clostridium spp. (e.g., Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani); Corynebacterium spp. (e.g., Corynebacterium diphtheriae); Enterococcus spp. (e.g., Enterococcus faecalis, Enterococcus faecium); Escherichia spp. (e.g., Escherichia coli, Enterotoxic E. coli, enteropathogenic E. coli; E. coli O157:H7); Francisella spp. (e.g., Francisella tularensis); Haemophilus spp. (e.g., Haemophilus influenzae); Helicobacter spp. (e.g., Helicobacter pylori); Legionella spp. (e.g., Legionella pneumophila); Leptospira spp. (e.g., Leptospira interrogans); Listeria spp. (e.g., Listeria monocytogenes); Mycobacterium spp. (e.g., Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans); Mycoplasma spp. (e.g., Mycoplasma pneumoniae); Neisseria spp. (e.g., Neisseria gonorrhoeae, Neisseria meningitidis); Pseudomonas spp. (e.g., Pseudomonas aeruginosa); Rickettsia spp. (e.g., Rickettsia rickettsii); Salmonella spp. (e.g., Salmonella typhi, Salmonella typhimurium); Shigella spp. (e.g., Shigella sonnei); Staphylococcus spp. (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus); Streptococcus spp. (e.g., Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes); Treponema spp. (e.g., Treponema pallidum); Pseudodiomarina spp.( e.g., P. maritima); Marinobacter spp. (e.g., Marinobacter hydrocarbonoclasticus, Marinobacter vinifirmus) Alcanivorax spp. (e.g., alcanivorax dieselolei);Acetinobacter spp. (e.g., A. venetianus); Halomonas spp. (e.g., H. shengliensis); Labrenzia spp.; Microbulifer spp. (e.g., M. schleiferi); Shewanella spp. (e.g., S. algae); Vibrio spp. (e.g., Vibrio cholerae, Vibrio alginolyticus, Vibrio hepatarius); and Yersinia spp. (e.g., Yersinia pestis).

[0348] In certain embodiments, the disease is a fibrotic disease, a cardiovascular disease, a graft rejection, or graft-versus-host disease. In certain embodiments, the disease is a mycobacterial infectious disease. In certain embodiments, the mycobacterial infectious disease is caused by a tuberculosis infection or a non-tuberculous mycobacterial infection.

[0349] In certain embodiments, the infectious disease is a viral infectious disease. In certain embodiments, the viral infectious disease is an infection caused by retroviruses, human immunodeficiency viruses including HIV-1, HDTV-III, LAVE, HTLV-III / LAV, HIV-III, HIV-LP, Cytomegaloviruses (CMV), Picornaviruses, polio viruses, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, Calciviruses, Togaviruses, equine encephalitis viruses, rubella viruses, Flaviruses, dengue viruses, encephalitis viruses, yellow fever viruses, Coronaviruses (e.g., SARS-CoV-2), Rhabdoviruses, vesicular stomatitis viruses, rabies viruses, Filoviruses, ebola virus, Paramyxoviruses, parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus (RSV), Orthomyxoviruses, influenza viruses, Bungaviruses, Hantaan viruses, phleboviruses and Nairo viruses, Arena viruses, hemorrhagic fever viruses, reoviruses, orbiviruses, rotaviruses, Bimaviruses, Hepadnaviruses, Hepatitis B virus, parvoviruses, Papovaviridae, papilloma viruses, polyoma viruses, Adenoviruses, varicella zoster virus, Poxviruses, variola viruses, vaccinia viruses, Irido viruses, African swine fever virus, delta hepatitis virus, non-A, non-B hepatitis virus, Hepatitis C, Norwalk viruses, astroviruses, and unclassified viruses. In certain embodiments, the viral infectious disease is an infection caused by adenovirus, polio virus, Eastern Equine Encephalitis, Ebola, herpes viruses (e.g., herpes simplex virus 1, herpes simplex virus 2, human herpesvirus 6, human herpesvirus 8), cytomegalovirus and varicella-zoster, measles, mumps, rubella, hepatitis A, hepatitis B, hepatitis C, human papilloma virus, Influenza, parainfluenza virus, rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus, respiratory syncytial virus, smallpox, monkeypox, yellow fever, or Zika Virus. In certain embodiments, the viral infectious disease is polio, chickenpox, or shingles. In certain embodiments, the viral infectious disease is an infection caused by human immunodeficiency virus (HIV) or respiratory syncytial virus (RSV). In certain embodiments, the viral infectious disease is an infection caused by influenza. In certain embodiments, the viral infectious disease is an infection caused by a coronavirus (e.g., SARS-Cov-2).

[0350] In certain embodiments, the infectious disease is a parasitic infectious disease. In certain embodiments, the parasitic infectious disease is an infection caused by Leishmania, another protozoan, or a helminth. In certain embodiments, the parasitic infectious disease is caused by Plasmodium species, such as Plasmodium species including Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax and Toxoplasma gondii. In certain embodiments, the parasitic infectious disease is caused by blood-borne and / or tissues parasites include Plasmodium species, Babesia species including babesia microti and Babesia divergens, Leishmania species including Leishmania tropica, Leishmania species, Leishmania braziliensis, Leishmania donovani, Trypanosoma species including Trypanosoma, gambi.ense, Trypanosoma rhodesien.se (African sleeping sickness), and Trypanosoma cruzi (Chagas1disease). In certain embodiments, the parasitic infectious disease is malaria or leishmaniasis. In certain embodiments, the infectious disease is a fungal infectious disease. In certain embodiments, the fungal infectious disease is caused by Cryptococcus species including Crytococcus neoformans, Histoplasma species including Histoplasma capsulatum, Coccidioides species including Coccidiodes immitis, Paracoccidioides species including Paracoccidioides brasiliensis, Blastomyces species including Blastomyces dermatitidis, Chlamydia species including Chlamydia trachomatis, Candida species including Candida albicans and Candida auris, Sporothrix species including Sporothrix schenckii, Aspergillus species, or fungi of mucormycosis. In some embodiments, the fungus is Candida spp., Aspergillus spp., Cryptococcus spp., Fusarium spp, Mucormycete, Blastomyces dermatitidis (causing blastomycosis), or endemic mycosis causing fungus such as Histoplasma capsulatum (causing histoplasmosis), or Sporothrix schenckii (causing sporotrichosis).

[0351] In certain embodiments, the vaccine provides broad heterologous protection against a range of pathogens, for example by enhancing subsequent innate immune responses. Other medically relevant microorganisms have been described extensively in the literature, e.g., see C. G. A Thomas, Medical Microbiology, Bailliere Tindall, Great Britain 1983, incorporated herein by reference.

[0352] In certain embodiments, the disease is a chronic disease. In certain embodiments, the chronic disease is arthritis, cardiovascular disease such as heart disease, stroke, cancer (e.g., breast cancer or colon cancer), chronic respiratory diseases, diabetes, epilepsy, seizures, obesity, or an oral health problem.

[0353] In certain embodiments, the disease is addiction. In certain embodiments, the disease is addiction to a psychoactive substance (e.g., opioids). In certain embodiments, the disease is risk of drug overdose. In certain embodiments, the disease is risk of drug overdose of a psychoactive substance (e.g., opioids).

[0354] In some embodiments, the compound, composition, or vaccine composition may be administered in combination with another therapeutic agent for the infectious diseases. Such other therapeutic agents may be, without limitation: antibiotics, anti-viral agents, anti-fungal agents, or anti-parasitic agents. One skilled in the art is familiar with how to select or administer the additional therapeutic agent based on the disease to be treated.

[0355] In some embodiments, the disease is an allergy (e.g., allergic rhinitis) or asthma. It has been demonstrated that Thl / Th2 imbalance results in the clinical manifestation of allergy or asthma (e.g., as described in Ngoc et al., Curr Opin Allergy Clin Immunol. 2005 Apr; 5 (2): 161-6, incorporated herein by reference). In certain embodiments, a compound of Formula (I) restores Thl / Th2 balance and possesses ability to treat allergy or asthma. In still another aspect, the present disclosure provides methods of preventing a a disease to be treated with a compound or pharmaceutical composition described herein in a subject in need thereof, the methods comprising administering to the subject a prophylactically effective amount of a compound, composition, pharmaceutical composition, vaccine, or vaccine composition described herein.

[0356] In certain embodiments, the subject has any of the diseases described herein (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft- versus-host disease, chronic disease, addiction, or risk of drug overdose). In some embodiments, the subject is at risk of developing any of the diseases described herein (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft- versus-host disease, chronic disease, ad...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1Ais substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted 6-membered heteroaryl;Z is -CN, substituted or unsubstituted heteroalkyl comprising at least one nitrogen atom, substituted heteroarylalkyl comprising at least one nitrogen atom, or a lipid group, wherein Z is not -CHoNHo or -OCH3;R1is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -ORa, or -N(Ralh; each instance of RAis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; each instance of RBis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; 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;each instance of Ralis 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, or two instances of Ralare joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; and q is 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is substituted or unsubstituted Ci-6 alkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4S -CH3.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein RAis substituted or unsubstituted Ci-6 alkyl.

5. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1is -CH3.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein a is 1.

7. The compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein b is 0.

8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R1A-Z is of formula:wherein: each instance of Rcis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; and c is 0, 1, 2, 3, or 4.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein c is 1.

10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein R1A-Z is of formula:

11. The compound of any of claims 8-10, or a pharmaceutically acceptable salt thereof, wherein Rcis substituted or unsubstituted Ci-6 alkyl.

12. The compound of any of claims 8-11, or a pharmaceutically acceptable salt thereof, wherein Rcis -CF3.

13. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R1A-Z is of formula:

14. The compound of any of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1Ais of formula:

15. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein q is 1.

16. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein q is 2.

17. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Z is substituted or unsubstituted heteroalkyl comprising at least one nitrogen atom, or substituted heteroarylalkyl comprising at least one nitrogen atom.

18. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:wherein:L1is substituted or unsubstituted alkylene;R10is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, -SO2Ra, or -C(=O)Ra; andR20is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, -SO2Ra, or -C(=O)Ra.

19. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:

20. The compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:

21. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:wherein:L1is substituted or unsubstituted alkylene; and R30is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; andR40is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

22. The compound of any of claims 1-17 or 21, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:

23. The compound of any of claims 1-17, 21, or 22, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:

24. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein Z is a lipid group.

25. The compound of any of claims 1-17 or 24, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:wherein:L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;X1is a bond,L2is a bond or substituted or unsubstituted alkylene;L3is a bond, substituted or unsubstituted alkylene, -NRalCH2-, or -NRa1-;R10is hydrogen or -Y-(CH2)m-CH3; each Y is independently -O-, -C(=O)O-, -O(O=)C-, -CH20(0=)C-, -NRa1-, - C(=O)NRa1-, -NRal(O=)C-, or -CH2-;X3is hydrogen or -ORa; n is 0-10; m is 8-30; and t is 8-30.

26. The compound of any of claims 1-17, 24, or 25, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:

27. The compound of any of claims 1-17 or 24-26, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:

28. The compound of any of claims 1-17 or 24-27, wherein Zis of formula:

29. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:wherein: each L1is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;L2is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; each R20is independently hydrogen, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and each R30is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

30. The compound of any of claims 1-17 or 29, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:wherein:

31. The compound of any of claims 1-17, 29, or 30, or a pharmaceutically acceptable salt thereof, wherein Z is of formula:

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

33. The compound of claim 1, wherein the compound is of Formula (I-b):or a pharmaceutically acceptable salt thereof, wherein:each instance of Rcis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; and c is 0, 1, 2, 3, or 4.

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

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

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

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

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

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

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

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

42. The compound of claim 1, wherein the compound is of Formula (I-b-1):or a pharmaceutically acceptable salt thereof, wherein: each instance of Rcis 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(Ral)2, -SRa, -CN, - C(=O)Ra, -C(=O)ORa, -C(=O)N(Ral)2, or -NO2; and c is 0, 1, 2, 3, or 4.

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

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

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

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

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

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

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

50. The compound of claim 1, wherein the compound is of the formula:(34);10 or a pharmaceutically acceptable salt thereof.

51. A pharmaceutical composition comprising the compound of any one of claims 1-50, and a pharmaceutically acceptable excipient.

52. The pharmaceutical composition of claim 33 further comprising an additional pharmaceutical agent.

53. A method of treating a disease in a subject in need thereof, the method comprising administering the compound of any of claims 1-50, the pharmaceutical composition of claim 51 or 52, the composition of any of claims 87-112, or the vaccine of claim 113 or 114.

54. The method of claim 53, wherein the disease is a proliferative disease, an inflammatory disease, an autoimmune disease, an infectious disease, an allergy, a fibrotic disease, a cardiovascular disease, a graft rejection, graft-versus-host disease, chronic disease, addiction, or risk of drug overdose.

55. The method of claim 53 or 54, wherein the disease is an infectious disease such as a viral infectious disease, sepsis, a pediatric infectious disease, a bacterial infectious disease, a mycobacterial infectious disease, a parasitic infectious disease, or a fungal infectious disease.

56. The method of any of claims 53-55, wherein the disease is a bacterial infectious disease caused by infection with Streptococcus spp., Bordetella spp., Escherichia coli, Haemophilus influenzae type b, Klebsiella spp., Neiserria spp., Pseudomonas spp, Vibrio spp., Yersinia spp., Staphylococci spp., or Salmonella spp.

57. The method of any of claims 53-55, wherein the disease is a bacterial infectious disease that is anthrax, diphtheria, tetanus, or cholera.

58. The method of any of claims 53-55, wherein the disease is a mycobacterial infectious disease caused by a tuberculosis infection or a non-tuberculous mycobacterial infection.

59. The method of any of claims 53-55, wherein the disease is a viral infectious disease caused by adenovirus, polio virus, Eastern Equine Encephalitis, Ebola, herpes viruses (e.g., herpes simplex virus 1, herpes simplex virus 2, human herpesvirus 6, human herpesvirus 8), cytomegalovirus, varicella-zoster virus, measles, mumps, rubella, hepatitis A, hepatitis B, hepatitis C, human papilloma virus, influenza, parainfluenza virus, coronavirus (e.g., SARS-CoV-2), rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus, respiratory syncytial virus, monkeypox, smallpox, yellow fever, or Zika Virus.

60. The method of any of claims 53-55, wherein the disease is a parasitic infectious disease that is malaria or leishmaniasis.

61. The method of claim 53 or 54, wherein the disease is cancer.

62. The method of any of claims 53-55, wherein the disease is a fungal infectious disease caused by Candida spp., Aspergillus spp., Cryptococcus spp., Mucormycete, Blastomyces dermatitidis, Fusarium spp, Histoplasma capsulatum, or Sporothrix schenckii.

63. The method of any of claims 53-62, wherein the composition is administered once to the subject.

64. The method of any of claims 53-63, wherein the composition is administered repeatedly to the subject.

65. The method of any of claims 53-64, wherein the composition is administered intradermally, intramuscularly, intravaginally, intravenously, intranasally, orally, subcutaneously, transdermally, topically, and / or sublingually.

66. The method of any of claims 53-65, wherein the composition is administered as a prophylactic.

67. The method of any of claims 53-66, wherein the 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.

68. The method of any of claims 53-67, wherein the subject is a human infant.

69. The method of claim 68, wherein the human infant is less than or equal to 28 days of age, less than or equal to 4 days of age, less than or equal to 2 days of age, or less than or equal to 24 hours of age at the time of administration, or the administration occurs at birth.

70. The method of claim 69, wherein a second administration occurs when the human infant is less than or equal to 28 days of age, or less than or equal to 6 months of age.

71. The method of claim 68, wherein the administration occurs when the human infant is 2 months, 4 months, and 6 months of age.

72. The method of any of claims 68-71, wherein the infant is born prematurely or has low birth weight.

73. The method of any of claims 53-67, wherein the subject is a pediatric human of up to 18 years of age.

74. The method of any of claims 53-67, wherein the subject is a human adult.

75. The method of any of claims 53-67, wherein the subject is a human adult of 65 years of age or older.

76. The method of any of claims 53-75, wherein the subject is immunocompromised due to primary immunodeficiency, acquired immunodeficiency and / or distinct immunity.

77. A method of enhancing an immune response in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-50, the pharmaceutical composition of claim 51 or 52, the composition of any of claims 87-112, or the vaccine of claim 113 or 114.

78. The method of claim 77, wherein the immune response is an innate immune response.

79. The method of claim 77 or 78, wherein the compound activates peripheral blood mononuclear cells (PBMCs).

80. The method of any of claims 77-79, wherein the compound activates one or more pattern recognition receptors (PRRs).

81. The method of claim 80, wherein the PRR is a Toll-like receptor (TLR), a NOD-like receptor (NLR), a RIG-I-like receptor, a C-type Lectin receptor, or STING.

82. The method of claim 81, wherein the Toll-like receptor is TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR9, and / or TLR10.

83. The method of claim 81, wherein the Toll-like receptor is TLR7 and / or TLR8.

84. The method of any of claims 77-83, wherein the compound induces the production of immunomodulatory cytokines and / or chemokines in the subject.

85. The method of claim 64, wherein the cytokines and chemokines include TNF, IL-12, IL-6, IL-ip, or CXCL-8.

86. A kit comprising the compound of any of claims 1-50, the pharmaceutical composition of claim 51 or 52, the composition of any of claims 87-111, or the vaccine of any of claims 112-114; and instructions for use.

87. A composition comprising an antigen and the compound of any of claims 1-50, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

88. The composition of claim 87, wherein the antigen comprises a protein or polypeptide.

89. The composition of claim 87 or 88, wherein the antigen comprises a nucleic acid encoding a protein or a polypeptide.

90. The composition of claim 89, wherein the nucleic acid is DNA or RNA.

91. The composition of any of claims 87-90, wherein the antigen is from a microbial pathogen.

92. The composition of claim 91, wherein the microbial pathogen is a bacterium, mycobacterium, fungus, virus, parasite, or prion.

93. The composition of claim 91, wherein the microbial pathogen is a bacterium selected from the group consisting of Bacillus spp. , Bordetella spp. , Corynebacterium spp, Clostridium spp, Escherichia coli, Haemophilus spp., Klebsiella spp, Pseudomonas spp., Streptococcus spp, Staphylococci spp., Mycobacterium spp., Neiserria spp., Salmonella spp., Vibrio spp., and Yersinia spp.

94. The composition of claim 91, wherein the microbial pathogen is a virus selected from the group consisting of adenovirus, enterovirus (e.g., polio virus), Eastern EquineEncephalitis, Ebola virus, herpes viruses (e.g., herpes simplex virus 1, herpes simplex virus 2, human herpesvirus 6, human herpesvirus 8), cytomegalovirus, varicella-zoster, measles, mumps, rubella, hepatitis A virus, hepatitis B virus, hepatitis C virus, human papilloma virus, influenza virus, parainfluenza virus, coronavirus (e.g., SARS-CoV-2), rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), smallpox, monkeypox, yellow fever, and Zika Virus.

95. The composition of claim 91, wherein the microbial pathogen is a parasite selected from Plasmodium spp., Leishmania, and a helminth.

96. The composition of claim 91, wherein the microbial pathogen is a fungus selected from the group consisting of Candida spp. , Aspergillus spp. , Cryptococcus spp. , Mucormycete, Blastomyces dermatitidis, Histoplasma capsulatum, and Sporothrix schenckii.

97. The composition of any one of claims 87-90, wherein the antigen is a cancer-specific antigen.

98. The composition of claim 97, wherein the antigen is a heteroclitic epitope or a cryptic epitope derived from the cancer- specific antigen.

99. The composition of claim 97, wherein the cancer- specific antigen is a neoantigen.

100. The composition of claim 87, wherein the antigen is a psychoactive substance or its hapten derivative (e.g., an opioid- specific antigen).

101. The composition of claim 87, wherein the antigen is a hapten.

102. The composition of claim 87, wherein the antigen comprises a lipopolysaccharide(LPS).

103. The composition of any of claims 87-102, further comprising a pharmaceutically acceptable carrier.

104. The composition of any of claims 87-103, wherein the composition is a vaccine composition.

105. The composition of claim 104, wherein the compound is an adjuvant.

106. The composition of claim 104 or 105, wherein the antigen is adsorbed onto alum.

107. The composition of any of claims 104-106, wherein the compound is adsorbed onto alum.

108. The composition of any of claims 105-107, wherein the vaccine composition further comprises a second adjuvant.

109. The composition of claim 108, wherein second adjuvant is an agonist of Pattern Recognition Receptors (PRRs) selected from the group consisting of Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptor, C-type Lectin receptors (CLRs), and a stimulator of interferon genes (STING).

110. The composition of claim 108 or 109, wherein second adjuvant is bound to or adsorbed to alum.

111. The composition of any of claims 108-110, wherein the second adjuvant is alum.

112. The composition of any of claims 108-111, wherein the second adjuvant includes an oil-in-water emulsion.

113. A vaccine comprising the composition of any of claims 87-112.

114. The vaccine of claim 113, wherein the vaccine is a subunit vaccine, an attenuated vaccine, or a conjugate vaccine.

115. A method of enhancing an immune response to an antigen in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any of claims 87-112.

116. The method of claim 115, wherein the antigen and the compound are administered simultaneously.

117. The method of claim 115 or 116, wherein the antigen and the compound are administered separately.

118. The method of any of claims 115-117, wherein the antigen and the compound are administered once to the subject.

119. The method of any of claims 115-118, wherein the antigen and the compound are administered repeatedly to the subject.

120. The method of any of claims 115-119, wherein the compound and / or the second adjuvant enhance antigen-presenting cell activity.

121. The method of any of claims 115-120, wherein the compound and / or second adjuvant activates B cell immunity.

122. The method of any of claims 115-121, wherein the production of antigen- specific antibodies is increased, compared to when the antigen is administered alone.

123. The method of any of claims 115-122, wherein the activation of antigen- specific cytotoxic T cells is increased, compared to when the antigen is administered alone.

124. The method of any of claims 115-123, wherein the compound polarizes the innate immune response toward T helper 1 (Thl) immunity, T helper 2 (Th2) immunity, T helper 17 (Thl7) immunity, and / or T follicular helper (Tfh) cell immunity.

125. The method of any of claims 115-124, wherein the compound prolongs the durability of protection in the subject against the antigen, compared to when the antigen is administered alone.

126. The method of any of claims 115-125, wherein the compound increases the rate of an immune response compared to when the antigen is administered alone.

127. The method of any of claims 115-126, wherein the compound achieves antigen dose sparing such that the antigen induces a same level of immune response at a lower dose in the presence of the compound, compared to when the antigen is administered alone.

128. The method of any of claims 115-127, wherein the subject has or is at risk of developing an infectious disease.

129. The method of claim 128, wherein the infectious disease is caused by a bacterium, a mycobacterium, a fungus, a virus, a parasite, or a prion.

130. The method of claim 128 or 129, wherein the infectious disease is bacterial, fungal or viral sepsis.

131. The method of any of claims 115-127, wherein the subject has or is at risk of developing cancer.

132. The method of claim 131, wherein the cancer is metastatic cancer.

133. The method of claim 131 or 132, wherein the cancer is a skin cancer, optionally wherein the skin cancer is melanoma, basal cell carcinoma, squamous cell carcinoma, or Merkel cell carcinoma.

134. The method of claim 132 or 133, wherein the cancer is colorectal cancer, lung cancer, bladder cancer, breast cancer, kidney cancer, anal cancer, or salivary gland cancer.

135. The method of claim 132 or 133, wherein the cancer is a lymphoma or leukemia.

136. The method of any one of claims 115-127, wherein the subject has or is at risk of developing allergy.

137. The method of any one of claims 115-127, wherein the subject has or is at risk of developing an addiction and / or death due to an overdose of a psychoactive substance.

138. The method of any one of claims 115-137, wherein the administration is systemic or local.

139. The method of any one of claims 115-138, wherein the administration is intramuscular, intradermal, oral, intravenous, topical, transdermal, intranasal, intravaginal, or sublingual.

140. The method of any one of claims 115-139, wherein the administration is prophylactic.

141. The method of any one of claims 115-139, wherein the administration is therapeutic.

142. The method of any one of claims 115-139, wherein the subject is a human infant, an adult, or an older adult.

143. The method of claim 142, wherein the subject is a human infant.

144. The method of claim 143, wherein the human infant is less or equal to 28 days of age or less than or equal to 24 hours of age at the time of administration, or the administration occurs at birth.

145. The method of claim 144, wherein a second administration occurs when the subject is less than or equal to 28 days of age or less than or equal to 6 months of age.

146. The method of claim 143, wherein the administration occurs when the human infant is 2 months, 4 months, and 6 months of age.

147. The method of any one of claims 115-146, wherein the subject is born prematurely or has low birth weight.

148. The method of claim 142, wherein the subject is a human adult.

149. The method of claim 142, wherein the subject is an older adult.

150. The method of claim 149, wherein the administration occurs when the subject is more than 65 years of age.

151. The method of any one of claims 115-150, wherein the subject is immunocompromised due to primary immunodeficiency, acquired immunodeficiency and / or distinct immunity.

152. The method of any one of claims 115-150, wherein the subject has a comorbidity such as obesity or diabetes or other chronic illness.

153. A method of vaccinating a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any one of claims 104- 112, or the vaccine of claim 113 or 114.

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