Indole alkaloid antiplasmodial agents and preparation thereof

Abstract

The present disclosure provides compounds of Formula (I) or (II). The provided compounds may be useful as anti-microbial agents (e.g. antiplasmodial agents). The present disclosure also provides pharmaceutical compositions comprising the provided compounds; kits comprising the provided compounds or pharmaceutical compositions; and methods of using the provided compounds and pharmaceutical compositions (e.g., for treating or preventing a disease).

Description

[0001] INDOLE ALKALOID ANTIPLASMODIAL AGENTS AND PREPARATION THEREOF

[0002] GOVERNMENT SUPPORT

[0003] This invention was made with government support under grant numbers R35 GM128621 and S10 OD021758 awarded by the National Institutes of Health and under grant number CHE-1828064 awarded by the National Science Foundation. The government has certain rights in the invention.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] In the past decade, Complexity-to-Diversity (CtD) strategies have gained traction as a means to generate diverse and stereochemically complex compound libraries from natural products.1 16The CtD strategy has been successfully applied to a wide range of natural products, including adrenosterone,1gibberellic acid,1quinine,1pleuromutilin,2 15abietic acid,9sinomenine,10yohimbine,3’6-7 11lycorine,12vincamine,4,8 16and other steroids.13 14CtD offers an orthogonal discovery approach to diversity-oriented synthesis (DOS; simple materials utilized in complexitygenerating reactions to explore chemical space)17 24and biology-oriented synthesis (BIOS; generation of natural product-like molecules based on cheminformatic analysis of natural products and conserved proteins)23 32utilizing chemosei ective “ring distortion” reactions (e.g., ring cleavage, ring expansion reactions) to rapidly accesses diverse compounds through the dramatic architectural reorganization of stereochemically complex natural products. The overarching goal of CtD (or “ring distortion”) is to access diverse molecular scaffolds to discover compounds with re-engineered biological activities in critical disease areas. Noteworthy examples of the CtD platform delivering reengineered small molecules include the discovery of vincamine-derived V2a, which demonstrates antagonistic activity against hypocretin receptor 2 and inhibits morphine-seeking behaviors in mouse models,16and the identification of pleuromutilin-derived ferroptocide, a thioredoxin inhibitor that positively modulates the immune system in a murine model of breast cancer.15

[0006] Chloroformate-mediated ring cleavage of gardnerine (1) and derivatives was reported by Sakai and colleagues in 1973.33In this reaction type, a polycyclic tryptoline system containing a tertiary amine is reacted with a chloroformate electrophile in the presence of an alcohol nucleophile, leading to an indole-promoted ring cleavage and the incorporation of carbamate and ether moieties. This methodology has been applied to a number of indole alkaloids and related scaffolds, with other examples such as (±)-desbromoarborescidine A (5).34-36The versatility of this reaction to diversity at two positions of the tryptoline framework while performing a regioselective ring cleavage transformation proved an attractive strategy to expand our ring distortion platform using multiple indole alkaloids. Additionally, certain reported CtD work on yohimbine and vincamine involved alternative indole-promoted ring cleavage reactions that resulted in the discovery of Nrf2- Antioxidant Response Element (ARE) inhibitor Y6q (8)11and antiplasmodial agent V3b (10).4There is a need for new methods of preparing alkaloids and using the alkaloids as antiplasmodial agents.

[0007] SUMMARY OF THE DISCLOSURE

[0008] In one aspect, the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof, wherein the compounds are of Formula I:

[0009] In another aspect, the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof, wherein the compounds are of Formula II:

[0010] The provided compounds may be useful as anti-microbial agents. In certain embodiments, the provided compounds are anti -parasitic agents. In certain embodiments, the provided compounds are parasitostatic agents. In certain embodiments, the provided compounds are antiplasmodial agents.

[0011] In another aspect, the present disclosure provides pharmaceutical compositions comprising a provided compound and optionally a pharmaceutically acceptable excipient.

[0012] In another aspect, the present disclosure provides kits comprising a provided compound or pharmaceutical composition, and instructions for using the provided compound or pharmaceutical composition.

[0013] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.

[0014] In another aspect, the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for treating a disease in a subject in need thereof.

[0015] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in treating a disease in a subject in need thereof.

[0016] In another aspect, the present disclosure provides methods of preventing a disease in a subject, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.

[0017] In another aspect, the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for preventing a disease in a subject.

[0018] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in preventing a disease in a subject.

[0019] In certain embodiments, the disease is an infection. In certain embodiments, the disease is a parasitic infection. In certain embodiments, the disease is malaria.

[0020] In another aspect, the present disclosure provides methods of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue, the methods comprising administering to the subject or contacting the biological sample or tissue with an effective amount of a provided compound or pharmaceutical composition.

[0021] In another aspect, the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue.

[0022] In another aspect, the present disclosure provides the provided compounds and pharmaceutical compositions for use in inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue.

[0023] In another aspect, the present disclosure provides in vitro methods of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a biological sample or tissue or on a surface, the method comprising contacting the biological sample, tissue, or surface with an effective amount of a provided compound or pharmaceutical composition.

[0024] The details of one or more embodiments of the present disclosure are set forth herein. Other features, objects, and advantages of the present disclosure will be apparent from the Detailed Description, Examples, Figures, and Claims.

[0025] DEFINITIONS

[0026] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March 's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0027] 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), supercritical fluid chromatography (SFC), 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 present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0028] In a formula, the bond — is a single bond, the dashed line — is a single bond or absent, and the bond — or — is a single or double bond.

[0029] Unless otherwise provided, a formula depicted herein includes compounds that do not include isotopically enriched atoms and also compounds that include isotopically enriched atoms. Compounds that include isotopically enriched atoms may be useful as, for example, analytical tools, and / or probes in biological assays.

[0030] The term “aliphatic” includes both saturated and unsaturated, nonaromatic, straight chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons. In some embodiments, an aliphatic group is optionally substituted with one or more functional groups (e.g., halo, such as fluorine). As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

[0031] When a range of values (“range”) is listed, it is intended to encompass each value and subrange within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “an integer between 1 and 4” refers to 1, 2, 3, and 4. For example “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, Cs, Ce, C1-6, C1-5, Ci-4, C1-3, C1-2, C2-6, C2-5, C2 4, C2 3, C3 6, C3 5, C3 4, C4 6, C4 5, and Cs 6 alkyl.

[0032] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 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 (“Ci-4 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), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (Cs), 3-pentanyl (C5), amyl (Cs), neopentyl (Cs), 3-methyl- 2-butanyl (Cs), tertiary amyl (Cs), and n-hexyl (Ce). 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 optionally substituted, e.g., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents. In certain embodiments, the alkyl group is unsubstituted C1-12 alkyl (e.g, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g, unsubstituted n-propyl ( / -Pr), unsubstituted isopropyl ( / -Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl ( / / -Bu), unsubstituted ze / 7-butyl (ze / z-Bu or / -Bu), unsubstituted .sec-butyl (sec- Bu or .s-Bu), unsubstituted isobutyl ( / -Bu)). In certain embodiments, the alkyl group is substituted C1-12 alkyl (such as substituted C1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2,- CH2CF3, or benzyl (Bn)). The attachment point of alkyl may be a single bond (e.g, as in -CH3), double bond (e.g., as in =CH2), or triple bond (e.g., as in =CH). The moieties =CH2 and =CH are also alkyl.

[0033] In some embodiments, an alkyl group is substituted with one or more halogens. “Perhaloalkyl” is a substituted alkyl group as defined herein wherein all of the hydrogen atoms are independently replaced by a halogen, e.g, fluoro, bromo, chloro, or iodo. In some embodiments, the alkyl moiety has 1 to 8 carbon atoms (“C1-8 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms (“Ci-6 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms (“Ci-4 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms (“C1-3 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms (“C1-2 perhaloalkyl”). In some embodiments, all of the hydrogen atoms are replaced with fluoro. In some embodiments, all of the hydrogen atoms are replaced with chloro. Examples of perhaloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCh, -CF2CI, and the like.

[0034] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more e.g., two, three, or four, as valency permits) carbon-carbon double bonds, and no triple bonds (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). 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 carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (Cs), 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, e.g., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified e.g., -

[0035] CH=CHCH3or ) may be in the (E)- or (.^-configuration.

[0036] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more (e.g., two, three, or four, as valency permits) 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 (“C2-10 alkynyl”). 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 carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include 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 (Cs), 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, e.g., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.

[0037] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 13 ring carbon atoms (“C3-13 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 7 ring carbon atoms (“C3-7 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 cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include 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 (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-l / f-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”). Carbocyclyl can be saturated, and saturated carbocyclyl is referred to as “cycloalkyl.” 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 (Cs) and cyclohexyl (Cs). 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. Carbocyclyl can be partially unsaturated. Carbocyclyl may include zero, one, or more (e.g., two, three, or four, as valency permits) C=C double bonds in all the rings of the carbocyclic ring system that are not aromatic or heteroaromatic. Carbocyclyl including one or more (e.g., two or three, as valency permits) C=C double bonds in the carbocyclic ring is referred to as “cycloalkenyl.” Carbocyclyl including one or more e.g., two or three, as valency permits) C=C triple bonds in the carbocyclic ring is referred to as “cycloalkynyl.” “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl 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, e.g., 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 a substituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 3- to 7-membered, and monocyclic. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 5- to 13-membered, and bicyclic.

[0038] 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 (Cs) and cyclohexyl (Cs). 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. In certain embodiments, the carbocyclyl includes oxo substituted thereon. “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 13-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-13 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”). A heterocyclyl group can be saturated or can be partially unsaturated. Heterocyclyl may include zero, one, or more (e. ., two, three, or four, as valency permits) double bonds in all the rings of the heterocyclic ring system that are not aromatic or heteroaromatic. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an “un substituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, and monocyclic. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 5- to 13-membered, and bicyclic. In certain embodiments, the heterocyclyl includes oxo substituted thereon.

[0039] 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, and sulfur (“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.

[0040] Exemplary 3-membered heterocyclyl groups containing one heteroatom include azirdinyl, oxiranyl, or thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include 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 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 tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0041] “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 7t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“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 (“C 14 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, e.g., 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.

[0042] “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 K 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, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0043] 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, e.g., unsubstituted (“un substituted heteroaryl”) or substituted (“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. In certain embodiments, the heteroaryl group is 5-6 membered, monocyclic. In certain embodiments, the heteroaryl group is 8-14 membered, bicyclic.

[0044] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazol yl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include 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 naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0045] “Partially unsaturated” refers to a group that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as herein defined. Likewise, “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.

[0046] In some embodiments, aliphatic, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “un substituted” 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. aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; each instance of Raais, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroal kynyl, 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, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-ioalkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-io alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Recgroups 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, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-ealkyl, heteroC2- ealkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 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-ealkenyl, 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, heteroal kynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgsgroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-ealkyl, heteroC2-ealkenyl, heteroC2-ealkynyl, C3-10 carbocyclyl, 3- 10 membered heterocyclyl, C6-10 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 Rsggroups; and each instance of Rggis, independently, halogen, , , I- 6 heteroC2-ealkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgssubstituents can be joined to form =0 or =S; wherein X is a counterion.

[0047] In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, - CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, OC(=O)N(Rbb)2, NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=0)N(Rbb)2. In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C -NRbbC02Raa, or -NRbbC(=0)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group (e.g, acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci- 6 alkyl, or a nitrogen protecting group. In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1-6 alkyl, ORaa, SRaa, ~N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group (e.g. , acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group.

[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 trivalent. Exemplary counterions include halide ions (e.g., F , Cl", Br , I"), NO3 , CIO4 , OH", H2PO4 , HCO3", HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, / 2-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthal ene-2-sulfonate, naphthalene-l-sulfonic acid-5- sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4 , PF 4", PFe , AsFe", SbF6", B[3,5-(CF3)2C6H3]4]", B(C6FS)4", BPIH , A1(OC(CF3)3)4 , and carborane anions (e.g., CB11H12" or (HCBnMesBre) ). Exemplary counterions which may be multivalent include CO32, HPO42, PO43B4O72, SO42, S2O32, carboxylate anions (e.g, tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, - Br), or iodine (iodo, -1).

[0049] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-ioalkyl, heteroC2-ioalkenyl, heteroC2- loalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Recgroups 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.

[0050] In certain embodiments, the nitrogen atom substituents are independently substituted (e.g, substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, the nitrogen atom substituents are independently substituted (e.g, substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci- 6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (c.g., substituted with one or more halogen) or unsubstituted Ci- 6 alkyl, or a nitrogen protecting group. In certain embodiments, the nitrogen atom substituents are independently substituted (c.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0051] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include -OH, - C(=S)SRCC, Ci-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rec, and 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.

[0052] Amide nitrogen protecting groups (e.g., -C(=O)Raa) include formamide, acetamide, chloroacetamide, tri chloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, A'-benzoylphenylalanyl derivative, benzamide, p- phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’~ dithiobenzyloxyacylamino)acetamide, 3-(u-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, A-acetylmethionine, o-nitrobenzamide, and o- -(benzoyloxymethyl)benzamide.

[0053] Carbamate nitrogen protecting groups (e.g., -C(=O)ORaa) include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2, 7— di— / —butyl— [9— ( 10, 10-dioxo-l 0, 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 / BOC), l,l-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), l-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), 1— (3,5— di— / -butyl phenyl )-l -methyl ethyl carbamate ( / Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(MA-dicyclohexylcarboxamido)ethyl carbamate, / -butyl carbamate (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), / ;-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, / ?-bromobenzyl carbamate, / ?-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-cyanoethyl carbamate, / w-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, / -amyl carbamate, S-benzyl thiocarbamate, / ?-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, / 2-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N, A'-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(7V,7V- 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 -methyl cyclohexyl carbamate, 1-methyl-l -cyclopropylmethyl carbamate, 1-methyl- l-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-l -( / 9-phcnylazophcnyl)cthyl carbamate, 1- methyl-l-phenylethyl carbamate, l-methyl-l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2, 4, 6-tri - / -butyl phenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0054] Sulfonamide nitrogen protecting groups (e.g., -S(=O)2Raa) include / Moluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),

[0055] 2.3.5.6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs),

[0056] 2.4.6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), 0- trimethyl silylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0057] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivative, N’-p- toluenesulfonylaminoacyl derivative, N ’-phenylaminothioacyl derivative, A-benzoylphenyl alanyl derivative, A'-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, / V-phthalimide, N- dithiasuccinimide (Dts), A-2,3-diphenylmal eimide, A-2,5-di methyl pyrrole, AM, 1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-mcthylaminc, A-allylamine, A-[2-(trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-( l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4-methoxyphenyl )methylamine, N-5- dibenzosuberylamine, AMriphenylmethylamine (Tr), A-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenyl fluor enyl amine (PhF), A-2,7-dichloro-9-fluorenylmethyleneamine, N- ferrocenylmethylamino (Fem), 2V-2-picolylamino TV ’-oxide, JV-l,l-dimethylthiomethyleneamine, JV-benzylideneamine, jV- / ?-methoxybenzylideneamine, JV-diphenylmethyleneamine, JV-[(2- pyridyl)mesityl]methyleneamine, jV-(jV’,2V’-dimethylaminomethylene)amine, N,N’~ isopropylidenediamine, A' / ?-nitrobenzylideneamine, JV-salicylideneamine, N-5- chlorosalicylideneamine, 7V-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, JV-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A-borane derivative, N- diphenylborinic acid derivative, jV-[phenyl(pentaacylchromium- or tungsten)acyl]amine, A'-copper chelate, A'-zinc chelate, Af-nitroamine, N-nitrosoamine, amine Afoxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3- nitropyridinesulfenamide (Npys).

[0058] In certain embodiments, a nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0059] In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CChR”, -C(=0)N(Rbb)2, or an oxygen protecting group. In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -C02Raa, -C(=0)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci- 6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci- 6 alkyl, or a nitrogen protecting group. In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or an oxygen protecting group.

[0060] 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 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.

[0061] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), / -butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), / ?-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p- AOM), guaiacolmethyl (GUM), / -butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (TEIP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, l-[(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, l-(2-chloroethoxy)ethyl, 1-methyl-l-methoxy ethyl, 1-methyl-l-benzyloxyethyl, l-methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, / -butyl, allyl, p-chlorophenyl, / 2-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 Aroxido, diphenylmethyl, p,p ’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a- naphthyldiphenylmethyl, p-methoxyphenyl diphenylmethyl, di(p-methoxyphenyl)phenyl methyl, tri(p-methoxyphenyl)rnethyl, 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-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropyl silyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, / -butyldimethylsilyl (TBDMS), / -butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylyl silyl, triphenyl silyl, diphenylmethylsilyl (DPMS), / - butylmethoxyphenyl silyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxy acetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxy crotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenyl sulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p- m ethoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl .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-(l, l,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 / V-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0062] In certain embodiments, an oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, / -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0063] In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -C02Raa, -C(=0)N(Rbb)2, or a sulfur protecting group. In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -C02Raa, -C(=0)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a sulfur protecting group.

[0064] 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 -Raa, -N(Rbb)2, 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. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0065] The “molecular weight” of-R, wherein -R is any monovalent moiety, is calculated by subtracting the atomic weight of a hydrogen atom from the molecular weight of the molecule R-H. The “molecular weight” of-L-, wherein -L- is any divalent moiety, is calculated by subtracting the combined atomic weight of two hydrogen atoms from the molecular weight of the molecule H-L-H.

[0066] In certain embodiments, the molecular weight of a substituent is lower than 200, lower than 150, lower than 100, lower than 50, or lower than 25 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, and / or fluorine atoms. In certain embodiments, a substituent does not comprise one or more, two or more, or three or more hydrogen bond donors. In certain embodiments, a substituent does not comprise one or more, two or more, or three or more hydrogen bond acceptors.

[0067] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, Figures, and Claims. The present disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.

[0068] “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. Pharmaceutically acceptable salts of the compounds describe 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 used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bi sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, 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-4alkyl)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, quaternary salts.

[0069] The term “solvate” refers to forms of the compound 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 provided compounds 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 isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0070] 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 wherein x is a number greater than 0. A given compound may form more than one type of hydrates, 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)).

[0071] The term “tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 71 electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0072] 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”.

[0073] 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”.

[0074] The term “polymorphs” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. 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.

[0075] The term “prodrugs” refer to compounds, including derivatives of the provided compounds, which have cleavable groups and become by solvolysis or under physiological conditions the provided compounds which are pharmaceutically active in vivo. Such examples include, but are not limited to, ester derivatives and the like. Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Ci to Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the provided compounds may be preferred.

[0076] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). In certain embodiments, the subject is a mammal. The subject may be a male or female and at any stage of development. A non-human animal may be a transgenic animal.

[0077] 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.

[0078] The terms “administer,” “administering,” or “administration,” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound, or a pharmaceutical composition thereof.

[0079] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a “pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0080] 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 regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population of subjects.

[0081] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0082] An “effective amount” of a provided compound refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a provided compound 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. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound may reduce the tumor burden or stop the growth or spread of a tumor.

[0083] A “therapeutically effective amount” of a provided compound 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 or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0084] A “prophylactically effective amount” of a provided compound is an amount sufficient 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.

[0085] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows exemplary key NOEs for stereochemical assignment at C3 of yohimbine products.

[0086] FIG. 2 shows that exemplary X-ray crystal structures of yohimbine products supported NMR trends for stereochemical assignment.

[0087] FIG. 3 shows an exemplary X-ray crystal structure of Compound 27.

[0088] FIG. 4 shows an exemplary free energy diagram for the ring cleavage pathway of yohimbine reacting with ethyl chloroformate and 2-iodobenzyl alcohol. Optimized structure of Int-2B (33) is shown in the top right of the diagram. The arrow is pointing to the most accessible face of the (planar) electrophilic center for nucleophilic approach, rationalizing the stereochemical outcome for the reaction.

[0089] FIG. 5 shows an exemplary free energy diagram for the ring cleavage pathway of apovincamine reacting with phenyl chloroformate and methanol. Optimized structure of V-Int-2A (37) is shown in the top right of the diagram. The arrow is pointing to the most accessible face of the (planar) electrophilic center for nucleophilic approach, rationalizing the stereochemical outcome for the reaction.

[0090] FIG. 6 shows exemplary results of kinetic kill experiments of P. falciparum Dd2 cultures to determine 40 and 41 as parasitostatic agents. Compounds were added at 10 * ECso concentrations to synchronous Dd2 culture at 1% parasitemia and 4% hematocrit starting at 6 hours post invasion (HPI). Dd2 culture was synchronized by using 5% sorbitol. Cultures were exposed to the compound of interest during 12, 24, and 48 h, followed by washing steps and continuous monitoring of parasite regrowth over the course of four days. PBS and 0.5% BSA were used for washing and blocking steps. Samples were collected every 24 h until the 96 h time point. A combination of Mitotracker Deep red (MTDR) and SYBR Green I dyes were used to stain mitochondrial content in live parasites and parasitemia, respectively. Uninfected red blood cells and no mitotracker controls were used to assist with flow-cytometry analysis. Dimethyl sulfoxide (DMSO) was used as a negative control. Dihydroartemisinin (DHA) was used as a positive control for rapid parasite killing (parasitocidal action), and atovaquone was also used as a positive control for slow parasite killing (parasitostatic action). GraphPad Prism was used to analyze the flow cytometry data. Results are expressed as the means of triplicate biological experiments and parasite viability.

[0091] FIG. 7shows exemplary stage-specific activity of Compound 41 in / < falciparum Dd2 parasites. Dd2 culture was synchronized by using 5% sorbitol. The culture was then diluted to 1% parasitemia and 2% hematocrit. Compound 41 was added at 5 * EC so concentrations at 6, 18, 30 and 42 HPI. DMSO and DHA were used as a negative and positive controls, respectively. Samples were collected every 12 h at every stage until reinvasion at 54 HPI. Giemsa smearing was used to observe the parasite morphology, and flow cytometry (FlowJo (v 10.8)) was used to observe parasite DNA content. Samples were fixed in 4% paraformaldehyde, and PBS was used for washing steps. Samples were permeabilized in 0.25% Triton X-100 and stained using DNA dye YOYO-1. Results are representative of triplicate biological experiments.

[0092] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE

[0093] In recent years, natural product ring distortion strategies have been pursued to generate novel, stereochemically complex compounds for discoveries relevant to human disease. Herein is described an indole-promoted ring-cleavage strategy using chloroformates paired with alcohols / thiols which enabled the synthesis of 49 novel ring-cleaved products from the indole alkaloids yohimbine, vincamine, and reserpine. Ring cleavage reactions of yohimbine and reserpine produced diastereomeric products in 33-96% yield, whereas apovincamine and vinburnine produced a single diastereomeric product in significantly lower yields ranging from 4-67%. Free energy calculations indicated that diastereoselectivity regarding select ring cleavage reactions from yohimbine and apovincamine is dictated by the geometry and three-dimensional structure of reactive cationic intermediates. Characterization of these compounds proved challenging as most required variable temperature NMR at 100 °C. In addition, NOE experiments and six X-ray structures were obtained for stereochemical assignment. These compounds were screened for antimalarial activity due to the need for novel agents against this disease (which is estimated to have caused 627,000 deaths worldwide in 2020). Reserpine derivative 41 was found to exhibit good antiplasmodial activity against Plasmodium falciparum parasites (ECso = 0.50 pM against Dd2 cultures), while its diastereomer 40 was found to be threefold less active (ECso = 1.78 pM). Overall, these studies demonstrate that employing the Complexity -to-Diversity approach using available indole alkaloids can lead to unique compound collections with re-engineered biological activities for exploring and treating disease.

[0094] During the course of these studies, three indole alkaloids or synthetic derivatives were subjected to chloroformate-mediated indole-promoted ring cleavage reactions to access new analogues. Nearly all ring cleaved analogues synthesized proved to be difficult to characterize by NMR due to the resulting medium-sized ring bearing a carbamate functional group. This robust methodology resulted in new stereochemically complex indole-containing small molecules bearing diversity elements in two positions (new carbamate and ether / thioether). Ring cleavage reactions from yohimbine and reserpine produced a mixture of diastereomeric products, while reactions from apovincamine / vinburnine produced a single diastereomeric product. Free energy calculations were used to study the energetics of this transformation from yohimbine and apovincamine. Finally, this new collection of compounds was screened against the malarial parasite Plasmodium falciparum to discover new antiplasmodial agents with re-engineered activities from reserpine.

[0095] Compounds

[0096] In one aspect, the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof, wherein: the compounds are of Formula I:

[0097] R1is 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, or an oxygen protecting group;

[0098] X1is oxygen or sulfur;

[0099] R2is 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, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; nl is 0; or: nl is 1, 2, 3, or 4; each instance of R3is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - and each instance of RAis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAattached to the same intervening atom are joined together with the intervening atom to form a substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; each of R4, R5, R6, and R7is independently hydrogen, 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, -ORB, -N(RB)2, -SRB, -SSRB, -CN, -SCN, -C(=O)RB, - each instance of RBis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RBattached to the same intervening atom are joined together with the intervening atom to form a substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring.

[0100] When Formula I includes two or more instances of a moiety, unless otherwise provided, any two instances of the moiety may be the same or different from each other. In certain embodiments, at least one instance is each instance.

[0101] In certain embodiments, R1is substituted or unsubstituted alkyl. R1is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R1is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R1is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R1is unsubstituted Ci-4 alkyl. In certain embodiments, R1is Me. In certain embodiments, R1is Et. In certain embodiments, R1is zz-Pr or z-Pr. In certain embodiments, R1is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, R1is Z-Bu. In certain embodiments, R1is fluorinated methyl. In certain embodiments, R1is fluorinated ethyl. In certain embodiments, R1is chlorinated methyl. In certain embodiments, R1is chlorinated ethyl. In certain embodiments, R1is -CH2CCI3. In certain embodiments, R1is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, R1is Bn. In certain embodiments, R1is -CH2-(4-mono-substituted phenyl). In certain embodiments, R1is - CH2-(3 -mono-substituted phenyl). In certain embodiments, R1is -CH2-(2 -mono-substituted phenyl). In certain embodiments, R1is -CH2-(di-substituted phenyl).

[0102] In certain embodiments, R1is substituted or unsubstituted alkenyl. In certain embodiments, R1is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, R1is unsubstituted C2-6 alkenyl. In certain embodiments, R1is unsubstituted vinyl. In certain embodiments, R1is unsubstituted allyl. In certain embodiments, R1is -CH=CHCH3. In certain embodiments, R1is - CH=CHCH2CH3. In certain embodiments, R1is -CH2CH=CHCH3. In certain embodiments, R1is -

[0103] In certain embodiments, R1is substituted or un substituted alkynyl. In certain embodiments, R1is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, R1is unsubstituted C2-6 alkynyl. In certain embodiments, R1is -C=CH. In certain embodiments, R1is -C^CCHi. In certain embodiments, . In certain embodiments, R1is -C^CCthCHs In certain embodiments, In certain embodiments,

[0104] In certain embodiments, R1is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R1is substituted or un substituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R1is saturated carbocyclyl. In certain embodiments, R1is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0105] In certain embodiments, R1is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R1is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R1is saturated heterocyclyl. In certain embodiments, R1is partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0106] In certain embodiments, R1is substituted or unsubstituted aryl. In certain embodiments, R1is substituted or unsubstituted phenyl. In certain embodiments, R1is unsubstituted phenyl. In certain embodiments, R1is 2-mono-substituted phenyl. In certain embodiments, R1is 3-mono-substituted phenyl. In certain embodiments, R’ is 4-mono-substituted phenyl. In certain embodiments, R1is disubstituted phenyl. In certain embodiments, R1is substituted or unsubstituted naphthyl. In certain embodiments, R1is substituted or unsubstituted heteroaryl. In certain embodiments, R1is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R1is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or un substituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R1is substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, R1is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R1is substituted or un substituted, 9- to 10-membered, bicyclic heteroaryl.

[0107] In certain embodiments, R1is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).

[0108] In certain embodiments, X1is oxygen. In certain embodiments, X1is sulfur.

[0109] _

[0110] In certain embodiments,

[0111] In certain embodiments, R2is substituted or unsubstituted alkyl. R2is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R2is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R2is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R2is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, R2is unsubstituted Ci-4 alkyl. In certain embodiments, R2is Me. In certain embodiments, R2is Et. In certain embodiments, R2is z?-Pr or z-Pr. In certain embodiments, R2is zz-Bu, z-Bu, or .vec-Bu. In certain embodiments, R2is Z-Bu In certain embodiments, R2is fluorinated methyl. In certain embodiments, R2is fluorinated ethyl. In certain embodiments, R2is chlorinated methyl. In certain embodiments, R2is chlorinated ethyl. In certain embodiments, R2is -CHi-( substituted or unsubstituted phenyl). In certain embodiments, R2is Bn. In certain embodiments, R2is -CH2-(phenyl substituted with one or more halogen). In certain embodiments, R2is -CH2-(phenyl substituted with one or more iodo). In certain embodiments, R2is -CH2-(4-mono-substituted phenyl). In certain embodiments, R2is -CH2-(4-halo phenyl). In certain embodiments, R2is -CH2-(2-mono-substituted phenyl). In certain embodiments, R2is -CH2-(2-halo phenyl). In certain embodiments, R2is -CH2-(2-iodo phenyl). In certain embodiments, R2is -CH2- (3-mono-substituted phenyl). In certain embodiments, R2is -CEh-Q-halo phenyl). In certain embodiments, R2is -CH2-(di-substituted phenyl). In certain embodiments, R2is -CH2-(di-halo phenyl).

[0112] In certain embodiments, R2is substituted or unsubstituted alkenyl. In certain embodiments, R2is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, R2is unsubstituted C2-6 alkenyl. In certain embodiments, R2is unsubstituted vinyl. In certain embodiments, R2is unsubstituted allyl. In certain embodiments, R2is -CH=CHCH3. In certain embodiments, R2is - CH=CHCH2CH3, -CH2CH=CHCH3, or -CH2CH2CH=CH2.

[0113] In certain embodiments, R2is substituted or unsubstituted alkynyl. In certain embodiments, R2is substituted or un substituted, C2-6 alkynyl. In certain embodiments, R2is unsubstituted C2-6 alkynyl. In certain embodiments, R2is -OCH. In certain embodiments, R2is -C=CCH3or - CH2CCH In certain embodiments, R2is C =CCH2CH3, -CH2C =CCH3, or -CH2CH2C =CH

[0114] In certain embodiments, R2is substituted or unsubstituted carbocyclyl (e.g, substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R2is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R2is saturated carbocyclyl. In certain embodiments, R2is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0115] In certain embodiments, R2is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R2is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R2is saturated heterocyclyl. In certain embodiments, R2is partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0116] In certain embodiments, R2is substituted or unsubstituted aryl. In certain embodiments, R2is substituted or unsubstituted phenyl. In certain embodiments, R2is unsubstituted phenyl. In certain embodiments, R2is 4-mono-substituted phenyl. In certain embodiments, R2is 3-mono-substituted phenyl. In certain embodiments, R2is 2-mono-substituted phenyl. In certain embodiments, R2is disubstituted phenyl. In certain embodiments, R2is substituted or unsubstituted naphthyl.

[0117] In certain embodiments, R2is substituted or unsubstituted heteroaryl. In certain embodiments, R2is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R2is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R2is substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, R2is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R2is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0118] In certain embodiments, R2is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom.

[0119] In certain embodiments, R2is a sulfur protecting group (e.g., acetamidomethyl, Z-Bu, 3-nitro- 2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.

[0120] In certain embodiments, nl is 0. In certain embodiments, nl is 1. In certain embodiments, nl is 2. In certain embodiments, nl is 3. In certain embodiments, nl is 4.

[0121]

[0122] In certain embodiments, at least one instance of R3is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R3is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, at least one instance of R3is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, at least one instance of R3is unsubstituted Ci- 6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, at least one instance of R3is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R3is unsubstituted Ci-4 alkyl. In certain embodiments, at least one instance of R3is Me. In certain embodiments, at least one instance of R3is Et. In certain embodiments, at least one instance of R3is n-Pr or z-Pr. In certain embodiments, at least one instance of R3is zz-Bu, z-Bu, or .scoBu. In certain embodiments, at least one instance of R3is Z-Bu. In certain embodiments, at least one instance of R3is fluorinated methyl. In certain embodiments, at least one instance of R3is fluorinated ethyl. In certain embodiments, at least one instance of R3is chlorinated methyl. In certain embodiments, at least one instance of R3is chlorinated ethyl. In certain embodiments, at least one instance of R3is - CH2-( substituted or unsubstituted phenyl). In certain embodiments, at least one instance of R3is Bn. In certain embodiments, at least one instance of R3is -CH2-(4-mono-substituted phenyl). In certain embodiments, at least one instance of R3is -CH2-(3-mono-substituted phenyl). In certain embodiments, at least one instance of R3is -CH2-(2-mono-substituted phenyl). In certain embodiments, at least one instance of R3is -CH2-(di-substituted phenyl).

[0123] In certain embodiments, at least one instance of R3is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R3is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, at least one instance of R3is unsubstituted C2-6 alkenyl. In certain embodiments, at least one instance of R3is unsubstituted vinyl. In certain embodiments, at least one instance of R3is unsubstituted allyl or -CH=CHCH3. In certain embodiments, at least one instance ofR3is -CH=CHCH2CH3, -CH2CH=CHCH3, or -CH2CH2CH=CH2.

[0124] In certain embodiments, at least one instance of R3is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R3is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, at least one instance of R3is unsubstituted C2-6 alkynyl. In certain embodiments, at least one instance of R3is -C=CH. In certain embodiments, at least one instance of R3is -C=CCH3or -CH2C=CH. In certain embodiments, at least one instance of R3is -C=CCH2CH3, -CH2C=CCH3, or -CH2CH2CCH

[0125] In certain embodiments, at least one instance of R3is substituted or unsubstituted carbocyclyl (e.g, substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R3is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R3is saturated carbocyclyl. In certain embodiments, at least one instance of R3is partially unsaturated carbocyclyl (e.g, comprising only one C=C bond in the carbocyclic ring system).

[0126] In certain embodiments, at least one instance of R3is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R3is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R3is saturated heterocyclyl. In certain embodiments, at least one instance of R3is partially unsaturated heterocyclyl (e.g, comprising only one C=C bond in the heterocyclic ring system).

[0127] In certain embodiments, at least one instance of R3is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R3is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R3is unsubstituted phenyl. In certain embodiments, at least one instance of R3is 4-mono-substituted phenyl. In certain embodiments, at least one instance of R3is 3- mono-substituted phenyl. In certain embodiments, at least one instance of R3is 2-mono- substituted phenyl. In certain embodiments, at least one instance of R3is di-substituted phenyl. In certain embodiments, at least one instance of R3is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R3is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R3is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R3is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R3is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of R3is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R3is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0128] In certain embodiments, at least one instance of R3is -ORA, halogen, substituted or unsubstituted alkyl, - OC(=O)N(RA)2. In certain embodiments, at least one instance of R3is -ORA. In certain embodiments, at least one instance of R3is -O( substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R3is -O(substituted or unsubstituted, Ci-6 alkyl). In certain embodiments, at least one instance of R3is -O(unsubstituted Ci-6 alkyl). In certain embodiments, at least one instance of R3is -OMe. In certain embodiments, at least one instance of R3is -O(Ci-6 alkyl substituted with one or more instances of halogen).

[0129] In certain embodiments, at least one instance of RAis hydrogen. In certain embodiments, each instance of RAis hydrogen. In certain embodiments, at least one instance of RAis not hydrogen. In certain embodiments, no instance of RAis hydrogen.

[0130] In certain embodiments, at least one instance of RAis substituted alkyl (e.g, alkyl substituted with one or more instances of halogen (e.g, F)). In certain embodiments, at least one instance of RAis unsubstituted alkyl. In certain embodiments, at least one instance of RAis unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of RAis Me. In certain embodiments, at least one instance of RAis Et, Pr, or Bu. In certain embodiments, at least one instance of RAis substituted Ci-6 alkyl. In certain embodiments, at least one instance of RAis substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of RAis substituted ethyl, substituted propyl, or substituted butyl.

[0131] In certain embodiments, at least one instance of RAis substituted or unsubstituted alkenyl. In certain embodiments, at least one instance ofRAis substituted or unsubstituted, C2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl).

[0132] In certain embodiments, at least one instance of RAis substituted or un substituted alkynyl. In certain embodiments, at least one instance ofRAis substituted or unsubstituted, C2-6 alkynyl (e.g., substituted or unsubstituted ethynyl).

[0133] In certain embodiments, at least one instance of RAis substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of RAis substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of RAis saturated carbocyclyl. In certain embodiments, at least one instance of RAis partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0134] In certain embodiments, at least one instance of RAis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of RAis substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of RAis saturated heterocyclyl. In certain embodiments, at least one instance of RAis partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0135] In certain embodiments, at least one instance of RAis substituted or unsubstituted aryl. In certain embodiments, at least one instance of RAis substituted or unsubstituted phenyl. In certain embodiments, at least one instance of RAis unsubstituted phenyl. In certain embodiments, at least one instance of RAis 2-mono-substituted phenyl. In certain embodiments, at least one instance of RA is 3-mono-substituted phenyl. In certain embodiments, at least one instance of RAis 4-mono- substituted phenyl. In certain embodiments, RAis di-substituted phenyl. In certain embodiments, at least one instance of RAis substituted or unsubstituted naphthyl.

[0136] In certain embodiments, at least one instance of RAis substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of RAis substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl. In certain embodiments, at least one instance of RAis substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of RAis substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of RAis substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of RAis substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0137] In certain embodiments, at least one instance of RAis a nitrogen protecting group (e.g, Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of RAis an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, at least one instance of RAis a sulfur protecting group (e.g., acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.

[0138] In certain embodiments, two instances of RAattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two instances of RAattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).

[0139] In certain embodiments, R4is hydrogen. In certain embodiments, R4is halogen.

[0140] In certain embodiments, R4is substituted or unsubstituted alkyl. In certain embodiments, R4is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R4is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R4is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R4is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, R4is unsubstituted C1-4 alkyl. In certain embodiments, R4is Me. In certain embodiments, R4is Et. In certain embodiments, R4is zz-Pr or z-Pr. In certain embodiments, R4is zz-Bu, z-Bu, or .sec-Bu. In certain embodiments, R4is Z-Bu In certain embodiments, R4is fluorinated methyl. In certain embodiments, R4is fluorinated ethyl. In certain embodiments, R4is chlorinated methyl. In certain embodiments, R4is chlorinated ethyl. In certain embodiments, R4is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, R4is Bn. In certain embodiments, R4is -CH2-(4-mono-substituted phenyl). In certain embodiments, R4is -CH2-(3-mono-substituted phenyl). In certain embodiments, R4is -CH2-(2-mono-substituted phenyl). In certain embodiments, R4is -CH2-(di-substituted phenyl).

[0141] In certain embodiments, R4is substituted or unsubstituted alkenyl. In certain embodiments, R4is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, R4is unsubstituted C2-6 alkenyl. In certain embodiments, R4is unsubstituted vinyl. In certain embodiments, R4is unsubstituted allyl or -CH=CHCH3. In certain embodiments, R4is -CH=CHCH2CH3, - CH2CH=CHCH3, or -CH2CH2CH=CH2.

[0142] In certain embodiments, R4is substituted or unsubstituted alkynyl. In certain embodiments, R4is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, R4is unsubstituted C2-6 alkynyl. In certain embodiments, R4is -OCH. In certain embodiments, R4is -OCCH3 or - CH2OCH. In certain embodiments, R4is -OCCH2CH3, -CH2C =CCH3, or -CH2CH2C =CH.

[0143] In certain embodiments, R4is substituted or unsubstituted carbocyclyl (e.g, substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R4is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R4is saturated carbocyclyl. In certain embodiments, R4is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0144] In certain embodiments, R4is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R4is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R4is saturated heterocyclyl. In certain embodiments, R4is partially unsaturated heterocyclyl (e.g, comprising only one C=C bond in the heterocyclic ring system).

[0145] In certain embodiments, R4is substituted or unsubstituted aryl. In certain embodiments, R4is substituted or unsubstituted phenyl. In certain embodiments, R4is unsubstituted phenyl. In certain embodiments, R4is 4-mono-substituted phenyl. In certain embodiments, R4is 3 -mono- substituted phenyl. In certain embodiments, R4is 2-mono-substituted phenyl. In certain embodiments, R4is disubstituted phenyl. In certain embodiments, R4is substituted or unsubstituted naphthyl.

[0146] In certain embodiments, R4is substituted or unsubstituted heteroaryl. In certain embodiments, R4is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R4is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R4is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, R4is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R4is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0147] In certain embodiments, R4is -C(=O)ORB, halogen, substituted or unsubstituted alkyl, - - C(=O)O(substituted or unsubstituted alkyl). In certain embodiments, R4is -C(=O)O(substituted or unsubstituted, C1-6 alkyl). In certain embodiments, R4is -C(=O)O(unsubstituted C1-6 alkyl). In certain embodiments, R4is -C(=O)OMe. In certain embodiments, R4is -C(=O)O(Ci-6 alkyl substituted with one or more instances of halogen).

[0148] In certain embodiments, In certain embodiments, In certain embodiments, R5is hydrogen. In certain embodiments, R3is halogen.

[0149] In certain embodiments, R5is substituted or unsubstituted alkyl. In certain embodiments, R3is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R5is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R5is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R3is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, R5is unsubstituted C1-4 alkyl. In certain embodiments, R3is Me. In certain embodiments, R5is Et. In certain embodiments, R5is zz-Pr or z-Pr. In certain embodiments, R3is z / -Bu, z-Bu, or sec-Bu. In certain embodiments, R3is z-Bu. In certain embodiments, R5is fluorinated methyl. In certain embodiments, R5is fluorinated ethyl. In certain embodiments, R3is chlorinated methyl. In certain embodiments, R5is chlorinated ethyl. In certain embodiments, R5is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, R3is Bn. In certain embodiments, R5is -CH2-(4-mono-substituted phenyl). In certain embodiments, R5is -CH2-(3-mono-substituted phenyl). In certain embodiments, R3is -CH2-(2-mono-substituted phenyl). In certain embodiments, R5is -CH2-(di-substituted phenyl).

[0150] In certain embodiments, R5is substituted or unsubstituted alkenyl. In certain embodiments, R3is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, R5is unsubstituted C2-6 alkenyl. In certain embodiments, R5is unsubstituted vinyl. In certain embodiments, R5is unsubstituted allyl or -CH=CHCH3. In certain embodiments, R5is -CH=CHCH2CH3, - CH2CH=CHCH3, or -CH2CH2CH=CH2.

[0151] In certain embodiments, R5is substituted or unsubstituted alkynyl. In certain embodiments, R5is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, R5is unsubstituted C2-6 alkynyl. In certain embodiments, R5is -OCH. In certain embodiments, R5is -OCCH3 or - CH2C =CH In certain embodiments, R5is -OCCH2CH3, -CH2OCCH3, or -CH2CH2C =CH.

[0152] In certain embodiments, R5is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R5is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R3is saturated carbocyclyl. In certain embodiments, R3is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0153] In certain embodiments, R5is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R5is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R5is saturated heterocyclyl. In certain embodiments, R5is partially unsaturated heterocyclyl (e.g, comprising only one C=C bond in the heterocyclic ring system).

[0154] In certain embodiments, R5is substituted or unsubstituted aryl. In certain embodiments, R5is substituted or unsubstituted phenyl. In certain embodiments, R5is unsubstituted phenyl. In certain embodiments, R3is 4-mono-substituted phenyl. In certain embodiments, R3is 3-mono-substituted phenyl. In certain embodiments, R5is 2-mono-substituted phenyl. In certain embodiments, R5is disubstituted phenyl. In certain embodiments, R5is substituted or unsubstituted naphthyl.

[0155] In certain embodiments, R5is substituted or unsubstituted heteroaryl. In certain embodiments, R5is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R3is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R5is substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, R3is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R3is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0156] In certain embodiments, R5is halogen, substituted or unsubstituted certain embodiments, R5is -OH. In certain embodiments, R5is -O(substituted or unsubstituted alkyl). In certain embodiments, R5is -O(substituted or unsubstituted, C1-6 alkyl). In certain embodiments, R5is -O(unsubstituted Ci-6 alkyl). In certain embodiments, R5is -OMe. In certain embodiments, R5is -O(Ci-6 alkyl substituted with one or more instances of halogen). In certain embodiments, R3is -OC(=O)RB. In certain embodiments, R3is -OC(=O)(substituted or unsubstituted alkyl). In certain embodiments, R5is -OC(=O)(substituted or unsubstituted, Ci-6 alkyl). In certain embodiments, R5is -OC(=O)(unsubstituted Ci-6 alkyl). In certain embodiments, R5is -OC(=O)Me. In certain embodiments, R5is -OC(=O)(substituted or unsubstituted phenyl). In certain embodiments, R5is -OC(=O)(substituted or unsubstituted heteroaryl). In certain embodiments, R5is -OC(=O)(substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl). In certain embodiments, R5is -OC(=O)(substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl). In certain embodiments, R5is -OC(=O)(substituted or unsubstituted furanyl).

[0157] In certain embodiments, . In certain embodiments, .

[0158] In certain embodiments, R6is hydrogen. In certain embodiments, R6is halogen.

[0159] In certain embodiments, R6is substituted or unsubstituted alkyl. In certain embodiments, R6is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R6is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R6is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R6is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, R6is unsubstituted Ci-4 alkyl. In certain embodiments, R6is Me. In certain embodiments, R6is Et. In certain embodiments, R6is zz-Pr or z-Pr. In certain embodiments, R6is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, R6is Z-Bu. In certain embodiments, R6is fluorinated methyl. In certain embodiments, R6is fluorinated ethyl. In certain embodiments, R6is chlorinated methyl. In certain embodiments, R6is chlorinated ethyl. In certain embodiments, R6is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, R6is Bn. In certain embodiments, R6is -CH2-(4-mono-substituted phenyl). In certain embodiments, R6is -CH2-(3-mono-substituted phenyl). In certain embodiments, R6is -CH2-(2 -mono-substituted phenyl). In certain embodiments, R6is -CH2-(di-substituted phenyl).

[0160] In certain embodiments, R6is substituted or un substituted alkenyl. In certain embodiments, R6is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, R6is unsubstituted C2-6 alkenyl. In certain embodiments, R6is unsubstituted vinyl. In certain embodiments, R6is unsubstituted allyl or -CH=CHCH3. In certain embodiments, R6is -CH=CHCH2CH3, - CH2CH=CHCH3, or -CH2CH2CH=CH2.

[0161] In certain embodiments, R6is substituted or unsubstituted alkynyl. In certain embodiments, R6is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, R6is unsubstituted C2-6 alkynyl. In certain embodiments, R6is -C=CH. In certain embodiments, R6is -C^C'CHi or - CH2C=CH. In certain embodiments, R6is -C=CCH2CH3, -CH2C=CCH3, or -CH2CH2C=CH.

[0162] In certain embodiments, R6is substituted or unsubstituted carbocyclyl (e.g, substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R6is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R6is saturated carbocyclyl. In certain embodiments, R6is partially unsaturated carbocyclyl (e.g, comprising only one C=C bond in the carbocyclic ring system).

[0163] In certain embodiments, R6is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R6is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R6is saturated heterocyclyl. In certain embodiments, R6is partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0164] In certain embodiments, R6is substituted or unsubstituted aryl. In certain embodiments, R6is substituted or unsubstituted phenyl. In certain embodiments, R6is unsubstituted phenyl. In certain embodiments, R6is 4-mono-substituted phenyl. In certain embodiments, R6is 3-mono-substituted phenyl. In certain embodiments, R6is 2-mono-substituted phenyl. In certain embodiments, R6is disubstituted phenyl. In certain embodiments, R6is substituted or unsubstituted naphthyl.

[0165] In certain embodiments, R6is substituted or unsubstituted heteroaryl. In certain embodiments, R6is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R6is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or un substituted pyrrolyl, substituted or un substituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R6is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, R6is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R6is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0166] In certain embodiments, R6is -OC(=O)RB, halogen, substituted or unsubstituted alkyl, - certain embodiments, R6is -OC(=O)RB, halogen, substituted or unsubstituted alkyl, -ORB, -N(RB)2, In certain embodiments, In certain embodiments, R6is -OC(=O)(substituted or unsubstituted alkyl). In certain embodiments, R6is -OC(=O)( substituted or unsubstituted, C1-6 alkyl). In certain embodiments, R6is - OC(=O)(unsubstituted C1-6 alkyl). In certain embodiments, R6is -OC(=O)Me. In certain embodiments, R6is -OC(=O)(Ci-6 alkyl substituted with one or more instances of halogen). In certain embodiments, R6is -OC(=O)(substituted or unsubstituted phenyl). In certain embodiments, R6is -OC(=O)(4-, 3-, or 2-mono-substituted phenyl). In certain embodiments, R6is -OC(=O)(di- substituted phenyl). In certain embodiments, R6is -OC(=O)(tri-substituted phenyl).

[0167] In certain embodiments, . In certain embodiments,

[0168] In certain embodiments, R7is hydrogen. In certain embodiments, R7is halogen.

[0169] In certain embodiments, R7is substituted or unsubstituted alkyl. In certain embodiments, R7is substituted or unsubstituted, C1-6 alkyl. In certain embodiments, R7is unsubstituted C1-6 alkyl or C1-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R7is unsubstituted C1-6 alkyl or C1-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R7is unsubstituted C1-6 alkyl or C1-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, R7is unsubstituted Ci-4 alkyl. In certain embodiments, R7is Me. In certain embodiments, R7is Et. In certain embodiments, R7is z / -Pr or z-Pr. In certain embodiments, R7is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, R7is Z-Bu. In certain embodiments, R7is fluorinated methyl. In certain embodiments, R7is fluorinated ethyl. In certain embodiments, R7is chlorinated methyl. In certain embodiments, R7is chlorinated ethyl. In certain embodiments, R7is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, R7is Bn. In certain embodiments, R7is -CH2-(4-mono-substituted phenyl). In certain embodiments, R7is -CH2-(3-mono-substituted phenyl). In certain embodiments, R7is -CH2-(2 -mono-substituted phenyl). In certain embodiments, R7is -CH2-(di-substituted phenyl).

[0170] In certain embodiments, R7is substituted or unsubstituted alkenyl. In certain embodiments, R7is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, R7is unsubstituted C2-6 alkenyl. In certain embodiments, R7is unsubstituted vinyl. In certain embodiments, R7is unsubstituted allyl or -CH=CHCH3 In certain embodiments, R7is -CH=CHCH2CH3, - CH2CH=CHCH3, or -CH2CH2CH-CH2.

[0171] In certain embodiments, R7is substituted or unsubstituted alkynyl. In certain embodiments, R7is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, R7is unsubstituted C2-6 alkynyl. In certain embodiments, R7is -C=CH. In certain embodiments, R7is -C^CCHi or - CH2C=CH. In certain embodiments, R7is C =CCH2CH3, -CH2C =CCH3, or -CH2CH2C =CH

[0172] In certain embodiments, R7is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R7is saturated carbocyclyl. In certain embodiments, R7is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0173] In certain embodiments, R7is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R7is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R7is saturated heterocyclyl. In certain embodiments, R7is partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0174] In certain embodiments, R7is substituted or unsubstituted aryl. In certain embodiments, R7is substituted or unsubstituted phenyl. In certain embodiments, R7is unsubstituted phenyl. In certain embodiments, R7is 4-mono-substituted phenyl. In certain embodiments, R7is 3-mono-substituted phenyl. In certain embodiments, R7is 2-mono-substituted phenyl. In certain embodiments, R7is disubstituted phenyl. In certain embodiments, R7is substituted or unsubstituted naphthyl.

[0175] In certain embodiments, R7is substituted or unsubstituted heteroaryl. In certain embodiments, R7is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R7is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R7is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, R7is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R7is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0176] In certain embodiments, R7is halogen, substituted or unsubstituted alkyl, -ORB, -N(RB)2, -

[0177] In certain embodiments, at least one instance of RBis hydrogen. In certain embodiments, each instance of RBis hydrogen. In certain embodiments, at least one instance of RBis not hydrogen. In certain embodiments, no instance of RBis hydrogen.

[0178] In certain embodiments, at least one instance of RBis substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g, F)). In certain embodiments, at least one instance of RBis unsubstituted alkyl. In certain embodiments, at least one instance of RBis unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of RBis Me. In certain embodiments, at least one instance of RBis Et, Pr, or Bu. In certain embodiments, at least one instance of RBis substituted C1-6 alkyl. In certain embodiments, at least one instance of RBis substituted methyl (t?.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of RBis substituted ethyl, substituted propyl, or substituted butyl.

[0179] In certain embodiments, at least one instance of RBis substituted or unsubstituted alkenyl. In certain embodiments, at least one instance ofRBis substituted or unsubstituted, C2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl).

[0180] In certain embodiments, at least one instance of RBis substituted or unsubstituted alkynyl. In certain embodiments, at least one instance ofRBis substituted or unsubstituted, C2-6 alkynyl (e.g., substituted or unsubstituted ethynyl).

[0181] In certain embodiments, at least one instance of RBis substituted or un substituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of RBis substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of RBis saturated carbocyclyl. In certain embodiments, at least one instance of RBis partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0182] In certain embodiments, at least one instance of RBis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of RBis substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of RBis saturated heterocyclyl. In certain embodiments, at least one instance of RBis partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0183] In certain embodiments, at least one instance of RBis substituted or unsubstituted aryl. In certain embodiments, at least one instance of RBis substituted or unsubstituted phenyl. In certain embodiments, at least one instance of RBis unsubstituted phenyl. In certain embodiments, at least one instance of RBis 2-mono-substituted phenyl. In certain embodiments, at least one instance of RBis 3-mono-substituted phenyl. In certain embodiments, at least one instance of RBis 4-mono- substituted phenyl. In certain embodiments, RBis di -substituted phenyl. In certain embodiments, at least one instance of RBis substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of RBis substituted or unsubstituted alkyl or substituted or unsubstituted phenyl. In certain embodiments, at least one instance of RBis substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of RBis substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of RBis substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of RBis substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of RBis substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of RBis substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0184] In certain embodiments, at least one instance of RBis a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of RBis an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, TUP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, at least one instance of RBis a sulfur protecting group (e.g., acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.

[0185] In certain embodiments, two instances of RBattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two instances of RBattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).

[0186] In certain embodiments, Formula I is of Formula 1-1 :

[0187] (1-1), optionally wherein R1and R2are as shown in Table 1 : Table 1 In certain embodiments, Formula I is of Formula 1-2: optionally wherein R1and R2are as shown in Table 2: Table 2 In certain embodiments, Formula I is of Formula 1-3: optionally wherein R1and R2are as shown in Table 3: Table 3 In certain embodiments, Formula I is of Formula 1-4: optionally wherein R1and R2are as shown in Table 4: Table 4 In certain embodiments, Formula I is of Formula 1-5: optionally wherein R1and R2are as shown in Table 5: Table 5 In certain embodiments, Formula I is of Formula 1-6: optionally wherein R1and R2are as shown in Table 6: Table 6 In certain embodiments, Formula I is of Formula 1-7: optionally wherein R1and R2are as shown in Table 7:

[0188] Table 7 In certain embodiments, Formula I is of Formula 1-8: optionally wherein R1and R2are as shown in Table 8: Table 8 In certain embodiments, Formula I is of Formula 1-9: optionally wherein R1and R2are as shown in Table 9: Table 9 In certain embodiments, Formula I is of Formula 1-10:

[0189] (1-10), optionally wherein R1and R2are as shown in Table 10: Table 10 In certain embodiments, Formula I is of Formula 1-11 : optionally wherein R1and R2are as shown in Table 11 : Table 11 In certain embodiments, Formula I is of Formula 1-12: optionally wherein R1and R2are as shown in Table 12: Table 12 In certain embodiments, Formula I is of Formula 1-13: optionally wherein R1and R2are as shown in Table 13: Table 13 In certain embodiments, Formula I is of Formula 1-14: optionally wherein R1and R2are as shown in Table 14: Table 14 In certain embodiments, Formula I is of Formula 1-15: optionally wherein R1and R2are as shown in Table 15: Table 15 In certain embodiments, Formula I is of Formula 1-16:

[0190] (1-16), optionally wherein R1and R2are as shown in Table 16: Table 16 In certain embodiments, Formula I is of Formula 1-17: optionally wherein R1and R2are as shown in Table 17: Table 17 In certain embodiments, Formula I is of Formula 1-18:

[0191] (1-18), optionally wherein R1and R2are as shown in Table 18: Table 18 In certain embodiments, Formula I is of Formula 1-19: optionally wherein R1and R2are as shown in Table 19: Table 19 In certain embodiments, Formula I is of Formula 1-20: optionally wherein R1and R2are as shown in Table 20: Table 20 In certain embodiments, Formula I is of Formula 1-21 :

[0192] (1-21), optionally wherein R1and R2are as shown in Table 21 : Table 21 In certain embodiments, Formula I is of Formula 1-22:

[0193] (1-22), optionally wherein R1and R2are as shown in Table 22: Table 22 In certain embodiments, Formula I is of Formula 1-23: optionally wherein R1and R2are as shown in Table 23: Table 23 In certain embodiments, Formula I is of Formula 1-24:

[0194] (1-24), optionally wherein R1and R2are as shown in Table 24: Table 24 In certain embodiments, Formula I is of any one of the formulae:

[0195]

[0196]

[0197]

[0198] In another aspect, the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof, wherein: the compounds are of Formula II:

[0199] (II);

[0200] R11is 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, or an oxygen protecting group;

[0201] X11is oxygen or sulfur;

[0202] R12is 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, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; ni l is 0; or: nl 1 is 1, 2, 3, or 4; each instance of R13is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or un substituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -OSi(ORc)3; and each instance of Rcis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rcattached to the same intervening atom are joined together with the intervening atom to form a substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; wherein each instance of R18is independently -C(=O)ORD, hydrogen, 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, and each instance of RDis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RDattached to the same intervening atom are joined together with the intervening atom to form a substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; and

[0203] R19is substituted or unsubstituted alkyl or hydrogen.

[0204] When Formula II includes two or more instances of a moiety, unless otherwise provided, any two instances of the moiety may be the same or different from each other. In certain embodiments, at least one instance is each instance.

[0205] In certain embodiments, R11is substituted or unsubstituted alkyl. R11is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R11is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R11is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R11is unsubstituted Ci-4 alkyl. In certain embodiments, R11is Me. In certain embodiments, R11is Et. In certain embodiments, R11is zz-Pr or z-Pr. In certain embodiments, R11is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, R11is / -Bu. In certain embodiments, R11is fluorinated methyl. In certain embodiments, R11is fluorinated ethyl. In certain embodiments, R11is chlorinated methyl. In certain embodiments, R11is chlorinated ethyl. In certain embodiments, R11is -CH2CCI3. In certain embodiments, R11is -CH2-(substituted or unsubstituted phenyl). In certain embodiments, R11is Bn. In certain embodiments, R11is -CH2-(4-mono-substituted phenyl). In certain embodiments, R11is - CH2-(3 -mono-substituted phenyl). In certain embodiments, R11is -CH2-(2-mono-substituted phenyl). In certain embodiments, R11is -CH2-(di-substituted phenyl).

[0206] In certain embodiments, R11is substituted or unsubstituted alkenyl. In certain embodiments, R11is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, R11is unsubstituted C2-6 alkenyl. In certain embodiments, R11is unsubstituted vinyl. In certain embodiments, R11is unsubstituted allyl. In certain embodiments, R11is -CH=CHCHs. In certain embodiments, R11is - CH=CHCH2CH3. In certain embodiments, R11is -CH2CH=CHCH3. In certain embodiments, R11is -

[0207] In certain embodiments, R11is substituted or unsubstituted alkynyl. In certain embodiments, R11is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, R11is unsubstituted C2-6 alkynyl. In certain embodiments, R11is -C=CH. In certain embodiments, R11is -C=CCH3. In certain embodiments, R11is - . In certain embodiments, . In certain embodiments, R11is - 3. In certain embodiments, R11is -

[0208] In certain embodiments, R11is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R11is substituted or un substituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R11is saturated carbocyclyl. In certain embodiments, R11is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0209] In certain embodiments, R11is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R11is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R11is saturated heterocyclyl. In certain embodiments, R11is partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0210] In certain embodiments, R11is substituted or unsubstituted aryl. In certain embodiments, R11is substituted or unsubstituted phenyl. In certain embodiments, R11is unsubstituted phenyl. In certain embodiments, R11is 2-m ono-substituted phenyl. In certain embodiments, R1 1is 3-mono-substituted phenyl. In certain embodiments, R11is 4-mono-substituted phenyl. In certain embodiments, R11is disubstituted phenyl. In certain embodiments, R11is substituted or unsubstituted naphthyl.

[0211] In certain embodiments, R11is substituted or unsubstituted heteroaryl. In certain embodiments, R11is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R11is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R11is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, R11is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R11is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0212] In certain embodiments, R11is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).

[0213] In certain embodiments, X11is oxygen. In certain embodiments, X11is sulfur.

[0214] In certain embodiments, is . In certain embodiments,

[0215] In certain embodiments, R12is substituted or unsubstituted alkyl. R12is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R12is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R12is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R12is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, R12is unsubstituted Ci-4 alkyl. In certain embodiments, R12is Me. In certain embodiments, R12is Et. In certain embodiments, R12is zz-Pr or i- Pr. In certain embodiments, R12is n-Bu, Z-Bu, or sec-Bu. In certain embodiments, R12is Z-Bu. In certain embodiments, R12is fluorinated methyl. In certain embodiments, R12is fluorinated ethyl. In certain embodiments, R12is chlorinated methyl. In certain embodiments, R12is chlorinated ethyl. In certain embodiments, R12is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, R12is Bn. In certain embodiments, R12is -CH2-(phenyl substituted with one or more halogen). In certain embodiments, R12is -CH2-(phenyl substituted with one or more iodo). In certain embodiments, R12is -CH2-(4-mono-substituted phenyl). In certain embodiments, R12is -CH2-(4- halo phenyl). In certain embodiments, R12is -CH2-(2-mono-substituted phenyl). In certain embodiments, R12is -CH2-(2-halo phenyl). In certain embodiments, R12is -CH2-(2-iodo phenyl). In certain embodiments, R12is -CH2-(3-mono-substituted phenyl). In certain embodiments, R12is - CH2-(3-halo phenyl). In certain embodiments, R12is -CH2-(di-substituted phenyl). In certain embodiments, R12is -CH2-(di-halo phenyl).

[0216] In certain embodiments, R12is substituted or unsubstituted alkenyl. In certain embodiments, R12is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, R12is unsubstituted C2-6 alkenyl. In certain embodiments, R12is unsubstituted vinyl. In certain embodiments, R12is unsubstituted allyl. In certain embodiments, R12is -CH=CHCH3. In certain embodiments, R12is -

[0217] In certain embodiments, R12is substituted or unsubstituted alkynyl. In certain embodiments, R12is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, R12is unsubstituted C2-6 alkynyl. In certain embodiments, R12is -C=CH. In certain embodiments, R12is -C^CCEh or - CH2C =CH In certain embodiments, R12is -OCCH2CH3, -CH2CCCH3, or -CH2CH2OCH.

[0218] In certain embodiments, R12is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R12is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R12is saturated carbocyclyl. In certain embodiments, R12is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0219] In certain embodiments, R12is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R12is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R12is saturated heterocyclyl. In certain embodiments, R12is partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0220] In certain embodiments, R12is substituted or unsubstituted aryl. In certain embodiments, R12is substituted or unsubstituted phenyl. In certain embodiments, R12is unsubstituted phenyl. In certain embodiments, R12is 4-m ono-substituted phenyl. In certain embodiments, R12is 3-mono-substituted phenyl. In certain embodiments, R12is 2-mono-substituted phenyl. In certain embodiments, R12is disubstituted phenyl. In certain embodiments, R12is substituted or unsubstituted naphthyl.

[0221] In certain embodiments, R12is substituted or unsubstituted heteroaryl. In certain embodiments, R12is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R12is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R12is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, R12is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R12is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0222] In certain embodiments, R12is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom.

[0223] In certain embodiments, R12is a sulfur protecting group (e.g, acetamidomethyl, Z-Bu, 3- nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.

[0224] In certain embodiments, ni l is 0. In certain embodiments, ni l is 1. In certain embodiments, nl 1 is 2. In certain embodiments, ni l is 3. In certain embodiments, nl 1 is 4.

[0225] In certain embodiments, at least one instance of R13is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R13is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, at least one instance of R13is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, at least one instance of R13is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, at least one instance of R13is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R13is unsubstituted C1-4 alkyl. In certain embodiments, at least one instance of R13is Me. In certain embodiments, at least one instance of R13is Et. In certain embodiments, at least one instance of R13is zz-Pr or z-Pr. In certain embodiments, at least one instance of R13is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, at least one instance of R13is z-Bu In certain embodiments, at least one instance of R13is fluorinated methyl. In certain embodiments, at least one instance of R13is fluorinated ethyl. In certain embodiments, at least one instance of R13is chlorinated methyl. In certain embodiments, at least one instance of R13is chlorinated ethyl. In certain embodiments, at least one instance of R13is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, at least one instance of R13is Bn. In certain embodiments, at least one instance of R13is -CH2-(4- mono-substituted phenyl). In certain embodiments, at least one instance of R13is -CH2-(3-mono- substituted phenyl). In certain embodiments, at least one instance of R13is -CH2-(2-mono- substituted phenyl). In certain embodiments, at least one instance of R13is -CH2-(di- substituted phenyl).

[0226] In certain embodiments, at least one instance of R13is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R13is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, at least one instance of R13is unsubstituted C2-6 alkenyl. In certain embodiments, at least one instance of R13is unsubstituted vinyl. In certain embodiments, at least one instance of R13is unsubstituted allyl or -CH=CHCH3. In certain embodiments, at least one instance of R13is -

[0227] In certain embodiments, at least one instance of R13is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R13is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, at least one instance of R13is unsubstituted C2-6 alkynyl. In certain embodiments, at least one instance of R13is -C=CH. In certain embodiments, at least one instance of R13is -C=CCH3or -CH2C=CH. In certain embodiments, at least one instance of R13is -

[0228] In certain embodiments, at least one instance of R13is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R13is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R13is saturated carbocyclyl. In certain embodiments, at least one instance of R13is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0229] In certain embodiments, at least one instance of R13is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R13is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R13is saturated heterocyclyl. In certain embodiments, at least one instance of R13is partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0230] In certain embodiments, at least one instance of R13is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R13is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R13is unsubstituted phenyl. In certain embodiments, at least one instance of R13is 4-mono-substituted phenyl. In certain embodiments, at least one instance of R13is 3- mono-substituted phenyl. In certain embodiments, at least one instance of R13is 2-mono- substituted phenyl. In certain embodiments, at least one instance of R13is di-substituted phenyl. In certain embodiments, at least one instance of R13is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R13is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R13is substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R13is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R13is substituted or unsubstituted pyridinyl (c.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of R13is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R13is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0231] In certain embodiments, at least one instance of R13is halogen, substituted or unsubstituted S(=O)2N(RC)2. In certain embodiments, at least one instance of R13is halogen, substituted or unsubstituted alkyl, -ORC, -N(RC)2, -SRC, -CN, -C(=O)Rc, -C(=O)ORc, -C(=O)N(Rc)2, -N©2, - N3, -NRCC(=O)RC, -NRCC(=O)ORC, -NRCC(=O)N(RC)2, -OC(=O)RC, -OC(=O)ORC, or - OC(=O)N(RC)2. In certain embodiments, at least one instance of R13is -ORC. In certain embodiments, at least one instance of R13is -©(substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R13is -©(substituted or unsubstituted, Ci-6 alkyl). In certain embodiments, at least one instance of R13is -©(unsubstituted Ci-6 alkyl). In certain embodiments, at least one instance of R13is -©Me. In certain embodiments, at least one instance of R13is -O(Ci-6 alkyl substituted with one or more instances of halogen).

[0232] In certain embodiments, at least one instance of Rcis hydrogen. In certain embodiments, each instance of Rcis hydrogen. In certain embodiments, at least one instance of Rcis not hydrogen. In certain embodiments, no instance of Rcis hydrogen.

[0233] In certain embodiments, at least one instance of Rcis substituted alkyl (e.g, alkyl substituted with one or more instances of halogen (e.g, F)). In certain embodiments, at least one instance of Rcis unsubstituted alkyl. In certain embodiments, at least one instance of Rcis unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of Rcis Me. In certain embodiments, at least one instance of Rcis Et, Pr, or Bu. In certain embodiments, at least one instance of Rcis substituted Ci-6 alkyl. In certain embodiments, at least one instance of Rcis substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of Rcis substituted ethyl, substituted propyl, or substituted butyl.

[0234] In certain embodiments, at least one instance of Rcis substituted or unsubstituted alkenyl. In certain embodiments, at least one instance ofRcis substituted or unsubstituted, C2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl).

[0235] In certain embodiments, at least one instance of Rcis substituted or un substituted alkynyl. In certain embodiments, at least one instance ofRcis substituted or unsubstituted, C2-6 alkynyl (e.g., substituted or unsubstituted ethynyl).

[0236] In certain embodiments, at least one instance of Rcis substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of Rcis substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of Rcis saturated carbocyclyl. In certain embodiments, at least one instance of Rcis partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0237] In certain embodiments, at least one instance of Rcis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of Rcis substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of Rcis saturated heterocyclyl. In certain embodiments, at least one instance of Rcis partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0238] In certain embodiments, at least one instance of Rcis substituted or unsubstituted aryl. In certain embodiments, at least one instance of Rcis substituted or unsubstituted phenyl. In certain embodiments, at least one instance of Rcis unsubstituted phenyl. In certain embodiments, at least one instance of Rcis 2-mono-substituted phenyl. In certain embodiments, at least one instance of Rcis 3-mono-substituted phenyl. In certain embodiments, at least one instance of Rcis 4-mono- substituted phenyl. In certain embodiments, Rcis di-substituted phenyl. In certain embodiments, at least one instance of Rcis substituted or unsubstituted naphthyl.

[0239] In certain embodiments, at least one instance of Rcis substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of Rcis substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of Rcis substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of Rcis substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of Rcis substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of Rcis substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0240] In certain embodiments, at least one instance of Rcis a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of Rcis an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, / -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, at least one instance of Rcis a sulfur protecting group (e.g., acetamidomethyl, / -Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.

[0241] In certain embodiments, two instances of Rcattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two instances of Rcattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).

[0242]

[0243] In certain embodiments, at least one instance of R18is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R18is substituted or unsubstituted, C1-6 alkyl. In certain embodiments, at least one instance of R18is unsubstituted C1-6 alkyl or C1-6 alkyl substituted with at least one instance of halogen. In certain embodiments, at least one instance of R18is unsubstituted

[0244] Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, at least one instance of R18is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R18is unsubstituted C1-4 alkyl. In certain embodiments, at least one instance of R18is Me. In certain embodiments, at least one instance of R18is Et. In certain embodiments, at least one instance of R18is zz-Pr or z-Pr. In certain embodiments, at least one instance of R18is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, at least one instance of R18is z-Bu. In certain embodiments, at least one instance of R18is fluorinated methyl. In certain embodiments, at least one instance of R18is fluorinated ethyl. In certain embodiments, at least one instance of R18is chlorinated methyl. In certain embodiments, at least one instance of R18is chlorinated ethyl. In certain embodiments, at least one instance of R18is -CFh-( substituted or unsubstituted phenyl). In certain embodiments, at least one instance of R18is Bn. In certain embodiments, at least one instance of R18is -CH2-(4- mono-substituted phenyl). In certain embodiments, at least one instance of R18is -CH2-(3-mono- substituted phenyl). In certain embodiments, at least one instance of R18is -CH2-(2-mono- substituted phenyl). In certain embodiments, at least one instance of R18is -CH2-(di- substituted phenyl).

[0245] In certain embodiments, at least one instance of R18is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R18is substituted or unsubstituted, C2-6 alkenyl. In certain embodiments, at least one instance of R18is unsubstituted C2-6 alkenyl. In certain embodiments, at least one instance of R18is unsubstituted vinyl. In certain embodiments, at least one instance of R18is unsubstituted allyl or -CH=CHCH3. In certain embodiments, at least one instance

[0246] In certain embodiments, at least one instance of R18is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R18is substituted or unsubstituted, C2-6 alkynyl. In certain embodiments, at least one instance of R18is unsubstituted C2-6 alkynyl. In certain embodiments, at least one instance of R18is -OCH. In certain embodiments, at least one instance of R18is -C=CCH3or -CHzC^CH. In certain embodiments, at least one instance of R18is -

[0247] In certain embodiments, at least one instance of R18is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R18is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R18is saturated carbocyclyl. In certain embodiments, at least one instance of R18is partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0248] In certain embodiments, at least one instance of R18is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R18is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R18is saturated heterocyclyl. In certain embodiments, at least one instance of R18is partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0249] In certain embodiments, at least one instance of R18is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R18is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R18is unsubstituted phenyl. In certain embodiments, at least one instance of R18is 4-mono-substituted phenyl. In certain embodiments, at least one instance of R18is 3- mono-substituted phenyl. In certain embodiments, at least one instance of R18is 2-mono- substituted phenyl. In certain embodiments, at least one instance of R18is di-substituted phenyl. In certain embodiments, at least one instance of R18is substituted or unsubstituted naphthyl.

[0250] In certain embodiments, at least one instance of R18is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R18is substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R18is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R18is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of R18is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R18is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0251] In certain embodiments, at least one instance of R18is -C(=O)ORD, substituted or unsubstituted In certain embodiments, at least one instance of R18is - substituted or unsubstituted alkyl, -C(=O)RD, or -C(=O)N(RD)2. In certain embodiments, at least one instance of R18is -C(=O)ORD. In certain embodiments, at least one instance of R18is -C(=O)O(substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R18is -C(=O)O(substituted or unsubstituted, Ci-6 alkyl). In certain embodiments, at least one instance of R18is -C(=O)O(unsubstituted Ci-6 alkyl). In certain embodiments, at least one instance of R18is -C(=O)OMe. In certain embodiments, at least one instance of R18is -C(=O)O(Ci-6 alkyl substituted with one or more instances of halogen). In certain embodiments, at least one instance of RDis hydrogen. In certain embodiments, each instance of RDis hydrogen. In certain embodiments, at least one instance of RDis not hydrogen. In certain embodiments, no instance of RDis hydrogen.

[0252] In certain embodiments, at least one instance of RDis substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of RDis unsubstituted alkyl. In certain embodiments, at least one instance of RDis unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of RDis Me. In certain embodiments, at least one instance of RDis Et, Pr, or Bu. In certain embodiments, at least one instance of RDis substituted Ci-6 alkyl. In certain embodiments, at least one instance of RDis substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of RDis substituted ethyl, substituted propyl, or substituted butyl.

[0253] In certain embodiments, at least one instance of RDis substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of RDis substituted or unsubstituted, C2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl).

[0254] In certain embodiments, at least one instance of RDis substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of RDis substituted or unsubstituted, C2-6 alkynyl (e.g., substituted or unsubstituted ethynyl).

[0255] In certain embodiments, at least one instance of RDis substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of RDis substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of RDis saturated carbocyclyl. In certain embodiments, at least one instance of RDis partially unsaturated carbocyclyl (e.g., comprising only one C=C bond in the carbocyclic ring system).

[0256] In certain embodiments, at least one instance of RDis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of RDis substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of RDis saturated heterocyclyl. In certain embodiments, at least one instance of RDis partially unsaturated heterocyclyl (e.g., comprising only one C=C bond in the heterocyclic ring system).

[0257] In certain embodiments, at least one instance of RDis substituted or unsubstituted aryl. In certain embodiments, at least one instance of RDis substituted or unsubstituted phenyl. In certain embodiments, at least one instance of RDis unsubstituted phenyl. In certain embodiments, at least one instance of RDis 2-mono-substituted phenyl. In certain embodiments, at least one instance of RDis 3-mono-substituted phenyl. In certain embodiments, at least one instance of RDis 4-mono- substituted phenyl. In certain embodiments, RDis di-substituted phenyl. In certain embodiments, at least one instance of RDis substituted or un substituted naphthyl.

[0258] In certain embodiments, at least one instance of RDis substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of RDis substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl. In certain embodiments, at least one instance of Ruis substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of RDis substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of RDis substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of RDis substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0259] In certain embodiments, at least one instance of RDis a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of RDis an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, at least one instance of RDis a sulfur protecting group (e.g., acetamidomethyl, / -Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.

[0260] In certain embodiments, two instances of RDattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two instances of RDattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).

[0261] In certain embodiments, R19is substituted or unsubstituted alkyl. R19is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R19is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R19is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R19is unsubstituted C1-4 alkyl. In certain embodiments, R19is Me. In certain embodiments, R19is Et. In certain embodiments, R19is zz-Pr or z-Pr. In certain embodiments, R19is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, R19is / -Bu. In certain embodiments, R19is fluorinated methyl. In certain embodiments, R19is fluorinated ethyl. In certain embodiments, R19is chlorinated methyl. In certain embodiments, R19is chlorinated ethyl. In certain embodiments, R19is -CH2CCI3. In certain embodiments, R19is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, R19is Bn. In certain embodiments, R19is -CH2-(4-mono-substituted phenyl). In certain embodiments, R19is - CH2-(3 -mono-substituted phenyl). In certain embodiments, R19is -CH2-(2-mono-substituted phenyl). In certain embodiments, R19is -CH2-(di- substituted phenyl). In certain embodiments, R19is hydrogen.

[0262] In certain embodimen+ts,

[0263] In certain embodiments, Formula II is of Formula II-l : optionally wherein R1and R2are as shown in Table 25:

[0264] Table 25

[0265] In certain embodiments, Formula II is of Formula II-2:

[0266] (n-2), optionally wherein R1and R2are as shown in Table 26: Table 26 In certain embodiments, Formula II is of Formula II-3: optionally wherein R1and R2are as shown in Table 27:

[0267] Table 27 In certain embodiments, Formula II is of Formula II-4: optionally wherein R1and R2are as shown in Table 28: Table 28 In certain embodiments, Formula II is of any one of the formulae:

[0268]

[0269] In certain embodiments, a provided compound (a compound provided herein or a compound of the present disclosure) is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0270] In certain embodiments, a provided compound (a compound provided herein or a compound of the present disclosure) is a compound of Formula II, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0271] In certain embodiments, the molecular weight of a compound of Formula I is lower than 400, between 400 and 500, between 500 and 600, between 600 and 800, between 800 and 1000, between 1000 and 1200, between 1200 and 1500, or between 1500 and 2000, inclusive, g / mol.

[0272] In certain embodiments, the molecular weight of a compound of Formula II is lower than 400, between 400 and 500, between 500 and 600, between 600 and 800, between 800 and 1000, between 1000 and 1200, between 1200 and 1500, or between 1500 and 2000, inclusive, g / mol.

[0273] Pharmaceutical Compositions and Administration

[0274] In another aspect, the present disclosure provides pharmaceutical compositions comprising a provided compound and optionally a pharmaceutically acceptable excipient.

[0275] In certain embodiments, the pharmaceutical composition comprises an effective amount of the provided compound. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is an amount effective for treating a disease in a subject in need thereof. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, an effective amount is an amount effective for preventing a disease in a subject. In certain embodiments, an effective amount is an amount effective for inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue. In certain embodiments, an effective amount is an amount effective for inhibiting the growth or reproduction of a microorganism or killing a microorganism in a biological sample or tissue or on a surface.

[0276] 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 is a human (e.g., an adult, juvenile, or child). 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. 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), dog, pig, or non-human primate. In certain embodiments, the subject is a genetically engineered animal. In certain embodiments, the subject is a transgenic animal (e.g., transgenic mice, transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0277] In certain embodiments, the biological sample, tissue, or cell (e.g, the biological sample, tissue, or cell being contacted with a provided compound or pharmaceutical composition) is in vitro. In certain embodiments, the biological sample, tissue, or cell is in vivo. In certain embodiments, the biological sample, tissue, or cell is ex vivo.

[0278] Pharmaceutical compositions can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the provided compound (“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.

[0279] 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.

[0280] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0281] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the pharmaceutical composition. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0282] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0283] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethyl cellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof. Exemplary binding agents include starch (e.g, cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g, acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VeegumE). and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0284] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0285] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0286] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g, sodium edetate, di sodium edetate, trisodium edetate, calcium di sodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0287] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0288] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0289] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, NeoIone®, Kathon®, and Euxyl®.

[0290] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0291] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0292] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof. Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0293] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0294] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0295] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. Pharmaceutical compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0296] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fdlers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0297] Solid pharmaceutical compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a pharmaceutical composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating pharmaceutical compositions which can be used include polymeric substances and waxes. Solid pharmaceutical compositions of a similar type can be employed as fdlers in soft and hard-fdled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0298] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a pharmaceutical composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0299] Dosage forms for topical and / or transdermal administration of a provided compound may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0300] Suitable devices for use in delivering intradermal pharmaceutical compositions include short needle devices. Intradermal pharmaceutical compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the provided compound in powder form through the outer layers of the skin to the dermis are suitable.

[0301] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients. A pharmaceutical composition can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such pharmaceutical compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0302] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the pharmaceutical composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0303] Pharmaceutical compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0304] Formulations as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0305] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients. A pharmaceutical composition can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable pharmaceutical composition and, optionally, one or more of the additional ingredients. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients.

[0306] A pharmaceutical composition can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1 -1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0307] Although the descriptions of the pharmaceutical compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical 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.

[0308] The provided compounds are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific pharmaceutical composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0309] The provided compounds and pharmaceutical compositions can be administered by any route, including enteral (e.g, oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), 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 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 provided compound or pharmaceutical composition is suitable for topical administration to the eye of a subject.

[0310] The exact amount of a provided compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amounts of a provided compound. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a provided compound. In certain embodiments, a dose includes independently between 1 mg and 3 mg, inclusive, of a provided compound. In certain embodiments, a dose includes independently between 3 mg and 10 mg, inclusive, of a provided compound. In certain embodiments, a dose includes independently between 10 mg and 30 mg, inclusive, of a provided compound. In certain embodiments, a dose includes independently between 30 mg and 100 mg, inclusive, of a provided compound.

[0311] Dose ranges as provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0312] In certain embodiments, the pharmaceutical composition further comprises an additional pharmaceutical agent. The additional pharmaceutical agent is different from the provided compound. In certain embodiments, the additional pharmaceutical agent is an additional therapeutically active agent. In certain embodiments, the additional pharmaceutical agent is an additional prophylactically active agent. A provided compound or pharmaceutical composition can be administered in combination with one or more additional pharmaceutical agents. The provided compounds or pharmaceutical 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, improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject, biological sample, or cell. 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 including a provided compound and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the provided compound and the additional pharmaceutical agent, but not both.

[0313] The provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g, combination therapies. 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 or premalignant condition. 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 a provided compound or pharmaceutical composition 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 provided compound 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. The additional pharmaceutical agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, antiproliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-microbial agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof In certain embodiments, at least one additional pharmaceutical agent is a microbicidal agent. In certain embodiments, at least one additional pharmaceutical agent is an anti-bacterial agent. In certain embodiments, at least one additional pharmaceutical agent is an anti-viral agent. In certain embodiments, at least one additional pharmaceutical agent is an anti-parasitic agent. In certain embodiments, at least one additional pharmaceutical agent is a parasitocidal agent. In certain embodiments, at least one additional pharmaceutical agent is a rapid malaria-parasite killing agent. In certain embodiments, at least one additional pharmaceutical agent is a parasitostatic agent. In certain embodiments, at least one additional pharmaceutical agent is an antiplasmodial agent. In some embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a kinase (e.g., tyrosine kinase). In certain embodiments, the additional pharmaceutical agent is an antibody or a fragment thereof (e.g., monoclonal antibody). In certain embodiments, the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In certain embodiments, the additional pharmaceutical agent is an immunosuppressor. In certain embodiments, the additional pharmaceutical agent is an immunoactivator. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein (PD-1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. In certain embodiments, the additional pharmaceutical agent is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, lymphocyte activation gene-3 (LAG3) inhibitor, V-set domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster of differentiation 276 (CD276 or B7-H3) inhibitor, B and T lymphocyte attenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpoint kinase 1 (Chkl) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indoleamine 2,3-dioxygenase (IDO) inhibitor, killer-cell immunoglobulin-like receptor (KIR) inhibitor, or V-domain Ig suppressor of T cell activation (VISTA) inhibitor. In certain embodiments, the additional pharmaceutical agent is metformin. In certain embodiments, the additional pharmaceutical agent is approved for human and / or veterinarian administration by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the provided compounds or pharmaceutical compositions can be administered in combination with surgery, radiation therapy, and / or transplantation (e.g., stem cell transplantation, bone marrow transplantation).

[0314] Kits

[0315] In another aspect, the present disclosure provides kits comprising a provided compound or pharmaceutical composition, and instructions for using the provided compound or pharmaceutical composition. In certain embodiments, the kit comprises a first container, wherein the first container comprises the provided compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for dilution or suspension of the provided compound or pharmaceutical composition). In certain embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kit further comprises a third container. In certain embodiments, the third container includes an additional pharmaceutical agent. In some embodiments, the provided compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form. In some embodiments, the provided compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.

[0316] In certain embodiments, the first container, second container, and third container do not comprise the instructions. In certain embodiments, the instructions are for administering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease). In certain embodiments, the instructions are for contacting a biological sample, tissue, or cell with the provided compound or pharmaceutical composition. In certain embodiments, the instructions comprise information required by a regulatory agency, such as the FDA or EMA. In certain embodiments, the instructions comprise prescribing information.

[0317] Methods of Preparing the Compounds

[0318] In another aspect, the present disclosure provides methods of preparing the compounds of

[0319] Formula I, the methods comprising reacting under suitable conditions a mixture comprising: a compound of Formula LA: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula I-B: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula I-C: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and a base.

[0320] In certain embodiments, In certain embodiments,

[0321] In another aspect, the present disclosure provides methods of preparing the compounds of Formula II, the methods comprising reacting under suitable conditions a mixture comprising: a compound of Formula II-A: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula ILB: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula ILC: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and a base.

[0322] In certain embodiments, . In certain embodiments,

[0323] In certain embodiments, the base is an inorganic base. In certain embodiments, the base is an alkali metal hydroxide. In certain embodiments, the base is LiOH, NaOH, or KOH. In certain embodiments, the base is an alkali metal carbonate. In certain embodiments, the base is Li2COs, Na2CO3, or K2CO3. In certain embodiments, the base is Na2CO3. In certain embodiments, the base is an alkali metal bicarbonate. In certain embodiments, the base is LiHCCh, NaHCOs, or KHCO3. In certain embodiments, the base is ammonia, ammonium carbonate, or ammonium hydroxide. In certain embodiments, the base is an organic base (e.g, mono-, di-, or tri-(unsubstituted C1-6 alkyl) amine, cyclic non-aromatic amine, or aromatic amine (e.g., pyridine)). In certain embodiments, the pKaat about 25 °C and about 1 atm of the conjugate acid of the base is between 4 and 6, between 6 and 8, between 8 and 10, between 10 and 12, or between 12 and 14, inclusive.

[0324] In certain embodiments, the mixture further comprises a solvent. In certain embodiments, the solvent is an organic solvent. In certain embodiments, the solvent of is one single solvent. In certain embodiments, the solvent is a mixture of two or more (e.g., three) solvents. In certain embodiments, the solvent is an aprotic solvent. In certain embodiments, the solvent is a chlorinated hydrocarbon solvent. In certain embodiments, the solvent is dichloromethane, chloroform, or a mixture thereof. In certain embodiments, the solvent is dichloromethane. In certain embodiments, the solvent is chloroform. In certain embodiments, the solvent is 1,2-di chloroethane. In certain embodiments, the solvent is an ether solvent. In certain embodiments, the solvent is a di(unsubstituted Ci-4 alkyl) ether. In certain embodiments, the solvent is diethyl ether, methyl te / 7-butyl ether, tetrahydrofuran, or 2- methyltetrahydrofuran. In certain embodiments, the solvent is a ketone solvent. In certain embodiments, the solvent is acetone, acetonitrile, dichloromethane, or ethyl acetate. In certain embodiments, the solvent is an alkane solvent. In certain embodiments, the solvent is pentane, hexane, or heptane, or a mixture thereof. In certain embodiments, the boiling point of the solvent at about 1 atm is between 30 and 50, between 50 and 70, between 70 and 100, or between 100 and 130 °C, inclusive.

[0325] In certain embodiments, the reaction temperature is between 0 and 20, between 20 and 30, between 30 and 40, or between 40 and 50 °C, inclusive, and the reaction pressure is between 0.5 and 1.1 atm, inclusive. In certain embodiments, the reaction temperature is between 50 and 60, between 60 and 70, or between 70 and 80 °C, inclusive, and the reaction pressure is between 0.5 and 1.1 atm, inclusive. In certain embodiments, the reaction temperature is between 60 and 80 °C, between 80 and 100 °C, or between 100 and 120 °C, inclusive, and the reaction pressure is between 1. 1 and 5, between 5 and 10, or between 10 and 20 atm, inclusive. In certain embodiments, the reaction temperature is substantially constant over the reaction time. In certain embodiments, the reaction temperature is variable temperature over at least part of the reaction time.

[0326] In certain embodiments, the suitable conditions further comprise microwave irradiation. In certain embodiments, the suitable conditions does not comprise microwave irradiation.

[0327] In certain embodiments, the reaction time is between 1 and 3 hours, between 3 and 6 hours, between 6 and 12 hours, between 12 and 24 hours, between 1 and 3 days, between 3 and 7 days, or between 7 and 14 days, inclusive.

[0328] In certain embodiments, the method further comprises isolating the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the step of isolating comprises liquid-liquid phase separation, drying, filtration, concentration, chromatography, decolorization, or recrystallization, or a combination thereof. In certain embodiments, the step of isolating comprises liquid-liquid phase separation, drying, filtration, concentration, decolorization, or recrystallization, or a combination thereof. In certain embodiments, the liquid-liquid phase separation is a separation of an organic phase and an aqueous phase. In certain embodiments, the drying is drying an organic phase over a solid drying agent (e.g., anhydrous Na2SO4, anhydrous MgSCU, anhydrous CaSCU, anhydrous CaCh, or activated molecular sieves). In certain embodiments, the filtration is a filtration of a mixture of an organic phase and a solid drying agent to remove the solid drying agent and hydrates thereof. In certain embodiments, the concentration is concentration of an organic phase to remove part or substantially all of the volatiles (e.g., organic solvents). In certain embodiments, the concentration is performed under a pressure lower than 1 atm (e.g., between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive). In certain embodiments, the concentration is performed under a temperature of between 0 and 10, between 10 and 20, between 20 and 25, between 25 and 35, between 35 and 50, or between 50 and 80 °C, inclusive. In certain embodiments, the chromatography is flash chromatography (e.g., normal-phase flash chromatography (e.g., over silica gel)). In certain embodiments, the step of isolating does not comprise chromatography. In certain embodiments, the chromatography is high-performance liquid chromatography. In certain embodiments, the chromatography is chiral chromatography. In certain embodiments, the decolorization comprises redissolving in an organic solvent, decolorization, and concentration. In certain embodiments, the decolorization comprises contacting with a solid decolorization agent (e.g., activated charcoal). In certain embodiments, the recrystallization is preferential recrystallization. In certain embodiments, the recrystallization is a single- solvent recrystallization. In certain embodiments, the recrystallization is a multi-solvent (e.g., bi-solvent or tri-solvent) recrystallization. In certain embodiments, the recrystallization is a hot filtrationrecrystallization. In certain embodiments, the step of isolating further comprises removing part or substantially all of the volatiles (e.g., organic solvents) by decreasing the pressure (e.g., to a pressure of lower than 1 atm (e.g., between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive) and / or increasing the temperature (e.g., to a temperature between 25 and 35, between 35 and 50, or between 50 and 80 °C, inclusive).

[0329] In certain embodiments, the step of isolating comprises chiral separation. In certain embodiments, the chiral separation comprises chiral chromatography, preferential recrystallization, or a combination thereof.

[0330] In certain embodiments, the rate of conversion of a compound of Formula I-A, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the rate of conversion of a compound of Formula II- A, or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, to a compound of Formula II, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is between 5% and 99% (e.g., between 5% and 20%, between 20% and 40%, between 40% and 60%, between 60% and 80%, or between 80% and 95%), inclusive.

[0331] In certain embodiments, when the methods yield a mixture of enantiomers or diastereomers, the enantiomeric excess or diastereomeric excess, respectively, of the compounds of Formula I or II, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, before or in the absence of chiral separation is between 2% and 10%, between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 60%, between 60% and 80%, or between 80% and 99%, inclusive.

[0332] Methods of Use and Uses

[0333] The present disclosure also provides methods of using the provided compounds and pharmaceutical compositions.

[0334] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.

[0335] In another aspect, the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for treating a disease in a subject in need thereof.

[0336] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in treating a disease in a subject in need thereof.

[0337] In another aspect, the present disclosure provides methods of preventing a disease in a subject, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.

[0338] In another aspect, the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for preventing a disease in a subject. In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in preventing a disease in a subject.

[0339] In certain embodiments, the disease is a disease described herein. In certain embodiments, the disease is an infection. In certain embodiments, the disease is a parasitic infection, bacterial infection, biofilm infection, mycosis, prion diseases, sepsis, or viral infection. In certain embodiments, the disease is a parasitic infection. In certain embodiments, the disease is a protozoal infection, ascariasis, heartwater, helminthiasis, ichthyophoniasis, microsporidiosis, mite infestation, parasitemia, parasitic ectoparasitic infectious disease, taeniasis, trichinosis, or trichuriasis. In certain embodiments, the disease is a protozoal infection. In certain embodiments, the disease is malaria, acanthamoeba keratitis, amebiasis, babesiosis, bovine babesiosis, canine babesiosis, chagas disease, coccidiosis, cyclosporiasis, equine piroplasmosis, giardiasis, granulomatous amoebic encephalitis, hi stom oniasis, leishmaniasis, theileriosis, trichomoniasis, or trypanosomiasis. In certain embodiments, the disease is malaria.

[0340] In certain embodiments, the provided method further comprises administering to the subject in need thereof an additional therapy. In certain embodiments, the additional therapy is one or more additional pharmaceutical agents. In certain embodiments, the additional pharmaceutical agents are as described in the present disclosure. In certain embodiments, a provided method that further comprises administering to the subject in need thereof the additional therapy is synergistic as compared to a provided method that does not comprise administering to the subject in need thereof the additional therapy and as compared to a method comprises administering to the subject in need thereof the additional therapy as the only active therapy. In certain embodiments, the subject is a subject that has been administered the additional therapy. In certain embodiments, the subject is resistant to the additional therapy. In certain embodiments, the effective amount of a provided compound or pharmaceutical composition is effective in decreasing the resistance to the additional therapy. The additional therapy may be administered to the subject concurrently with, prior to, or subsequent to the administration of the provided compound or pharmaceutical composition.

[0341] In another aspect, the present disclosure provides methods of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue, the methods comprising administering to the subject or contacting the biological sample or tissue with an effective amount of a provided compound or pharmaceutical composition.

[0342] In another aspect, the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue.

[0343] In another aspect, the present disclosure provides the provided compounds and pharmaceutical compositions for use in inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue.

[0344] In another aspect, the present disclosure provides in vitro methods of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a biological sample or tissue or on a surface, the method comprising contacting the biological sample, tissue, or surface with an effective amount of a provided compound or pharmaceutical composition.

[0345] In certain embodiments, the microorganism is a parasite, bacterium, fungus, prion, or virus. In certain embodiments, the microorganism is a parasite. In certain embodiments, the parasite is of the family Plasmodiidae . In certain embodiments, the parasite is of the genus Plasmodium, Bioccala, Biguetiella, Billbraya, Dionisia, Hepatocystis, Mesnilium, Nycteria, Polychromophilus, Rayella, Saurocytozoon, or Vetufebrus. In certain embodiments, the parasite is of the genus Plasmodium . In certain embodiments, the parasite is of the species Plasmodium falciparum.

[0346] EXAMPLES

[0347] In order that the present disclosure may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, kits, uses, and methods provided herein and are not to be construed in any way as limiting their scope.

[0348] Example 1. Indole-Promoted Ring Cleavage of Yohimbine with Diverse Chloroformates and A Icohols / Thiols

[0349] Our initial experiments subjected yohimbine 7 (free base) to phenyl chloroformate and methanol in chloroform at 60 °C for three hours to afford a mixture of products at a 1.2:1 diastereomeric ratio (dr) in 96% combined yield (Table 29, entry 1; general diastereomeric products are referred to the “inversion product” 11 and “retention product” 12). Encouraged by the excellent yield and separability of the target diastereomers using column chromatography, the scope of this reaction was explored with yohimbine 7 to assess six chloroformate electrophiles and six alcohol or thiol nucleophiles (Table 29). Collectively, these efforts afforded fourteen diastereomeric product pairs ranging from 33 - 96% combined yields with diastereomeric ratios of 1 : 1 to 1 :3 (inversion product 11 to retention product 12). To probe reaction performance, ring cleavage reactions of 7 were typically carried out at (1) room temperature, (2) 60 °C in an oil bath, or (3) 60 °C in a microwave reactor. Reactions performed on yohimbine 7 at room temperature generally required more time to complete compared to reactions heated in an oil bath; however, microwave heated reactions were completed in 15 minutes. Interestingly, reactions demonstrating some diastereoselectivity had the retention product 12 as the major product in nearly all cases. In general, bulkier nucleophiles tended to produce lower overall yields of the desired products upon reaction with yohimbine and chloroformates (e.g., Table 29, entry 4, / e / 7-butanol produced 33% combined yield of diastereomeric products); however, higher diastereoselectivities were observed.

[0350] We find the ring cleavage of yohimbine 7 to be a remarkable transformation as the chloroformate and alcohol / thiol in the reaction could react together without yohimbine’s involvement to produce undesired materials. Our studies show these reactions to be unexpectedly chemoselective as the tertiary amine of yohimbine 7 must first react with the electrophilic chloroformate to generate an activated A-acyl ammonium intermediate that then undergoes a spontaneous indole-promoted ring cleavage to form a resonance-stabilized carbocation, which is finally reacted with the alcohol / thiol nucleophile to produce the diastereomeric products 11 and 12. Exploration of this reaction-type was further probed to assess the tolerance of this ring cleavage transformation in the presence of alternative electrophiles, nucleophiles, and solvents. We found the electrophilic character of chloroformates to be important for reaction progression, as our attempts involving sulfonyl chlorides and acyl chlorides did not proceed. Similarly, reactions employing nonalcohol or thiol nucleophiles, such as benzoic acid, trimethyl silyl azide, and tosyl amide, were less successful. Additionally, similar ring cleavage reactions using solely chloroformates (i.e., the displaced chloride serving as the nucleophile) have been reported with other indole-containing compounds bearing a tryptoline motif,37however, attempts to perform this reaction with yohimbine 7 in the absence of an alcohol / thiol nucleophile were less successful. Solvent selection was also found to be important for the desired indole-promoted ring cleavage transformation to occur, as less reaction with yohimbine was observed in tetrahydrofuran, toluene, or acetone. Reactions using chloroform or dichloromethane as the solvent showed successful ring cleavage of yohimbine 7 (see Table 29). Table 29. Indole-Promoted Ring Cleavage of Yohimbine to Diverse Molecules.

[0351] The absolute stereochemical assignment of the diastereomeric products from yohimbine 7 proved to be non-trivial due to the nature of the medium-sized ring bearing a carbamate. The diastereomeric pairs from yohimbine 7 were characterized using NMR and X-ray analysis to support and confirm chemical shift trends observed among this series (the “inversion product” had the chemical shift of H3 upfield relative to the H3 proton signal in the “retention product” based onJH NMR studies conducted in C2D2CI4; one exception being diastereomers 23 and 24, where NMRs were taken in rfc-DMSO; see FIG. 1 and FIG. 2). Our observations aligned with previous work4 11,38-40requiring variable temperature NMR to characterize medium-size ring compounds. High temperature NMR experiments may produce well-resolved signals (peaks) as the ring-cleaved products from yohimbine may exist as a mixture of slowly interconverting conformers at room temperature which produce distinct but often broad or nonexistent signals in NMR spectra. After performing NMR experiments at 100 °C in C2D2CI4, however, interconversion between conformers occurred at an adequate rate such that previously distinct conformer peaks coalesced, and broad, weak peaks became sharper, allowing for definitive structural elucidation. While this trend was generally met with success across the diastereomeric products synthesized from yohimbine, there were select instances where peaks remained broad or nonexistent.

[0352] Prior to the acquisition of high-quality crystals for X-ray diffraction studies to unambiguously assign stereochemistry at the C3 position of yohimbine-derived ring cleavage products (i.e., analogues of general structure 11 and 12), stereochemical assignments were made using selective one-dimensional nuclear Overhauser effect spectroscopy (NOESY) experiments (FIG. 1). Upon irradiation of the H3 of inversion product 13, a through-space correlation was observed by the C15 methine (FIG. 1 & FIG. 2). In addition, a NOESY correlation is also observed in the reverse direction regarding 13, following irradiation of Hl 5 (which NOEs to H3), confirming that H3 of 13 is on the same face of the newly formed medium sized ring as Hl 5. Conversely, upon irradiation of the H3 methine of 14, a NOE correlation was observed with H20 and Hl 6, which are anti to Hl 5, indicating the stereochemistry correlates to the retention product (FIG. 1). The absolute stereochemistry of 14 was further validated by X-ray analysis (FIG. 2), which aligned with our NOE findings. Similar NOE profiles were observed for products 15 and 16 (FIG. 1).

[0353] Using the chloroformate and alcohol / thiol ring cleavage reaction, we were able to collectively synthesize 28 new compounds (14 diastereomeric pairs) from yohimbine 7. From this focused series of diastereomeric product pairs, an observable trend in chemical shifts at H3 was clear between the inversion 11 and retention 12 products, allowing us to assign stereochemistry for all synthetic analogues. As demonstrated in FIG. 2, the 6H3 for the inversion products were typically observed to be 0.3 - 0.5 ppm upfield (e.g., 13, 17, 19, 21) when compared to the corresponding retention product diastereomers (e.g., 14, 18, 20, 22). We observed a similar trend in previous studies with the cyanogen bromide-mediated ring cleavage of yohimbine11and synthesized additional analogues to align and confirm these NMR trends between new ring-cleaved cyanamides and chloroformates during these studies. The lone exception we observed during this study can be seen in the chemical shifts of thioether diastereomers 23 and 24 (FIG. 2; we obtained an X-ray of 24); however, we attribute this result from being the only diastereomeric pair that used <UDMS0 in NMR experiments. Interestingly, we found five retention products synthesized from yohimbine readily produced high-quality single crystals for X-ray diffraction studies compared to the inversion products (included in FIG. 2).

[0354] The chloroformate-mediated ring cleavage of yohimbine not only enabled rapid access to a focused series of analogues, but also allowed for further synthetic transformations to expand the diversity of compounds accessed through this method. Select yohimbine ring-cleaved compounds were subjected to the removal of carbonate functional groups to yield the corresponding secondary amine that could be acylated. In addition, the indole nitrogen and secondary alcohol of a select yohimbine analogue were methylated using Williamson ether synthesis conditions while another analogue was subjected to a copper-catalyzed C-N coupling between the indole nitrogen and aryl iodide from the ring cleavage reaction to access ring fusion compound 16. Overall, the chloroformate-mediated ring cleavage of yohimbine proved to be a robust transformation leading to the synthesis of 35 new derivatives.

[0355] Example 2. Indole-Promoted Ring Cleavage of Apovincamine and Vinburnine

[0356] In parallel studies, we performed chloroformate-mediated ring cleavage reactions on vincamine-derived compounds apovincamine 25 and vinburnine 28 (Table 30). Vincamine can be purchased on decagram scale and readily converted to apovincamine and vinburnine,4 16which was important for these efforts as the ring cleavage reactions on 25 and 28 were lower yielding (i.e., 4 - 67% yield) compared to yohimbine. We believe the additional ring fused onto the indole heterocycle of these vincamine-derived substrates may have negatively impacted the efficiency of this ring cleavage transformation, which we discuss in more detail later. Despite these challenges, we were able to synthesize 12 new ring-cleaved analogues from 25 and 28 using a diversity of chloroformates with alcohols / thiols.

[0357] Ring cleavage reactions with apovincamine 25 involved harsh conditions (100 °C via microwave for one hour, or in a sealed tube for days) and typically gave low yields with significant amounts of starting material following the end of the reaction (with up to 76% starting material recovered following reaction). For these reactions, di chloromethane was found to be superior to chloroform as a solvent. Despite low yields, all ring cleavage reactions with 25 and 28 produced a single diastereomeric product which we characterize as the inversion product based on the X-ray of derivative 27 (FIG. 3). Based on the molecular architecture of the resonance-stabilized intermediate that forms directly after C-N bond cleavage, subsequent nucleophilic attack from the alcohol / thiol nucleophile would be expected on the opposite face of the new carbamate to yield the desired product as a single diastereomer (computational studies detailed in a later section). The close proximity of the newly formed carbamate to the highly electrophilic carbon center generated during the course of the reaction may explain why significant amounts of starting materials may be present at the end of the reaction as the indole-stabilized intermediate may readily convert back to starting material. Vinburnine 28 was found to be a poor substrate for ring cleavage reactions with chloroformates probably because the indole nitrogen was more electron-deficient due to the amide appendage. Despite some unsuccessful reactions with vinburnine 28, we were able to use methyl chloroformate in combination with methanol to obtain the desired ring-cleaved product 29 in 4% yield (Scheme 1).

[0358] Table 30. Chloroformate-mediated ring cleavage of apovincamine 25 and vinbumine 28 with various alcohol and thiol nucleophiles to give single diastereomer products (i.e., 27, where R1is Me, and - XR2is -OMe). Example 3. Computational Analysis of Yohimbine and Apovincamine Ring Cleavage Reactions

[0359] Density functional theory calculations were pursued through Gaussian41’42(Functional: M06- 2X43; Basis sets: 6-31 1 G++(d,p)44 47and MIDI!48) in order to gain greater insight into the mechanism of the chloroformate / nucleophile-mediated ring cleavage reactions on yohimbine 7 and apovincamine 25. Our goal was to discern the relationship between this reaction pathway and di aster eom eric ratios observed in our experiments using computational tools. As shown in FIG. 4 and FIG. 5, the tertiary amine of 7 and 25 may first react with the chloroformate to afford acyl ammonium intermediates, which may be primed for the indole-promoted ring cleavage step to afford highly reactive carbocation intermediates. We were curious to explore the geometry of possible carbocation intermediates to see if this could potentially dictate the facial selectivity of the subsequent nucleophilic attack from alcohols or thiols, providing the basis for the observed di aster eom eric ratios of products.

[0360] The results for DFT calculations on yohimbine 7 are shown in FIG. 4. Due to the large, complex nature of these compounds, the focus of these calculations was on stable intermediates rather than assessing potential transition states. Initial data suggested many local minima and maxima exist, providing a rugged potential energy landscape over the course of this reaction. The intermediates (local minima) shown, however, provide good insight into the reaction pathway. The energetically preferred conformation of yohimbine contains the lone pair of electrons on the tertiary amine in an axial position, rather than equatorial. The axially oriented lone pair on the amine of 7 reacts with ethyl chloroformate to form Int-IA (intermediate 30) preferentially. From there, ring- cleaved carbocations were proposed with either cis (structures 32 and 33) or trans (structure 34) resonance-stabilized geometry. Trans carbocation Int-2C (structure 34) was found to have the lowest energy compared to the cis intermediates (AG = +30.9 kcal / mol); however, upon C-N bond cleavage, cis olefin 33 would initially form. Given that benzylic carbocations have a very high energy barrier to rotation (AG = 44.9 kcal / mol),49it is therefore unlikely that conversion between cis 33 and trans 34 carbocations occurs after the initial C-N bond cleavage event in this reaction.

[0361] Upon closer examination of Int-IA (structure 30), the dihedral angle between the indole NH and the C3 proton is 104.1°, and orbital overlap of the indole K electrons with the resultant carbocation would favor the formation of a cis carbocation (resonance structures Int-2A and Int-2B) over a trans carbocation. Indeed, upon conducting a relaxed potential energy surface scan wherein the C-N bond of Int-IA was incrementally increased in length, it was shown that this proton orients to form a cis carbocation as the bond lengthens before cleavage. Comparing two cis carbocation minima in which the carbamate potentially shielded, or blocked, either the top or the bottom face of the reactive center indicated that the latter of the orientations was energetically preferred (Int-2B AG = +36.5 kcal / mol compared to Int-2A AG = +37.1 kcal / mol), and this preference was reflected regardless of the solvent model used within the calculation. With the combination of the cis orientation of the stabilized carbocation and the obstruction of the bottom face from attack due to the position of the carbamate, this may favor the formation of the retention product over the inversion product, indicating kinetic control of product formation over thermodynamic control. This provides a rationale as to why larger nucleophiles, such as 2-iodobenzyl alcohol, may preferentially form the retention product, while smaller nucleophiles (e.g., methanol), which are less affected by sterics, may form the product diastereomers in roughly a 1 :1 ratio from yohimbine. This also provides a rationale as to why ring-cleaved carbamates with larger groups (e.g., phenyl) may experience a slightly increased preference for retention products compared to ring-cleaved carbamates with smaller groups (e.g., ethyl). It should be noted, though, that it is possible that there is interconversion between Int-2B and Int-2A during the course of the reaction as well.

[0362] DFT calculations were also conducted for ring cleavage reactions involving apovincamine 25 (FIG. 5). Apovincamine’s pentacyclic structure with two chiral centers lends itself to a cup-shaped architecture wherein the tertiary amine’s lone pair sits on the convex face of the structure. As a result, it has a strong energetic preference to form the corresponding acyl ammonium intermediate V-Int-IB (36, AG = +16.3 kcal / mol compared to V-Int-IA 35, AG = +24.5 kcal / mol) upon reaction with phenyl chloroformate. Upon indole-promoted ring cleavage, the newly formed carbamate in V- Int-2A (structure 37) clearly shields one face of the indole-stabilized carbocation from nucleophilic attack, guiding the formation of the single diastereomer (inversion product 38) observed. Experimentally, the chloroformate-mediated ring cleavage reaction with apovincamine 25 is low- yielding and significant starting material was observed, which may be rationalized as constrained intermediate V-lnt-2A (37) reverting back to starting apovincamine following nitrogen-mediated ring closure to V-Int-IB (36) before final acyl transfer back to 25 (FIG. 5). Although the desired product is more energetically favored, the intramolecular cyclization of key intermediate V-Int-2A (37) to apovincamine 25 may be kinetically favored in this dynamic reactive pathway.

[0363] Example 4. Ring Cleavage of Reserpine and Discovery of Re-engineered Antiplasmodial Agents Reserpine was subjected to the indole-promoted ring cleavage reaction in the presence of phenyl chloroformate and 2-iodobenzyl alcohol at room temperature to afford desired diastereomers 40 (5% yield) and 41 (38% yield; Scheme 2). Despite fewer attempts to develop the chloforormate ring cleavage reaction on reserpine, we note this indole alkaloid to be sensitive to temperature under the reaction conditions utilized for yohimbine. Such chloroformate-based reactions involving reserpine at 60 °C may lead to decomposition or significant product impurities that may not yield pure products, likely a result of the electron-rich methoxy group on this indole alkaloid further enhancing reactivity towards the indole-promoted ring cleavage pathway.

[0364] Similar to the C3 position of yohimbine ring-cleaved products, stereochemical validation of the Cl position of these reserpine derivatives was not trivial. While acceptable-quality 'H and13C NMR spectra could be obtained for diastereomeric products 40 and 41 at room temperature, through- space correlations to this position were more challenging to acquire due in part to the large molecular weight of the products and the low yields of 40. The latter aspect was exacerbated by the near-coelution of diastereomers 40 and 41 during chromatographic purification, rendering purification a challenge. Analogous obstacles have been documented by Hoye51and Seo52with related reactions of reserpine. Hoye and Ross reported two ring-cleavage reactions with reserpine using innovative benzyne-mediated chemistry; however, separation was achieved for only one of the diastereomeric pairs and the stereochemistry at Cl was not determined.50Seo and co-workers reported highly diastereoselective (>20: 1; 56% yield of the analogous “inversion product” in their study)51ring cleavage of reserpine using difluorocarbene transfer chemistry which required 1-D selective NOESY to assign stereochemistry and proved important for our work with reserpine.

[0365] To determine the absolute stereochemistry for 40 and 41, we performed one-dimensional and two-dimensional NOESY and rotating frame Overhauser effect spectroscopy (ROESY) experiments for each diastereomer. For diastereomer 41 (major product), the stereochemistry at Cl was defined by a key NOE observed between the methyl ester and the Cl proton (Scheme 2). Through this key NOE, the stereochemistry at Cl of this diastereomer was able to be definitively assigned, indicating that this is the “inversion product” similar to the reaction profile for reserpine observed by Seo and co-workers, who report an analogous NOE to assign the stereochemistry of their major diastereomer formed in their studies.51

[0366] Following the chloroformate-based ring cleavage synthesis efforts described with the indole alkaloids reported herein, our team screened all new ring-cleaved products for antiplasmodial activity against chloroquine-resistant Dd2 Plasmodium falciparum parasites in an unbiased SYBR Green I assay system.52'54While none of the yohimbine- or vincamine-derived compounds exhibited activity in this phenotypic screen against Dd2, the reserpine-derived compound 41 was found to inhibit 93% Dd2 parasite growth at 1 pM (the screening concentration for all compounds in this study). We then evaluated both reserpine ring-cleavage diastereomers 40 and 41 in dose-response experiments against Dd2 (resistant) and 3D7 (wild-type) parasites for validation of our preliminary findings and to gain some initial structure-activity relationship (SAR) insights regarding reserpine ring-cleaved compounds. From dose-response experiments, we found compound 41 to demonstrate good antipl asmodial activities against Dd2 (ECso = 0.50 ± 0.10 pM) and 3D7 (ECso = 0.35 ± 0.04 pM) parasites (Scheme 2). Interestingly, diastereomer 40 showed a 3- to 5-fold reduction in activity against Dd2 and 3D7 parasites in dose-response experiments (ECso = 1.78 pM against both strains) compared to 41. Importantly, reserpine displayed no inhibitory activities against Dd2 or 3D7 parasites (ECso >

[0367] 100 pM) when tested alongside 40 and 41, demonstrating our ring cleavage efforts are indeed fruitful as we have re-engineered the biological activity of reserpine. In addition, compounds 40 and 41 were tested for cytotoxicity in HepG2 (hepatocellular carcinoma) cells and found to be inactive (ECso > 25 pM) demonstrating excellent selectivity indices of > 14 and > 50, respectively (selectivity indices were determined by comparing the EC50 value against HepG2 to the EC 50 value against Dd2 parasites; [ECsovs. HepG2] / [ECso vs. Dd2]). From these initial results against P. falciparum parasites and HepG2 cells, compound 41 demonstrated good antiplasmodial activities, and the stereochemistry at Cl may be important for activity as can be seen from the lower activity of analogue 40.

[0368]

[0369] Scheme 2. Indole-promoted ring cleavage of reserpine leads to re-engineered antipasmodial agent.

[0370] Following the initial discovery that reserpine-derived compounds 40 and 41 demonstrated re- engineered antiplasmodial activities, we wanted to gain further insights using kill kinetic and stage specific activity assays. Kinetic kill experiments with Dd2 parasites were performed to determine if compounds 40 and 41 were operating through a parasitocidal or parasitostatic mechanism. Asynchronous Dd2 cultures were treated with 10 * EC50 concentration of compounds 40 and 41 for predetermined periods of time (12, 24, and 48 h). Following each time point, compounds 40 and 41 were washed out, and parasite growth was evaluated for 96 h. Based on kill kinetic experiments, compounds 40 and 41 required 48 h treatment in Dd2 cultures to demonstrate the most significant reduction in parasitemia. This slow-killing phenotype is indicative of a parasitostatic mode of action, similar to slow-killing antimalarial agent atovaquone (Dihydroartemisinin, or DHA, was used as a rapid-killing agent in kill kinetic experiments; see FIG. 6). It is to be noted that slow-acting antiplasmodial compounds have utility as partner drugs in artemisinin combination therapies?5

[0371] Finally, we evaluated the developmental stage specific action of compounds 40 and 41 by microscopy and flow cytometry to further explore their activities (FIG. 7). The precise delineation regarding the timing of action for a small molecule can provides valuable insights into the developmental growth and clinical clearance of P. falciparum. For these experiments, tightly synchronized Dd2 cultures were treated at 6 hours post-invasion of merozoites with 5 * EC so concentration of compounds 40 and 41. Following this, microscopic evaluation of Giemsa-stained- thin smears and flow cytometric assessments were performed at 12 h intervals. Negative controls represented infected red blood cells that were exposed to vehicle (0.1% DMSO) only. When compared to untreated Dd2 cultures, compounds 40 and 41 inhibited parasites later in the life cycle between the trophozoite and schizogony stages (FIG. 7). Compound 41 prevented reinvasion (FIG. 7) and increases in parasitemia when added to Dd2 cultures 18 h post-invasion (HPI). In addition, we note that 41 caused vacuolization in the schizont stage parasites, which do not overlap with heme, distinguishing these newly formed vacuoles from the digestive vacuole in / < falciparum. When 40 and 41 were added to Dd2 cultures 30 HPI, both reinvasion and increases in parasite mass were not altered as these compounds do not operate this late in the parasite’s life cycle.

[0372] Conclusions

[0373] During these studies, we demonstrate multiple indole alkaloids or derivatives to be viable substrates for a chloroformate-mediated ring cleavage reaction in combination with alcohol / thiol nucleophiles. This robust reaction was most explored with yohimbine 7, which formed two diastereomeric products under moderate reaction conditions. Extensive NMR studies in combination with X-rays were employed to define the absolute stereochemistry for new compounds. Apovincamine 25 and vinburnine 28 were also utilized as substrates; however, these molecules were less ideal starting materials resulting in lower yields of the desired product (formed as a single diastereomer) under harsh reaction conditions. Free energy calculations were utilized to explore the energetics of this indole-promoted reaction pathway to better understand our experimental findings with yohimbine 7 and apovincamine 25. In addition, we explored this chloforomate-based reaction with reserpine 39, which was sensitive to elevated reaction temperatures, but worked well at lower reaction temperatures, e.g., room temperature, to produce two diastereomeric products (where NOE was used to determine stereochemistry). This focused collection of ring-cleaved indole alkaloids was screened for biological activity against the Dd2 P. falciparum parasites, and we found compounds 40 and 41 (derived from reserpine) to demonstrate exciting re-engineered antiplasmodial activities.

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[0432] EQUIVALENTS AND SCOPE

[0433] In the claims and throughout, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Embodiments or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0434] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claims that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included.

[0435] Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0436] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the embodiments. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any embodiment, for any reason, whether or not related to the existence of prior art.

[0437] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended embodiments. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: the compound is of Formula I:R1is 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, or an oxygen protecting group;X1is oxygen or sulfur;R2is 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, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; nl is 0; or: nl is 1, 2, 3, or 4; each instance of R3is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -N(RA)2, -SRA, -SSRA, -CN, -instance of RAis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAattached to the same intervening atom are joined together with the intervening atom to form a substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; each of R4, R5, R6, and R7is independently hydrogen, 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,each instance of RBis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RBattached to the same intervening atom are joined together withthe intervening atom to form a substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted alkyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted, Ci-6 alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen.

7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted alkenyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted, C2-6 alkenyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is unsubstituted C2-6 alkenyl.

10. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted alkynyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted, C2-6 alkynyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is unsubstituted C2-6 alkynyl.

13. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted aryl.

14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted phenyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is unsubstituted phenyl.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, hydrate,polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein X1is oxygen.

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein X1is sulfur.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein20. The compound of any one of claims I- 19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is substituted or unsubstituted alkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is substituted or unsubstituted, Ci-6 alkyl.

22. The compound of claim 21, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is -CH2-(substituted or unsubstituted phenyl).

24. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is substituted or unsubstituted alkenyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is substituted or unsubstituted, C2-6 alkenyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is unsubstituted C2-6 alkenyl.

27. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is substituted or unsubstituted alkynyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is substituted or unsubstituted, C2-6 alkynyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2is unsubstituted C2-6 alkynyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein nl is 0.

31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, hydrate,polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein nl is 1.

32. The compound of claim 31, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein33. The compound of any one of claims 1-29 and 31-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R3is -ORA, halogen, substituted or unsubstituted34. The compound of claim 33, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R3is -ORA.

35. The compound of any one of claims 1-29 and 31-34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of RAis substituted or unsubstituted alkyl.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R4is -C(=O)ORB, halogen, substituted or unsubstituted alkyl, -ORB, -N(RB)2, -SRB, -37. The compound of claim 36, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R4is -C(=O)ORB38. The compound of claim 37, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R4is -C(=O)O(substituted or unsubstituted, Ci-6 alkyl).

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein40. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,. wherein41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R5is -ORB, -OC(=O)RB, halogen, substituted or unsubstituted alkyl, -N(RB)2, -SRB, -42. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R?is -ORB43. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R5is44. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R5is -O(substituted or unsubstituted, Ci-6 alkyl), -OH, -OC(=O)(substituted or unsubstituted, Ci-6 alkyl), or -OC(=O)(substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,! . wherein46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R6is hydrogen.

47. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R6is -OC(=O)RB, halogen, substituted or unsubstituted48. The compound of claim 47, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R6is-OC(=O)RB.

49. The compound of claim 48, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R6is -OC(=O)(substituted or unsubstituted phenyl).

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R7is hydrogen.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of RBis hydrogen.

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of RBis substituted or unsubstituted alkyl or substituted or unsubstituted phenyl.

54. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

55. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: the compound is of Formula II:(II);R11is 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, or an oxygen protecti ng group ;X11is oxygen or sulfur;R12is 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, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; nl 1 is 0; or: nl 1 is 1, 2, 3, or 4; each instance of R13is 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,instance of Rcis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rcattached to the same intervening atom are joined together with the intervening atom to form a substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring;wherein each instance of R18is independently -C(=O)ORD, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted or un substituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -S(=O)RD, -each instance of RDis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RDattached to the same intervening atom are joined together with the intervening atom to form a substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; andR19is substituted or unsubstituted alkyl or hydrogen.

56. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is substituted or unsubstituted alkyl.

57. The compound of claim 56, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is substituted or unsubstituted, Ci-6 alkyl.

58. The compound of claim 57, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen.

59. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is substituted or unsubstituted alkenyl.

60. The compound of claim 59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is substituted or unsubstituted, C2-6 alkenyl.

61. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is unsubstituted C2-6 alkenyl.

62. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is substituted or unsubstituted alkynyl.

63. The compound of claim 62, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is substituted or unsubstituted, C2-6 alkynyl.

64. The compound of claim 63, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is unsubstituted C2-6 alkynyl.

65. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is substituted or unsubstituted aryl.

66. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is substituted or unsubstituted phenyl.

67. The compound of claim 66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R11is unsubstituted phenyl.

68. The compound of any one of claims 55-67, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein X11is oxygen.

69. The compound of any one of claims 55-67, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein X11is sulfur.

70. The compound of any one of claims 55-69, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein71. The compound of any one of claims 55-70, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is substituted or unsubstituted alkyl.

72. The compound of claim 71, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is substituted or unsubstituted, Ci-6 alkyl.

73. The compound of claim 72, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl.

74. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is -CH2-(substituted or unsubstituted phenyl).

75. The compound of any one of claims 55-70, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is substituted or unsubstituted alkenyl.

76. The compound of claim 75, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is substituted or unsubstituted, C2-6 alkenyl.

77. The compound of claim 76, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is unsubstituted C2-6 alkenyl.

78. The compound of any one of claims 55-70, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is substituted or unsubstituted alkynyl.

79. The compound of claim 78, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is substituted or unsubstituted, C2-6 alkynyl.

80. The compound of claim 79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is unsubstituted C2-6 alkynyl.

81. The compound of any one of claims 55-80, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ni l is 0.

82. The compound of any one of claims 55-80, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ni l is 1.

83. The compound of any one of claims 55-80 and 82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R13is halogen, substituted or unsubstituted alkyl, -ORC, - N(RC)2, -SRC, -SSRC, -CN, -SCN, -C(=O)RC, -C(=O)ORC, -C(=O)N(RC)2, -NO2, -N.3, - NRcC(=O)Rc, -NRcC(=O)ORc, -NRcC(=O)N(Rc)2, -OC(=O)Rc, -OC(=O)ORc, -OC(=O)N(Rc)2,84. The compound of any one of claims 55-80 and 82-83, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of Rcis substituted or unsubstituted alkyl.

85. The compound of any one of claims 55-84, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein86. The compound of any one of claims 55-85, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R18is -C(=O)ORD, substituted or unsubstituted alkyl, -87. The compound of claim 86, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R18is -C(=O)ORD.

88. The compound of any one of claims 55-87, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of RDis substituted or unsubstituted alkyl.

89. The compound of any one of claims 55-84, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug90. The compound of any one of claims 55-89, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R19is substituted or unsubstituted alkyl.

91. The compound of claim 90, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R19is substituted or unsubstituted, Ci-6 alkyl.

92. The compound of claim 91, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R19is unsubstituted Ci-6 alkyl.

93. The compound of claim 92, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R19is Et.

94. The compound of any one of claims 55-93, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein95. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

96. The compound of any one of claims 1-95, or a pharmaceutically acceptable salt thereof.

97. A pharmaceutical composition comprising a compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable excipient.

98. The pharmaceutical composition of claim 97 further comprising one or more additional pharmaceutical agents.

99. The pharmaceutical composition of claim 98, wherein at least one additional pharmaceutical agent is a microbicidal agent.

100. The pharmaceutical composition of claim 99, wherein at least one additional pharmaceutical agent is a parasitocidal agent.

101. The pharmaceutical composition claim 100, wherein at least one additional pharmaceutical agent is a rapid malaria-parasite killing agent.

102. A kit comprising: a compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; or a pharmaceutical composition of any one of claims 97-101; and instructions for using the compound, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or pharmaceutical composition.

103. A method of treating a disease in a subject in need thereof comprising administering to the subject an effective amount of: a compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; or a pharmaceutical composition of any one of claims 97-101.

104. Use of a compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 97-101, for the manufacture of a medicament for treating a disease in a subject in need thereof.

105. A compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 97-101, for use in treating a disease in a subject in need thereof.

106. A method of preventing a disease in a subject, the method comprising administering to the subject an effective amount of:a compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; or a pharmaceutical composition of any one of claims 97-101.

107. Use of a compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 97-101, for the manufacture of a medicament for preventing a disease in a subject.

108. A compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 97-101, for use in preventing a disease in a subject.

109. The method of any one of claims 103 and 106, the use of any one of claims 104 and 107, or the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of any one of claims 105 and 108, wherein the disease is an infection.

110. The method, the use, or the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of claim 109, wherein the disease is a parasitic infection, bacterial infection, biofilm infection, mycosis, prion diseases, sepsis, or viral infection.

111. The method, the use, or the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of claim 110, wherein the disease is a parasitic infection.

112. The method, the use, or the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of claim 111, wherein the disease is a protozoal infection,ascariasis, heartwater, helminthiasis, ichthyophoniasis, microsporidiosis, mite infestation, parasitemia, parasitic ectoparasitic infectious disease, taeniasis, trichinosis, or trichuriasis.

113. The method, the use, or the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of claim 112, wherein the disease is a protozoal infection.

114. The method, the use, or the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of claim 113, wherein the disease is malaria, acanthamoeba keratitis, amebiasis, babesiosis, bovine babesiosis, canine babesiosis, chagas disease, coccidiosis, cyclosporiasis, equine piroplasmosis, giardiasis, granulomatous amoebic encephalitis, histomoniasis, leishmaniasis, theileriosis, trichomoniasis, or trypanosomiasis.

115. The method, the use, or the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of claim 114, wherein the disease is malaria.

116. A method of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue, the method comprising administering to the subject or contacting the biological sample or tissue with an effective amount of: a compound of any one of claims 1-95, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; or a pharmaceutical composition of any one of claims 97-101.

117. Use of a compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 97-101, for the manufacture of a medicament for inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue.

118. A compound of any one of claims 1-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 97-101, for use in inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue.

119. The method of any one of claims 103, 106, and 109-116, the use of any one of claims 104, 107, 109-115, and 117, or the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of any one of claims 105, 108-115, and 118, wherein the subject is a human.

120. An in vitro method of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a biological sample or tissue or on a surface, the method comprising contacting the biological sample, tissue, or surface with an effective amount of: a compound of any one of claims 1-95, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; or a pharmaceutical composition of any one of claims 97-101.

121. The method of claim 116 or 119, the use of claim 117 or 119, the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use of claim 118 or 119, or the in vitro method of claim 120, wherein the microorganism is a parasite, bacterium, fungus, prion, or virus.

122. The method, the use, the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use, or the in vitro method of claim 121, wherein the microorganism is a parasite.

123. The method, the use, the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, orpharmaceutical composition for use, or the in vitro method of claim 122, wherein the parasite is of the family Plasmodiidae .

124. The method, the use, the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use, or the in vitro method of claim 123, wherein the parasite is of the genus Plasmodium, Bioccala, Biguetiella, Billbraya, Dionisia, Hepatocystis, Mesnilium, Nycteria, Polychromophilus, Rayella, Saurocytozoon, or Vetufebrus.

125. The method, the use, the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use, or the in vitro method of claim 124, wherein the parasite is of the genus Plasmodium .

126. The method, the use, the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition for use, or the in vitro method of claim 125, wherein the parasite is of the species Plasmodium falciparum.

127. A method of preparing a compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, the method comprising reacting under suitable conditions a mixture comprising: a compound of Formula I-A:(I-A), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula I-B:or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula I-C:or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and a base.

128. The method of claim 127, wherein129. A method of preparing a compound of any one of claims 55-95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, the method comprising reacting under suitable conditions a mixture comprising: a compound of Formula ILA:or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula ILB:or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula ILC:or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and a base.

130. The method of claim 129, wherein131. The method of any one of claims 127-130, wherein the base is an inorganic base.

132. The method of claim 131, wherein the base is an alkali metal carbonate.

133. The method of any one of claims 127-132, wherein the mixture further comprises a solvent.

134. The method of claim 133, wherein the solvent is a chlorinated hydrocarbon.

135. The method of claim 134, wherein the solvent is dichloromethane, chloroform, or a mixture thereof.

136. The method of any one of claims 127-135, wherein suitable conditions comprise a reaction temperature and a reaction pressure, the reaction temperature is between 0 and 20, between 20 and 30, between 30 and 40, or between 40 and 50 °C, inclusive, and the reaction pressure is between 0.5 and 1.1 atm, inclusive.

137. The method of any one of claims 127-135, wherein suitable conditions comprise a reaction temperature and a reaction pressure, the reaction temperature is between 50 and 60, between 60 and 70, or between 70 and 80 °C, inclusive, and the reaction pressure is between 0.5 and 1.1 atm, inclusive.

138. The method of any one of claims 127-135, wherein suitable conditions comprise a reaction temperature and a reaction pressure, the reaction temperature is between 60 and 80 °C, between 80and 100 °C, or between 100 and 120 °C, inclusive, and the reaction pressure is between 1.1 and 5, between 5 and 10, or between 10 and 20 atm, inclusive.

139. The method of any one of claims 127-135 and 138, wherein the suitable conditions further comprise microwave irradiation.

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