WO2022256480A1

WO2022256480A1 - Arylcoumarin synthesis with azeotropic removal of water

Info

Publication number: WO2022256480A1
Application number: PCT/US2022/031886
Authority: WO
Inventors: Suizhou Yang; Oliver YU
Original assignee: Conagen Inc.
Priority date: 2021-06-03
Filing date: 2022-06-02
Publication date: 2022-12-08

Abstract

The present disclosure provides a method of preparing certain 3,4-dihydro-4-aryl coumarin derivatives. Cinnamic acid, or a certain derivative thereof, may react with phenol, or a certain derivative thereof (e.g., resorcinol), with removal of water azeotropically in the presence of a catalyst and an organic solvent to form a certain 3,4-dihydro-4-aryl coumarin derivative. The present disclosure also provides certain novel 3,4-dihydro-4-aryl coumarin derivatives, and compositions, kits, and methods of use thereof.

Description

ARYLCOUMARIN SYNTHESIS WITH AZEOTROPIC REMOVAL OF WATER

RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63/196,656 filed on June 3, 2021 and entitled ARYLCOUMARIN SYNTHESIS WITH AZEOTROPIC REMOVAL OF WATER,” the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE DISCLOSURE

Certain 3,4-dihydro-4-aryl coumarin derivatives have been found to be useful in a number of applications, such as antibiotics and unpleasant-flavor masking agents However, the processes of preparing 3,4-dihydro-4-aryl coumarin derivatives are complicated, expensive, and/or low-yielding. See, e.g., Rodrigues-Santos eta/., Tetrahedron Letters, (2007), 48(26), 4505-4508; Das et a/., Journal of Chemical Research, Synopses, (2000, (12), 556-557); Suthunuru et al., Arkivoc (Gainesville, FL, United States) (2004), (1), 138-145; Li et al., Chemi dry of Natural Compounds, (2017), 53(5), 860-865; U.S. Patent Application Publication No. US 2013-0078192 A1; Yun eta/., Bioorganic & Medicinal Chemistry Letters, (2020), 30(4), 126900; and Chinese Patent Application Publication No. CN 105541773 A.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure provides processes of preparing certain 3,4- dihydro-4-aryl coumarin derivatives. Cinnamic acid, or a certain derivative thereof, may react with phenol, or a certain derivative thereof (e.g., resorcinol), with removal of water azeotropicalIy in the presence of a catalyst (e.g., a Bronsted acid) and an organic solvent (e.g., benzene, toluene, and/or xylene) to form a certain 3, 4-di hydro-4-aryl coumarin derivative. In certain embodiments, the present disdosureprovides a process of preparing a product, wherein the process comprises:

(a) reacting a compound of Formula A:

or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, with a compound of Formula B: or a tautomer, stereoisomer, isotopica

, lt, solvate, polymorph, or co- crystal thereof, in the presence of a catalyst and an organic solvent; and

(b) azeotropical I y removing water, wherein the water is formed by step (a); wherein: each of R¹, R², R³, R⁴, R⁵, and R⁶ is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alky nyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^a, -N(R^a)₂, -SR^a, -CN, - SCN, -C(=O)R^a, -C(=O)OR^a, -C(=O)N(R^a)₂, -C(=NR^a)R^a, -C(=NR^a)OR^a, -C(=NR^a)N(R^a)₂, -NO₂, -N₃, -NR^aC(=O)R^a, -NR^aC(=O)OR^a, -NR^aC(=O)N(R^a)₂, -NR^aC(=NR^a)R^a, - NR^aC(=NR^a)OR^a, -NR^aC(=NR^a)N(R^a)₂, -OC(=O)R^a, -OC(=O)OR^a, -OC(=O)N(R^a)₂, - OC(=NR^a)R^a, -OC(=NR^a)OR^a, -OC(=NR^a)N(R^a)₂, -NR^aS(=O)₂R^a -NR^aS(=O)₂OR^a, - NR^aS(=O)₂N(R^a)₂, -OS(=O)₂R^a, -OS(=O)₂OR^a, -OS(=O)₂N(R^a)₂, -S(=O)₂R^a, -S(=O)₂OR^a, - S(=O)₂N(R^a)₂, -P(=O)(R^a)₂, or -Si(R^a)₃; each R^a is 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 R^a on a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of R⁷ and R⁸ is independently hydrogen, halogen, unsubstituted cyclopropyl, - OR^b, -N(R^b)₂, -SR^b, -CN, -SCN, -NO₂, -N₃, unsubstituted C_1-3alkyl, or C_1-3alkyl substituted with one or more halogen; each R^b is independently hydrogen, unsubstituted C_1-23 alkyl, or C_1-23 alkyl substituted with one or more halogen; and

R⁹ is hydrogen, and the product is a compound of Formula 1-1 or I -2:

or a tautomer, stereoiso

, , , , , or co- crystal thereof, or a mixture thereof; or R⁹ is halogen, unsubstituted cyclopropyl, -OR^b, -N(R^b)₂, -SR^b, -CN, -SCN, -NO₂, -N₃, unsubstituted C_1-3 alkyl , or C_1-3 alkyl substituted with one or more halogen, and the product is a compound of Formula 1-1, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof. h Compared to known processes of preparing 3,4-di hydro-4-aryl coumarin derivatives, the processes descri bed herein may be simpler, faster, easier to purify, less expensive, less energy-demanding, higher yielding, and/or more sealable, and/or may reduce side-product pollution.

In another aspect, the present disclosure provides a compound of the f ormul a

or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co- crystal , or prodrug thereof.

In another aspect, the present disclosure provides compositions comprising:

Compound SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal, or prodrug thereof; and opti onal I y an exci pi ent .

In certain embodiments, the composition is a pharmaceutical composition.

In another aspect, the present disclosure provides ki ts comprising: Compound SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal, or prodrug thereof, or a composition thereof; and instruct! ons for using the compound, tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal, prodrug, or composition.

In another aspect, the present disclosure provides methods of treati ng a di sease i n a subject in need thereof comprising administering to the subject in need thereof Compound SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, pharmaceutically acceptable co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.

In another aspect, the present disclosure provides methods of masking an unpleasant flavor of an unpleasantly flavored substance comprising contacting or mixing the unpleasantly flavored substance with the compound of Formula SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, pharmaceutically acceptable co-crystal, or prodrug thereof, or a composition thereof.

Whi I e the disclosure i s suscepti bl e to vari ous modi f i cati ons and al ternati ve forms, sped f i c embodiments thereof are shown by way of exampl e i n the drawl ng and wi 11 herei n be described in detail. It should be understood, however, that the detai led description presented herein are not intended to limit the disclosure to the particular embodiments di sdosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure as defined by the appended daims.

Other features and advantages of thi s disclosure will become apparent i n the fol I owi ng detai I ed descri pti on of certai n embodiments of the disclosure.

DEFINITIONS

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moietiesand reactivity, are described in Thomas SorrelI , Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5^th Edition, 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, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

Compounds descri bed herei n can comprise one or more asymmetri c centers, and thus can exist in various isomeric forms, eg., enantiomers and/or diastereomers. For example, the compounds descri bed 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 mixturesand mixtures enriched in one or more stereoisomer. Isomerscan be isolated from mi xtures by methods known to those ski 11 ed i n the art, i ncl udi ng chi ral hi gh pressure I i qui d chromatography (HPLC), supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomerscan be prepared by asymmetric syntheses. See, for example, Jacques eta/., Enantiomers, Racemates and Resol c/t ions (\N\\ey Interscience, New York, 1981); Wilen etal., Tetrahedron 33:2725 (1977); Eliel, Stereochemi dry of Carbon Compounds (McGraw- Hi II, NY, 1962); and Wilen, Tables of Resolving Agentsand Optical Resoiutionsp. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds descri bed herein as individual isomers substantially free of other isomers, and alternatively, as mi xtures of various isomers.

In a f ormul a, the bond j s a si ngl e bond where the stereochemi stry i s not sped f i ed.

Unless otherwise provided, a formula depicted herein includes compounds that do not i nd ude i sotopi cal I y enri ched atoms and al so compounds thatinclu ude i sotopi cal I y enri ched atoms. Compounds thatinclu ude i sotopi cal I y enri ched atoms may be useful as, for example, analytical tools, and/or probes in biological assays

When a range of val ues ( range”) i s I i sted, it i s i ntended to encompass each val ue and sub- range wi thi n the range. A range i s incl uusi ve of the val ues at the two ends of the range uni ess otherwi se provi ded. For exampl e, ch i nteger between 1 and 4” refers to 1 , 2, 3, and 4. For example C_1-6 alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1- ₃, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6 alkyl.

Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group havi ng from 1 to 20 carbon atoms ( C_1-20 alkyl ”). In some embodiments, an alkyl group has 1 to 12 carbon atoms ( C_1-12 alkyl ”). In some embodiments, an alkyl group has 1 to 10 carbon atoms ( C_1-10 alkyl ”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ( C_1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ( C_1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms ( C_{1 -7} alkyl ”). In some embodiments, an alkyl group has 1 to 6 carbon atoms ( C_1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms ( C_1-5 alkyl ”). In some embodiments, an alkyl group has 1 to 4 carbon atoms ( C_1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ( C_1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ( C_1-2 alkyl”) . In some embodiments, an alkyl group has 1 carbon atom ( C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms ( C_2-6 alkyl ”) . Exampl es of C_1-6 al ky I groups i undcelu methyl ( C₁), ethyl ( C₂), n-propyl ( C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), iso- butyl (C₄), n- pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkyl groups incl ude n- heptyl (C₇), n-octyl (C₈) 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 certai n embodiments, the alkyl group is unsubstituted C_1-12 alkyl (e.g., -CH₃(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group issubstituted C_1-12 alkyl (such as substituted C_1-6 alkyl, e.g., - CH₂F, -CHF₂, -CF₃, -CH₂CH₂F, -CH₂CHF₂,-CH₂CF₃, or benzyl (Bn)). The attachment point of alkyl may beasingle bond (e.g., as in -CH₃), double bond (e.g., as in =CH₂), or tri pie bond (e.g, as in CH). Themoieties =CH₂ and CH are al so alkyl.

In some embodiments, an alkyl group i s substi tuted wi th one or more hal ogens.

Perhal oalkyl” i s a substituted alkyl group as def i ned herei n wherein al I 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 ( C_1-8 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms ( C_1-6 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms ( C_1-4 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ( C_1-3 perhaloalkyl”). In some embodiments, the alkyl moi ety has 1 to 2 carbon atoms ( C_1-2 perhaloalkyl ”). In some embodiments, al I of the hydrogen atoms are repl aced wi th fl uoro. In some embodiments, al I of the hydrogen atoms are repl aced with chloro. Examples of perhaloalkyl groups include -CF₃, -CF₂CF₃, -CF₂CF₂CF₃, -CCI₃, -CFCI₂, -CF₂CI, and the like.

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 doubl e bonds, and no tri pl e bonds ( C_2-20 al kenyl ”). In some embodiments, an al kenyl group has 2 to 10 carbon atoms ( C_2-10 al kenyl ”). In some embodiments, an al kenyl group has 2 to 9 carbon atoms ( C₂-9 al kenyl ”). In some embodiments, an al kenyl group has 2 to 8 carbon atoms ( C_2-8 al kenyl ”). In some embodiments, an al kenyl group has 2 to 7 carbon atoms ( C_2-7 alkenyl ”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ( C_2-6 alkenyl ”). In some embodiments, an al kenyl group has 2 to 5 carbon atoms ( C₂-5 al kenyl ”). In some embodiments, an al kenyl group has 2 to 4 carbon atoms ( C_2-4 al kenyl ”). In some embodiments, an al kenyl group has 2 to 3 carbon atoms ( C_2-3 al kenyl ”). In some embodiments, an al kenyl group has 2 carbon atoms ( C_2- a₆l kenyl ”) . The one or more carbon- carbon double bonds can be i nternal (such as i n 2- butenyl ) or termi nal (such as i n 1 - butenyl ). Examples of C_2-4 al kenyl groups i ncl ude ethenyl (C₂), 1 -propenyl (C₃), 2- propenyl (C₃), 1- butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and thelike. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 alkenyl groups aswell as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyilnclu ude heptenyl (C₇), octenyl (C₆), octatrienyl (C₆), and the like. Uni ess otherwise sped fied, each instance of an alkenyl group is independently optionally substituted, e.g., unsubstituted (an unsubstituted alkenyl”) or substituted (a Substituted al kenyl ”) with one or more substituents. In certain embodiments, the alkenyl group is unsubstituted C_2-10 alkenyl. In certain embodiments, the al kenyl group is substituted C_2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not spedfied (e.g., -CH=CHCH₃ or ) may be in the (E)- or (Z)- configuration.

Alkynyl” refers to a radi cal 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 tri pl e bonds, and opti onal I y one or more doubl e bonds ( C_2-20 al kyny I ”) . In some embodiments, an alkynyl group has2 to 10 carbon atoms ( C_2-10 alkynyl”). In some embodiments, an al kyny I group has 2 to 9 carbon atoms ( C_2-9 al kyny I ”). In some embodiments, an al kyny I group has 2 to 8 carbon atoms ( C_2-8 al kyny I ”). In some embodiments, an al kyny I group has 2 to 7 carbon atoms ( C_2-7 al kyny I ”). In some embodiments, an al kynyl group has 2 to 6 carbon atoms ( C_2-6 al kynyl ”). In some embodiments, an al kynyl group has 2 to 5 carbon atoms ( C_2-5 al kynyl ”). In some embodiments, an al kynyl group has 2 to 4 carbon atoms ( C_2-4 al kynyl ”). In some embodiments, an al kynyl group has 2 to 3 carbon atoms ( C_2-3 al kynyl ”). In some embodiments, an al kynyl group has 2 carbon atoms ( C_2- a₆l kynyl ”). The one or more carbon- carbon tri pl e bonds can be i nternal (such as i n 2- butynyl ) or terminal (such as i n 1 - butynyl ). Examples of C_2-4 al kynyl groupsinclu ude ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1- butynyl (C₄), 2- butynyl (C₄), and the I ike. Exampl es of C_2-6 alkenyl groups include the aforementioned C_2-4 alky ny I groups as well as pentynyl (C₆), hexynyl (C₆), and the I ike. Additional exampl es of alky ny I incl uude heptynyl (C₇), octynyl (C₆), and the I ike. 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 C_2-10 al ky ny I . In certai n embodiments, the al ky ny I group i s substi tuted C₂- 10 al ky nyl .

Carbocycl y I ” or carbocycl i c” refers to a radi cal of a non - aromati c cycl i c hydrocarbon group havi ng from 3 to 13 ring carbon atoms ( C₃-13 carbocycl y I ”) and zero heteroatoms i n the non- aromati c ring system. In some embodiments a carbocyd yl group has 3 to 8 ring carbon atoms ( C_3-8 carbocycl y I ”). In some embodiments, a carbocycl y I group has 3 to 7 ring carbon atoms ( C_3-7 carbocycl y I ”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms( C_3-6 carbocyclyl”). In some embodiments a carbocyclyl group has 5 to 10 ring carbon atoms ( C_5-10 carbocyclyl”). Exemplary C_3-6 carbocyclyl groupsinclude cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₆), cyclopentenyl (C₆), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3-8 carbocyclyl groups include the aforementioned C_3-6 carbocyclyl groups as well ascycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₆), cyclooctenyl (C₆), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₆), and the like. Exemplary C_3-10 carbocyclyl groups include the aforementioned C_3-8 carbocyclyl groups aswell ascyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H- indeny I (C₉), decahydronaphthal enyl (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 bi cycl ic system ( Bi cycl ic carbocyclyl”). Carbocyclyl can be saturated, and saturated carbocycl y I i s referred to as cycl oalkyl . ” In some embodiments, carbocycl y I i s a monocycl i c, saturated carbocyclyl group havi ng from 3 to 10 ring carbon atoms ( C_3-10 cycloalkyl ”). In some embodiments, a cycl oalkyl group has 3 to 8 ring carbon atoms ( C_3-8 cycloalkyl ”). In some embodiments, a cycl oalkyl group has 3 to 6 ring carbon atoms ( C_3-6 cycloalkyl”). In some embodiments, a cycl oalkyl group has 5 to 6 ring carbon atoms ( C₆-s cycloalkyl ”). In some embodiments, a cycl oalkyl group has 5 to 10 ring carbon atoms ( C_5-10 cycloalkyl ”). Exampl es of C_5-6 cyc lalkyl groups include cyclopentyl (C₆) and cyclohexyl (C₆). Examples of C_3-6 cycl oalkyl groupsinclu ude the aforementi oned C_5-6 cycl oalkyl groups as wel I as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3-8 cycloalkyl groupsinclu ude the aforementioned C_3-6 cycloalkyl groups as well ascycloheptyl (C₇) and cyclooctyl (C₆). 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 C_3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C_3-10 cycloalkyl. Carbocyclyl can be partially unsaturated. Carbocyclyl may include zero, one, or more (eg., two, three, or four, as val ency permi ts) C=C doubl e bonds i n al I the rings of the carbocycl i c ring system that are not aromaticor heteroaromatic. Carbocyclyl including one or more(e.g., two or three, as valency permi ts) C=C doubl e bonds i n the carbocycl i c ring i s referred to as 6yd oal kenyl . ”

Carbocycl y I incl uudi ng one or more (eg. , two or three, as val ency permi ts) Cl C tri pl e bonds i n the carbocycl ic ring is referred to as cycloalkynyl.” Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as def i ned above, is fused with one or more aryl or heteroaryl groups wherein the poi nt of attachment i s on the carbocyclyl ring, and i n such i nstances, the number of carbons conti nue to desi gnate the number of carbons i n the carbocycl i c ring system. Unless otherwise spedfied, 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 C_3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C_3-10 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.

In some embodiments, carbocycl yl ” i s a monocycl i c, saturated carbocycl yl group having from 3 to 10 ring carbon atoms( C_3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ( C_3-8 cycloalkyl ”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ( C_3-6 cycloalkyl ”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ( C_5-6 cycloalkyl ”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ( C_5-10 cycloalkyl ”). Exampl es of C_5-6 cycloalkyl groups incl udecyclopentyl (C₅) and cyclohexyl (C₅). Exampl es of C_3-6 cycloalkyl groups include the aforementi oned C_5-6 cycloalkyl groups as well ascyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3-8 cycloalkyl groups include the aforementi oned C_3-6 cycloalkyl groups as well ascycloheptyl (C₇) and cyclooctyl (C₆). Unless otherwisespedfied, each i nstance of a cycl oalkyl group i s i ndependentl y unsubsti tuted (an unsubsti tuted cycloalkyl ”) or substituted (a substituted cycloalkyl ”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C_3-10 cycloalkyl. In certain embodiments, thecycloalkyl group is substituted C_3-10 cycloalkyl. I n certai n embodiments, the carbocycl yl inclu udes oxo substi tuted thereon.

Heterocyclyl ” or heterocycl i c” refers to a radi cal of a 3- to 13- membered non- aromati c ring system havi ng ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is i ndependently 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 ( fhonocyclic heterocyclyl”) or afused, bridged, or spiro ring system such as a bi cycl i c system ( bi cycl i c heterocycl yl”) . A heterocycl y I group can be saturated or can be partially unsaturated. Heterocyclyl may include zero, one, or more(e.g., two, three, or four, as val ency permi ts) doubl e bonds i n al I the rings of the heterocyd i c ring system that are not aromati c or heteroaromati c. Heterocycl yl bi cycl i c ring systems can incl uude one or more heteroatoms i n one or both rings. Heterocy d y I” al so incl uudes 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 poi nt of attachment is on the heterocyclyl ring, and in such instances, the number of ring members conti nue to desi gnate the number of ring members i n the heterocycl yl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an unsubstituted heterocyclyl”) or substituted (a substituted heterocyclyl”) with one or more substituents. In certai n 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 heterocyclylinclu udes oxo substituted thereon.

I n some embodiments, a heterocycl yl group i s a 5- 10 membered non- aromati c ring system having ring carbon atomsand 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 a5-8 membered non-aromatic ring system having ring carbon atomsand 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 atomsand 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 sei ected 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.

Exempl ary 3- membered heterocycl yl groups contai ni ng one heteroatominclu ude azi rdi nyl , oxi ranyl , or thi i ranyl . Exempl ary 4- membered heterocycl yl groups contai ni ng one heteroatom includeazetidinyl, oxetanyl and thietanyl. Exemplary 5- membered heterocycl y I groups contai ni ng one heteroatominclu ude tetrahydrofuranyl , di hydrofuranyl , tetrahydrothiophenyl, di hydrothiophenyl, pyrrolidinyl, di hydropyrrol y I and pyrrolyl-2,5- dione. Exemplary 5- membered heterocyclyl groups contai ni ng two heteroatoms inclu ude dioxolanyl, oxasul furanyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocycl y I groups contai ni ng three heteroatomsinclu ude tri azol i nyl , oxadi azol i nyl , and thiadi azol i nyl. Exemplary 6- membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocycl y I groups contai ni ng two heteroatomsinclu ude pi perazi nyl , morphol i ny I , di thi any I , and dioxanyl. Exemplary 6- membered heterocycl yl groups contai ni ng two heteroatoms i nd ude tri azi nanyl . Exempl ary 7- membered heterocycl yl groups contai ni ng one heteroatom includeazepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups contai ni ng one heteroatominclu ude azocany I , oxecanyl , and thi ocany I . Exempl ary 5-membered heterocycl y I groups fused to a C₆ ary I ring (al so referred to herei n as a 5,6-bi cycl i c heterocycl i c ring) incl uude i ndol i nyl , i soi ndol i nyl , di hydrobenzofuranyl , di hydrobenzothi enyl , benzoxazol i nonyl , and the I i ke. Exempl ary 6-membered heterocycl y I groups fused to an aryl ring (al so referred to herei n as a 6,6-bi cycl i c heterocycl i c ring) in ucdleu tetrahydroqui nol i nyl , tetrahydroi soqui nol i nyl , and the I i ke.

Aryl ” refers to a radi cal of a monocycl i c or pol ycycl i c (e.g., bi cycl i c or tri cycl i c) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 el ectrons shared in a cycl ic array) having 6-14 ring carbon atoms and zero heteroatoms provi ded i n the aromati c ring system ( C_6-14 aryl ”). In some embodiments, an aryl group has six ring carbon atoms ( C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ( C₁₀ aryl 4.g., naphthyl such as 1 - naphthyl and 2- naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ( Cuaryl”; e.g., anthracyl). Aryl” also includes ring systems wherein the aryl ring, asdefined above, isfused with oneor morecarbocyclyl or heterocyclyl groups wherein the radi cal 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. Uni ess otherwise specified, each instance of an aryl group is independently optionally substituted, eg., unsubstituted (an unsubstituted aryl ”) or substituted (a substituted aryl ”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C_{6- 14} aryl. In certain embodiments, the aryl group is substituted C_6-14 aryl .

Aeteroaryl ” refers to a radi cal of a 5- 10 membered monocycl i c or bi cycl i c 4n+2 aromati c ring system (eg., havi ng 6 or 10 > el ectrons shared i n a cycl i c array) havi ng ring carbon atoms and 1 -4 ring heteroatoms provi ded i n the aromati c ring system, wherein each heteroatom is i ndependently selected from nitrogen, oxygen and sulfur ( 5-10 membered heteroaryl ”). In heteroaryl groups that contai n one or more nitrogen atoms, the poi nt of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems caninclu ude one or more heteroatoms i n one or both rings. A eteroary I ” inc uludes ring systems wherein the heteroaryl ring, as defined above, is fused with one or morecarbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such i nstances, the number of ring members conti nue to desi gnate the number of ring members i n the heteroaryl ring system. Aeteroaryl ” al so incl uudes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the poi nt of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members desi gnates the number of ring members i n the fused (aryl /heteroaryl ) ring system. B i cycl i c heteroaryl groups wherein one ring does not contai n a heteroatom (eg., i ndolyl , qui nol i nyl , carbazolyl, and the like) the poi nt of attachment can be on either ring, eg., either the ring bearing a heteroatom (eg., 2-indolyl) or the ring that does not contain a heteroatom (eg., 5- i ndolyl).

In some embodiments, a heteroaryl group i s a 5- 10 membered aromati c ring system havi ng ring carbon atoms and 1 - 4 ring heteroatoms provi ded i n the aromati c ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( 5-10 membered heteroaryl”). In some embodiments, a heteroaryl group isa5-8 membered aromatic ring system having ring carbon atomsand 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 aromati c ring system havi ng ring carbon atoms and 1 -4 ring heteroatoms provi ded i n 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. Uni ess otherwise specified, each instance of a heteroaryl group is independently optionally substituted, e.g., unsubstituted ( unsubstituted heteroaryl ”) or substituted ( Substituted heteroaryl ”) with one or more substituents. In certai n embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl . In certai n 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.

Exempl ary 5- membered heteroaryl groups contai ni ng one heteroatominclu ude pyrrolyl , furanyl and thiophenyl. Exemplary 5- membered heteroaryl groups contai ni ng two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroary I groups contai ni ng three heteroatomsinclu ude tri azol y I , oxadi azol y I , and thiadiazolyl. Exemplary 5- membered heteroaryl groups containing four heteroatomsinclu ude tetrazol yl. Exemplary 6- membered heteroaryl groups contai ni ng 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 tri aziny I and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing one heteroatominclu ude azepi nyl, oxepinyl, and thiepinyl. Exemplary 5,6- bi cyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothi azolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6- bi cyclic heteroaryl groupsinclu ude naphthyri di nyl , pteri di nyl , qui nol i nyl , i soqui nol i nyl , d nnol i nyl , qui noxal i nyl , phthal azi ny I , and qui nazol i nyl .

Parti al I y unsaturated” refers to a group thatinclu udes at I east one doubl e or tri pl e bond. The term partially unsaturated” is intended to encompass rings having multi pie 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 tri pie bond, i.e., contai ns all single bonds.

In some embodiments, alkyl , al kenyl , al kynyl , carbocycl yl , heterocyclyl , aryl , and heteroaryl groups, asdefined herein, areoptionally substituted (e.g., substituted” or unsubstituted” alkyl, substituted” or unsubstituted” alkenyl, substituted” or unsubstituted” al kynyl, 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 opti onal I y ” or not, means that at I east 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 oneor more substitutable posi ti ons of the group, and when more than one posi ti on i n any gi ven structure i s substi tuted, 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 contempl ates any and al I such combi nati ons i n order to arri ve at a stabl e compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy thevalendesof the heteroatoms and resul ts i n the format! on of a stabl e moi ety .

Exemplary carbon atom substituents include halogen, -CN, -NO₂, -N₃, -SO₂H, -SO₃H, -OH, -OR^aa , -ON(R^bb)₂, -N(R^bb)₂, -N(R^bb)₃ ⁺X", -N(OR^oc)R^bh, -SH, -SR^aa , -SSR^cc -C(=O)R^aa, -CO₂H, -CHO, -CCOR^cc , -CO₂R^aa, -OC(=O)R^aa , -OCO₂R^aa , -C(=O)N(R^bb)₂, -OC(=O)N(R^bb)₂, -NR^bbC(=O)R^aa , -NR^bbCO₂R^aa, -NR^bbC(=O)N(R^bb)₂, -C(=NR^bb)R^aa, -C(=NR^bb)OR^aa , -OC(=NR^bb)R^aa , -OC(=NR^bb)OR^aa , -C(=NR^bb)N(R^bb)₂, -OC(=NR^bb)N(R^bb)₂, -NR^bbC(=NR^bb)N(R^bb)₂, -C(=O)NR^bbSO₂R^aa, -NR^bbSO₂R^aa, -SO₂N(R^bb)₂, -SO₂R^aa , -SO₂OR^aa, -OSO₂R^aa, -S(=O)R^aa , -OS(=O)R^aa, -SiCR^aa ^, -OSj(R^aa)₃, -C(=S)N(R^bb)₂, -C(=O)SR^aa, -C(=S)SR^aa , -SC(=S)SR^aa, -SC(=O)SR^aa , -OC(=O)SR^aa, -SC(=O)OR^aa, -SC(=O)R^aa, -P(=O)(R^aa)₂, -P(=O)(OR^cc)₂,-OP(=O)(R^aa)₂, -OP(=O)(OR^cc)₂, -P(=O)(N(R^bb)₂)₂, -OP(=O)(N(R^bb)₂)₂, -NR^bbP(=O)(R^aa)₂, -NR^bbP(=O)(OR^cc)₂, -NR^bbP(=O)(N(R^bb)₂)₂, -P(R^cc)₂, -PtOR^cc)₂, -PfR^X’, -PfOR^cc -P(R^cc)₄, -PCOR^, -OP(R^cc)₂, -OP^X; -OP(OR^cc)₂, -OP(OR^cc)3⁺X", -OP(R^cc)₄, -OPCOR^cc)₄ -BCR^aa ^, -B(OR^cc)₂, -BR^aaOR⁰⁰), C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C₂-w alkynyl, heteroC_1-3 10 alkyl, heteroC_2-10 alkenyl, heteroC_2-10 al kynyl , C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 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 R^dd groups; wherein X” is a counterion; or two gemi nal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R^bb)₂, =NNR^bbC(=O)R^aa, =NNR^bbC(=O)OR^aa, =NNR^bbS(=O)₂R^aa, =NR^bb, or =NOR^cc; each instance of R^aa is, independently, selected from C_1-10 alkyl , C_1-10 perhaloalkyl, C₂- 10 alkenyl , C_2-10 al kynyl , heteroC_1-10 alkyl , heteroC_2-10al kenyl, heteroC_2-10al kynyl , C_3-10 carbocyclyl , 3-14 membered heterocyclyl , C_{6- 14} aryl , and 5-14 membered heteroaryl , or two R^aa groups arejoined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where n each alkyl , al kenyl , al kynyl , heteroalkyl , heteroal kenyl , heteroal kynyl , carbocyclyl , heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; each instance of R^bb is, independently, selected from hydrogen, -OH, -OR^aa , -N(R^cc)₂, -ON, -C(=O)R^aa, -C(=O)N(R^cc)₂, -CO₂ R^aa , -SO₂R^aa , -C(=NR^cc)OR^aa , -C(=NR^cc)N(R^cc)₂, -SO₂N(R^cc)₂, -SO₂R^cc, -SO₂OR^cc, -SOR^aa , -C(=S)N(R^cc)₂, -C(=O)SR^cc, -C(=S)SR^cc, -P(=O)(R^aa)₂, -P(=O)(OR^cc)₂, -P(=O)(N(R^cc)₂)₂, C_1-10 alkyl, C_1-10 perhdoalkyl, C_2-10 al kenyl , C_2-10 al kynyl , heteroC_{1 -10}alkyl , heteroC_2-10al kenyl, heteroC_2-10al kynyl , C_3-10 carbocyclyl, 3-14 membered heterocyclyl , C_{6- 14} aryl , and 5-14 membered heteroaryl , or two R^bb groups are joined to form a 3- 14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, al kynyl, heteroalkyl , heteroalkenyl, heteroal kynyl , carbocyclyl, heterocyclyl , aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 R^dd groups; wherein X" is a counterion; each instance of R⁰⁰ is, independently, selected from hydrogen, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl , C_2-10 al kynyl, heteroCi_-10 alkyl , heteroC_2-10 alkenyl, heteroC_2-10 alkynyl , C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_{6- 14} aryl, and 5-14 membered heteroaryl , or two R⁰⁶ groups arejoi ned to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl , heteroalkyl , heteroal kenyl, heteroal kynyl , carbocyclyl, heterocyclyl , aryl , and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; each instance of R^dd is, independently, selected from halogen, -CN, -NO₂, -N₃, -SO₂H, -SO₃H, -OH, -OR^ee, -ON(R^ff)₂, -N(R^ff)₂, -N(R^ff)₃ ⁺X", -N(OR^ee)R^ff, -SH, -SR^ee, -SSR^ee, -C(=O)R^ee, -CO₂H, -CO₂R^ee, -OC(=O)R^ee, -OCO₂R^ee, -C(=O)N(R^ff)₂, -OC(=O)N(R^ff)₂, -NR^ffC(=O)R^ee, -NR^ffCO₂R^ee, -NR^ffC(=O)N(R^ff)₂, -C(=NR^ff)OR^ee, -OC(=NR^ff)R^ee, -OC(=NR^ff)OR^ee, -C(=NR^ff)N(R^ff)₂, -OC(=NR^ff)N(R^ff)₂, -NR^ffC(=NR^ff)N(R^ff)₂, -NR^ffSO₂R^ee, -SO₂N(R^ff)₂, -SO₂R^ee, -SO₂OR^ee, -OSO₂R^ee, -S(=O)R^ee, -8(^3, -OSi(R^ee)3, -C(=S)N(R^ff)₂, -C(=O)SR^ee, -C(=S)SR^ee, -SC(=S)SR^ee, -P(=O)(OR^ee)₂, -P(=O)(R^ee)₂, -OP(=O)(R^6e)₂, -OP(=O)(OR^6e)₂, C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, heteroC_{1 -6}alkyl , heteroC_2-6al kenyl , heteroC_2-6al kynyl , C_3-10 carbocyclyl, 3-10 membered heterocyclyl , C_6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl , heteroalkenyl, heteroal kyny I, carbocyclyl, heterocyclyl , aryl , and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 R" groups, or two gemi nal R^dd substituents can be j oi ned to form =O or =S; wherein X" is a counterion; each instance of R^ee is, independently, selected from C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 al keny I , C_2-6 al kyny I , heteroC_{1 -6} alkyl , heteroC_2-6al keny I , heteroC_2-6 al kyny I , C_3-10 carbocycl y I , C_6-10 aryl , 3-10 membered heterocyclyl , and 3-10 membered heteroaryl, wherein each alkyl , alkenyl, alkynyl , heteroalkyl , heteroal kenyl , heteroal kynyl , carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R" groups; each instance of R^ff is, independently, selected from hydrogen, C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 al kenyl, C_2-6 al kynyl, heteroC_{1 -6}alkyl , hetero C_2-6al kenyl , het ero C_2-6al kynyl, C_3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl and 5-10 membered heteroaryl, or two R^ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl , al kenyl , al kynyl , heteroalkyl , heteroal kenyl , heteroal kynyl , carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R" groups; and each instanceof R" is, independently, halogen, -CN, -NO₂, -N₃, -SO₂H, -SO₃H, -OH, -OC_1-6 alkyl, -ON (C_1-6 alkyl )₂, -N(C_1-6 alkyl)₂, -N(C_1-6 alkyl ₃ ⁺X", -NH(C_1-6 alkyl)₂ ⁺X", -NH₂(C_1-6 alkyl ) ⁺X“, -NH₃ ⁺X“, -N(OC_1-6 alkyl)(C_1-6 alkyl), -N(OH)(C_1-6 alkyl , -NH(OH), -SH, -S C_1-6 alkyl , -SS(C_1-6 alkyl), -C(=O)(C_1-6 alkyl), -CO₂H, -CO₂(C_1-6 alkyl ), -OC(=O)(C_1-6 alkyl , -OCO₂(C_1-6 alkyl , -C(=O)NH₂, -C(=O)N(C_1-6 alkyl)₂, -OC(=O)NH(C_1-6 alkyl), -NHC(=O)( C_1-6 alkyl), -N(C_1-6 alkyl)C(=O)( C_1-6 alkyl , -NHCO₂(CI_-6 alkyl), -NHC(=O)N( C_1-6 alkyl ₂, -NHC(=O)NH(C_1-6 alkyl , -NHC(=O)NH₂, -C(=NH)O(C_1-6 alkyl), -OC(=NH)(C_1-6 alkyl), -OC(=NH)OC_1-6 alkyl, -C(=NH)N(C_1-6 alkyl )₂, -C(=NH)NH(C_1-6 alkyl), -C(=NH)NH₂, -OC(=NH)N(C_1-6 alkyl )₂, -OC(NH)NH(C_1-6 alkyl), -OC(NH)NH₂, -NHC(NH)N(C_1-6 alkyl )₂, -NHC(=NH)NH₂, -NHSO₂(C_1-6 alkyl), -SO₂N(C_1-6 alkyl)₂, -SO₂NH(C_1-6 alkyl , -SO₂NH₂, -SO₂C_1-6 alkyl, -SO₂OC_1-6 alkyl, -OSO₂C_1-6 alkyl, -SOC_1-6 alkyl, -Si (C_1-6 alkyl )₃, -OSi(C_1-6 alkyl )₃ -C(=S)N(C_1-6 alkyl )₂, C(=S)NH(C_1-6 alkyl), C(=S)NH₂, -C(=O)S(C_1-6 alkyl , -C(=S)SC_1-6 alkyl, -SC(=S)SC_1-6 alkyl, -P(=O)(OC_1-6 alkyl )₂, -P(=O)(C₁.6 alkyl)₂, -OP(=O)(C₁.6 alkyl)₂, -OP(=O)(O C_1-6 alkyl )₂, C_1-6 alkyl , C_1-6 perhaloalkyl , C_2-6 al kenyl , C_2-6 al kynyl , heteroC_1-6alkyl , heteroC₂ ealkenyl, heteroC_2-6al kynyl , C_3-10 carbocyclyl , C_6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl ; or two gemi nal R" substi tuents can be j oi ned to form =O or =S; wherein X" is a counter! on. In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, -OR^aa , -SR^aa , -N(R^bb)₂, -CN, -SCN, -NO₂, -C(=O)R^aa , -CO₂R^aa , -C(=O)N(R^bb)₂, -OC(=O)R^aa , -OCO₂R^aa, -OC(=O)N(R^bb)₂, -NR^bbC(=O)R^aa, -NR^bbCO₂R^aa, or -NR^bbC(=O)N(R^bb)₂. In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl , -OR^aa , -SR^aa , -N(R^bb)₂, - CN, -SCN, -NO₂, -C(=O)R^aa , -CO₂R^aa , -C(=O)N(R^bb)₂, -OC(=O)R^aa, -OCO₂R^aa, -OC(=O)N(R^bb)₂, -NR^bbC(=O)R^aa , -NR^bbCO₂R^aa, or-NR^bbC(=O)N(R^bb)₂, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidometht-yl, Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or tri phenyl methyl ) when attached to a sul fur atom; and each R^bb i s i ndependentl y hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, ora nitrogen protecting group. In certai n embodiments, the carbon atom substituents are independently halogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C_1-6 alkyl , -OR^aa , -SR^aa , -N(R^bb)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 C_1-6 alkyl, -OR^aa , -SR^aa , -N(R^bb)₂, -CN, -SCN, or -NO₂, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl , an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t- Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or tri phenyl methyl) when attached to a sulfur atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, or a nitrogen protecting group.

A counter ion” or anionic counter! on” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monoval ent (i.e., including oneformal negative charge). An anionic counterion may also be multivalent (i.e., including more than oneformal 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, tri fluoromethanesulfonate, p- toluenesulf onate, benzenesulfonate, 10- camphor sulfonate, naphthal ene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid -2- sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycol ate, gluconate, and the like), BF₄-, PF₄-, PF₆-, AsF₆-, SbF₆-, B[3,5-(CF₃)₂C₆H₃]₄]-, B(C₆F₅)₄-, BFh₄-, AI(OC(CF₃)₃)₄-, and carborane anions (e.g., CB11H12" or (HCB₁₁Me₅Br₆)"). Exemplary counterions which may be multi valent include CO₃ ^2-, HPO₄ ^2-, PO₄ ^3-, B4O₇ ^2-, SO₄ ^2-, S₂O₃ ^2-, carboxyl ate anions (e.g, tartrate, citrate, fumarate, maleate, malate, mal onate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the I ike), and carboranes.

Aal o” or Hal ogen” refers to fl uori ne (fl uoro, - F), chi ori ne (chi oro, - Cl ), bromi ne (bromo, -Br), or iodine(iodo, -I).

Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR^aa , -N(R^cc)₂, -CN, -C(=O)R^aa , -C(=O)N(R^cc)₂, -CO₂R^aa , -SO₂R^aa , -C(=NR^bb)R^aa, -C(=NR^cc)OR^aa , -C(=NR^cc)N(R^cc)₂, -SO₂N(R^cc)₂, -SO₂R^cc, -SO₂OR^cc, -SOR^aa , -C(=S)N(R^cc)₂, -C(=O)SR^cc, -C(=S)SR^cc, -P(=O)(OR^cc)₂, -P(=O)(R^aa )₂, -P(=O)(N(R^cc)₂)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 al kynyl , heteroC_1-w₃ alkyl , heteroC_2-10al kenyl , heteroC₂-wal kynyl , C_3-10 carbocyclyl, 3-14 membered heterocyclyl , C_6-14 aryl , and 5-14 membered heteroaryl , or two R“ groups attached to an N atom arejoi ned to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl , al kenyl , al kynyl , heteroalkyl , heteroal kenyl , heteroal kynyl , carbocyclyl , heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa , R^bb, Rc ancd R^dd are as defined above.

In certain embodiments, the nitrogen atom substituents are independently substituted (e.g, substituted with one or more halogen) or unsubstituted C_1-6 alkyl , -C(=O)R^aa, -CC^R^aa , -C(=O)N(R^bb)₂, or a nitrogen protecting group. In certai n embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, -C(=O)R^aa, -CO₂R^aa , -C(=O)N(R^bb)₂, or a nitrogen protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl , or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl , or a nitrogen protecting group. In certai n embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl or a nitrogen protecting group.

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, -OR^aa , -N(R^cc)₂, -C(=O)R^aa , -C(=O)N(R^cc)₂, -COz-R^aa , -SO^³³, -C(=NR^cc)R^aa, -C(=NR^cc)OR^aa , -C(=NR^cc)N(R^cc)₂, -SO₂N(R^cc)₂, -SO₂R^cc, -SO₂OR^cc, -SOR^aa , - C(=S)N(R^cc)₂, -C(=O)SR^RC, -C(=S)SR^cc, C_1-310 alkyl (e.g., aralkyl, heteroaralkyl , C_2-10 alkenyl , C_2-10 al kynyl , C_3-10 carbocyclyl , 3-14 membered heterocyclyl , C_6-14 aryl , and 5- 14 membered heteroaryl groups, wherein each alkyl, alkenyl, al kynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R³⁹, R^bb, R^cc, and R^dd are as defined herein. Nitrogen protecting groups are well known i n the art and i ncl ude those descri bed i n detai I i n Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

Amide nitrogen protecting groups (e.g., -C(=O)R^aa) incl ude formamide, acetamide, chloroacetamide, tri chloroacetamide, trifl uoroacetami de, phenyl acetamide, 3- phenylpropanamide, pi col inamide, 3- pyridyl carboxamide, N- benzoyl phenyl al any I derivative, benzamide, p- phenyl benzamide, o-nitophenyl acetamide, o -nitrophenoxy acetamide, acetoacetamide, (/V'- di thiobenzyl oxyacyl ami no)acetami de, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2- methyl -2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N- acetyl methionine, o- nitrobenzamide, and o -(benzoyl oxy methyl )benzami de.

Carbamate nitrogen protecting groups (e.g., -C(=O)OR^aa) incl ude methyl carbamate, ethyl carbamante, 9-fluorenyl methyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl -[9-(10,10-dioxo- 10,10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4- methoxy phenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- tri methyl silyl ethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1 - methyl ethyl carbamate (Adpoc), 1,1 -dimethyl - 2- haloethyl carbamate, 1,1 -dimethyl -2, 2- di bromoethyl carbamate (DB-t- BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 - methyl -1 -(4- bi phenyl yl)ethyl carbamate (Bpoc), 1 - (3, 5-di -t- butyl phenyl )-1-methylethy I carbamate(t- Bumeoc), 2-(2’- and 4’ -pyridyl )ethyl carbamate (Pyoc), 2-(A/,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1- isopropyl allyl carbamate (I paoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p- bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4- methyl sulfinyl benzyl carbamate (Msz), 9- anthryl methyl carbamate, di phenyl methyl carbamate, 2- methyl thioethyl carbamate, 2 -methyl sulfonyl ethyl carbamate, 2- (p- toluenesulf ony I )ethy I carbamate, [2-(1,3- dithianyl )]methyl carbamate (Dmoc), 4- methyl thiophenyl carbamate (Mtpc), 2,4- di methyl thiophenyl carbamate (Bmpc), 2-phosphonioeihyl carbamate (Peoc), 2- tri phenyl phosphonioisopropy I carbamate (Ppoc), 1,1 -dimethyl -2- cyanoethyl carbamate, m- chloro-p-acyloxybenzyl carbamate, p- (di hydroxy boryl)benzyl carbamate, 5- benzisoxazoly I methyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (T croc), m-nitrophenyl carbamate, 3,5 dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- di methoxy -6- nitrobenzyl carbamate, phenyl (o- nitrophenyl )methy I carbamate, t-amyl carbamate, S- benzyl thiocarbamate, p -cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p- decyl oxy benzyl carbamate, 2, 2 -di methoxy acyl vinyl carbamate, o-(N,N- di methyl carboxamido)benzyl carbamate, 1,1 -dimethyl -3-(/V,A/-di methyl carboxamido)propyl carbamate, 1,1 -dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-f uranyl methyl carbamate, 2- iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isoni cotinyl carbamate, p-(p’- methoxy phenyl azo)benzyl carbamate, 1 - methyl cyclobutyl carbamate, 1- methy I cyclohexyl carbamate, 1 - methyl -1-cyclopropyl methyl carbamate, 1~methyl ~1 -(3,5- dimethoxyphenyl)ethyl carbamate, 1 - methyl -1-(p- phenyl azophenyl )ethyl carbamate, 1- methyl-1 -phenyl ethyl carbamate, 1 -methyl- 1 -(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenyl azo)benzyl carbamate, 2,4,6-tri -t- butyl phenyl carbamate, 4-

(tri methyl ammonium)benzyl carbamate, and 2,4,6-tri methyl benzyl carbamate.

Sulfonamide nitrogen protecting groups (e.g., -S(=O)₂R^aa) includep- toluenesulfonamide (Ts), benzenesulfonamide, 2, 3, 6, -tri methyl s- methoxy benzenesulf onami de (Mtr), 2,4,6-tri methoxybenzenesulfonamide (Mtb), 2,6- di methyl -4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl -4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- tri methyl benzenesulfonamide (Mts), 2,6-di methoxy-4- methyl benzenesulfonamide (i Mds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), 0- tri methyl si lylethanesulfonami de (SES), 9-anthracenesulfonamide, 4-(4’,8’- di methoxynaphthyl methyl )benzenesul f onami de (D N M BS) , benzyl sul f onami de, tri fluoromethyl sulfonamide, and phenacyl sulfonamide

Other nitrogen protecting groups include phenothiazinyl -(10)-acyl derivative, N’-p- toluenesulfonyl ami noacyl derivative,N- phenyl aminothioacyl derivative, N- benzoylphenylalanyl derivative, N-acetyl methionine derivative, 4,5-diphenyl -3-oxazolin-2- one, N-phthal imide, N-dithiasucdnimide (Dts), A/-2,3-di phenyl mal eimide, N-2,5- di methyl pyrrole, N- 1,1 , 4, 4- tetramethyl di si lyl azacyclopentane adduct (STABASE), 5- substituted 1, 3-di methyl - 1 ,3,5-triazacyclohexan-2-one, 5-substituted 1, 3-di benzyl -1,3,5- triazacyclohexan-2-one, 1 -substituted 3,5-dinitro-4-pyridone, N- methyl amine, N- al lyl amine, N- [2- (tri methyl si I yl)ethoxy] methyl ami ne (SEM), N- 3- acetoxy propyl amine, N- (1 -isopropyl -4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N- benzyl amine, A/-di(4-methoxyphenyl)methylamine, A/-5-dibenzosuberylamine, N- tri phenyl methyl ami ne (T r), N- [(4- methoxyphenyl )di phenyl methyl ] ami ne (MMTr), A/-9- phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenyl methyleneamine, N- ferrocenyl methyl ami no (F₆m), N- 2 -picolyl ami no A/'-oxide, N- 1,1 - di methyl thiomethy I eneamine, N- benzylideneamine, N-p- methoxy benzylideneamine, N- di phenyl methyleneamine, A/-[(2-pyridyl)mesityl]methyleneamine, N-(N’,N’- di methyl ami nomei hy I ene)ami ne, N, N i sopropy I i denedi ami ne, N-p- ni trobenzy I i deneami ne, N- salicylideneamine, N-5- chlorosalicylideneamine, N- (5- chloro- 2- hydroxy phenyl )pheny I methyl eneami ne, N- cycl ohexyl i deneami ne, N- (5, 5- di methyl - 3- oxo- 1 - cyclohexenyl)amine, N- borane derivative, N- di phenyl borinic acid derivative, N-

[ phenyl (pentaacyl chromium- or tungsten)acyl] amine, N- copper chelate, N- zinc chelate, N- nitroamine, N- nitrosoamine, amine A/ -oxi de, diphenylphosphinamide(Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphorami dates, di benzyl phosphorami date, diphenyl phosphorami date, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachl orobenzenesulfenami de, 2- ni tro-4- methoxybenzenesul fenami de, tri phenyl methyl sulfenami de, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, a nitrogen protecting group is Bn, Boc, Cbz, Fmoc, tri fl uoroacety I , tri phenyl methyl , acetyl , or Ts.

In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl , -C(=O)R^aa, -CC^R^aa , -C(=O)N(R^bb)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 C_1-6 alkyl , -C(=O)R^aa, -CO₂R”, -C(=O)N(R^bb)₂, or an oxygen protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl , or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-e₃ alkyl , or a nitrogen protecting group. In certai n embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl or an oxygen protecting group.

In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (al so referred to herei n as an hydroxyl protecting group”) . Oxygen protecting groups include -R^aa, -N(R^bb)₂, -C(=O)SR^aa , -C(=O)R^aa, -CO₂R^aa , -C(=O)N(R^bb)₂, -C(=NR^bb)R^aa, -C(=NR^bb)OR^aa, -C(=NR^bb)N(R^bb)₂, -S(=O)R^aa, -SO₂R⁸⁸, -Si(R^aa)₃, -P(R^cc)₂, -P(R^cc)₃ ⁺X-,-P(OR^oc)₂, -P(OR^cc)₃ ⁺X“, -P(=O)(R^aa)₂, -P(=O)(OR^cc)₂, and -P(=O)(N(R^bb) ₂)₂, wherein X-, R^aa , R^bb, and R⁰⁰ are as defined herein. Oxygen protecting groups are well known i n the art and i ncl ude those descri bed i n detai I i n Protecting Groups i n Organ! c Synthesi s, T . W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

Exempl ary oxygen protecting groups i ncl ude methyl , methoxyl methyl (MOM ), methyl thiomethyl (MTM), t- butyl thiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyl oxy methyl (BOM), p- methoxy benzyl oxy methyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guai acol methyl (GUM), t- butoxymethyl , 4- pentenyl oxymethyl (POM), siloxymethyl , 2-methoxyethoxymethyl (M EM), 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl , 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl , tetrahydrothiopyranyl, 1- methoxycyclohexyl , 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1 -[(2-chloro-4-methyl)phenyl] -4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl , tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-tri methyl -4,7-methanobenzofuran-2-yl , 1 -ethoxyethyl , 1 - (2-chloroethoxy)ethyl, 1 - methyl -1-methoxyethyl, 1 -methyl - 1-benzyloxyethyl, 1 -methyl -1 - benzyloxy-2-fluoroethyl, 2, 2, 2- tri chloroethyl, 2-tri methyl silyl ethyl , 2-(phenylselenyl)ethyl , t-butyl, allyl, p- chlorophenyl , p- methoxy phenyl , 2,4- di nitrophenyl, benzyl (Bn), p- methoxybenzyl , 3, 4- di methoxy benzyl, o-nitrobenzyl, p- nitrobenzyl , p-halobenzyl, 2,6- di chlorobenzyl, p- cy anobenzyl, p- phenyl benzyl, 2-picolyl, 4-picolyl, 3- methyl -2- picolyl N- oxido, di phenyl methyl , p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, tri phenyl methyl, a- naphthyl di phenyl methyl, p-methoxypheny I di phenyl methyl, di(p- methoxyphenyl )phenyl methyl , tri (p- methoxyphenyl )methyl, 4-(4'- bromophenacyl oxyphenyl )di phenyl methyl , 4,4' ,4" -tri s(4,5- di chi orophthal i mi dopheny I )methy 1 , 4, 4', 4" - tri s( I evul i noy I oxy phenyl )methy 1 , 4,4' ,4" - tris(benzoyloxyphenyl)methyl , 3-(imidazol - 1 -yl)bis(4^,,4"- di methoxyphenyl )methyl , 1,1 - bis(4-methoxyphenyl)-T-pyrenylmethyl , 9-anthryl , 9-(9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, tri methyl silyl (TMS), triethylsilyl (TES), tri isopropyl silyl (TIPS), di methyl isopropyl silyl (IPDMS), di ethyl isopropyl silyl (DEI PS), di methyl thexyl silyl, t- butyl di methyl silyl (TBDMS), t- butyl di phenyl silyl (TBDPS), tri benzyl silyl, tri -p-xylyl silyl, tri phenyl silyl, di phenyl methyl silyl (DPMS),t- butyl methoxy phenyl silyl (TBM PS), formate, benzoyl formate, acetate, chloroacetate, di chloroacetate, tri chloroacetate, tri fluoroacetate, methoxyacetate, tri phenyl methoxyacetate, phenoxyacetate, p- chlorophenoxyacetate, 3- phenyl propionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p- phenyl benzoate, 2,4,6- tri methyl benzoate (mesitoate), alkyl methyl carbonate, 9-fluoreny I methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2, 2, 2-tri chloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TM SEC), 2- (phenylsulfonyl) ethyl carbonate (Psec), 2- (tri phenyl phosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p- nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p- methoxy benzyl carbonate, alkyl 3,4- dimethoxybenzyl carbonate, alkyl o- nitrobenzyl carbonate, alkyl p- nitrobenzyl carbonate, alkyl S- benzyl thiocarbonate, 4~ ethoxy- 1 ~napththy I carbonate, methyl di thiocarbonate, 2- iodobenzoate, 4-azidobutyrate, 4- nitro-4- methyl pentanoate, o- (di bromomethy I) benzoate, 2- formy I benzenesulfonate, 2-(methylthiomethoxy)ethyl , 4- (methyl thiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methyl phenoxyacetate, 2,6-dichloro-4- (1,1 ,3, 3- tetramethyl butyl )phenoxyacetate, 2,4- bi s( 1 ,1 - di methy I propyl )phenoxyacetate, chlorodi phenyl acet ate, isobutyrate, monosucd noate, (E)-2-methyl -2-butenoate, o- ( methoxyacyl )benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodi ami date, alkyl N- phenyl carbamate, borate, di methyl phosphi nothioyl, alkyl 2,4- di nitrophenyl sulf enate, sulfate, methanesulfonate (mesyl ate), benzyl sulfonate, and tosyl ate (Ts).

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

In certain embodiments, the sulfur atom substituents are i ndependently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6₃ alkyl , -C(-O)R^aa, -CC^R^aa , -C(=O)N(R^bb)₂, or a sulfur protecting group. In certai n embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-63 alkyl , -C(=O)R^aa, -CO₂R^aa, -C(=O)N(R^bb)₂, or a sulfur protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-e₃ alkyl , or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, or a nitrogen protecting group. In certai n embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl or a sulfur protecting group.

In certain embodiments, the substituent present on a sulfur atom isasulfur protecting group (al so referred to as a (hi ol protecting group”) . Sul fur protecting groups incl uude -R^aa , -N(R^bb)₂, -C(=O)SR^aa , -C(=O)R^aa, -CO₂R”, -C(=O)N(R^bb)₂, -C(=NR^bb)R^aa, -C(=NR^bb)OR^aa , -C(=NR^bb)N(R^bb)₂, -S(=O)R^aa, -SO₂R^aa , -Si(R^aa)₃, -P(R^cc)₂, -P(R^cc)₃ ⁺X-, -P(OR^cc)₂, -P(OR^cc)₃ ⁺X-, -P(=O)(R^aa)₂, -P(=O)(OR^cc)₂, and -P(=O)(N(R^bb)₂)₂, wherein R^aa , R^bb, and R⁰⁰ are as def i ned herei n. Sulfur protecting groups are wei I known i n the art and inclu ude those descri bed i n detai I i n Protecting Groups i n Organ! c Synthesi s, T . W . Greene and P. G. M. Wuts, 3^rd edition, 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 tri phenyl methyl .

The mol ecul ar weight” of -R, wherein -R isany monovalent moiety, iscalculated by subtracting the atomi c wei ght of a hydrogen atom from the mol ecul ar wei ght of the mol ecul e R-H. The molecular weight” of L-, wherein -L- isany divalent moiety, iscalculated by subtracting the combi ned atomic weight of two hydrogen atoms from the molecular weight of the molecule H-L-H.

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 certai n embodiments, a substituent does not compri se one or more, two or more, or three or more hydrogen bond acceptors.

The term salt” refers to ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a nd: charge). Sal ts of the compounds of thi s i nventi on inc ulude those deri ved from i norgani c and organ! c acidsand bases. Examples of acid addition salts are salts of an ami no group formed with inorganic ad ds, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organicacids, such as acetic acid, oxalic acid, maleicacid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bi sulfate, borate, butyrate, camphorate, camphorsulfonate, dtrate, cyclopentanepropi onate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, 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- phenyl propionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulf onate, undecanoate, valerate, hi ppurate, and the I i ke. Salts derived from appropriate basesinclu ude al kali metal , alkaline earth metal, ammonium and N⁺(CI_-4 alkyl )₄ salts. Representative al kali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further saltsinclu ude ammoni um, quaternary ammoni um, and ami ne cati ons formed usi ng counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humansand other animals without undue toxidty, irritation, allergic response, and thelike, and are commensurate wi th a reasonabl e benef i t/ri sk rati o. Pharmaceuti cal I y acceptabl e sal ts are wel I known i n the art. For example, Berge ef a/., descri be pharmaceuti cal I y acceptable salts in detai I i n J. Pharmaceutical Sciences ( 1977) 66: 1 - 19. Pharmaceuti cal I y acceptabl e sal ts of the compounds descri be herei n incl uude those deri ved from sui tabl e i norgani c and organ! c aci ds and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic ad ds 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 pharmaceutical I y acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bi sulfate, borate, butyrate, camphorate, camphorsulfonate, dtrate, cyclopentanepropi onate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, 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- phenyl propionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the I ike. Salts deri ved from appropri ate basesinclu ude al kal i metal , al kal i ne earth metal , ammoni um and N⁺(C_1-4₃alky 1)₄ salts Representative al kali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, quaternary salts.

The term Sol vate” refers to forms of the compound that are associ ated wi th a sol vent, usually by a solvolysis reaction. This physical association mayinclu ude hydrogen bonding. Conventional sol vents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the I i ke. The provided compounds may be prepared, e.g, i n crystal I i ne form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and furtherinclu ude both stoi chi ometri c sol vales and non-stoi chi ometri c sol vates In certai n i nstances, the sol vate wi 11 be capabl e of i sol ati on, for exampl e, when one or more sol vent mol ecul es are incorporated in thecrystal lattice of a crystal line sol id. Solvate” encompasses both solution- phase and i sol able sol vates. Representative solvates include hydrates, ethanol at es, and methanol at es.

The term hydrate" refers to a compound that is assodated with water. Typically, the number of the water mol ecul es contai ned i n a hydrate of a compound i s In a def i ni te rati o to the number of the compound mol ecul es i n the hydrate. Therefore, a hydrate of a compound may be represented, for exampl e, by the general f ormul a Rix H₂O, wherein R i s the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates,inclu udi ng, e.g. , monohydrates (x i s 1 ), I ower hydrates (x i s a number greater than 0 and smaller than 1, e.g., hemi hydrates (R 0.5 H₂O)), and polyhydrates (x is a number greater than 1, e.g., di hydrates (RE2 H₂O) and hexahydrates (RES H₂O)).

The term tautomers” refer to compounds that are i nterchangeabl e forms of a parti cul ar compound structure, and that vary in the displacement of hydrogen atoms and electrons Thus, two structures may be i n equi I i bri um through the movement of n el ectrons and an atom (usually H). For example, enol sand ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the ad - and nitro- forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.

T automeri c forms may be rel evant to the attai nment of the opti mal chemi cal reacti vi ty and biological activity of a compound of interest. 11 i s al so to be understood that compounds that have the same mol ecul ar f ormul a but differ i n the nature or sequence of bonding of the! r atoms or the arrangement of the! r atoms i n space are termed i somers”. I somers that differ i n the arrangement of thei r atoms i n space are termed Stereoisomers”.

Stereoi somers that are not mi rror i mages of one another are termed di astereomers” and those that are non-superi mposabl e mi rror i mages of each other are termed enanti omers” . When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possi ble. An enantiomer can be characterized by the absolute conf i gurati on of i ts asymmetri c center and i s descri bed by the R- and S-sequend ng rul es of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (/.e, as (+) or (-)-i somers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture contai ni ng equal proporti ons of the enanti omers i s cal I ed a racemi c mi xture”.

The term pol y morphs” refers to a crystal I i ne form of a compound (or a sal t, hydrate, or sol vate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystal line forms usually havedifferent 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 domi nate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

The term co-crystal ” refers to a crystal I i ne structure compri si ng at I east two di ff erent components (e.g., a provided compound and an acid), wherein each of the components is independently an atom, ion, or molecule. In certai n embodiments, none of the components is a sol vent. In certai n embodiments, at I east one of the components i s a solvent. A co-crystal of a provided compound and an acid is different from a salt formed from a provided compound and the acid. In the salt, a provided compound is complexed with the acid in away that proton transfer (e.g., a complete proton transfer) from the acid to a provided compound easi ly occurs at room temperature. In the co-crystal , however, a provi ded compound i s compl exed wi th the ad d i n a way that proton transfer from the ad d to a provi ded herei n does not easi I y occur at room temperature. In certai n embodiments, i n the co-crystal , there is no proton transfer from the aci d to a provi ded compound. In certai n embodiments, i n the co-crystal , there i s parti al proton transfer from the acid to a provided compound. Co-crystal s may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a provided compound. The term prodrugs” refer to compounds,inclu udi ng deri vati ves of the provi ded compounds, which have deavable groups and become by solvolysis or under physiological conditions the provided compounds which are pharmaceutically active in vivo. Such examplesinclu ude, but are not I i mi ted to, ester derivatives and the I i ke. Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitiveform often off ers advantages of solubility, tissue compatibility, or delayed rd ease in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives wd I 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 nonaromatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of this i nventi on are parti cul ar prodrugs In some cases i t i s desi rabl e to prepare doubl e ester type prodrugs such as (acyl oxy)alkyl esters or ((al koxycarbonyl)oxy)alkyl esters. C₁ to C₆ alkyl, C₂- C₆ al kenyl , C₂-C₈ alkynyl , aryl , C₇-C₁₂ substituted aryl , and C₇-C₁₂ aryl alkyl esters of the provided compounds may be preferred.

An azeotrope” or azeotropic mixture” is a mixture of two or m8re liquids whose proportions cannot be altered or changed by simple distillation. Uni ess otherwise provi ded, the azeotrope i s a mi ni mum boi I i ng azeotrope, where the boi I i ng poi nt of the azeotrope i s I ower than the boi I i ng poi nt of any of the two or more I i qui ds.

A subject” to which administration is contemplated includes, but is not limited to, humans (/.e., a male or female of any age group, eg., a pediatric subject (eg., infant, child, adolescent) or adult subject (eg., young adult, middle-aged adult, or senior adult)) and/or other non- human animals, for example, mammals (e.g., pri mates (eg., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (eg., commercially relevant bi rds such as chickens, ducks, geese, and/or turkeys). In certai n embodiments, thesubject is a mammal. The subject may bea male or femal e and at any stage of devel opment. A non- human ani mal may be a transgeni c ani mal .

Theterms Administer,” Administering,” or Administration,” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound, or a pharmaceutical composition thereof.

Theterms treatment,” treat,” and treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a pathological condition” (eg., a disease, disorder, or condi ti on, or one or more si gns or symptoms thereof) descri bed herei n. In some embodi merits, 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 admi nistered to a susceptible individual prior to the onset of symptoms (e.g., i n light of a hi story of symptoms and/or i n I i ght of geneti c or other suscepti bi I i ty factors) . T reatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

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 thisart, the effective amount of a provided compound may vary depending on such factors as the desi red bi ol ogi cal endpoi nt, the pharmacoki neti cs of the compound, the condition being treated, the mode of administration, and the age and health of the subject.

A f herapeuti cal I y effect! ve amount” of a provi ded compound i s an amount suff i ci ent to provi de a therapeuti c benef i t i n the treatment of a condi ti on or to del ay or mi ni mi ze one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or i n combi nation with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term therapeutically effective amount” can encompass an amount that i mproves overal I therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE

In some aspects, the present disclosure provides processes of preparing certai n 3,4- dihydro_-4-aryl coumarin derivatives; and Compounds SW2, SW9a, and SW9b, and tautomers, stereoisomers, isotopically labeled compounds, salts, solvates, polymorphs, co-crystals, and prodrugs thereof , and compositions, kits, and methods of use thereof.

Processes of Preparing Certain 3,4-Dihydro-4-Aryl Coumarin Derivatives

In one aspect, the present di scl osure provides a process of preparing a product, wherein the process compri ses:

(a) reacting a compound of Formula A:

or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, with a compound of Formula B:

or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, in the presence of a catalyst and an organic solvent; and

(b) azeotropical I y removing water, wherein the water is formed by step (a); wherein: each of R¹, R², R³, R⁴, R⁵, and R⁶ is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl , substituted or unsubstituted alky nyl , substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl , -OR^a, N(R^a)₂, SR^a, CM, - SCN, -C(=O)R^a, -C(=O)OR^a, -C(=O)N(R^a)₂, -C(=NR^a)R^a, -C(=NR^a)OR^a, -C(=NR^a)N(R^a)₂, -NO₂, -N₃, -NR^OJR⁹, -NR^aC(=O)OR^a, -NR^aC(=O)N(R^a)₂, -NR^dC(=NR^d)R^a, - NR^aC(=NR^a)OR^a, -NR^aC(=NR^a)N(R^a)₂, -OC(=O)R^a, -OC(=O)OR^a, -OC(=O)N(R^a)₂, - OC(=NR^a)R^a, -OC(=NR^a)OR^a, -OC(=NR^a)N(R^a)₂, -NR^aS(=O)₂R^a, -NR^aS(=O)₂OR^a, - NR^aS(=O)₂N(R^a)₂, -OS(=O)₂R^a, -OS(=O)₂OR^a, -OS(=O)₂N(R^a)₂, -S(=O)₂R^a, -S(=O)₂OR^a, - S(=O)₂N(R^a)₂, -F\=O)(R^a)₂, or -Si(R^a)₃; each R^a is 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 sul fur atom, or two i nstances of R^a on a ni trogen atom are j oi ned wi th the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of R⁷ and R⁸ is independently hydrogen, halogen, unsubstituted cyclopropyl, -

OR^b, -N(R^b)₂, -SR^b, -CN, -SCN, -NO₂, -N₃, unsubstituted C_1-3alkyl, or C_1-3alkyl substituted with one or more halogen; each R^b is independently hydrogen, unsubstituted C_1-2 alkyl, or C_1-2 alkyl substituted with one or more halogen; and

R⁹ is hydrogen, and the product is a compound of Formula 1-1 or I -2:

or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, or a mixture thereof; or R⁹ is halogen, unsubstituted cyclopropyl, -OR^b, -N(R^b)₂, -SR^b, -CN, -SCN, -NO₂, -N₃, unsubstituted C_1-3 alkyl , or C_1-3 alkyl substituted with one or more halogen, and the product is a compound of Formula 1-1, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof.

In certain embodiments, the compound of Formula A is of the formula

or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof.

In certain embodiments, the compound of Formula A is of the formula

In certain embodiments, in certain embodiments,

In certain embodiments, the compound of Formula B isof the formula:

When a formula (eg, -N(R^a)₂)inclu udes two or more instances of a moi ety (eg, R^a), uni ess otherwi se provi ded, any two Instances of the moi ety may be the same or di ff erent from each other.

In certain embodiments, R¹ is hydrogen. In certai n embodiments, R¹ is not hydrogen. In certain embodiments, R¹ is halogen. In certain embodiments, R¹ is F. In certai n embodiments, R¹ is Cl. In certain embodiments, R¹ is Br. In certain embodiments, R¹ is unsubstituted alkyl (eg, unsubstituted C_1-6 alkyl). In certai n embodiments, R¹ is Me. In certain embodiments, R¹ is Et. In certai n embodiments, R¹ is Pr, or Bu. In certai n embodiments, R¹ is substituted alkyl (eg, alkyl substituted with one or more instances of halogen (eg, F)). In certain embodiments, R¹ is substituted C_1-6 alkyl. In certain embodiments, R¹ is substituted methyl (eg., fluorinated methyl or Bn). In certain embodiments, R¹ is -CF₃. In certain embodiments, R¹ is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R¹ is substituted or unsubstituted alkenyl. In certain embodiments, R¹ issubstituted or unsubstituted, C_2-6 alkenyl (eg, substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, R¹ issubstituted or unsubstituted alky nyl. In certain embodiments, R¹ is substituted or unsubstituted, C_2-6alkynyl (eg, substituted or unsubstituted ethynyl). In certain embodiments, R¹ issubstituted or unsubstituted carbocyclyl (eg, substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R¹ issubstituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl , substituted or unsubstituted cyclohexyl , or substituted or unsubstituted cycloheptyl. In certain embodiments, R¹ issubstituted or unsubstituted heterocyclyl (eg, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R¹ is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl , substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrol i di ny I, substituted or unsubstituted pi peri di ny I, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R¹ is substituted or unsubstituted aryl. In certain embodiments, R¹ is substituted or unsubstituted phenyl. In certai n embodiments, R¹ is unsubstituted phenyl. In certain embodiments, R¹ is substituted or unsubstituted naphthyl. In certai n embodiments, R¹ is substituted or unsubstituted heteroaryl. In certain embodiments, R¹ issubstituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R¹ is 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, R¹ issubstituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R¹ is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certai n embodiments, R¹ is -OR^a. In certain embodiments, R¹ is - OH. In certain embodiments, R¹ is -O(substituted or unsubstituted alkyl). In certain embodiments, R¹ is - ©(substituted alkyl). In certain embodiments, R¹ is -O(alkyl substituted at least with -P(R^a)3X (eg., -P(substituted or unsubstituted phenyl )₃X), wherein X is a counter! on). In certain embodiments, R¹ is -O- (unsubstituted C_2-12 alkylene)- P(substituted or unsubstituted phenyl)₃X (eg., -O- (unsubstituted C_2-12 alkylene)- P(unsubstituted phenyl )₃X). In certain embodiments, R¹ is - ©(substituted or unsubstituted, C_1-6 alkyl). In certai n embodiments, R¹ is -O(unsubstituted C_1-6 alkyl). In certain embodiments, R¹ is -OMe, -OCF₃, -OEt, -OPr, -OBu, or -OBn). In certain embodiments, R¹ is -O(substituted or unsubstituted phenyl) (eg, -OPh). In certain embodiments, R¹ is -OMe In certain embodiments, R¹ is -OEt. In certain embodiments, R¹ is -SR^a (eg, -SH, - ^substituted or unsubstituted, C_1-6 alkyl) (eg., -SMe, -SCF₃, -SEt, -SPr, - SBu, or -SBn), or -S substituted or unsubstituted phenyl) (eg, -SPh)). In certain embodiments, R¹ is -N(R^a)₂ (eg, -NH₂, -NH(substituted or unsubstituted, C_1-6 alkyl) (eg, - NHMe), or -N (substituted or unsubstituted, C_1-6 alkyl)-(substituted or unsubstituted, C_1-6 alkyl) (eg, -NMes)). In certain embodiments, R¹ is -CN or -SCN. In certain embodiments, R¹ is -NO₂. In certain embodiments, R¹ is -C(=NR^a)R^a, -C(=NR^a)OR^a, or -C(=NR^a)N(R^a)₂. In certain embodiments, R¹ is -C(=O)R^a (eg., -C(=O)(substituted or unsubstituted alkyl) (eg., - C(=O)Me) or -C(=O)(substituted or unsubstituted phenyl)). In certain embodiments, R¹ is - C(=O)OR^a(eg, -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (eg, -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In certai n embodiments, R¹ is - C(=O)N(R^a)₂ (eg., -C(=O)NH₂, -C(=O)NH (substituted or unsubstituted alkyl (eg., - C(=O)NHMe), -C(=O)NH (substituted or unsubstituted phenyl), -C(=O)N (substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -C(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R¹ is - NR^aC(=O)R^a (eg, -NHC(=O)(substituted or unsubstituted, C_1-6 alkyl) (eg., -NHC(=O)Me) or -NHC(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R¹ is - NR^aC(=O)OR^a. In certain embodiments, R¹ is -NR^aC(=O)N(R^a)₂(eg, -NHC(=O)NH₂, - NHC(=O)NH (substituted or unsubstituted, C_1-6 alkyl) (eg., -NHC(=O)NHMe)). In certain embodiments, R¹ is -OC(=O)R^a (eg, -OC(=O)(substituted or unsubstituted alkyl) or - OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR^a(eg, -OC(=O)O(substituted or unsubstituted alkyl) or -OC(=O)O(substituted or unsubstituted phenyl)), or -OC(=O)N(R^a)₂ (eg, -OC(=O)NH₂, -OC(=O)NH(substituted or unsubstituted alkyl), -OC(=O)NH (substituted or unsubstituted phenyl), -OC(=O)N(substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -OC(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R¹ is -NR^aS(=O)₂R^a (eg, -NHS(=O)₂R^a, - NHS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R¹ is -NR^aS(=O)₂OR^a (eg, -NHS(=O)₂OR^a, -NHS(=O)₂OH, - NHS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R¹ is -NR^aS(=O)₂N(R^a)₂ (eg, -NHS(=O)₂N(R^a)₂, -NHS(=O)₂NH₂, - NHS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), - NHS(=O)₂N(substituted or unsubstituted alkyl )₂, -NHS(=O)₂N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certai n embodiments, R¹ is -OS(=O)₂R^a (eg., - OS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R¹ is -OS(=O)₂OR^a (eg., -OS(=O)₂OH, -OS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R¹ is - OS(=O)₂N(R^a)₂ (eg, -OS(=O)₂NH₂, -OS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -OS(=O)₂N (substituted or unsubstituted alkyl )₂, - OS(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R¹ is -S(=O)₂R^a (eg, -S(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R¹ is -S(=O)₂OR^a (eg, -S(=O)₂OH, - S(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R¹ is -S(=O)₂N(R^a)₂ (e.g., -S(=O)₂NH₂, -S(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -S(=O)₂N (substituted or unsubstituted alkyl)₂, -S(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R¹ is -P(=O)(R^a)₂ (e.g, -P(=O) (substituted or unsubstituted phenyl )₂). In certain embodiments, R¹ is -Si(R^a)₃ (eg., -Si (substituted or unsubstituted alkyl )₃). In certain embodiments, R¹ is hydrogen, -OH, substituted or unsubstituted alkyl, or - O(substituted or unsubstituted alkyl). In certain embodiments, R¹ is -OH or -OCH₃.

In certain embodiments, R² is hydrogen. In certain embodiments, R² is not hydrogen. In certain embodiments, R² is halogen. In certain embodiments, R² is F. In certai n embodiments, R² is Cl. In certain embodiments, R² is Br. In certain embodiments, R² is unsubstituted alkyl (eg., unsubstituted C_1-6 alkyl). In certai n embodiments, R² is Me. In certain embodiments, R² is Et. In certai n embodiments, R² is Pr, or Bu. In certai n embodiments, R² is substituted alkyl (eg., alkyl substituted with one or more instances of halogen (eg., F)). In certain embodiments, R² is substituted C_1-6 alkyl. In certain embodiments, R² is substituted methyl (eg., fluorinated methyl or Bn). In certain embodiments, R² is -CF₃. In certain embodiments, R² is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R² is substituted or unsubstituted alkenyl. In certain embodiments, R² issubstituted or unsubstituted, C_2-6 alkenyl (eg., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, R² issubstituted or unsubstituted alky nyl. In certain embodiments, R² is substituted or unsubstituted, 02_-6alkynyl (eg., substituted or unsubstituted ethynyl). In certain embodiments, R² issubstituted or unsubstituted carbocyclyl (eg., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R² issubstituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl , substituted or unsubstituted cyclohexyl , or substituted or unsubstituted cycloheptyl. In certain embodiments, R² issubstituted or unsubstituted heterocyclyl (eg., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R² issubstituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl , substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrol i di nyl, substituted or unsubstituted pi peri di nyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R² issubstituted or unsubstituted aryl. In certain embodiments, R² issubstituted or unsubstituted phenyl. In certai n embodiments, R² is unsubstituted phenyl. In certain embodiments, R² issubstituted or unsubstituted naphthyl. In certai n embodiments, R² is substituted or unsubstituted heteroaryl. In certain embodiments, R² issubstituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R² is 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, R² issubstituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl , substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl . In certain embodiments, R² is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certai n embodiments, R² is -OR^a. In certain embodiments, R² is -OH. In certain embodiments, R² is -O(substituted or unsubstituted alkyl). In certain embodiments, R² is - ©(substituted alkyl). In certain embodiments, R² is -O(alkyl substituted at least with -P(R^a)3X (eg., -P(substituted or unsubstituted phenyl )₃X), wherein X is a counter! on). In certain embodiments, R² is -O- (unsubstituted C_2-12 alkylene)- P(substituted or unsubstituted phenyl)₃X (eg., -O- ( unsubstituted C_2-12 alkylene)- P(unsubstituted phenyl)₃X). In certain embodiments, R² is - ©(substituted or unsubstituted, C_1-6 alkyl). In certai n embodiments, R² is -O(unsubstituted C_1-6 alkyl). In certain embodiments, R² is -OMe, -OCF₃, -OEt, -OPr, -OBu, or -OBn). In certain embodiments, R² is -O(substituted or unsubstituted phenyl) (eg., -OPh). In certain embodiments, R² is -OMe. In certain embodiments, R² is -OEt. In certain embodiments, R² is -SR^a (eg, -SH, -S substituted or unsubstituted, C_1-6 alkyl) (eg., -SMe, -SCF₃, -SEt, -SPr, - SBu, or -SBn), or -S substituted or unsubstituted phenyl) (eg., -SPh)). In certain embodiments, R² is -N(R^a)₂ (eg., -NH₂, -NH(substituted or unsubstituted, C_1-6 alkyl) (eg., - NHMe), or -N (substituted or unsubstituted, C_1-6 alkyl)-(substituted or unsubstituted, C_1-6 alkyl) (eg., -NMe₂)). In certain embodiments, R² is -CN or -SCN. In certain embodiments, R² is -NO₂. In certain embodiments, R² is -C(=NR^a)R^a, -C(=NR^a)OR^a, or -C(=NR^a)N(R^a)₂. In certain embodiments, R² is -C(=O)R^a (eg., -C(=O)(substituted or unsubstituted alkyl) (eg., - C(=O)Me) or -C(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R² is - C(=O)OR^a(eg., -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (eg., -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In certai n embodiments, R² is - C(=O)N(R^a)₂ (e.g., -C(=O)NH₂, -O(=©) NH (substituted or unsubstituted alkyl) (eg., - C(=O)NHMe), -C(=O)NH (substituted or unsubstituted phenyl), -C(=O)N (substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -C(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R² is - NR^aC(=O)R^a (eg., -NHC(=O)(substituted or unsubstituted, C_1-6 alkyl) (eg., -NHC(=O)Me) or -NHC(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R² is - NR^aC(=O)OR^a. In certain embodiments, R² is -NR^aCO)N(R^a )₂eg., -NHC(=O)NH₂, - NHC(=O)NH (substituted or unsubstituted, C_1-6 alkyl) (e.g., -NHC(=O)NHMe)). In certain embodiments, R² is -OC(=O)R^a (e.g., -OC(=O)(substituted or unsubstituted alkyl) or - OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR^a(e.g., -OC(=O)O(substituted or unsubstituted alkyl) or -OC(=O)O(substituted or unsubstituted phenyl)), or -OC(=O)N(R^a)₂ (e.g., -OC(=O)NH₂, -OC(=O)NH(substituted or unsubstituted alkyl), -OC(=O)NH (substituted or unsubstituted phenyl), -OC(=O)N(substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -OC(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R² is -NR^aS(=O)₂R^a (e.g., -NHS(=O)₂R^a, - NHS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R² is -NR^aS(=O)₂OR^a (eg., -NHS(=O)₂OR^a, -NHS(=O)₂OH, - NHS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R² is -NR^aS(=O)₂N(R^a)₂ (eg., -NHS(=O)₂N(R^a)₂, -NHS(=O)₂NH₂, - NHS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), - NHS(=O)₂N(substituted or unsubstituted alkyl )₂, -NHS(=O)₂N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certai n embodiments, R² is -OS(=O)₂R^a (eg., - OS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R² is -OS(=O)₂OR^a (eg., -OS(=O)₂OH, -OS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R² is - OS(=O)₂N(R^a)₂ (eg., -OS(=O)₂NH₂, -OS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -OS(=O)₂N (substituted or unsubstituted alkyl )₂, - OS(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R² is -S(=O)₂R^a (eg., -S(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R² is -S(=O)₂OR^a (eg., -S(=O)₂OH, - S(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R² is -S(=O)₂N(R^a)₂ (eg., -S(=O)₂NH₂, -S(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -S(=O)₂N (substituted or unsubstituted alkyl )₂, -S(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R² is -P(=O)(R^a)₂ (eg., -P(=O) (substituted or unsubstituted phenyl )₂). In certain embodiments, R² is -Si(R^a)3 (eg., -Si (substituted or unsubstituted alkyl)₃).

In certain embodiments, R³ is hydrogen. In certai n embodiments, R³ is not hydrogen. In certain embodiments, R³ is halogen. In certain embodiments, R³ is F. In certai n embodiments, R³ is Cl. In certain embodiments, R³ is Br. In certain embodiments, R³ is unsubstituted alkyl (e.g., unsubstituted C_1-6₃ alkyl). In certain embodiments, R³ is Me. In certain embodiments, R³ is Et. In certai n embodiments, R³ is Pr, or Bu. In certai n embodiments, R³ is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R³ is substituted C_1-e₃ alkyl. In certain embodiments, R³ is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, R³ is -CF₃. In certain embodiments, R³ is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R³ is substituted or unsubstituted alkenyl. In certain embodiments, R³ issubstituted or unsubstituted, C_2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, R³ issubstituted or unsubstituted alky nyl. In certain embodiments, R³ is substituted or unsubstituted, ©2_-6alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, R³ issubstituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R³ issubstituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl , substituted or unsubstituted cyclohexyl , or substituted or unsubstituted cycloheptyl. In certain embodiments, R³ issubstituted or unsubstituted heterocyclyl (eg., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R³ issubstituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrol i di nyl, substituted or unsubstituted pi peri di nyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R³ issubstituted or unsubstituted aryl. In certain embodiments, R³ issubstituted or unsubstituted phenyl. In certai n embodiments, R³ is unsubstituted phenyl. In certain embodiments, R³ issubstituted or unsubstituted naphthyl. In certai n embodiments, R³ is substituted or unsubstituted heteroaryl. In certain embodiments, R³ issubstituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R³ is 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, R³ issubstituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R³ is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certai n embodiments, R³ is -OR^a. In certain embodiments, R³ is - OH. In certain embodiments, R³ is -O(substituted or unsubstituted alkyl). In certain embodiments, R³ is - ©(substituted alkyl). In certain embodiments, R³ is -O(alkyl substituted at least with -P(R^a)3X (eg, -P(substituted or unsubstituted phenyl )₃X), wherein X is a counterion). In certain embodiments, R³ is -O- (unsubstituted C_2-12 alkylene)- P(substituted or unsubstituted phenyl)₃X (eg, -O- (unsubstituted C_2-12 alkylene)- P(unsubstituted phenyl )₃X). In certain embodiments, R³ is - O(substituted or unsubstituted, C_1-6 alkyl). In certai n embodiments, R³ is -O( unsubstituted C_1-6 alkyl). In certain embodiments, R³ is -OMe, -OCF₃, -OEt, -OPr, -OBu, or -OBn). In certain embodiments, R³ is -O(substituted or unsubstituted phenyl) (eg, -OPh). In certain embodiments, R³ is -OMe. In certain embodiments, R³ is -OEt. In certain embodiments, R³ is -SR^a (eg, -SH, -S substituted or unsubstituted, C_1-6 alkyl) (eg., -SMe, -SCFs, -SEt, -SPr, - SBu, or -SBn), or -S substituted or unsubstituted phenyl) (eg, -SPh)). In certain embodiments, R³ is -N(R^a)₂ (eg., -NH₂, -NH (substituted or unsubstituted, C_1-6 alkyl) (eg., - NHMe), or -N (substituted or unsubstituted, C_1-6 alkyl)-(substituted or unsubstituted, C_1-6 alkyl) (eg, -NMe₂)). In certain embodiments, R³ is -ON or -SCN. In certain embodiments, R >3³ is -NO₂. In certan embodiments, R³ is -C(=NR^a)R^a, -C(=NR^a)OR^a, or -C(=NR^a)N(R^a)₂. In certain embodiments, R³ is -C(=O)R^a (eg, -C(=O)(substituted or unsubstituted alkyl) (eg, - C(=O)Me) or -C(=O)(substituted or unsubstituted phenyl)). In certain embodiments, R³ is - C(=O)OR^a(eg, -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (eg, -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In certai n embodiments, R³is - C(=O)N(R^a)₂ (eg., -C(=O)NH₂, -C(=O)NH (substituted or unsubstituted alkyl) (eg., - C(=O)NHMe), -C(=O)NH (substituted or unsubstituted phenyl), -C(=O)N (substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -C(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R³ is - NR^aC(=O)R^a (eg, -NHC(=O)(substituted or unsubstituted, C_1-6 alkyl) (eg, -NHC(=O)Me) or -NHC(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R³ is - NR^aC(=O)OR^a. In certan embodiments, R³ is -NR^aC(=O)N(R^a)₂(eg., -NHC(=O)NH₂, - NHC(=O)NH (substituted or unsubstituted, C_1-6 alkyl) (eg., -NHC(=O)NHMe)). In certain embodiments, R³ is -OC(=O)R^a (eg, -OC(=O)(substituted or unsubstituted alkyl) or - OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR^a(eg., -OC(=O)O(substituted or unsubstituted alkyl) or -OC(=O)O(substituted or unsubstituted phenyl)), or -OC(=O)N(R^a)₂ (eg, -OC(=O)NH₂, -OC(=O)NH(substituted or unsubstituted alkyl), -OC(=O)NH (substituted or unsubstituted phenyl), -OC(=O)N(substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -OC(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R³ is -NR^aS(=O)₂R^a (eg, -NHS(=O)₂R^a, - NHS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R³ is -NR^aS(=O)₂OR^a (e.g., -NHS(=O)₂OR^a, -NHS(=O)₂OH, - NHS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R³ is -NR^aS(=O)₂N(R^a)₂ (e.g., -NHS(=O)₂N(R^a)₂, -NHS(=O)₂NH₂, - NHS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), - NHS(=O)₂N(substituted or unsubstituted alkyl )₂, -NHS(=O)₂N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certai n embodiments, R³ is -OS(=O)₂R^a (e.g., - OS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R³ is -OS(=O)₂OR^a (e.g., -OS(=O)₂OH, -OS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R³ is - OS(=O)₂N(R^a)₂ (e.g., -OS(=O)₂NH₂, -OS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -OS(=O)₂N (substituted or unsubstituted alkyl )₂, - OS(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R³ is -S(=O)₂R^a (e.g., -S(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R³ is -S(=O)₂OR^a (e.g., -S(=O)₂OH, - S(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R³ is -S(=O)₂N(R^a)₂ (e.g., -S(=O)₂NH₂, -S(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -S(=O)₂N (substituted or unsubstituted alky 1)₂, -S(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R³ is -P(=O)(R^a)₂ (e.g, -P(=O) (substituted or unsubstituted phenyl >2). In certain embodiments, R³ is -Si(R^a)3 (e.g., -Si (substituted or unsubstituted alkyl)₃).

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is not hydrogen. In certain embodiments, R⁴ is halogen. In certain embodiments, R⁴ is F. In certai n embodiments, R⁴ is Cl. In certain embodiments, R⁴ is Br. In certain embodiments, R⁴ is unsubstituted alkyl (e.g., unsubstituted C_1-6 alkyl). In certain embodiments, R⁴ is Me. In certain embodiments, R⁴ is Et. In certai n embodiments, R⁴ is Pr, or Bu. In certai n embodiments, R⁴ is substituted alkyl (e.g, alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R⁴ is substituted C_1-6 alkyl. In certain embodiments, R⁴ is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, R⁴ is -CF₃. In certain embodiments, R⁴ is substituted ethyl , substituted propyl, or substituted butyl. In certain embodiments, R⁴ is substituted or unsubstituted alkenyl. In certain embodiments, R⁴ issubstituted or unsubstituted, C_2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, R⁴ issubstituted or unsubstituted alky nyl. In certain embodiments, R⁴ is substituted or unsubstituted, C_2-6alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, R⁴ is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R⁴ issubstituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl , substituted or unsubstituted cyclohexyl , or substituted or unsubstituted cycloheptyl. In certai n embodiments, R⁴ issubstituted or unsubstituted heterocyclyl (eg., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R⁴ issubstituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azdi di ny I, substituted or unsubstituted pyrrol i di ny I, substituted or unsubstituted pi peri di ny I, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R⁴ issubstituted or unsubstituted aryl. In certain embodiments, R⁴ issubstituted or unsubstituted phenyl. In certai n embodiments, R⁴ is unsubstituted phenyl. In certain embodiments, R⁴ issubstituted or unsubstituted naphthyl. In certai n embodiments, R⁴ is substituted or unsubstituted heteroaryl. In certain embodiments, R⁴ issubstituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R⁴ is 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, R⁴ issubstituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certai n embodiments, R⁴ is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certai n embodiments, R⁴ is -OR^a. In certain embodiments, R⁴ is -OH. In certain embodiments, R⁴ is -O(substituted or unsubstituted alkyl). In certai n embodiments, R⁴ is - ©(substituted alkyl). In certain embodiments, R⁴ is -O(alkyl substituted at least with -P(R^a)3X (eg., -P(substituted or unsubstituted phenyl)₃X), wherein X is a counterion). In certain embodiments, R⁴ is -O- (unsubstituted C_2-12 alkylene)- P(substituted or unsubstituted phenyl)₃X (eg., -O- (unsubstituted C_2-12 alkylene)- P(unsubstituted phenyl )₃X). In certain embodiments, R⁴ is - ©(substituted or unsubstituted, C_1-6 alkyl). In certai n embodiments, R⁴ is -O(unsubstituted C_1-6 alkyl). In certain embodiments, R⁴ is -OMe, -OCF₃, -OEt, -OPr, -OBu, or -OBn). In certain embodiments, R⁴ is -O(substituted or unsubstituted phenyl) (eg, -OPh). In certain embodiments, R⁴ is -OMe. In certain embodiments, R⁴ is -OEt. In certain embodiments, R⁴ is -SR^a (eg., -SH, -S substituted or unsubstituted, C_1-6 alkyl) (eg., -SMe, -SCF₃, -SEt, -SPr, - SBu, or -SBn), or -S substituted or unsubstituted phenyl) (eg., -SPh)). In certain embodiments, R⁴ is -N(R^a)₂ (eg., -NH₂, -NH (substituted or unsubstituted, C_1-6 alkyl) (eg., - NHMe), or -N (substituted or unsubstituted, C_1-6 alkyl)-(substituted or unsubstituted, C_1-6 alkyl) (eg., -NMe₂)). In certain embodiments, R⁴ is -CN or -SCN. In certain embodiments, R >4⁴ is -NO₂. In certan embodiments, R⁴ is -C(=NR^a)R^a, -C(=NR^a)OR^a, or -C(=NR^a)N(R^a)₂. In certain embodiments, R⁴ is -C(=O)R^a (eg., -C(=O)(substituted or unsubstituted alkyl) (eg., - C(=O)Me) or -C(=O)(substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is - C(=O)OR^a(eg., -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (eg., -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In certai n embodiments, R⁴is - C(=O)N(R^a)₂ (eg., -C(=O)NH₂, -C(=O)NH(substituted or unsubstituted alkyl) (eg., - C(=O)NHMe), -C(=O)NH (substituted or unsubstituted phenyl), -C(=O)N (substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -C(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R⁴ is - NR^aC(=O)R^a (eg., -NHC(=O)(substituted or unsubstituted, C_1-6 alkyl) (eg., -NHC(=O)Me) or -NHC(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R⁴ is - NR^aC(=O)OR^a. In certan embodiments, R⁴ is -NR^aC(=O)N(R^a)₂(eg., -NHC(=O)NH₂, - NHC(=O)NH (substituted or unsubstituted, C_1-6 alkyl) (eg., -NHC(=O)NHMe)). In certain embodiments, R⁴ is -OC(=O)R^a (eg., -OC(=O)(substituted or unsubstituted alkyl) or - OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR^a(eg., -OC(=O)O(substituted or unsubstituted alkyl) or -OC(=O)O(substituted or unsubstituted phenyl)), or -OC(=O)N(R^a)₂ (eg., -OC(=O)NH₂, -OC(=O)NH(substituted or unsubstituted alkyl), -OC(=O)NH (substituted or unsubstituted phenyl), -OC(=O)N(substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -OC(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R⁴ is -NR^aS(=O)₂R^a (eg., -NHS(=O)₂R^a, - NHS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is -NR^aS(=O)₂OR^a (eg., -NHS(=O)₂OR^a, -NHS(=O)₂OH, - NHS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is -NR^aS(=O)₂N(R^a)₂ (eg., -NHS(=O)₂N(R^a)₂, -NHS(=O)₂NH₂, - NHS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), - NHS(=O)₂N(substituted or unsubstituted alkyl )₂, -NHS(=O)₂N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certai n embodiments, R⁴ is -OS(=O)₂R^a (eg., - OS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is -OS(=O)₂OR^a (eg., -OS(=O)₂OH, -OS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is - OS(=O)₂N(R^a)₂ (eg., -OS(=O)₂NH₂, -OS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -OS(=O)₂N (substituted or unsubstituted alkyl )₂, - OS(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is -S(=O)₂R^a (e.g., -S(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is -S(=O)₂OR^a (e.g., -S(=O)₂OH, - S(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is -S(=O)₂N(R^a)₂ (e.g., -S(=O)₂NH₂, -S(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -S(=O)₂N (substituted or unsubstituted alky 1)₂, -S(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R⁴ is -P(=O)(R^a)₂ (e.g., -P(=O) (substituted or unsubstituted phenyl >2). In certain embodiments, R⁴ is -Si(R^a)₃ (e.g., -Si (substituted or unsubstituted alkyl)₃).

In certain embodiments, R⁵ is hydrogen. In certai n embodiments, R⁵ is not hydrogen. In certain embodiments, R⁵ is halogen. In certain embodiments, R⁵ is F. In certain embodiments, R⁵ is Cl . In certain embodiments, R⁵ is Br. In certain embodiments, R⁵ is unsubstituted alkyl (e.g., unsubstituted C_1-6 alkyl). In certai n embodiments, R⁵ is Me. In certain embodiments, R⁵ is Et. In certai n embodiments, R⁵ is Pr, or Bu. In certai n embodiments, R⁵ is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R⁵ is substituted C_1-6 alkyl. In certain embodiments, R⁵ is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, R⁵ is -CF₃. In certain embodiments, R⁵ is substituted ethyl , substituted propyl, or substituted butyl. In certain embodiments, R⁵ is substituted or unsubstituted alkenyl. In certain embodiments, R⁵ issubstituted or unsubstituted, C_2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, R⁵ issubstituted or unsubstituted alky nyl. In certain embodiments, R⁵ is substituted or unsubstituted, C_2-6alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, R⁵ issubstituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R⁵ issubstituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl , substituted or unsubstituted cyclopentyl , substituted or unsubstituted cyclohexyl , or substituted or unsubstituted cycloheptyl. In certai n embodiments, R⁵ is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R⁵ issubstituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrol i di nyl, substituted or unsubstituted pi peri di nyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R⁵ is substituted or unsubstituted aryl. In certain embodiments, R⁵ is substituted or unsubstituted phenyl . In certai n embodiments, R⁵ is unsubstituted phenyl . In certain embodiments, R⁵ is substituted or unsubstituted naphthyl . In certai n embodiments, R⁵ is substituted or unsubstituted heteroaryl. In certain embodiments, R⁵ issubstituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R⁵ is 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, R⁵ issubstituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl , substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl . In certai n embodiments, R⁵ is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certai n embodiments, R⁵ is -OR^a. In certain embodiments, R⁵ is -OH. In certain embodiments, R⁵ is -O(substituted or unsubstituted alkyl). In certai n embodiments, R⁵ is - ©(substituted alkyl). In certain embodiments, R⁵ is -O(alkyl substituted at least with -P(R^a)3X (e.g., -P(substituted or unsubstituted phenyl )₃X), wherein X is a counter! on). In certain embodiments, R⁵ is -O- (unsubstituted C_2-12 alkylene)- P(substituted or unsubstituted phenyl)₃X (e.g., -O- (unsubstituted C_2-12 alkylene)- P(unsubstituted phenyl )₃X). In certain embodiments, R⁵ is - ©(substituted or unsubstituted, C_1-6 alkyl). In certai n embodiments, R⁵ is -O(unsubstituted C_1-6 alkyl). In certain embodiments, R⁵ is -OMe, -OCF₃, -OEt, -OPr, -OBu, or -OBn). In certain embodiments, R⁵ is -O(substituted or unsubstituted phenyl) (e.g., -OPh). In certain embodiments, R⁵ is -OMe. In certain embodiments, R⁵ is -OEt. In certain embodiments, R⁵ is -SR^a (e.g, -SH, -S(substituted or unsubstituted, C_1-6 alkyl) (e.g., -SMe, -SCF₃, -SEt, -SPr, - SBu, or -SBn), or -S substituted or unsubstituted phenyl) (e.g., -SPh)). In certain embodiments, R⁵ is -N(R^a)₂ (e.g., -NH₂, -NH(substituted or unsubstituted, C_1-6 alkyl) (e.g., - NHMe), or -N (substituted or unsubstituted, C_1-6 alkyl)-(substituted or unsubstituted, C_1-6 alkyl) (e.g., -NMea)). In certain embodiments, R⁵ is -CN or -SCN. In certain embodiments, R⁵ is -NO₂. In certain embodiments, R⁵ is -C(=NR^a)R^a, -C(=NR^a)OR^a, or -C(=NR^a)N(R^a)₂. In certain embodiments, R⁵ is -C(=O)R^a (e.g., -C(=O)(substituted or unsubstituted alkyl) (e.g, - C(=O)Me) or -C(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R⁵ is - C(=O)OR^a(e.g., -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (e.g., -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In certai n embodiments, R⁵ is - C(=O)N(R^a)₂ (e.g., -C(=O)NH₂, -C(=O)NH (substituted or unsubstituted alkyl) (e.g., - C(=O)NHMe), -C(=O)NH (substituted or unsubstituted phenyl), -C(=O)N (substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -C(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R⁵ is - NR^aC(=O)R^a (eg., -NHC(=O)(substituted or unsubstituted, C_1-6 alkyl) (eg., -NHC(=O)Me) or -NHC(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R⁵ is - NR^aC(=O)OR^a. In certai n embodiments, R⁵ is -NR^aC(=O)N(R^a)₂ (e.g., -NHC(=O)NH₂, - NHC(=O)NH (substituted or unsubstituted, C_1-e₃ alkyl) (eg., -NHC(=O)NHMe)). In certain embodiments, R⁵ is -OC(=O)R^a (eg., -OC(=O)(substituted or unsubstituted alkyl) or - OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR^a(eg., -OC(=O)O(substituted or unsubstituted alkyl) or -OC(=O)O(substituted or unsubstituted phenyl)), or -OC(=O)N(R^a)₂ (eg., -OC(=O)NH₂, -OC(=O)NH(substituted or unsubstituted alkyl), -OC(=O)NH (substituted or unsubstituted phenyl), -OC(=O)N(substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -OC(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R⁵ is -NR^aS(=O)₂R^a (eg., -NHS(=O)₂R^a, - NHS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁵ is -NR^aS(=O)₂OR^a (e.g., -NHS(=O)₂OR^a, -NHS(=O)₂OH, - NHS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁵ is -NR^aS(=O)₂N(R^a)₂ (eg., -NHS(=O)₂N(R^a)₂, -NHS(=O)₂NH₂, - NHS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), - NHS(=O)₂N(substituted or unsubstituted alkyl )₂, -NHS(=O)₂N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certai n embodiments, R⁵ is -OS(=O)₂R^a (eg., - OS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁵ is -OS(=O)₂OR^a (eg., -OS(=O)₂OH, -OS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁵ is - OS(=O)₂N(R^a)₂ (eg., -OS(=O)₂NH₂, -OS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -OS(=O)₂N (substituted or unsubstituted alkyl )₂, - OS(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R⁵ is -S(=O)₂R^a (eg., -S(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁵ is -S(=O)₂OR^a (eg., -S(=O)₂OH, - S(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁵ is -S(=O)₂N(R^a)₂ (eg., -S(=O)₂NH₂, -S(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -S(=O)₂N (substituted or unsubstituted alkyl )₂, -S(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R⁵ is -P(=O)(R^a)₂ (eg., -P(=O) (substituted or unsubstituted phenyl >2). In certain embodiments, R⁵ is -Si(R^a)₃ (eg., -Si (substituted or unsubstituted alkyl)3). In certain embodiments, R⁵ is hydrogen, substituted or unsubstituted alkyl, or - O(substituted or unsubstituted alkyl). In certai n embodiments, R⁵ is hydrogen or -CH₃.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is not hydrogen. In certain embodiments, R⁶ is halogen. In certain embodiments, R⁶ is F. In certain embodiments, R⁶ is Cl. In certain embodiments, R⁶ is Br. In certain embodiments, R⁶ is unsubstituted alkyl (e.g., unsubstituted C_1-6 alkyl). In certain embodiments, R⁶ is Me. In certain embodiments, R⁶ is Et. In certai n embodiments, R⁶ is Pr, or Bu. In certa n embodiments, R⁶ is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R⁶ is substituted C_1-6 alkyl. In certain embodiments, R⁶ is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, R⁶ is -CF₃. In certain embodiments, R⁶ is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R⁶ is substituted or unsubstituted alkenyl. In certain embodiments, R⁶ issubstituted or unsubstituted, C_2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, R⁶ issubstituted or unsubstituted alky nyl. In certain embodiments, R⁶ is substituted or unsubstituted, C_2-6alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, R⁶ issubstituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R⁶ issubstituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl , substituted or unsubstituted cyclohexyl , or substituted or unsubstituted cycloheptyl. In certai n embodiments, R⁶ issubstituted or unsubstituted heterocyclyl (eg., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R⁶ issubstituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrol i di nyl, substituted or unsubstituted pi peri di nyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R⁶ issubstituted or unsubstituted aryl. In certain embodiments, R⁶ issubstituted or unsubstituted phenyl. In certai n embodiments, R⁶ is unsubstituted phenyl. In certain embodiments, R⁶ issubstituted or unsubstituted naphthyl. In certai n embodiments, R⁶ is substituted or unsubstituted heteroaryl. In certain embodiments, R⁶ issubstituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R⁶ is 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, R⁶ issubstituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl , substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl . In certai n embodiments, R⁶ is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certai n embodiments, R⁶ is -OR^a. In certain embodiments, R⁶ is - OH. In certain embodiments, R⁶ is -O(substituted or unsubstituted alkyl). In certai n embodiments, R⁶ is - ©(substituted alkyl). In certain embodiments, R⁶ is -O(alkyl substituted at least with -P(R^a)3X (eg, -P(substituted or unsubstituted phenyl )₃X), wherein X is a counterion). In certain embodiments, R⁶ is -O- (unsubstituted C_2-12 alkylene)- P(substituted or unsubstituted phenyl)₃X (eg, -O- (unsubstituted C_2-12 alkylene)- P(unsubstituted phenyl )₃X). In certain embodiments, R⁶ is - ©(substituted or unsubstituted, C_1-6 alkyl). In certai n embodiments, R⁶ is -O(unsubstituted C_1-6 alkyl). In certain embodiments, R⁶ is -OMe, -OCF₃, -OEt, -OPr, -OBu, or -OBn). In certain embodiments, R⁶ is -O(substituted or unsubstituted phenyl) (eg, -OPh). In certain embodiments, R⁶ is -OMe. In certain embodiments, R⁶ is -OEt. In certain embodiments, R⁶ is -SR^a (eg, -SH, -S substituted or unsubstituted, C_1-6 alkyl) (eg., -SMe, -SCF₃, -SEt, -SPr, - SBu, or -SBn), or -S substituted or unsubstituted phenyl) (eg, -SPh)). In certain embodiments, R⁶ is -N(R^a)₂ (e.g, -NH₂, -NH(substituted or unsubstituted, C_1-6 alkyl) (eg, - NHMe), or -N (substituted or unsubstituted, C_1-6 alkyl)-(substituted or unsubstituted, C_1-6 alkyl) (eg, -NMe₂)). In certain embodiments, R⁶ is -CN or -SCN. In certain embodiments, R⁶ is -NO₂. In certain embodiments, R⁶ is -C(=NR^a)R^a, -C(=NR^a)OR^a, or -C(=NR^a)N(R^a)₂. In certain embodiments, R⁶ is -C(=O)R^a (eg., -C(=O)(substituted or unsubstituted alkyl) (eg., - C(=O)Me) or -C(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R⁶ is - C(=O)OR^a(eg., -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (eg, -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In certai n embodiments, R⁶ is - C(=O)N(R^a)₂ (eg, -C(=O)NH₂, -C(=O)NH (substituted or unsubstituted alkyl (eg, - C(=O)NHMe), -C(=O)NH (substituted or unsubstituted phenyl), -C(=O)N (substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -C(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R⁶ is - NR^aC(=O)R^a (eg, -NHC(=O)(substituted or unsubstituted, C_1-6 alkyl) (eg, -NHC(=O)Me) or -NHC(=O)(substituted or unsubstituted phenyl)). In certai n embodiments, R⁶ is - NR^aC(=O)OR^a. In certai n embodiments, R⁶ is -NR^aC(=O)N(R^a)₂ (eg, -NHC(=O)NH₂, - NHC(=O)NH (substituted or unsubstituted, C_1-6 alkyl) (eg., -NHC(=O)NHMe)). In certain embodiments, R⁶ is -OC(=O)R^a (eg, -OC(=O)(substituted or unsubstituted alkyl) or - OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR^a(eg, -OC(=O)O(substituted or unsubstituted alkyl) or -OC(=O)O(substituted or unsubstituted phenyl)), or -OC(=O)N(R^a)₂ (e.g., -OC(=O)NH₂, -OC(=O)NH(substituted or unsubstituted alkyl), -OC(=O)NH (substituted or unsubstituted phenyl), -OC(=O)N(substituted or unsubstituted alkyl)- (substituted or unsubstituted alkyl), or -OC(=O)N (substituted or unsubstituted phenyl)- (substituted or unsubstituted alkyl)). In certai n embodiments, R⁶ is -NR^aS(=O)₂R^a (e.g., -NHS(=O)₂R^a, - NHS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁶ is -NR^aS(=O)₂OR^a (e.g., -NHS(=O)₂OR^a, -NHS(=O)₂OH, - NHS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁶ is -NR^aS(=O)₂N(R^a)₂ (e.g., -NHS(=O)₂N(R^a)₂, -NHS(=O)₂NH₂, - NHS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), - NHS(=O)₂N(substituted or unsubstituted alkyl )₂, -NHS(=O)₂N(substi tuted or unsubstituted alkyl)(substi tuted or unsubstituted phenyl)). In certai n embodiments, R⁶ is -OS(=O)₂R^a (eg., - OS(=O)₂(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁶ is -OS(=O)₂OR^a (eg., -OS(=O)₂OH, -OS(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁶ is - OS(=O)₂N(R^a)₂ (eg., -OS(=O)₂NH₂, -OS(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -OS(=O)₂N (substituted or unsubstituted alkyl )₂, - OS(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R⁶ is -S(=O)₂R^a (eg., -S(=O)₂(substi tuted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁶ is -S(=O)₂OR^a (eg., -S(=O)₂OH, - S(=O)₂O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, R⁶ is -S(=O)₂N(R^a)₂ (eg., -S(=O)₂NH₂, -S(=O)₂NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), -S(=O)₂N (substituted or unsubstituted alkyl)₂, -S(=O)₂N (substituted or unsubstituted alkyl )(substituted or unsubstituted phenyl)). In certain embodiments, R⁶ is -P(=O)(R^a)₂ (eg., -P(=O) (substituted or unsubstituted phenyl )₂). In certain embodiments, R⁶ is -Si(R^a)₃ (eg., -Si (substituted or unsubstituted alkyl)₃). In certai n embodiments, R⁶ is hydrogen, substituted or unsubstituted alkyl, or - O(substituted or unsubstituted alkyl). In certai n embodiments, R⁶ is hydrogen or -CH₃.

In certai n embodiments, R⁴ and R⁶ are the same. In certai n embodiments, each of R⁴ and R⁶ is - OH. In certain embodiments, R⁴ and R⁶ are different from each other.

In certai n embodiments, at I east one i nstance of R^a i s hydrogen. In certai n embodiments, each i nstance of R^a i s hydrogen. In certai n embodiments, at I east one i nstance of R^a is not hydrogen. In certain embodiments, no instance of R^a is hydrogen. In certain embodiments, at I east one i nstance of R^a i s substi tuted al ky I (e.g. , alkyl substi tuted wi th one or more i nstances of halogen (e.g., F)). In certain embodiments, at least one instance of R^a is unsubstituted alkyl. In certain embodiments, at least one instance of R^a is unsubstituted C_1-6 alkyl. In certain embodiments, at least one i nstance of R^a is Me. In certain embodiments, at least one instance of R^a is Et, Pr, or Bu. In certain embodiments, at least one instance of R^a is substituted C_1-6 alkyl. In certain embodiments, at least one i nstance of R^a issubstituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one i nstance of R^a is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R^a is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R^a is substituted or unsubstituted, C_2-6 alkenyl (eg., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R^a i s substi tuted or unsubsti tuted al ky ny I . In certai n embodiments, at I east one i nstance of R^a i s substituted or unsubstituted, C_2-6alkynyl (eg., substituted or unsubstituted ethynyl). In certain embodiments, at I east one i nstance of R^a i s substi tuted or unsubsti tuted carbocycl y I (eg. , substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 doubl e bonds i n the carbocycl i c ring system, as val ency permi ts) . In certai n embodiments, at least one instanceof R^a issubstituted 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 oneinstanceof R^a is substituted or unsubstituted heterocyclyl (eg., substituted or unsubstituted, 3- to 7-membered, monocycl i c heterocycl y I ) . In certai n embodiments, at I east one i nstance of R^a i s substi tuted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrol i di ny I, substituted or unsubstituted pi peri di ny I, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one i nstance of R^a i s substi tuted or unsubsti tuted aryl . In certai n embodiments, at I east one i nstance of R^a is substituted or unsubstituted phenyl . In certai n embodiments, at I east one i nstance of R^a issubstituted or unsubstituted naphthyl. In certain embodiments, at least one instanceof R^a is substituted or unsubstituted heteroaryl. In certain embodiments, at least one i nstance of R^a is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at I east one i nstance of R^a i s substi tuted or unsubsti tuted furanyl , substi tuted 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 i nstance of R^a i s substituted or unsubstituted pyridi nyl , substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one i nstance of R^a is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R^a is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, tri phenyl methyl , acetyl , or Ts) when attached to a nitrogen atom. In certai n embodiments, at least one i nstance of R^a is 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 certai n embodiments, two i nstances of R^a are j oi ned to form substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two i nstances of R^a arejoined to form substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).

In certain embodiments, R⁷ is hydrogen. In certai n embodiments, R⁷ is halogen. In certain embodiments, R⁷ is F. In certain embodiments, R⁷ is CL In certai n embodiments, R⁷ is Br. In certain embodiments, R⁷ is unsubstituted cyclopropyl. In certain embodiments, R⁷ is - OR^b (e.g., -OH, -O(unsubstituted C_1-2 alkyl), or -O(C_1-2 alkyl substituted with one or more halogen)). In certain embodiments, R⁷ is -N(R^b)₂ (e.g., -NH₂, -NH(unsubstituted C_1-2 alkyl), - NH(CI-2 alkyl substituted with one or more halogen), -N (independently unsubstituted C_1-2 alkyl or C_1-2 alkyl substituted with one or more halogen^). In certain embodiments, R⁷ is -SR^b (e.g., -SH, -S(unsubstituted C_1-2alkyl), or -S(C_1-2alkyl substituted with oneor more halogen)). In certain embodiments, R⁷ is -CN, -SCN, -NO₂, or -N₃. In certai n embodiments, R⁷ is unsubstituted C_1-2alkyl (e.g., Meor Et). In certai n embodiments, R⁷ isC_1-2alkyl substituted with oneor more halogen (e.g., F). In certain embodiments, R⁷ is -CF₃.

In certain embodiments, R⁸ is hydrogen. In certai n embodiments, R⁸ is halogen. In certain embodiments, R⁸ is F. In certain embodiments, R⁸ is CI. In certai n embodiments, R⁸ is Br. In certain embodiments, R⁸ is unsubstituted cyclopropyl. In certain embodiments, R⁸ is - OR^b (e.g., -OH, -O(unsubstituted C_1-2 alkyl), or -O(C_1-2 alkyl substituted with one or more halogen)). In certain embodiments, R⁸ is -N(R^b)₂ (e.g., -NH₂, -NH(unsubstituted C_1-2 alkyl), - NH(C_1-2alkyl substituted with one or more halogen), -N(independently unsubstituted C_1-2 alkyl or C_1-2 alkyl substituted with one or more halogen^). In certain embodiments, R⁸ is -SR^b (e.g., -SH, -S(unsubstituted C_1-2 alkyl), or -S(C_1-2alkyl substituted with oneor more halogen)). In certain embodiments, R⁸ is -CN, -SCN, -NO₂, or -N₃. In certai n embodiments, R⁸ is unsubstituted C_1-2alkyl (e.g., Meor Et). In certai n embodiments, R⁸ isC_1-2alkyl substituted with oneor more halogen (e.g., F). In certain embodiments, R⁸ is -CF₃. In certai n embodi merits, at I east one i nstance of R^b i s hydrogen. In certai n embodiments, each instance of R^b is hydrogen. In certain embodiments, at least one instance of R^b is not hydrogen. In certain embodiments, no instance of R^b is hydrogen. In certain embodiments, at least one instanceof R^b is unsubstituted C_1-2 alkyl (e.g., Me). In certain embodiments, at I east one i nstance of R^b i s C_1-2 al ky I substi tuted wi th one or more hal ogen (e.g., F), In certain embodiments, at least one instanceof R^b is -CF₃.

In certain embodiments, R⁹ is hydrogen, and the product is a compound of Formula 1-1 or I-2:

or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, or a mixture thereof. In certain embodiments, the mol ar rati o of the compound of Formula 1-1, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, to the compound of Formula I -2, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, (e.g., immediately after step (b), step (c), step (d), or step (e)) is between 1:0.01 and 1:0.03, between 1:0.03 and 1:0.1, between 1:0.1 and 1:0.3, between 1:0.3 aid 1:1, between 1:1 aid 1:3, between 1:3 and 1:10, between 1:10 and 1:30, or between 1:30 and 1:100, inclusive.

In certain embodiments, R⁹ is halogen, unsubstituted cyclopropyl, -OR^b, -N(R^b)₂, - SR^b, -CN, -SCN, -NO₂, -N₃, unsubstituted C_1-3alkyl, or C_1-3alkyl substituted with one or more halogen, and the product is a compound of Formula 1-1 , or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof. In certain embodiments, R⁹ is hydrogen. In certain embodiments, R⁹ is halogen. In certain embodiments, R⁹ is F. In certain embodiments, R⁹ isCL In certain embodiments, R⁹ is Br. In certain embodiments, R⁹ is unsubstituted cyclopropyl. In certai n embodiments, R⁹ is -OR^b (e.g., -OH, -O(unsubsti tuted C_1-2 alkyl), or -O(C_1-2 alkyl substituted with one or more halogen)). In certain embodiments, R⁹ is -N(R^b)₂ (e.g., -NH₂, -NH(unsubsti tuted C_1-2alkyl), -NH(C_1-2alkyl substituted with one or more halogen), -N(i ndependently unsubstituted C_1-2alkyl or C_1-2 alkyl substituted with one or more halogen^). In certain embodiments, R⁹ is -SR^b (e.g., -SH, - S( unsubstituted C_1-2 alkyl), or -S(C_1-2₃ alkyl substituted with one or more halogen)). In certain embodiments, R⁹ is -CN, -SCN, -NO₂, or -N₃. In certain embodiments, R⁹ is unsubstituted C_1-3 alkyl (e.g., Meor Et). In certain embodiments, R⁹ isC_1-3₃ alkyl substituted with one or more halogen (e.g., F). In certain embodiments, R⁹ is -CF₃.

In certain embodiments, the product is a compound of the formula

In certain embodiments, the product is a compound described herein, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof. In certain embodiments, the product is a compound described herein, or a tautomer, stereoisomer, isotopically labeled compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, or pharmaceutically acceptabl e co-crystal thereof. In certain embodiments, the product is a compound described herein, or a tautomer, stereoisomer, isotopically labeled compound, or salt thereof. In certai n embodiments, the product i s a compound descri bed herein, or a tautomer, stereoisomer, isotopically labeled compound, or salt thereof. In certain embodiments, the product is a compound described herein, or a tautomer, stereoisomer, isotopically labeled compound, or pharmaceutically acceptable salt thereof. In certain embodiments, the product is a compound described herein, or a tautomer or salt thereof. In certai n embodiments, the product is a compound descri bed herei n, or a tautomer or pharmaceutically acceptable salt thereof. In certain embodiments, the product isa mixtureof two or more compounds (e.g., Compounds SW9a and SW9b), or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof.

In certain embodiments, the catalyst is an organic catalyst. In certain embodiments, the catalyst is an inorganic catalyst. In certain embodiments, the catalyst is an acid (e.g., organic acid or inorganic acid). In certain embodiments, the catalyst isa Bronsted acid. In certain embodiments, the catalyst isan organic Bremsted acid. In certai n embodiments, the catalyst is an inorganic Bresnsted acid. In certain embodiments, the catalyst is Lewis acid (e.g., organic Lewisacid or inorganic Lewisacid). In certain embodiments, the catalyst is a sulfonic acid, or a solvate thereof (e.g., hydrate). In certain embodiments, the catalyst isp-toluenesulfonic acid, or a solvate thereof (e.g., hydrate). In certain embodiments, the catalyst is boric acid or benzene sulfonic acid, or a solvate thereof (e.g., hydrate). In certain embodiments, the catalyst is methanesulfonic acid or trifl uoromethanesulfonic acid. In certain embodiments, the catalyst is a carboxylic acid. In certain embodiments, the catalyst is tri fluoroacetic acid. In certain embodiments, the catalyst is HCI, HBr, HI, HCIO₄, HNO₃, H₂SO₄, or H₃PO₄. In certain embodiments, the catalyst isasalt of an acid described in this paragraph. In certain embodiments, the catal yst i s a mi xture of an aci d descri bed i n thi s paragraph and a sal t of the acid.

In certain embodiments, the catalyst isatri alkylsilyl halide, a trialkyl silyl tri fluoromethanesulfonate, or a tetraalkyl ammonium halide. In certain embodiments, the catalyst is boron tri fluoride etherate. In certain embodiments, the catalyst is a transition metal salt. In certain embodiments, the catalyst is an ad die cation-exchange resin. In certain embodiments, the catalyst is a strong acidic cation-exchange resi n (e.g., comprisi ng a sulfonic acid moiety, or a salt thereof). In certain embodiments, the catalyst is a weak acidic cation- exchange resin (e.g., comprising a carboxylic acid moiety, or a salt thereof).

In certain embodiments, the organic solvent is capable of forming an azeotrope with water. In certain embodiments, the azeotrope is heterogeneous. In certain embodiments, the azeotrope i s homogeneous. In certai n embodiments, the organi c sol vent i s one si ngl e organi c solvent. In certain embodiments, the organic sol vent isa mixture of two or more (e.g., three) organic solvents (e.g., organic sol vents described in this paragraph). In certain embodiments, the organi c sol ventc i s an aromati c organi c sol vent. In certai n embodiments, the organi c sol vent is benzene, toluene, o-xylene, m-xylene, or p-xylene, or a mixture thereof. In certain embodiments, the organi c solvent i s benzene. In certai n embodiments, the organi c solvent i s tol uene. In certai n embodiments, the organic solvent is ethanol or isopropanol . In certai n embodiments, the organic solvent is acetonitrile, ethyl acetate, tetrahydrofuran, or di chloromethane.

In certain embodiments, the reaction mixture of step (a) is substantially a solution (as opposed to a suspension or emulsion).

In certain embodiments, the reaction mixture of step (a) is in a first container.

In certain embodiments, step (a) further comprises afirst temperature. In certain embodiments, the f i rst temperature i s about the boi I i ng poi nt of the azeotrope at the f i rst pressure. In certai n embodiments, the f i rst temperature i s the boi I i ng poi nt of the azeotrope ± 1%, ± 2%, ± 5%, ± 10%, ± 20%, or ± 50%, inclusive, at the first pressure. In certain embodiments, the f i rst temperature i s substanti al I y constant over the ti me durati on of step (a).

In certain embodiments, step (a) further comprises afi rst pressure. In certain embodiments, the fi rst pressure is about 1 atm. In certai n embodiments, the fi rst pressure is between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive.

In certain embodiments, the amount of the compound of Formula B, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, in step (a) is between 0.1 and 0.3, between 0.3 and 1 , between 1 and 3, between 3 and 10, or between 10 and 30 mmol, inclusive. In certain embodiments, the amount of the compound of Formula B, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, in step (a) is between 0.03 and 0.1 , between 0.1 and 0.3, between 0.3 and 1, between 1 and 10, between 10 and 100, or between 100 and 1,000 mol, inclusive.

In certai n embodiments, the mol ar rati o of the amount of the compound of Formul a A , or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, to the catalyst i n step (a) is between 1:0.001 and 1 :0.003, between 1 :0.003 and 1:0.01, between 1:0.01 and 1:0.03, between 1:0.03 and 1:0.1, between 1:0.1 and 1:0.3, or between 1:0.3 and 1:1, inclusive. In certain embodiments, the mol ar rati o of the amount of the compound of Formula A, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, to the catalyst in step (a) is between 1:0.01 and 1:0.2, inclusive.

In certai n embodiments, the mol ar rati o of the amount of the compound of Formul a A , or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, to the amount of the compound of Formula B, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, in step (a) is between 0.33:1 and 0.67:1, between 0.67:1 and 0.99:1, between 0.99:1 and 1.01:1, between 1.01 : 1 and 1.2:1, between 1.2: 1 and 1.5:1, between 1.5: 1 and 2: 1 , and between 2: 1 and 3: 1 ,inclu usi ve. In certai n embodiments, the mol ar rati o of the amount of the compound of Formul a A, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, to the amount of the compound of Formula B, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, in step (a) is between 0.67:1 and 1.5:1, inclusive. In certain embodiments, the mol ar ratio of the amount of the compound of Formula A, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, to the amount of the compound of Formula B, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, in step (a) is between 1.01:1 and 1.5:1, inclusive.

In certain embodiments, the time duration of step (a) 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, or between 3 and 7 days, inclusive. In certain embodiments, the time duration of step (a) is between 2 and 10 hours, inclusive.

In certain embodiments, steps (a) and (b) are concurrent, the first and second temperatures are the same, and the f i rst and second pressures are the same. In certai n embodiments, steps (a) is before step (b).

In certain embodiments, the reaction mixture of step (b) is in a second container. In certai n embodiments, the f i rst contai ner i s the second contai ner ( one-pot”). In certai n embodiments, the f i rst contai ner i s di ff erent from the second contai ner.

In certai n embodiments, the azeotropi cal I y removi ng water compri ses di st i 11 i ng the azeotrope. In certai n embodiments, step (b) further compri ses condensing the removed (eg., di st i 11 ed) azeotrope i nto a thi rd contai ner. In certai n embodiments, the thi rd contai ner i s different from the f i rst contai ner and second contai ner.

In certain embodiments, step (b) further comprises liquid-liquid phase separation of the organic solvent and water of the removed azeotrope. In certai n embodiments, step (b) further comprises returning (eg., continuously or non-continuously) the organic sol vent of the removed azeotrope back to the second contai ner. In certai n embodiments, step (b) further compri ses discarding the water of the removed azeotrope.

In certain embodiments, the reaction mixture of step (b) is substantially a solution (as opposed to a suspension or emulsion).

In certai n embodiments, step (b) further compri ses a second temperature. In certai n embodiments, the second temperature i s about the boi I i ng poi nt of the azeotrope at the second pressure. In certai n embodiments, the second temperature i s the boi I i ng poi nt of the azeotrope ± 1%, ± 2%, ± 5%, ± 10%, ± 20%, or ± 50%, inclusive, at the second pressure. In certain embodiments, the second temperature is substantial I y constant over the ti me duration of step (b).

In certain embodiments, step (b) further comprises a second pressure In certain embodiments, the second pressure is about 1 atm. In certai n embodiments, the second pressure is between 0.001 and 0.01, between 0.01 and 0.1 , or between 0.1 and 1 atm, inclusive.

In certain embodiments, the time duration of step (b) 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, or between 3 and 7 days, inclusive. In certain embodiments, the time duration of step (b) is between 2 and 10 hours, inclusive. In certain embodiments, the time duration of step (a) and/or step (b) is between 2 and 10 hours, inclusive.

In certain embodiments, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, or between 90% and 99%, inclusive, of water formed by step (a) is removed by step (b).

In certain embodiments, the process further comprises (c) washing the reaction mixture after step (b) with a basi c aqueous sol uti on. In certai n embodiments, the basi c aqueous sol uti on i s an aqueous sol uti on of an i norgani c base. In certai n embodiments, the basi c aqueous sol uti on is an aqueous sol uti on of LiOH, NaOH, or KOH. In certain embodiments, the basic aqueous solution is an aqueous sol uti on of Li₂CO₃, Na₂CO₃, or K₂CO₃. In certain embodiments, the basic aqueous sol uti on is an aqueous sol uti on of LiHCO₃, NaHCO₃, or KHCO₃. In certain embodiments, the basi c aqueous sol uti on i s an aqueous sol uti on of ammoni a, ammoni um carbonate, or ammoni um hydroxi de. In certai n embodiments, the basi c aqueous sol uti on i s an aqueous sol uti on of an organic base.

In certain embodiments, step (c) further comprises a third temperature. In certain embodiments, the thi rd temperature is between 20 and 25 °C, i ncl usi ve. In certai n embodiments, the thi rd temperature is between 0 and 10, between 10 and 20, or between 25 and 35 °C, inclusive.

In certai n embodiments, step (c) further compri ses a thi rd pressure. In certai n embodiments, the thi rd pressure is about 1 atm.

In certain embodiments, the process further comprises (d) isolating the product. In certain embodiments, step (d) is after step (c). In certain embodiments, step (d) comprises liquid-liquid phase separation, dying, filtration, concentration, chromatography, decolorization, or recrystallization, or a combi nation thereof. In certai n embodiments, step (d) comprises liquid-liquid phase separation, dying, filtration, concentration, decolorization, or recrystallization, or a combination thereof. In certain embodiments, the liquid-liquid phase separati on i s a separati on of an organ! c phase and an aqueous phase. In certai n embodiments, the dyi ng is dyi ng an organi c phase over a sol id dry i ng agent (e.g., anhydrous Na₂SO₄, anhydrous MgSO₄, anhydrous CaSO₄, anhydrous CaCI₂, or activated molecular sieves). In certain embodiments, the filtration isafiltration of a mixture of an organic phase and a sol id drying agent to remove the sol id drying agent. In certain embodiments, the concentration is concentration of an organic phase to remove part or substantial I y al I of the volatiles (e.g., organic solvents). In certai n 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,inclu usi ve). In certai n embodiments, the concentrati on i s 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 fl ash chromatography (e.g., over silica gel)). In certain embodiments, step (d) does not comprise chromatography. In certain embodiments, the decolorization comprises redissolving in an orgnaic solvent, decolorization, and concentration.

In certai n embodiments, the decol ori zati on compri ses contacting wi th a sol i d decol ori zati on agent (e.g., actived charcoal). In certain embodiments, the recrystallization is a single-solvent recrystallization. In certai n embodiments, the recrystallization is a multi-solvent (e.g., bi- solvent or tri -sol vent) recrystallization. In certain embodiments, the recrystallization is a hot filtration-recrystallization. In certain embodiments, thesovlent(s) employed in the recrystallization are hexanes and ethyl acetate. In certain embodiments, thesovlent(s) employed in the recrystallization are heptanes and ethyl acetate, or petroleum ether and ethyl acetate. In certain embodiments, step (d) 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,inclu usi ve) and/or i ncreasi ng the temperature (e.g. , to a temperature between 25 and 35, between 35 and 50, or between 50 and 80 °C, inclusive).

In certai n embodiments, the combi ned mol ar yi el d of the product i s between 30% and 50%, between 50% and 70%, between 70% and 90%, or between 90% and 95%, inclusive. In certai n embodiments, the combi ned mol ar y i el d of the product i s between 30% and 90%, inclusive.

In certain embodiments, when R⁹ is hydrogen, the molar ratio of the compound of Formula 1-1, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, to the compound of Formula I -2, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, is between 1 :0.01 and 1:0.1, between 1:0.1 and 1:0.3, between 1:0.3 and 1:1, between 1:1 and 1:3, between 1:3 and 1 :10, or between 1:10 and 1:100, inclusive.

In certain embodiments, the carbon atom at the4-position of Formula 1-1 or I -2 is a chiral center:

In certain embodiments, the carbon atom at the4-position of Formula 1-1 or I -2 is of theR configuration. In certain embodiments, the carbon atom at the4-postion of Formula 1-1 or I -2 isof the Sconfiguration. In certai n embodiments, the product is a substantially racemic mixture of Rand S enanti omers with respect to the carbon atom at the4-position of Formula I- 1 or I -2.

In certain embodiments, the process further comprises (e) chiral separation. In certain embodiments, step (e) i s after step (d) . In certai n embodiments, the product i s a mi xture of enantiomers with respect to the carbon atom at the4-position of Formula 1-1 or I-2 where the enantiomeric excess of the R enantiomer is between 50% and 70%, between 70% and 90%, between 90% and 95%, between 95% and 99%, inclusive. In certain embodiments, the product is a mixture of enantiomers with respect to the carbon atom at the4-position of Formula 1-1 or I -2 where the enanti omeri c excess of the S enanti omer i s between 50% and 70%, between 70% and 90%, between 90% and 95%, between 95% and 99%, inclusive.

The processes descri bed herei n are unexpectedly advantageous over known processes. Compared to known processes, the processes descri bed herein are simpler (e.g., involving one- pot, fewer steps, and/or no extremely high and/or extremely low temperature and/or pressure), faster, easier to purify (e.g., involving no chromatography; and/or excess acidic reactants, aci di c catal ysts, and aci di c si de-products bei ng easi I y removed by washing the react! on mixture after step (b) with a basic aqueous solution), I ess expensive (e.g., involving less expensive reactants, reagents, catalysts, and/or organic solvents), I ess energy-demanding (e.g., involving no extremely high and/or extremely low temperature and/or pressure) higher yielding (e.g., involving fewer types and/or amounts of side-products), and/or more scalable (e.g., seal able to reactions where the amount of the compound of Formula B, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, in step (a) is between 0.03 and 0.1, between 0.1 and 0.3, between 0.3 and 1 , between 1 and 10, between 10 and 100, or between 100 and 1,000 mol , inclusive), and/or may reduce sideproduct pollution. Compounds

In another aspect, the present di scl osure provides a compound of the formal a

or a tautomer, stereoisomer, isotopically labeled compound, salt (e.g, pharmaceutically acceptable salt), solvate (e.g., pharmaceutically acceptable solvate), polymorph, co-crystal (e.g., pharmaceutically acceptable co-crystal), or prodrug thereof (collectively, the provided compounds). In certain embodiments, the provided compound is Compound SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof. In certai n embodiments, the provided compound is Compound SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, or salt thereof. In certain embodiments, the provided compound is Compound SW2, SW9a, or SW9b, or a tautomer or salt thereof. In certain embodiments,

. certai n

embodiments, Formal a SW2 is HO O o . In certai n embodiments, Formal a SW9a i s In certain embodiments, Formula SW9a is H In certai n

embodiments, Formul a SW9b i s in certain embodiments, Formula SW9b is

The provi ded compounds may be useful for treati ng di seases or masking unpl easant flavors of unpleasantly flavored substances.

Compositions, Administration, Kits, Methods of Uses

In another aspect, the present di scl osure provides composi ti ons compri si ng a compound of Formula SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal, or prodrug thereof; and optionally an excipient. In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises the compound of FormulaSW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, pharmaceutically acceptable co-crystal , or prodrug thereof; and opti onal I y a pharmaceuti cal I y acceptabl e exci pi ent.

In certain embodiments, the pharmaceutical composition further comprises an additional pharmaceutical agent. Theadditional pharmaceutical agent isdifferent from the provided compound. In certain embodiments, theadditional pharmaceutical agent is an additional therapeutically 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, improve bioavail ability, 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 pharmaceuti cal compositi on i ncl udi ng one of the provi ded compound and the addi ti onal pharmaceutical agent, but not both.

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., combi nation therapies. Pharmaceutical agents include small organic molecules such as drug compounds (e.g, compounds approved for human or veteri nary use by the U .S. Food and Drug Admi ni strati on as provi ded i n 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, anti sense oligonudeoti des, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceuti cal agent useful for treating a disease or premalignant condition. Each additional pharmaceuti cal agent may be admi ni stered at a dose and/or on a ti me schedul e determi ned 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 i n a regi men wi 11 take i nto account compati bi I i ty of the provi ded compound wi th the addi ti onal pharmaceutical agent(s) and/or the desired therapeutic 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 level sat which they are utilized individually. In some embodiments, the levels uti I i zed i n combi nati on wi 11 be I ower than those uti I i zed i ndi vi dual I y .

The additional pharmaceutical agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, anti -proliferative agents, anti -cancer agents, anti -angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, chol esterol -I owed ng agents, anti -di abetic agents, anti -allergic agents, contraceptive agents, pai n-rel i evi ng agents, and a combi nati on thereof. In some embodiments, the addi ti onal pharmaceutical agent is a topoisomerase inhibitor, aMCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a B RCA 1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji hi stone demethy I ase inhibitor, or a DNA damage inducer. In certai n 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 isan immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In certain embodiments, the additional pharmaceutical agent isan immunosuppressor. In certain embodiments, the additional pharmaceutical agent isan immunoactivator. In certain embodiments, the additional pharmaceutical agent isan 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 (TIM 3) 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 (Chk1) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indol eamine 2, 3-di oxygenase (I DO) inhibitor, killer-cell immunoglobulin-like receptor (KIR) inhibitor, or V-domain I g 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).

In another aspect, the present disclosure provides ki ts compri si ng the compound of Formula SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal , or prodrug thereof, or the composition (e.g., pharmaceutical composition); and instructions for using the compound, tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal , prodrug, or composition thereof (e.g., pharmaceutical composition). In certai n embodiments, the kit compri ses a f i rst contai ner, wherein the f i rst contai ner compri ses the provi ded compound or composition. In some embodiments, the kit further compri ses a second container. In certain embodiments, the second contai ner incl uudes an exci pi ent. In certai n embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kit further compri ses a thi rd contai ner. In certai n embodiments, the thi rd contai ner i ncl udes an addi ti onal pharmaceutical agent. In some embodiments, the provided compound or composition included i n the f i rst contai ner and the exci pi ent or addi ti onal pharmaceuti cal agent inc uldued i n the second conta ner are combi ned to form one unit dosage form. In some embodiments, the provided compound or compositioninclu uded in the first container, the exci pi ent incl uuded in the second container, and the additional pharmaceutical agentinclu uded 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. In certain embodiments, the first container, second container, and third container do not compri se the i nstructi ons. In certai n embodiments, the i nstructi ons are for admi ni stering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment of a di sease) . In certai n embodiments, the i nstructi ons are for contacting a bi ol ogi cal sample, tissue, or cell with the provided compound or pharmaceutical composition. In certain embodiments, the instruct! ons comprise information required by a regulatory agency, such as the FDA or EMA. In certai n embodiments, the instructions comprise prescribing information.

In another aspect, the present disclosure provides methods of treating a di sease i n a subject in need thereof comprising administering to the subject in need thereof the compound of Formula SW2, SW9a, or SW9b, or a tautomer, stereoisomer, isotopically labeled compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, pharmaceutically acceptable co-crystal , or prodrug thereof, or a pharmaceutical composition thereof. In certai n embodiments, the di sease i s a barter! al i nf ecti on or vi ral i nfecti on. In certai n embodiments, the bacterial infection is caused by Gram-positive bacteria In certain embodiments, the bacterial infection is caused by Gram-negative bacteria. In certain embodiments, the viral infection is caused by human immunodeficiency virus. In certain embodiments, the di sease i s acqui red i mmunodef i ci ency syndrome. In certai n embodiments, the di sease i s associ ated wi th estrogen def i ci ency. In certai n embodiments, the di sease i s associ ated wi th excess! ve bl ood cl otti ng. In certai n embodiments, the subj ect i s a mammal . In certai n embodiments, the subj ect I s a human.

The provided compounds and pharmaceutical compositions can be administered by any route, i ncl udi ng enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal , subcutaneous, intraventricular, transdermal , interdermal, rectal, intravagi nal, 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 admi ni strati on wi 11 depend upon a vari ety of factorsinclu udi ng the nature of the agent (e. g. , i ts stabi I i ty i n the envi ronment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certai n embodiments, the provided compound or pharmaceutical composition is suitable for topical administration to the eye of a subject.

EXAMPLES

In order that the invention described herein may be more fully understood, the fol I owi ng ecampl es are set forth. The exampl es are offered to i 11 ustrate the methods and uses descri bed herei n and are not to be construed i n any way as I i miti ng thei r scope.

Exarrple 1. 7-Hydroxy-4-(4-hydroxy-3-methoxyphenyl)-chroman-2-one (SW1) F₆rulicacid (1.76 g, 9.08 mmol), resorcinol (1.00 g, 9.08 mmol), p-toluenesulfonic acid monohydrate (0.17 g, 0.91 mmol) and benzene (25 ml) were mixed. The mixture was stirred and heated to reflux for four hours with removal of water azeotropical I y. After cooled to room temperature, most of benzene was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml) and water (100 ml) and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was purif i ed by si I ica gel col umn wi th hexane/ethyl acetate (from 100/0 to 60/40) as elute, decolorize with activated charcoal and recrystallized from hexane/ethyl acetate to give 1.50 g white solid. Molecular Formula: C16H14O5; Exact Mass: 286.08; (-) m/z: 285. ¹H NMR: (400 MHz, DMSO-de): 3.00 (dd, 1 H), 3.05(dd, 1H), 3.70 (s, 3H), 4.24(t,1 H), 6.43(dd, 1H),6.59 (d, 1 H), 6.53(dd, 1H), 6.68 (d, 1H), 6.77 (d, 1 H), 6.83(dd, 1H), 8.91 (s, 1H), 9.70 (s, 1H).

Exarrple 2. 7-Hydroxy-4-(4-hydroxy-3-meihoxyphenyl)-chroman-2-one (SW1) F₆rulic acid (2.00 g, 10.30 mmol), resorcinol (1.13 g, 10.30 mmol), p-toluenesulfonic acid monohydrate (0.20 g, 1.03 mmol) and toluene (25 ml) were mixed. The mixture was stirred and heated to reflux for three hours with removal of water azeotropically. After cooled to room temperature, most of toluene was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml) and water (100 ml) and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column with hexane' ethyl acetate (from 100/0 to 60/40) as elute, decolorize with activated charcoal and recrystal I ized from hexane/ethyl acetate to give 1.54 g white sol id.

Example 3. 7-Hydroxy-4-(4-hydroxy-3-methoxyphenyl)-6-methyl-chroman-2-one (SW2) F₆rulic acid (1.56 g, 8.06 mmol), 4-methyl resorci nol (1.00 g, 8.06 mmol), p- toluenesulfonic acid monohydrate (0.15 g, 0.81 mmol) and benzene (25 ml ) were mixed. The mixture was stirred and heated to reflux for four hours with removal of water azeotropically. After cooled to room temperature, most of benzene was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml) and water (100 ml) and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column with hexane/ethyl acetate (from 100/0 to 60/40) as elute, decolorize with actived charcoal and recrystallized from hexane/ethyl acetate to give 1.77 g white solid. Molecular Formula: C₁₇HI₆O₅; Exact Mass: 300.10; (-) m/z: 299. ¹H NMR: (400 MHz, DMSO-d₆): 2.01 (s, 3H), 2.98 (m, 2 H), 3.70 (s, 3H), 4.19(t,1 H), 6.41 (dd, 1 H),6.52 (s, 1 H), 6.68(d, 1H), 6.72 (s, 1H), 6.77 (d, 1 H), 8.88 (s, 1H), 9.61(s, 1H).

Example 4. 7-Hydroxy-4-(4-hydroxy-3-methoxyphenyl)-6-methyl-chroman-2-one (SW2) Ferulic acid (1.56 g, 8.06 mmol), 4-methyl resorci nol (1.00 g, 8.06 mmol), p- toluenesulfonic acid monohydrate (0.15 g, 0.81 mmol) and toluene (25 ml) were mixed. The mixture was stirred and heated to reflux for three hours with removal of water azeotropically. After cooled to room temperature, most of tol uene was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml) and water (100 ml) and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column with hexane/ethyl acetate (from 100/0 to 60/40) as elute, decolorize with activated charcoal and recrystallized from hexane/ethyl acetate to give 1.67 g white sol id. Exarrple 5. 4-(3,4-Di hydroxyphenyl )-7-hydroxy-5-methyl-chroman-2-one (SW9a) and 4-(3,4- Di hydroxyphenyl )-5-hydroxy- 7-methyl-chroman-2-one ( SW9b)

Caffeic acid (1.60 g, 8.88 mmol), orcinol monohydrate (1.26 g, 8.88 mmol ), p- toluenesulfonic acid monohydrate (0.17 g. 0.89 mmol) and benzene were mixed. The mixture was st i rred and heated to refl ux for four hours wi th removal of water azeotropi cal I y . After cooled to room temperature, most of the benzene was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml) and water (100 ml) and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column with hexane/ethyl acetate (from 90/10 to 60/40) to give yellowish product, which was decolorized with activated charcoal and recrystallized from hexane and ethyl acetate (1 :1) to give 1.35 g of white sol id as pure product. Molecular Formula: C₁₆H₁₄O₅; Exact Mass: 286.08; (-) rri/z: 285. NMR showed two isomers with ratio of around 10:1.

Example 6. 4-(3,4-Dihydroxyphenyl)-7-hydroxy-5-methyl-chroman-2-one (SW9a) and 4-(3,4- Di hydroxyphenyl )-5-hydr oxy- 7-methyl -chroman-2-one ( SW9)

Caffeic acid (1.60 g, 8.88 mmol), ordnol (1.10 g, 8.88 mmol), p-toluenesulfonic acid and tol uene were mixed. The mi xture was sti rred and heated to refl ux for four hours with removal of water azeotropi cal ly. After cooled to room temperature, most of tol uene was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml ) and water (100 ml) and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column with hexane/ethyl acetate (from 90/10 to 60/40) to give yellowish product, which was decolorized with activated charcoal and recrystal I i zed from hexane and ethyl acetate ( 1 : 1 ) to gi ve 0.85 g of whi te sol i d as pure product. Molecular Formula: C16H14O5; Exact Mass: 286.08; (-) m/z: 285. NMR showed two isomers with ratio of around 10:3.6.

Exarrple 7. 7-Hydroxy-4-(4-hydroxy-3-methoxyphenyl)-chroman-2-one (SW1) F₆rulic acid (2.00 g, 10.30 mmol), resorcinol (1.00 g, 9.08 mmol), p-toluenesulfonic acid monohydrate (0.17 g, 0.91 mmol) and benzene (25 ml) were mixed. The mi xture was stirred and heated to reflux for four hours with removal of water azeotropi cal ly. After cooled to room temperature, most of benzene was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml) and saturated sodium bi carbonate solution (80 ml) and separated. The organic layer was washed with water (80 ml), 1.0 N hydrochloric acid solution (80 ml), brine (80 ml), dried over anhydrous magnesi um sulfate, filtered and concentrated under reduced pressure to gi ve crude product. The crude product was decol ori zed wi th acti vated charcoal and recrystal I i zed from hexane' ethy I acetate to gi ve 1.57 g whi te sol i d as pure product.

Exarrple 8. 7-Hydroxy-4-(4-hydroxy-3-methoxyphenyl)-chroman-2-one (SW1) F₆rulicacid (20.00 g, 10.30 mmol), resorcinol (10.00 g, 90.82 mmol), p- toluenesulfonic acid monohydrate (1.73 g, 9.08 mmol) and benzene (100 ml) were mixed. The mixture was stirred and heated to reflux for four hours with removal of water azeotropicdly. After cooled to room temperature, most of benzene was evaporated under reduced pressure. The residue was mixed with ethyl acetate (600 ml) and saturated sodium bi carbonate solution (300 ml) and separated. The organic layer was washed with water (100 ml), 1.0 N hydrochloric acid solution (100 ml), brine(100 ml), dried over anhydrous magnesi um sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was decolorized with activated charcoal and recrystallized from hexane/ethyl acetate to give 14.97 g white solid as pure product.

EQUIVALENTSAND SCOPE

In the claims, arti d es such as S,” an ” and the” may mean one or more than one uni ess i ndi cated to the contrary or otherwi se evi dent from the context. Cl ai ms or descri pti ons 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 otherwi serelevant to a given product or process unless i ndi cated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise rd evant to a given product or process. The present disclosureincl uudes embodiments i n whi ch more than one, or al I of the group members are present in, employed in, or otherwise rd evant to a given product or process.

Furthermore, the present disclosure encompasses al I variations, combinations, and permutati ons i n whi ch one or more I i mi tat i ons, d ements, d auses, and descri pti ve terms from one or more of the I i sted claims i s i ntroduced i nto another claim. For exampl e, any cl ai m that is dependent on another daim can be modified to include one or more I imitations found in any other claim that i s dependent on the same base claim. Where d ements are presented as I i sts, e.g. , i n M arkush group format, each subgroup of the d ements i s al so di sd osed, and any dement(s) can be removed from the group. It should it be understood that, in general, where the present di sol osure, or aspects of the present disclosure, i s/are referred to as compri si ng parti cul ar el ements and/or features, certai n embodiments of the present di scl osure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features. For purposes of si mpl i city, those embodiments have not been specifi cal ly set forth in haec verba herein. It isalso noted that the terms comprising” and containing” are intended to beopen and permits the inclusion of additional el ements or steps. Where ranges are given, endpoints areinclu uded. Furthermore, uni ess otherwi se i ndi cated or otherwi se evi dent from the context and understanding of one of ordi nary ski 11 in the art, val ues that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, uni ess the context d earl y di ctates otherwi se.

Thi s appl i cati on refers to vari ous i ssued patents, publ i shed patent appl i cati ons, j ournal art i d es, and other publ i cati ons, al I of whi ch are i ncorporated herei n by reference. I f there i s a conf I i ct between any of the i ncorporated references and the i nstant sped f i cati on, the spedfication shall control. In addition, any particular embodiment of the present invention that f al I s wi thi n the pri or art may be expl i ci tl y exd uded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordi nary ski 11 in the art, they may be excl uded even if the exdusion is not set forth explidtly herein. Any particular embodi ment of the present disclosure can be exd uded from any claim, for any reason, whether or not related to the existence of prior art.

Those ski 11 ed i n the art wi 11 recogni ze or be abl e to ascertai n usi ng no more than routi ne expert mentati on many equi val ents to the spedf i c embodiments descri bed herei n. The scope of the present embodiments descri bed herei n is not i ntended to be I i mi ted to the above Descri pti on , but rather i s as set forth i n the appended claims. Those of ordi nary ski 11 i n the art wi 11 appred ate that vari ous changes and modif i cati ons to thi s descri pti on may be made wi thout departi ng from the spi ri t or scope of the present i nventi on, as def i ned i n the fol I owi ng claims.

Claims

CLAIMS What is claimed is:

1. A process of preparing a product, wherein the process comprises:

(a) reacting a compound of Formula A:

(b) azeotropical I y removing water, wherein the water is formed by step (a); wherein: each of R¹, R², R³, R⁴, R⁵, and R⁶ is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl , substituted or unsubstituted alky nyl , substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl , -OR^a, -N(R^a)₂, -SR^a, -CN, - SCN, -C(=O)R^a, -C(=O)OR^a, -C(=O)N(R^a)₂, -C(=NR^a)R^a, -C(=NR^a)OR^a, -C(=NR^a)N(R^a)₂, -NO₂, -N₃, -NR^aC(=O)R^a, -NR^aC(=O)OR^a, -NR^aC(=O)N(R^a)₂, -NR^aC(-NR^a)R^a, - NR^aC(=NR^a)OR^a, -NR^aC(=NR^a)N(R^a)₂, -OC(=O)R^a, -OC(=O)OR^a, -OC(=O)N(R^a)₂, - OC(=NR^a)R^a, -OC(=NR^a)OR^a, -OC(=NR^a)N(R^a)₂, -NR^aS(=O)₂R^a, -NR^aS(=O)₂OR^a, - NR^aS(=O)₂N(R^a)₂, -OS(=O)₂R^a, -OS(=O)₂OR^a, -OS(=O)₂N(R^a)₂, -S(=O)₂R^a, -S(=O)₂OR^a, - S(=O)₂N(R^a)₂, -P(=O)(R^a)₂, or -Si(R^a)₃; each R^a is 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 sul fur atom, or two i nstances of R^a on a ni trogen atom are j oi ned wi th the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of R⁷ and R⁸ is independently hydrogen, halogen, unsubstituted cyclopropyl, - OR^b, -N(R^b)₂, -SR^b, -CN, -SCN, -NO₂, -N₃, unsubstituted C_1-3 alkyl, or C_1-3alkyl substituted with one or more halogen; each R^b is independently hydrogen, unsubstituted C_1-2 alkyl, or C_1-2 alkyl substituted with one or more halogen; and

R⁹ is hydrogen, and the product is a compound of Formula 1-1 or I -2:

or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co- crystal thereof, or a mixture thereof; or R⁹ is halogen, unsubstituted cyclopropyl, -OR^b, -N(R^b)₂, -SR^b, -CN, -SCN, -NO₂, -Ng, unsubstituted C_1-3 alkyl, or C_1-3 alkyl substituted with one or more halogen, and the product is a compound of Formula 1-1, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof.

2. The process of cl ai m 1 , wherein the compound of Formul a A i s of the f or mul a:

3. The process of claim 1 , wherein the compound of Formul a A i s of the f or mul a:

4. The process of any one of claims 1 -3, wherein

5. The process of any one of claims 1-4, wherein the compound of Formula B is of the formula:

6. The process of any one of claims 1-2 and 4-5, wherein R¹ is hydrogen, -OH, substituted or unsubstituted alkyl, or -O(substituted or unsubstituted alkyl).

7. The process of claim 6, wherein R¹ is - OH or -OCH₃.

8. The process of any one of claims 1 and 4-7, wherein R² i s - OH .

9. The process of any one of claims 1 and 4-8, wherein R³ is hydrogen.

10. The process of any one of claims 1 -4 and 6-9, wherein R⁴ i s - OH .

11. The process of any one of claims 1-4 and 6-10, wherein R⁵ is hydrogen, substituted or unsubstituted alkyl, or -O(substituted or unsubstituted alkyl).

12. The process of claim 11 , wherein R⁵ i s hydrogen or - CH₃.

13. The process of any one of claims 1-4 and 6-12, wherein R⁶ is hydrogen, substituted or unsubstituted alkyl, or -O(substituted or unsubstituted alkyl).

14. The process of claims 13, wherein R⁶ is hydrogen or -CH₃.

15. The process of any one of claims 1 -4 and 6- 14, wherein R⁴ and R⁶ are the same.

16. The process of any one of claims 1 and 4-15, wherein R⁷ is hydrogen.

17. The process of any one of claims 1 and 4-16, wherein R⁸ is hydrogen.

18. The process of any one of claims 1 -4 and 6-17, wherein R⁹ i s hydrogen.

19. The process of claim 1 , wherein the product i s a compound of the f ormul a:

20. The process of any one of claims 1-19, wherein the catalyst is a Bronsted acid.

21. The process of claim 20, wherein the catal yst i s p-tol uenesul f oni c ad d , or a sol vate thereof.

22. The process of claim 20, wherein the catal yst i s bori c ad d or benzene sul f oni c ad d, or a sol vate thereof.

23. The process of any one of claims 1-19, wherein the catalyst is an acidic cation- exchange resi n.

24. The process of any one of claims 1 -23, wherein the organic solvent i s benzene, tol uene, o-xylene, m-xylene, orp-xylene, or a mixture thereof.

25. The process of any one of claims 1 -24, wherein step (a) further compri ses a f i rst temperature and a fi rst pressure, wherein the fi rst temperature is about the boi I i ng poi nt of the azeotrope at the f i rst pressure.

26. The process of claim 25, wherein the fi rst pressure is about 1 atm.

27. The process of any one of claims 1-26, wherein the molar ratio of the amount of the compound of Formula A, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, to the catalyst in step (a) is between 1:0.01 and 1:0.2, inclusive.

28. The process of any one of claims 1-27, wherein the molar ratio of the amount of the compound of Formula A, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, to the amount of the compound of Formula B, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, in step (a) is between 0.67:1 and 1.5:1, inclusive.

29. The process of claim 28, wherein the mol ar rati o of the amount of the compound of Formula A, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, to the amount of the compound of Formula B, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, in step (a) is between 1.01:1 and 1.5:1, inclusive.

30. The process of any one of claims 1-29, wherein the ti me duration of step (a) and/or step (b) is between 2 and 10 hours, inclusive.

31. The process of any one of claims 1-30 further comprising (c) washing the readion mixture after step (b) with a basic aqueous sol ution.

32. The process of any one of claims 1 -31 further compri si ng (d) i sol ati ng the product.

33. The process of claim 32, wherein step (d) compri ses I i qui d-l i qui d phase separati on, dying, filtration, concentration, chromatography, decolorization, or recrystallization, or a combination thereof.

34. The process of any one of claims 1 -33, wherein the combi ned mol ar yi el d of the product is between 30% and 90%, inclusive.

35. A compound of the formula:

36. A composition comprising: the compound of claim 35, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal , or prodrug thereof; and opti onal I y an exci pi ent .

37. The composi ti on of claim 36 compri si ng: the compound of claims 35, or a tautomer, stereoisomer, isotopically labeled compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, pharmaceutically acceptable co-crystal , or prodrug thereof; and opti onal I y a pharmaceuti cal I y acceptabl e exd pi ent.

38. A kit comprising: the compound of claim 35, or a tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal , or prodrug thereof, or the composition of claim 36 or 37; and instructions for using the compound, tautomer, stereoisomer, isotopically labeled compound, salt, solvate, polymorph, co-crystal, prodrug, or composition.

39. A method of treating a disease in a subject in need thereof comprising administering to the subject in need thereof the compound of claim 35, or a tautomer, stereoisomer, isotopically labeled compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, pharmaceutically acceptable co-crystal , or prodrug thereof, or the composition of claim 37.

40. The method of claim 39, wherein the di sease i s a bacteri al i nf ecti on or vi ral i nf ecti on .

41. A method of masking an unpleasant flavor of an unpleasantly flavored substance comprising contacting or mixing the unpleasantly flavored substance with the compound of claim 35, or a tautomer, stereoisomer, isotopically labeled compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, pharmaceutically acceptable co-crystal , or prodrug thereof, or the composition of cl ai m 36 or 37.