AZASILANE DETECTABLE COMPOUNDS

[0001] This application is a continuation application of U.S. patent application Ser. No. 18/621,997, filed Mar. 29, 2024, which is a continuation of U.S. patent application Ser. No. 17/882,448, filed Aug. 5, 2022, now issued as U.S. Pat. No. 11,987,709, which is a continuation of U.S. patent application Ser. No. 17/737,899, filed May 5, 2022, now issued as U.S. Pat. No. 11,535,754, which is a continuation of PCT/US2020/058916, filed Nov. 4, 2020, which claims the benefit of U.S. Provisional Application No. 62/932,296, filed Nov. 7, 2019, which are incorporated herein by reference in their entirety and for all purposes.

[0002] Rhodamine, acridine, and rhodol dyes are photostable with large absorption coefficients. The synthesis of red shifted fluorescent dyes is challenging because it requires building up the carbocyclic framework. The brightness, photostability and aqueous solubility of red shifted fluorescent dyes can suffer when the carbocyclic framework is extended. Disclosed herein, inter alia, are solutions to these and other problems in the art.

[0003] In an aspect is provided a compound, or salt thereof, having the formula:

[0004] R¹, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,

—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —PO₃H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. R² and R³ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen, —CF₃, —CBr₃, —CCl₃, “—CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —COOH, —CONH₂, —SH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L¹-R¹³. R⁴ and R⁵ substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁶ and R⁷ substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁴ and R⁹ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁷ and R¹⁰ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁵ and R¹¹ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁶ and R¹² substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R¹ and R⁹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl; substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁸ and R¹⁰ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl; substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. In embodiments, no more than one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² is -L¹-R¹³. R¹³ is a bioconjugate reactive moiety, a nucleotide, a nucleoside, or a nucleic acid moiety. L¹ is a covalent linker or a bond.

[0005] In an aspect is provided a monovalent nucleotide or monovalent nucleoside covalently bound to a monovalent form of a compound described herein (e.g., wherein the R¹³ moiety of a compound described herein has reacted with a bioconjugate reactive group to form a bioconjugate linker thereby covalently bonding the monovalent compound to the monovalent nucleotide or monovalent nucleoside).

[0006] In an aspect is provided a method of detecting the presence of an agent. In embodiments, the agent is covalently bound to a monovalent form of a compound (e.g., a compound as described herein). In embodiments, the agent is a monovalent oligonucleotide, monovalent protein, or monovalent second compound (e.g., a monovalent molecule).

[0007] In yet another aspect, is provided a kit including a compound described herein. In embodiments, the kit further includes one or more sets of instructions. In embodiments, the kit includes nucleotides or nucleosides.

[0009] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0010] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

[0011] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C₁-C₁₀ means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

[0012] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

[0013] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—S—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CHO—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or three heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0014] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as —NR′R″ or the like, it will be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″ or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.

[0015] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0016] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH₂)_w, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0017] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH₂)_w, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.

[0018] In embodiments, a heterocycloalkyl is a heterocyclyl. The term “heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0019] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0020] The term “acyl” means, unless otherwise stated, —C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0021] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. In embodiments, the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). In embodiments, the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings. A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be —O— bonded to a ring heteroatom nitrogen.

[0022] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocyclic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0023] The symbol “” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0024] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0025] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0026] An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0027] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0028] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R, R′, R″, R′″, and R″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, and R″″ group when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

[0029] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: —OR′, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″, R′″, and R″″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, and R″″ groups when more than one of these groups is present.

[0030] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0031] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0032] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0033] A “substituent group,” as used herein, means a group selected from the following moieties:

• • [0034] (A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —PO₃H, —PO₄H, —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
  • [0035] (B) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:
    • [0036] (i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —PO₃H, —PO₄H, —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
    • [0037] (ii) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:
      • [0038] (a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —PO₃H, —PO₄H, —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
      • [0039] (b) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —PO₃H, —PO₄H, —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0040] A “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0041] A “lower substituent” or “lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0042] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0043] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0044] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound (e.g., nucleotide analogue) is a chemical species set forth in the Examples section, claims, embodiments, figures, or tables below.

[0045] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively).

[0046] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

[0047] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0048] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.

[0049] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different.

[0050] Where a moiety is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene), the moiety is substituted with at least one substituent (e.g., a substituent group, a size-limited substituent group, or lower substituent group) and each substituent is optionally different. Additionally, where multiple substituents are present on a moiety, each substituent may be optionally different.

[0051] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0052] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0053] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0054] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0055] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0056] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0057] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0058] “Analog,” or “analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0059] The terms “a” or “an,” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C₁-C₂₀ alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0060] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R¹³ substituents are present, each R¹³ substituent may be distinguished as R^13A, R^13B, R^13C, R^13D, etc., wherein each of R^13A, R^13B, R^13C, R^13D, etc. is defined within the scope of the definition of R¹³ and optionally differently.

[0061] Descriptions of the compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0062] The compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (−)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0063] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0064] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.

[0065] A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

[0066] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells, or bioconjugate reactive moieties) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture. The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a nucleotide, linker, protein, or enzyme.

[0067] The terms “inhibitor” or “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0068] The term “streptavidin” refers to a tetrameric protein (including homologs, isoforms, and functional fragments thereof) capable of binding biotin. The term includes any recombinant or naturally-occurring form of streptavidin variants thereof that maintain streptavidin activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype streptavidin).

[0069] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0070] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist.

[0071] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0072] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

[0073] The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0074] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples.

[0075] “Nucleic acid” or “oligonucleotide” or “polynucleotide” or grammatical equivalents used herein means at least two nucleotides covalently linked together. The term “nucleic acid” includes single-, double-, or multiple-stranded DNA, RNA and analogs (derivatives) thereof. Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length. Nucleic acids and polynucleotides are polymers of any length, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. In certain embodiments the nucleic acids herein contain phosphodiester bonds. In other embodiments, nucleic acid analogs are included that may have alternate backbones, comprising, e.g., phosphoramidate, phosphorothioate, phosphorodithioate, or O-methylphosphoroamidite linkages (see, Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press); and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, and non-ribose backbones, including those described in U.S. Pat. Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, Carbohydrate Modifications in Antisense Research, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. A residue of a nucleic acid, as referred to herein, is a monomer of the nucleic acid (e.g., a nucleotide).

[0076] A particular nucleic acid sequence also encompasses “splice variants.” Similarly, a particular protein encoded by a nucleic acid encompasses any protein encoded by a splice variant of that nucleic acid. “Splice variants,” as the name suggests, are products of alternative splicing of a gene. After transcription, an initial nucleic acid transcript may be spliced such that different (alternate) nucleic acid splice products encode different polypeptides. Mechanisms for the production of splice variants vary, but include alternate splicing of exons. Alternate polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any products of a splicing reaction, including recombinant forms of the splice products, are included in this definition. An example of potassium channel splice variants is discussed in Leicher, et al., J. Biol. Chem. 273(52):35095-35101 (1998).

[0077] Nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, “operably linked” means that the DNA sequences being linked are near each other, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

[0078] “Nucleotide,” as used herein, refers to a nucleoside-5′-polyphosphate compound, or a structural analog thereof, which can be incorporated (e.g., partially incorporated as a nucleoside-5′-monophosphate or derivative thereof) by a nucleic acid polymerase to extend a growing nucleic acid chain (such as a primer). Nucleotides may include bases such as guanine (G), adenine (A), thymine, (T), uracil (U), cytosine (C), or analogues thereof, and may comprise 2, 3, 4, 5, 6, 7, 8, or more phosphates in the phosphate group. Nucleotides may be modified at one or more of the base, sugar, or phosphate group. A nucleotide may have a label or tag attached (a “labeled nucleotide” or “tagged nucleotide”). In embodiments, the nucleotide is a modified nucleotide which terminates primer extension reversibly. In embodiments, nucleotides may further include a polymerase-compatible cleavable moiety covalently bound to the 3′ oxygen.

[0079] A “nucleoside” is structurally similar to a nucleotide but lacks the phosphate moieties. An example of a nucleoside analog would be one in which the label is linked to the base and there is no phosphate group attached to the sugar molecule.

[0080] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, or non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see, Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g., phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Pat. Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, Carbohydrate Modifications in Antisense Research, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0081] In embodiments, “nucleotide analogue,” “nucleotide analog,” or “nucleotide derivative” shall mean an analogue of A, G, C, T or U (that is, an analogue or derivative of a nucleotide comprising the base A, G, C, T or U), including a phosphate group, which may be recognized by DNA or RNA polymerase (whichever is applicable) and may be incorporated into a strand of DNA or RNA (whichever is appropriate). Examples of nucleotide analogues include, without limitation, 7-deaza-adenine, 7-deaza-guanine, the analogues of deoxynucleotides shown herein, analogues in which a label is attached through a cleavable linker to the 5-position of cytosine or thymine or to the 7-position of deaza-adenine or deaza-guanine, and analogues in which a small chemical moiety is used to cap the —OH group at the 3′-position of deoxyribose. Nucleotide analogues and DNA polymerase-based DNA sequencing are also described in U.S. Pat. No. 6,664,079, which is incorporated herein by reference in its entirety for all purposes.

[0082] The term “bioconjugate group” or “bioconjugate reactive moiety” or “bioconjugate reactive group” refers to a chemical moiety which participates in a reaction to form bioconjugate linker (e.g., covalent linker). Non-limiting examples of bioconjugate groups include —NH₂, —COOH, —COOCH₃, —N-hydroxysuccinimide, -maleimide,

In embodiments, the bioconjugate reactive group may be protected (e.g., with a protecting group). In embodiments, the bioconjugate reactive moiety is

or —NH₂. Additional examples of bioconjugate reactive groups and the resulting bioconjugate reactive linkers may be found in the Bioconjugate Table below:

Bioconjugate reactive group 1	Bioconjugate reactive group 2
(e.g., electrophilic bioconjugate	(e.g., nucleophilic bioconjugate	Resulting Bioconjugate
reactive moiety)	reactive moiety)	reactive linker
activated esters	amines/anilines	carboxamides
acrylamides	thiols	thioethers
acyl azides	amines/anilines	carboxamides
acyl halides	amines/anilines	carboxamides
acyl halides	alcohols/phenols	esters
acyl nitriles	alcohols/phenols	esters
acyl nitriles	amines/anilines	carboxamides
aldehydes	amines/anilines	imines
aldehydes or ketones	hydrazines	hydrazones
aldehydes or ketones	hydroxylamines	oximes
alkyl halides	amines/anilines	alkyl amines
alkyl halides	carboxylic acids	esters
alkyl halides	thiols	thioethers
alkyl halides	alcohols/phenols	ethers
alkyl sulfonates	thiols	thioethers
alkyl sulfonates	carboxylic acids	esters
alkyl sulfonates	alcohols/phenols	ethers
anhydrides	alcohols/phenols	esters
anhydrides	amines/anilines	carboxamides
aryl halides	thiols	thiophenols
aryl halides	amines	aryl amines
aziridines	thiols	thioethers
boronates	glycols	boronate esters
carbodiimides	carboxylic acids	N-acylureas or anhydrides
diazoalkanes	carboxylic acids	esters
epoxides	thiols	thioethers
haloacetamides	thiols	thioethers
haloplatinate	amino	platinum complex
haloplatinate	heterocycle	platinum complex
haloplatinate	thiol	platinum complex
halotriazines	amines/anilines	aminotriazines
halotriazines	alcohols/phenols	triazinyl ethers
halotriazines	thiols	triazinyl thioethers
imido esters	amines/anilines	amidines
isocyanates	amines/anilines	ureas
isocyanates	alcohols/phenols	urethanes
isothiocyanates	amines/anilines	thioureas
maleimides	thiols	thioethers
phosphoramidites	alcohols	phosphite esters
silyl halides	alcohols	silyl ethers
sulfonate esters	amines/anilines	alkyl amines
sulfonate esters	thiols	thioethers
sulfonate esters	carboxylic acids	esters
sulfonate esters	alcohols	ethers
sulfonyl halides	amines/anilines	sulfonamides
sulfonyl halides	phenols/alcohols	sulfonate esters

[0083] As used herein, the term “bioconjugate” or “bioconjugate linker” refers to the resulting association between atoms or molecules of bioconjugate reactive groups. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., —NH₂, —COOH, —N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., —N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -sulfo-N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., —COOH) is covalently attached to the second bioconjugate reactive group

thereby forming a bioconjugate

In embodiments, the first bioconjugate reactive group (e.g., —NH₂) is covalently attached to the second bioconjugate reactive group

thereby forming a bioconjugate

In embodiments, the first bioconjugate reactive group (e.g., a coupling reagent) is covalently attached to the second bioconjugate reactive group

thereby forming a bioconjugate

[0084] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example:

• • [0085] (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters;
  • [0086] (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.
  • [0087] (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom;
  • [0088] (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups;
  • [0089] (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition;
  • [0090] (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides;
  • [0091] (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides;
  • [0092] (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized;
  • [0093] (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc;
  • [0094] (j) epoxides, which can react with, for example, amines and hydroxyl compounds;
  • [0095] (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis;
  • [0096] (l) metal silicon oxide bonding;
  • [0097] (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds;
  • [0098] (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and
  • [0099] (o) biotin conjugate can react with avidin or strepavidin to form a avidin-biotin complex or streptavidin-biotin complex.

[0100] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.

[0101] The term “monophosphate” is used in accordance with its ordinary meaning in the arts and refers to a moiety having the formula:

The term “polyphosphate” refers to at least two phosphate groups, having the formula:

wherein np is an integer of 1 or greater. In embodiments, np is an integer from 0 to 5. In embodiments, np is an integer from 0 to 2. In embodiments, np is 2.

[0102] The term “base” as used herein refers to a purine or pyrimidine (e.g., divalent purine or pyrimidine) compound or a derivative thereof, that may be a constituent of nucleic acid (i.e., DNA or RNA, or a derivative thereof). In embodiments, the base is a derivative of a naturally occurring DNA or RNA base (e.g., a base analogue). In embodiments, the base is a monovalent purine or monovalent pyrimidine or a derivative thereof. In embodiments, the base is a divalent purine or divalent pyrimidine or a derivative thereof. In embodiments, the base is a hybridizing base. In embodiments, the base hybridizes to a complementary base. In embodiments, the base is capable of forming at least one hydrogen bond with a complementary base (e.g., adenine hydrogen bonds with thymine, adenine hydrogen bonds with uracil, guanine pairs with cytosine). Non-limiting examples of a base include divalent forms of cytosine or a derivative thereof (e.g., cytosine analogue), guanine or a derivative thereof (e.g., guanine analogue), adenine or a derivative thereof (e.g., adenine analogue), thymine or a derivative thereof (e.g., thymine analogue), uracil or a derivative thereof (e.g., uracil analogue), hypoxanthine or a derivative thereof (e.g., hypoxanthine analogue), xanthine or a derivative thereof (e.g., xanthine analogue), 7-methylguanine or a derivative thereof (e.g., 7-methylguanine analogue), deaza-adenine or a derivative thereof (e.g., deaza-adenine analogue), deaza-guanine or a derivative thereof (e.g., deaza-guanine), deaza-hypoxanthine or a derivative thereof, 5,6-dihydrouracil or a derivative thereof (e.g., 5,6-dihydrouracil analogue), 5-methylcytosine or a derivative thereof (e.g., 5-methylcytosine analogue), or 5-hydroxymethylcytosine or a derivative thereof (e.g., 5-hydroxymethylcytosine analogue). In embodiments, the base is a divalent form of adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, or isoguanine. In embodiments, the base is

[0103] The term “non-covalent linker” is used in accordance with its ordinary meaning and refers to a divalent moiety which includes at least two molecules that are not covalently linked to each other but are capable of interacting with each other via a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond) or van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion). In embodiments, the non-covalent linker is the result of two molecules that are not covalently linked to each other that interact with each other via a non-covalent bond.

[0104] The term “cleavable linker” or “cleavable moiety” as used herein refers to a divalent or monovalent, respectively, moiety which is capable of being separated (e.g., detached, split, disconnected, hydrolyzed, a stable bond within the moiety is broken) into distinct entities. A cleavable linker is cleavable (e.g., specifically cleavable) in response to external stimuli (e.g., enzymes, nucleophilic/basic reagents, reducing agents, photo-irradiation, electrophilic/acidic reagents, organometallic and metal reagents, or oxidizing reagents). A chemically cleavable linker refers to a linker which is capable of being split in response to the presence of a chemical (e.g., acid, base, oxidizing agent, reducing agent, Pd(0), tris-(2-carboxyethyl)phosphine, dilute nitrous acid, fluoride, tris(3-hydroxypropyl)phosphine), sodium dithionite (Na₂S₂O₄), or hydrazine (N₂H₄)). In embodiments, a chemically cleavable linker is non-enzymatically cleavable. In embodiments, the cleavable linker is cleaved by contacting the cleavable linker with a cleaving agent. In embodiments, the cleaving agent is a phosphine containing reagent (e.g., TCEP or THPP), sodium dithionite (Na₂S₂O₄), weak acid, hydrazine (N₂H₄), Pd(0), or light-irradiation (e.g., ultraviolet radiation).

[0105] A photocleavable linker (e.g., including or consisting of an o-nitrobenzyl group) refers to a linker which is capable of being split in response to photo-irradiation (e.g., ultraviolet radiation). An acid-cleavable linker refers to a linker which is capable of being split in response to a change in the pH (e.g., increased acidity). A base-cleavable linker refers to a linker which is capable of being split in response to a change in the pH (e.g., decreased acidity). An oxidant-cleavable linker refers to a linker which is capable of being split in response to the presence of an oxidizing agent. A reductant-cleavable linker refers to a linker which is capable of being split in response to the presence of an reducing agent (e.g., Tris(3-hydroxypropyl)phosphine). In embodiments, the cleavable linker is a dialkylketal linker, an azo linker, an allyl linker, a cyanoethyl linker, a 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl linker, or a nitrobenzyl linker.

[0106] The term “orthogonally cleavable linker” or “orthogonal cleavable linker” as used herein refer to a cleavable linker that is cleaved by a first cleaving agent (e.g., enzyme, nucleophilic/basic reagent, reducing agent, photo-irradiation, electrophilic/acidic reagent, organometallic and metal reagent, oxidizing reagent) in a mixture of two or more different cleaving agents and is not cleaved by any other different cleaving agent in the mixture of two or more cleaving agents. For example, two different cleavable linkers are both orthogonal cleavable linkers when a mixture of the two different cleavable linkers are reacted with two different cleaving agents and each cleavable linker is cleaved by only one of the cleaving agents and not the other cleaving agent. In embodiments, an orthogonally cleavable linker is a cleavable linker that, following cleavage (e.g., following exposure to a cleaving agent), the two separated entities (e.g., fluorescent dye, bioconjugate reactive group) do not further react and form a new orthogonally cleavable linker.

[0107] The term “polymer” refers to a molecule including repeating subunits (e.g., polymerized monomers). For example, polymeric molecules may be based upon polyethylene glycol (PEG), tetraethylene glycol (TEG), polyvinylpyrrolidone (PVP), poly(xylene), or poly(p-xylylene). The term “polymerizable monomer” is used in accordance with its meaning in the art of polymer chemistry and refers to a compound that may covalently bind chemically to other monomer molecules (such as other polymerizable monomers that are the same or different) to form a polymer. In embodiments, polymer refers to PEG, having the formula:

wherein n1 is an integer from 1 to 30.

[0108] The term “small molecule” is used in accordance with its well understood meaning and refers to a low molecular weight organic compound that may regulate a biological process. In embodiments, the small molecule is a compound that weighs less than 1000 daltons. In embodiments, the small molecule is a compound that weighs less than 900 daltons. In embodiments, the small molecule weighs less than 800 daltons. In embodiments, the small molecule weighs less than 700 daltons. In embodiments, the small molecule weighs less than 600 daltons. In embodiments, the small molecule weighs less than 500 daltons. In embodiments, the small molecule weighs less than 450 daltons. In embodiments, the small molecule weighs less than 400 daltons.

[0109] The term “solution” is used in accordance with its plain ordinary meaning in the arts and refers to a liquid mixture in which the minor component (e.g., a solute or compound) is distributed (e.g., uniformly distributed) within the major component (e.g., a solvent).

[0110] The term “organic solvent” as used herein is used in accordance with its ordinary meaning in chemistry and refers to a solvent which includes carbon. Non-limiting examples of organic solvents include acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether, diglyme (diethylene glycol, dimethyl ether), 1,2-dimethoxyethane (glyme, DME), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, hexamethylphosphoramide (HMPA), hexamethylphosphorous, triamide (HMPT), hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyrrolidinone (NMP), nitromethane, pentane, petroleum ether (ligroine), 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethyl amine, o-xylene, m-xylene, or p-xylene. In embodiments, the organic solvent is or includes chloroform, dichloromethane, methanol, ethanol, tetrahydrofuran, or dioxane.

[0111] As used herein, the term “salt” refers to acid or base salts of the compounds described herein. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. In embodiments, compounds may be presented with a positive charge, for example

and it is understood an appropriate counter-ion (e.g., chloride ion, fluoride ion, or acetate ion) may also be present, though not explicitly shown. Likewise, for compounds having a negative charge

it is understood an appropriate counter-ion (e.g., a proton, sodium ion, potassium ion, or ammonium ion) may also be present, though not explicitly shown. The protonation state of the compound (e.g., a compound described herein) depends on the local environment (i.e., the pH of the environment), therefore, in embodiments, the compound may be described as having a moiety in a protonated state

or an ionic state

and it is understood these are interchangeable. In embodiments, the counter-ion is represented by the symbol M (e.g., M⁺ or M⁻).

[0112] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/−10% of the specified value. In embodiments, about includes the specified value.

[0113] The term “protecting group” is used in accordance with its ordinary meaning in organic chemistry and refers to a moiety covalently bound to a heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions performed prior to removal of the protecting group. Typically a protecting group is bound to a heteroatom (e.g., O) during a part of a multipart synthesis wherein it is not desired to have the heteroatom react (e.g., a chemical reduction) with the reagent. Following protection the protecting group may be removed (e.g., by modulating the pH). In embodiments the protecting group is an alcohol protecting group. Non-limiting examples of alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethylsilyl (TMS)). In embodiments the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), and tosyl (Ts).

[0114] The term “polymerase-compatible cleavable moiety” or a “reversible terminator moiety” as used herein refers to a cleavable moiety which does not interfere with the function of a polymerase (e.g., DNA polymerase, modified DNA polymerase) in incorporating the nucleotide to which the polymerase-compatible moiety is attached to the 3′ end of the newly formed nucleotide strand. The polymerase-compatible moiety does, however, interfere with the polymerase function by preventing the addition of another nucleotide to the 3′ oxygen of the nucleotide to which the polymerase-compatible moiety is attached. Methods for determining the function of a polymerase contemplated herein are described in B. Rosenblum et al. (Nucleic Acids Res. 1997 Nov. 15; 25(22): 4500-4504); and Z. Zhu et al. (Nucleic Acids Res. 1994 Aug. 25; 22(16): 3418-3422), which are incorporated by reference herein in their entirety for all purposes. In embodiments, the polymerase-compatible cleavable moiety does not decrease the function of a polymerase relative to the absence of the polymerase-compatible cleavable moiety. In embodiments, the polymerase-compatible cleavable moiety does not negatively affect DNA polymerase recognition. In embodiments, the polymerase-compatible cleavable moiety does not negatively affect (e.g., limit) the read length of the DNA polymerase. Additional examples of a polymerase-compatible cleavable moiety may be found in U.S. Pat. No. 6,664,079, Ju J. et al. (2006) Proc Natl Acad Sci USA 103(52):19635-19640; Ruparel H. et al. (2005) Proc Natl Acad Sci USA 102(17):5932-5937; Wu J. et al. (2007) Proc Natl Acad Sci USA 104(104):16462-16467; Guo J. et al. (2008) Proc Natl Acad Sci USA 105(27): 9145-9150 Bentley D. R. et al. (2008) Nature 456(7218):53-59; or Hutter D. et al. (2010) Nucleosides Nucleotides & Nucleic Acids 29:879-895, which are incorporated herein by reference in their entirety for all purposes. In embodiments, a polymerase-compatible moiety includes hydrogen, —N₃, —CN, or halogen. In embodiments, a polymerase-compatible cleavable moiety includes an azido moiety or a dithiol linking moiety. In embodiments, the polymerase-compatible cleavable moiety is independently —NH₂, —CN, —CH₃, C₂-C₆ allyl (e.g., —CH₂—CH═CH₂), methoxyalkyl (e.g., —CH₂—O—CH₃), or —CH₂N₃. In embodiments, the polymerase-compatible cleavable moiety comprises a disulfide moiety. In embodiments, a polymerase-compatible cleavable moiety is a cleavable moiety on a nucleotide, nucleobase, nucleoside, or nucleic acid that does not interfere with the function of a polymerase (e.g., DNA polymerase, modified DNA polymerase). In embodiments, the reversible terminator moiety is

In embodiments, the reversible terminator moiety is

[0115] The term “allyl” as described herein refers to an unsubstituted methylene attached to a vinyl group (i.e., —CH═CH₂), having the formula

An “allyl linker” refers to a divalent unsubstituted methylene attached to a vinyl group, having the formula

[0116] The terms “DNA polymerase” and “nucleic acid polymerase” are used in accordance with their plain ordinary meaning and refer to enzymes capable of synthesizing nucleic acid molecules from nucleotides (e.g., deoxyribonucleotides). Typically, a DNA polymerase adds nucleotides to the 3′-end of a DNA strand, one nucleotide at a time. In embodiments, the DNA polymerase is a Pol I DNA polymerase, Pol II DNA polymerase, Pol III DNA polymerase, Pol IV DNA polymerase, Pol V DNA polymerase, Pol β DNA polymerase, Pol μ DNA polymerase, Pol λ DNA polymerase, Pol σ DNA polymerase, Pol α DNA polymerase, Pol δ DNA polymerase, Pol ε DNA polymerase, Pol η DNA polymerase, Pol ι DNA polymerase, Pol κ DNA polymerase, Pol ζ DNA polymerase, Pol γ DNA polymerase, Pol θ DNA polymerase, Pol υ DNA polymerase, or a thermophilic nucleic acid polymerase (e.g., Taq polymerase, Therminator γ, 9° N polymerase (exo-), Therminator II, Therminator III, or Therminator IX).

[0117] A person of ordinary skill in the art will understand when a variable (e.g., moiety or linker) of a compound or of a compound genus (e.g., a genus described herein) is described by a name or formula of a standalone compound with all valencies filled, the unfilled valence(s) of the variable will be dictated by the context in which the variable is used. For example, when a variable of a compound as described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable is understood to represent a monovalent form (i.e., capable of forming a single bond due to an unfilled valence) of a standalone compound (e.g., if the variable is named “methane” in an embodiment but the variable is known to be attached by a single bond to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is actually a monovalent form of methane, i.e., methyl or —CH₃). Likewise, for a linker variable (e.g., L¹, L², L³, or L⁴ as described herein), a person of ordinary skill in the art will understand that the variable is the divalent form of a standalone compound (e.g., if the variable is assigned to “PEG” or “polyethylene glycol” in an embodiment but the variable is connected by two separate bonds to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds through two unfilled valences) form of PEG instead of the standalone compound PEG).

[0118] The term “leaving group” is used in accordance with its ordinary meaning in chemistry and refers to a moiety (e.g., atom, functional group, or molecule) that separates from the molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, or cross-coupling reaction) involving an atom or chemical moiety to which the leaving group is attached, also referred to herein as the “leaving group reactive moiety”, and a complementary reactive moiety (i.e., a chemical moiety that reacts with the leaving group reactive moiety) to form a new bond between the remnants of the leaving groups reactive moiety and the complementary reactive moiety. Thus, the leaving group reactive moiety and the complementary reactive moiety form a complementary reactive group pair. Non limiting examples of leaving groups include hydrogen, hydroxide, halogen (e.g., Br), perfluoroalkylsulfonates (e.g., triflate), tosylates, mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, boronic acid, boronate esters, substituted or unsubstituted piperazinyl, and alkoxides. In embodiments, two molecules are allowed to contact, wherein at least one of the molecules has a leaving group, and upon a reaction and/or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, or Stille reaction) the leaving group(s) separate from the respective molecule. In embodiments, a leaving group is a bioconjugate reactive moiety. In embodiments, the leaving groups is designed to facilitate the reaction. In embodiments, the leaving group is a substituent group.

[0119] The terms “detect” and “detecting” as used herein refer to the act of viewing (e.g., imaging, indicating the presence of, quantifying, or measuring (e.g., spectroscopic measurement), an agent based on an identifiable characteristic of the agent, for example, the light emitted from the present compounds. For example, the compound described herein can be bound to an agent, and, upon being exposed to an absorption light, will emit an emission light. The presence of an emission light can indicate the presence of the agent. Likewise, the quantification of the emitted light intensity can be used to measure the concentration of the agent.

[0120] As used herein, the term “kit” refers to any delivery system for delivering materials. In the context of reaction assays, such delivery systems include systems that allow for the storage, transport, or delivery of reaction reagents (e.g., oligonucleotides, enzymes, etc. in the appropriate containers) and/or supporting materials (e.g., buffers, written instructions for performing the assay, etc.) from one location to another. For example, kits include one or more enclosures (e.g., boxes) containing the relevant reaction reagents and/or supporting materials. As used herein, the term “fragmented kit” refers to a delivery system comprising two or more separate containers that each contain a subportion of the total kit components. The containers may be delivered to the intended recipient together or separately. For example, a first container may contain an enzyme for use in an assay, while a second container contains oligonucleotides. In contrast, a “combined kit” refers to a delivery system containing all of the components of a reaction assay in a single container (e.g., in a single box housing each of the desired components). The term “kit” includes both fragmented and combined kits.

[0121] The terms “fluorophore” or “fluorescent agent” are used interchangeably and refer to a substance, compound, agent, or composition (e.g., compound) that can absorb light at one or more wavelengths and re-emit light at one or more longer wavelengths, relative to the one or more wavelengths of absorbed light. Examples of fluorophores that may be included in the compounds and compositions described herein include fluorescent proteins, xanthene derivatives (e.g., fluorescein, rhodamine, Oregon green, eosin, or Texas red), cyanine and derivatives (e.g., cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, or merocyanine), napththalene derivatives (e.g., dansyl or prodan derivatives), coumarin and derivatives, oxadiazole derivatives (e.g., pyridyloxazole, nitrobenzoxadiazole or benzoxadiazole), anthracene derivatives (e.g., anthraquinones, DRAQ5, DRAQ7, or CyTRAK Orange), pyrene derivatives (e.g., cascade blue and derivatives), oxazine derivatives (e.g., Nile red, Nile blue, cresyl violet, or oxazine 170), acridine derivatives (e.g., proflavin, acridine orange, acridine yellow), arylmethine derivatives (e.g., auramine, crystal violet, or malachite green), tetrapyrrole derivatives (e.g., porphin, phthalocyanine, bilirubin), CF Dye™, DRAQ™, CyTRAK™, BODIPY™, Alexa Fluor™, DyLight Fluor™, Atto™, Tracy™, FluoProbes™, Abberior Dyes™, DY™ dyes, MegaStokes Dyes™, Sulfo Cy™, Seta™ dyes, SeTau™ dyes, Square Dyes™, Quasar™ dyes, Cal Fluor™ dyes, SureLight Dyes™, PerCP™, Phycobilisomes™, APC™, APCXL™, RPE™, and/or BPE™. A fluorescent moiety is a radical of a fluorescent agent. The emission from the fluorophores can be detected by any number of methods, including but not limited to, fluorescence spectroscopy, fluorescence microscopy, fluorimeters, fluorescent plate readers, infrared scanner analysis, laser scanning confocal microscopy, automated confocal nanoscanning, laser spectrophotometers, fluorescent-activated cell sorters (FACS), image-based analyzers and fluorescent scanners (e.g., gel/membrane scanners).

[0122] In an aspect is provided a compound, or salt thereof, having the formula:

[0123] R¹, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each independently hydrogen, halogen, —CCl₃,

—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —PO₃H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. R² and R³ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —COOH, —CONH₂, —SH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L¹-R¹³. R⁴ and R⁵ substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁶ and R⁷ substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁴ and R⁹ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁷ and R¹⁰ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁵ and R¹¹ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁶ and R¹² substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R¹ and R⁹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl; substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁸ and R¹⁰ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl; substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. In embodiments, no more than one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² is -L¹-R¹³. R¹³ is a bioconjugate reactive moiety, a monovalent nucleotide, a monovalent nucleoside, or a nucleic acid. L¹ is a covalent linker or a bond.

[0124] In embodiments, compounds may be presented with a positive charge, for example

and it is understood an appropriate counter-ion (e.g., chloride ion, fluoride ion, or acetate ion) may also be present, though not explicitly shown. Likewise, for compounds having a negative charge

it is understood an appropriate counter-ion (e.g., a proton, sodium ion, potassium ion, or ammonium ion) may also be present, though not explicitly shown. The protonation state of the compound (e.g., a compound described herein) depends on the local environment (i.e., the pH of the environment), therefore, in embodiments, the compound may be described as having a moiety in a protonated state

or an ionic state

and it is understood these are interchangeable. In embodiments, the counter-ion is represented by the symbol M (e.g., M⁺ or M⁻).

[0125] In embodiments, the compound is

and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as described herein. In embodiments, the compound is

and R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as described herein. In embodiments, the compound is

and R¹, R², R³, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as described herein.

[0126] In embodiments, one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² is -L¹-R¹³. In embodiments, when R¹ is -L¹-R¹³; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R² is -L¹-R¹³; R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R³ is -L¹-R¹³; R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R⁴ is -L¹-R¹³; R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R⁵ is -L¹-R¹³; R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R⁶ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R⁷ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R⁸ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R⁹ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R¹⁰ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R¹¹ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹² are not -L¹-R¹³. In embodiments, when R¹² is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are not -L¹-R¹³. In embodiments, when R¹⁴ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R¹⁵ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R¹⁶ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R¹⁷ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R³⁴ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R³⁶ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, when R¹⁴ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁵, R¹⁶, R¹⁷, R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, when R¹⁵ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁶, R¹⁷, R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, when R¹⁶ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁷, R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, when R¹⁷ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, when R³⁴ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R³⁶ are not -L¹-R¹³. In embodiments, when R³⁶ is -L¹-R¹³; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R³⁴ are not -L¹-R¹³.

[0127] In embodiments, when R¹ is -L¹-R¹³, no other substituent on the compound (e.g., R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R² is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R³ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R⁴ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R⁵ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R⁶ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R⁷ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R⁸ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R⁹ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R¹⁰ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R¹¹ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R¹² is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R¹⁴ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R¹⁵ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R¹⁶ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁷, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R¹⁷ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R³⁴, or R³⁶) is -L¹-R¹³. In embodiments, when R³⁴ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, or R³⁶) is -L¹-R¹³. In embodiments, when R³⁶ is -L¹-R¹³, no other substituent on the compound (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶, R¹⁷, or R³⁴) is -L¹-R¹³.

[0128] In embodiments, the compound has the formula:

R¹, R², R³, R⁵, R⁶, R⁸, R¹¹, R¹² are as described herein. R¹⁴ and R¹⁵ are each independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —PO₃H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. In embodiments, no more than one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, and R¹⁵ is -L¹-R¹³. The symbols z14 and z15 are each independently an integer from 0 to 8. In embodiments, the compound has the formula:

and z14, z15, R¹, R², R³, R⁵, R⁶, R⁸, R¹¹, R¹², R¹⁴, and R¹⁵ are as described herein. In embodiments, the compound has the formula:

and z14, z15, R¹, R², R³, R⁵, R⁶, R⁸, R¹¹, R¹², R¹⁴, and R¹⁵ are as described herein. In embodiments, the compound has the formula:

and z14, z15, R¹, R², R³, R⁵, R⁶, R⁸, R¹¹, R¹², R¹⁴, and R¹⁵ are as described herein. In embodiments, the compound has the formula:

and z14, z15, R¹, R², R³, R⁸, R¹⁴, and R¹⁵ are as described herein.

[0129] In embodiments, the compound has the formula:

wherein it is understood that R¹, R², R³, R⁵, R⁶, R⁸, R¹¹, R¹², z14 and R¹⁴ are described herein and are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein it is understood that R¹, R², R³, R⁵, R⁶, R⁸, R¹¹, R¹², z15 and R¹⁵ are described herein and are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein it is understood that R¹, R², R³, R⁶, R⁸, R¹¹, and R¹² are described herein and are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein it is understood that R², R³, and R⁶ are described herein and are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein it is understood that R⁶ is as described herein and is not -L¹-R¹³. In embodiments, the compound has the formula:

wherein it is understood that R⁶ is as described herein and is not -L¹-R¹³. In embodiments, the compound has the formula:

wherein it is understood that R⁶ is as described herein and is not -L¹-R¹³.

[0130] In embodiments, the compound has the formula:

and z15, R¹, R², R³, R⁶, R⁸, R¹¹, R¹², and R¹⁵ are as described herein. In embodiments, the compound has the formula:

and z15, R¹, R², R³, R⁶, R⁸, R¹¹, R¹², and R¹⁵ are as described herein. In embodiments, the compound has the formula:

and z15, R¹, R², R³, R⁶, R⁸, R¹¹, R¹², and R¹⁵ are as described herein. In embodiments, the compound has the formula:

and z15, R¹, R², R³, R⁸, and R¹⁵ are as described herein.

[0131] In embodiments, the compound has the formula:

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as described herein.

[0132] R¹⁶ and R¹⁷ are each independently

halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,
—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —PO₃H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. In embodiments, no more than one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁶, and R¹⁷ is -L¹-R¹³. The symbols z16 and z17 are each independently an integer from 0 to 4.

[0133] In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein and wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein and wherein R¹, R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R³, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein and wherein R¹, R³, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³.

[0134] In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein and each formula includes no more than one -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³.

[0135] In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein and each formula includes no more than one -L¹-R¹³.

[0136] In embodiments, the compound has the formula:

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹² are not L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R², R³, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁹, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁹, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁸, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁸, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁸, R⁹, R¹⁰, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁸, R⁹, R¹⁰, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁸, R⁹, R¹⁰, R¹¹ are not -L¹-R¹³.

[0137] In embodiments, the compound has the formula

wherein R³, R⁴, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R³, R⁴, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁴, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R⁴, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R¹⁶, R¹⁷, R¹¹, R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁷, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁷, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁶, R¹⁷, and R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R³, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R³, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R⁶, R⁷, R¹⁶, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁷, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁷, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R¹⁶, R¹⁷, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R¹⁶, R¹⁷, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R¹⁶, R¹⁷, R¹¹, z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R¹⁶, R¹⁷ and R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R³, R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R³, R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R¹⁶, R¹⁷, R¹¹, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R¹⁶, R¹⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R¹⁶, R¹⁷, R¹², z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R¹⁶, R¹⁷, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R¹⁶, R¹⁷, R¹¹, z16, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R¹⁶, R¹⁷, and R¹¹ are not -L¹-R¹³.

[0138] In embodiments, the compound has the formula:

wherein R³, R⁴, R⁵, R⁶, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R³, R⁴, R⁵, R⁶, R⁷, R¹¹, and R¹² and -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁴, R⁵, R⁶, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R⁴, R⁵, R⁶, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R³, R⁶, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R³, R⁶, R⁷, R¹¹, R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁶, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R⁶, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁵, R⁶, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁵, R⁶, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁶, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁶, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R¹¹, R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, and R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, and R¹¹ are not -L¹-R¹³.

[0139] In embodiments, the compound has the formula

wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R¹⁰, R¹¹, R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹¹, R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R¹⁰, R¹¹, R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁸, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁸, R¹¹, R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², R⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹², R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹², and R¹⁷ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹⁷, z17, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹⁷ are not -L¹-R¹³.

[0140] In embodiments, the compound has the formula

wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁷, R⁸, R¹⁰, R¹¹, R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁷, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R³, R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R³, R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R⁸, R¹⁰, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R⁸, R¹⁰, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁸, R¹⁰, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁸, R¹⁰, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹⁰, R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R¹², R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R¹², R¹⁰, R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹², R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹², R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R¹², R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R¹², R¹⁰, R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁸, R¹², R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁸, R¹², R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹², R¹⁰, R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹², R¹⁰, R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹¹, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹², R¹¹ are not -L¹-R¹³.

[0141] In embodiments, the compound has the formula

wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁶, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁶, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R³, R⁶, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R³, R⁶, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R⁶, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R⁶, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁶, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁶, R⁷, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁶, R⁷, R⁹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁹, R¹², R¹⁶. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁶, R⁷, R⁹, R¹¹, R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁹, R¹¹, and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R³, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ areas described herein, and wherein R¹, R³, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁹, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R², R³, R⁹, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R¹¹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R¹¹, R¹², and R¹⁶ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁹, R¹², R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁹, R¹², R¹⁶. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁹, R¹¹, R¹⁶, z16, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁹, R¹¹, and R¹⁶ are not -L¹-R¹³.

[0142] In embodiments, the compound has the formula

wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁵, R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁶, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹¹, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, and R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R³, R⁶, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R³, R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R⁶, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁶, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁶, R⁷, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁶, R⁷, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁶, R⁷, R⁹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁶, R⁷, R⁹, R¹¹, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁶, R⁷, R⁹, and R¹¹ are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R³, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R³, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R², R³, R⁹, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R², R³, R⁶, R⁷, R⁹, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R¹¹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R¹¹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁹, R¹², L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁹, and R¹² are not -L¹-R¹³. In embodiments, the compound has the formula

wherein R¹, R², R³, R⁹, R¹¹, L¹, and R¹³ are as described herein, and wherein R¹, R², R³, R⁹, and R¹¹ are not -L¹-R¹³.

[0143] In embodiments, the compound has the formula:

Ring A and Ring B are each independently a heterocycloalkyl. R¹, R², R³, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as described herein. In embodiments, no more than one of R¹, R², R³, R⁸, R⁹, R¹⁰, R¹¹, and R¹² is -L¹-R¹³. The symbols z34 and z36 are each independently an integer from 0 to 12. R³⁴ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). R³⁶ is independently oxo, halogen, —CF₃, —CCl₃, —C₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0144] In embodiments, the compound is

wherein R², R³, R⁸, R⁹, R¹⁰, R¹¹, R¹², R³⁴, R³⁶, z34, z36, L¹, and R¹³ are as described herein, and wherein R², R³, R⁸, R⁹, R¹⁰, R¹¹, R¹², R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, the compound is

wherein R², R³, R¹, R⁹, R¹⁰, R¹¹, R¹², R³⁴, R³⁶, z34, z36, L¹, and R¹³ are as described herein, and wherein R², R³, R¹, R⁹, R¹⁰, R¹¹, R¹², R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, the compound is

wherein R², R³, R⁸, R¹, R¹⁰, R¹¹, R¹², R³⁴, R³⁶, z34, z36, L¹, and R¹³ are as described herein, wherein R², R³, R⁸, R¹, R¹⁰, R¹¹, R¹², R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, the compound is

wherein R², R³, R⁸, R⁹, R¹, R¹¹, R¹², R³⁴, R³⁶, z34, z36, L¹, and R¹³ are as described herein, wherein R², R³, R⁸, R⁹, R¹, R¹¹, R¹², R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, the compound is

wherein R², R³, R⁸, R⁹, R¹⁰, R¹¹, R¹², R³⁴, R³⁶, z34, z36, L¹, and R¹³ are as described herein, and wherein R², R³, R⁸, R⁹, R¹⁰, R¹, R¹², R³⁴, and R³⁶ are not -L¹-R¹³. In embodiments, the compound is

wherein R², R³, R⁸, R⁹, R¹⁰, R¹¹, R¹, R³⁴, R³⁶, z34, z36, L¹, and R¹³ are as described herein, and wherein R², R³, R⁸, R⁹, R¹⁰, R¹¹, R¹, R³⁴, and R³⁶ are not -L¹-R¹³.

[0145] In embodiments, Ring A and Ring B are each independently a 3 to 8 membered heterocycloalkyl. In embodiments, Ring A is a 3 to 8 membered heterocycloalkyl. In embodiments, Ring A is a 3 membered heterocycloalkyl. In embodiments, Ring A is a 4 membered heterocycloalkyl. In embodiments, Ring A is a 5 membered heterocycloalkyl. In embodiments, Ring A is a 6 membered heterocycloalkyl. In embodiments, Ring A is a 7 membered heterocycloalkyl. In embodiments, Ring A is an 8 membered heterocycloalkyl. In embodiments, Ring A is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In embodiments, Ring A is aziridinyl. In embodiments, Ring A is azetidinyl. In embodiments, Ring A is pyrrolidinyl. In embodiments, Ring A is piperidinyl. In embodiments, Ring A is morpholinyl.

[0146] In embodiments, Ring B is a 3 to 8 membered heterocycloalkyl. In embodiments, Ring B is a 3 membered heterocycloalkyl. In embodiments, Ring B is a 4 membered heterocycloalkyl. In embodiments, Ring B is a 5 membered heterocycloalkyl. In embodiments, Ring B is a 6 membered heterocycloalkyl. In embodiments, Ring B is a 7 membered heterocycloalkyl. In embodiments, Ring B is an 8 membered heterocycloalkyl. In embodiments, Ring B is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In embodiments, Ring B is aziridinyl. In embodiments, Ring B is azetidinyl. In embodiments, Ring B is pyrrolidinyl. In embodiments, Ring B is piperidinyl. In embodiments, Ring B is morpholinyl.

[0147] In embodiments, R¹ is hydrogen,

halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,
—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —PO₃H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. In embodiments, R¹ is -L¹-R¹³. In embodiments, R¹ is hydrogen.

[0148] In embodiments, R¹ is hydrogen,

halogen, —OH, —NH₂, —COOH, —CONH₂, —NO₂,
—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —SF₅, —PO₃H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. In embodiments, R¹ is hydrogen, —SO₃H, —SO₄H, —SO₂NH₂, —PO₃H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³. In embodiments, R¹ is hydrogen, —SO₃H, —SO₄H, —SO₂NH₂, —PO₃H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or -L¹-R¹³. In embodiments, R¹ is hydrogen, substituted C₁-C₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹ is hydrogen, —CH₂NH₂, —SO₃H, or —PO₃H.

[0149] In embodiments, R¹ is hydrogen,

halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,
—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —PO₃H, R⁴³-substituted or unsubstituted alkyl, R⁴³-substituted or unsubstituted heteroalkyl, or -L¹-R¹³. R⁴³ is as described herein, including in embodiments.

[0150] In embodiments, R¹ is independently hydrogen, R⁴³-substituted or unsubstituted alkyl, or R⁴³-substituted or unsubstituted heteroalkyl. In embodiments, R¹ is hydrogen. In embodiments, R¹ is substituted or unsubstituted C₁ alkyl. In embodiments, R¹ is substituted or unsubstituted C₂ alkyl. In embodiments, R¹ is substituted or unsubstituted C₃ alkyl. In embodiments, R¹ is substituted or unsubstituted C₄ alkyl. In embodiments, R¹ is substituted or unsubstituted C₅ alkyl. In embodiments, R¹ is substituted or unsubstituted C₆ alkyl. In embodiments, R¹ is substituted C₁ alkyl. In embodiments, R¹ is substituted C₂ alkyl. In embodiments, R¹ is substituted C₃ alkyl. In embodiments, R¹ is substituted C₄ alkyl. In embodiments, R¹ is substituted C₅ alkyl. In embodiments, R¹ is substituted C₆ alkyl. In embodiments, R¹ is unsubstituted C₁ alkyl. In embodiments, R¹ is unsubstituted C₂ alkyl. In embodiments, R¹ is unsubstituted C₃ alkyl. In embodiments, R¹ is unsubstituted C₄ alkyl. In embodiments, R¹ is unsubstituted C₅ alkyl. In embodiments, R¹ is unsubstituted C₆ alkyl. In embodiments, R¹ is R⁴³-substituted or unsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R⁴³ is independently —NH₂, —COOH, —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

[0151] In embodiments, R¹ is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl.

[0152] In embodiments, R² is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³.

[0153] In embodiments, R² is substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R² is substituted or unsubstituted C₁-C₆ alkyl. In embodiments, R² is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R² is substituted C₁-C₆ alkyl. In embodiments, R² is substituted 2 to 6 membered heteroalkyl. In embodiments, R² is unsubstituted C₁-C₆ alkyl. In embodiments, R² is unsubstituted 2 to 6 membered heteroalkyl.

[0154] In embodiments, R² is an unsubstituted C₄ alkyl. In embodiments, R² is an unsubstituted C₃ alkyl. In embodiments, R² is an unsubstituted C₂ alkyl. In embodiments, R² is an unsubstituted methyl.

[0155] In embodiments, R² is R³²-substituted or unsubstituted alkyl, or R³²-substituted or unsubstituted heteroalkyl. In embodiments, R² is R³²-substituted or unsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³² is independently —NH₂, —COOH, —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

[0156] R³² is independently oxo,

halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂,
—CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R³² is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H. In embodiments, R³² is independently —SO₃H. In embodiments, R³² is independently —PO₃H. In embodiments, R³² is independently —SO₂NH₂. In embodiments, R³² is independently —SO₄H. In embodiments, R³² is independently —COOH. In embodiments, R³² is independently —NH₂.

[0157] In embodiments, R² is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R² is independently substituted or unsubstituted C₁-C₃ alkyl. In embodiments, R² is independently substituted or unsubstituted methyl. In embodiments, R² is independently substituted or unsubstituted ethyl. In embodiments, R² is independently substituted or unsubstituted C₃ alkyl (e.g., n-propyl or isopropyl).

[0158] In embodiments, R² is independently substituted or unsubstituted C₁ alkyl. In embodiments, R² is independently substituted or unsubstituted C₂ alkyl. In embodiments, R² is independently substituted or unsubstituted C₃ alkyl. In embodiments, R² is independently substituted or unsubstituted C₄ alkyl. In embodiments, R² is independently substituted or unsubstituted C₅ alkyl. In embodiments, R² is independently substituted or unsubstituted C₆ alkyl. In embodiments, R² is independently substituted C₁ alkyl. In embodiments, R² is independently substituted C₂ alkyl. In embodiments, R² is independently substituted C₃ alkyl. In embodiments, R² is independently substituted C₄ alkyl. In embodiments, R² is independently substituted C₅ alkyl. In embodiments, R² is independently substituted C₆ alkyl. In embodiments, R² is independently unsubstituted C₁ alkyl. In embodiments, R² is independently unsubstituted C₂ alkyl. In embodiments, R² is independently unsubstituted C₃ alkyl. In embodiments, R² is independently unsubstituted C₄ alkyl. In embodiments, R² is independently unsubstituted C₅ alkyl. In embodiments, R² is independently unsubstituted C₆ alkyl.

[0159] In embodiments, R² is substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂) or substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R² is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R² is unsubstituted alkyl or unsubstituted heteroalkyl.

[0160] In embodiments, R² is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R² is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R² is unsubstituted alkyl. In embodiments, R² is substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² is substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² is unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

[0161] In embodiments, R³ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or -L¹-R¹³.

[0162] In embodiments, R³ is substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R³ is substituted or unsubstituted C₁-C₆ alkyl. In embodiments, R³ is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R³ is substituted C₁-C₆ alkyl. In embodiments, R³ is substituted 2 to 6 membered heteroalkyl. In embodiments, R³ is an unsubstituted C₁-C₆ alkyl. In embodiments, R³ is unsubstituted 2 to 6 membered heteroalkyl.

[0163] In embodiments, R³ is an unsubstituted C₄ alkyl. In embodiments, R³ is an unsubstituted C₃ alkyl. In embodiments, R³ is an unsubstituted C₂ alkyl. In embodiments, R³ is an unsubstituted methyl.

[0164] In embodiments, R³ is R³³-substituted or unsubstituted alkyl, or R³³-substituted or unsubstituted heteroalkyl. In embodiments, R³ is R³³-substituted or unsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³³ is independently —NH₂, —COOH, —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

[0165] R³³ is independently oxo,

halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂,
—CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R³³ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H. In embodiments, R³³ is independently —SO₃H. In embodiments, R³³ is independently —PO₃H. In embodiments, R³³ is independently —SO₂NH₂. In embodiments, R³³ is independently —SO₄H. In embodiments, R³³ is independently —NH₂.

[0166] In embodiments, R³ is substituted or unsubstituted C₁-C₆ alkyl. In embodiments, R³ is substituted or unsubstituted C₁-C₃ alkyl. In embodiments, R³ is substituted or unsubstituted methyl. In embodiments, R³ is substituted or unsubstituted ethyl. In embodiments, R³ is substituted or unsubstituted C₃ alkyl (e.g., n-propyl or isopropyl).

[0167] In embodiments, R³ is independently substituted or unsubstituted C₁ alkyl. In embodiments, R³ is independently substituted or unsubstituted C₂ alkyl. In embodiments, R³ is independently substituted or unsubstituted C₃ alkyl. In embodiments, R³ is independently substituted or unsubstituted C₄ alkyl. In embodiments, R³ is independently substituted or unsubstituted C₅ alkyl. In embodiments, R³ is independently substituted or unsubstituted C₆ alkyl. In embodiments, R³ is independently substituted C₁ alkyl. In embodiments, R³ is independently substituted C₂ alkyl. In embodiments, R³ is independently substituted C₃ alkyl. In embodiments, R³ is independently substituted C₄ alkyl. In embodiments, R³ is independently substituted C₅ alkyl. In embodiments, R³ is independently substituted C₆ alkyl. In embodiments, R³ is independently unsubstituted C₁ alkyl. In embodiments, R³ is independently unsubstituted C₂ alkyl. In embodiments, R³ is independently unsubstituted C₃ alkyl. In embodiments, R³ is independently unsubstituted C₄ alkyl. In embodiments, R³ is independently unsubstituted C₅ alkyl. In embodiments, R³ is independently unsubstituted C₆ alkyl.

[0168] In embodiments, R³ is substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), or substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R³ is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl. In embodiments, R³ is unsubstituted alkyl or unsubstituted heteroalkyl.

[0169] In embodiments, R³ is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R³ is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R³ is unsubstituted alkyl. In embodiments, R³ is substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R³ is substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R³ is unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

[0170] In embodiments, R⁴ is hydrogen,

halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂,
—CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —COOH, —CONH₂, —SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L¹-R¹³. In embodiments, R⁴ is -L¹-R¹³.

[0171] In embodiments, R⁴ is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R⁴ is hydrogen. In embodiments, R⁴ is substituted or unsubstituted C₁-C₆ alkyl. In embodiments, R⁴ is substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0172] In embodiments, R⁴ is independently hydrogen,

halogen, —CF₃, —CCl₃, —CI₃, —CBr₃,
—CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, or —N₃. In embodiments, R⁴ is independently hydrogen. In embodiments, R⁴ is independently halogen. In embodiments, R⁴ is independently —CF₃. In embodiments, R⁴ is independently —CCl₃. In embodiments, R⁴ is independently —CI₃. In embodiments, R⁴ is independently —CBr₃. In embodiments, R⁴ is independently —CHF₂. In embodiments, R⁴ is independently —CHCl₂. In embodiments, R⁴ is independently —CHI₂. In embodiments, R⁴ is independently —CHBr₂. In embodiments, R⁴ is independently —CH₂F. In embodiments, R⁴ is independently —CH₂Cl. In embodiments, R⁴ is independently —CH₂I. In embodiments, R⁴ is independently —CH₂Br. In embodiments, R⁴ is independently —OCH₂F. In embodiments, R⁴ is independently —OCH₂Cl. In embodiments, R⁴ is independently —OCH₂I. In embodiments, R⁴ is independently —OCH₂Br. In embodiments, R⁴ is independently —OCHF₂. In embodiments, R⁴ is independently —OCHCl₂. In embodiments, R⁴ is independently —OCHI₂. In embodiments, R⁴ is independently —OCHBr₂. In embodiments, R⁴ is independently —OCF₃. In embodiments, R⁴ is independently —OCCl₃. In embodiments, R⁴ is independently —OCI₃. In embodiments, R⁴ is independently —OCBr₃. In embodiments, R⁴ is independently —CN. In embodiments, R⁴ is independently —OH. In embodiments, R⁴ is independently —NH₂. In embodiments, R⁴ is independently —COOH. In embodiments, R⁴ is independently —CONH₂. In embodiments, R⁴ is independently —NO₂. In embodiments, R⁴ is independently —SH. In embodiments, R⁴ is independently —SO₃H. In embodiments, R⁴ is independently —SO₄H. In embodiments, R⁴ is independently —SO₂NH₂. In embodiments, R⁴ is independently —NHNH₂. In embodiments, R⁴ is independently —ONH₂. In embodiments, R⁴ is independently —NHC═(O)NHNH₂. In embodiments, R⁴ is independently —NHC═(O)NH₂. In embodiments, R⁴ is independently —NHSO₂H. In embodiments, R⁴ is independently —NHC═(O)H. In embodiments, R⁴ is independently —NHC(O)OH. In embodiments, R⁴ is independently —NHOH.

[0173] In embodiments, R⁴ is hydrogen,

halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂,
—CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —COOH, —CONH₂, —SH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, R³⁴-substituted or unsubstituted alkyl, R³⁴-substituted or unsubstituted heteroalkyl, R³⁴-substituted or unsubstituted cycloalkyl, R³⁴-substituted or unsubstituted heterocycloalkyl, R³⁴-substituted or unsubstituted aryl, or R³⁴-substituted or unsubstituted heteroaryl, or -L¹-R¹³.

[0174] In embodiments, R⁴ is R³⁴-substituted or unsubstituted alkyl, R³⁴-substituted or unsubstituted heteroalkyl, R³⁴-substituted or unsubstituted cycloalkyl, R³⁴-substituted or unsubstituted heterocycloalkyl, R³⁴-substituted or unsubstituted aryl, or R³⁴-substituted or unsubstituted heteroaryl.

[0175] R³⁴ is independently oxo,

halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂,
—CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R³⁴ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H. In embodiments, R³⁴ is independently —SO₃H. In embodiments, R³⁴ is independently —PO₃H. In embodiments, R³⁴ is independently —SO₂NH₂. In embodiments, R³⁴ is independently —SO₄H. In embodiments, R³⁴ is independently —NH₂. In embodiments, R³⁴ is independently —COOH.

[0176] In embodiments, R⁴ is hydrogen, or substituted or unsubstituted C₁-C₆ alkyl. In embodiments, R⁴ is hydrogen. In embodiments, R⁴ is substituted or unsubstituted C₁-C₆ alkyl. In embodiments, R⁴ is substituted or unsubstituted C₁ alkyl. In embodiments, R⁴ is substituted or unsubstituted C₂ alkyl. In embodiments, R⁴ is substituted or unsubstituted C₃ alkyl. In embodiments, R⁴ is substituted or unsubstituted C₄ alkyl. In embodiments, R⁴ is substituted or unsubstituted C₅ alkyl. In embodiments, R⁴ is substituted or unsubstituted C₆ alkyl. In embodiments, R⁴ is substituted C₁ alkyl. In embodiments, R⁴ is substituted C₂ alkyl. In embodiments, R⁴ is substituted C₃ alkyl. In embodiments, R⁴ is substituted C₄ alkyl. In embodiments, R⁴ is substituted C₅ alkyl. In embodiments, R⁴ is substituted C₆ alkyl. In embodiments, R⁴ is unsubstituted C₁ alkyl. In embodiments, R⁴ is unsubstituted C₂ alkyl. In embodiments, R⁴ is unsubstituted C₃ alkyl. In embodiments, R⁴ is unsubstituted C₄ alkyl. In embodiments, R⁴ is unsubstituted C₅ alkyl. In embodiments, R⁴ is unsubstituted C₆ alkyl. In embodiments, R⁴ is R³⁴-substituted or unsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³⁴ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H. In embodiments, R⁴ is not

[0177] In embodiments, R⁴ is substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁴ is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R⁴ is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0178] In embodiments, R⁴ is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl. In embodiments, R⁴ is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl. In embodiments, R⁴ is unsubstituted alkyl. In embodiments, R⁴ is substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁴ is substituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁴ is unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

[0179] In embodiments, R⁵ is hydrogen,

halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂,
—CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —COOH, —CONH₂, —SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L¹-R¹³. In embodiments, R⁵ is -L¹-R¹³.

[0180] In embodiments, R⁵ is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R⁵ is hydrogen. In embodiments, R⁵ is substituted or unsubstituted C₁-C₆ alkyl. In embodiments, R⁵ is substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0181] In embodiments, R⁵ is independently hydrogen,

halogen, —CF₃, —CCl₃, —CI₃, —CBr₃,
—CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, or —N₃. In embodiments, R⁵ is independently hydrogen. In embodiments, R⁵ is independently halogen. In embodiments, R⁵ is independently —CF₃. In embodiments, R⁵ is independently —CCl₃. In embodiments, R⁵ is independently —CI₃. In embodiments, R⁵ is independently —CBr₃. In embodiments, R⁵ is independently —CHF₂. In embodiments, R⁵ is independently —CHCl₂. In embodiments, R⁵ is independently —CHI₂. In embodiments, R⁵ is independently —CHBr₂. In embodiments, R⁵ is independently —CH₂F. In embodiments, R⁵ is independently —CH₂Cl. In embodiments, R⁵ is independently —CH₂I. In embodiments, R⁵ is independently —CH₂Br. In embodiments, R⁵ is independently —OCH₂F. In embodiments, R⁵ is independently —OCH₂Cl. In embodiments, R⁵ is independently —OCH₂I. In embodiments, R⁵ is independently —OCH₂Br. In embodiments, R⁵ is independently —OCHF₂. In embodiments, R⁵ is independently —OCHCl₂. In embodiments, R⁵ is independently —OCHI₂. In embodiments, R⁵ is independently —OCHBr₂. In embodiments, R⁵ is independently —OCF₃. In embodiments, R⁵ is independently —OCCl₃. In embodiments, R⁵ is independently —OCI₃. In embodiments, R⁵ is independently —OCBr₃. In embodiments, R⁵ is independently —CN. In embodiments, R⁵ is independently —OH. In embodiments, R⁵ is independently —NH₂. In embodiments, R⁵ is independently —COOH. In embodiments, R⁵ is independently —CONH₂. In embodiments, R⁵ is independently —NO₂. In embodiments, R⁵ is independently —SH. In embodiments, R⁵ is independently —SO₃H. In embodiments, R⁵ is independently —SO₄H. In embodiments, R⁵ is independently —SO₂NH₂. In embodiments, R⁵ is independently —NHNH₂. In embodiments, R⁵ is independently —ONH₂. In embodiments, R⁵ is independently —NHC═(O)NHNH₂. In embodiments, R⁵ is independently —NHC═(O)NH₂. In embodiments, R⁵ is independently —NHSO₂H. In embodiments, R⁵ is independently —NHC═(O)H. In embodiments, R⁵ is independently —NHC(O)OH. In embodiments, R⁵ is independently —NHOH. In embodiments, R⁵ is not

[0182] In embodiments, R⁵ is hydrogen,

halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂,
—CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —COOH, —CONH₂, —SH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, R³⁵-substituted or unsubstituted alkyl, R³⁵-substituted or unsubstituted heteroalkyl, R³⁵-substituted or unsubstituted cycloalkyl, R³⁵-substituted or unsubstituted heterocycloalkyl, R³⁵-substituted or unsubstituted aryl, or R³⁵-substituted or unsubstituted heteroaryl, or -L¹-R¹³.