Deconstructive Functionalization Methods and Compounds

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62/694,956, filed July 6, 2018, and U.S. Provisional Application No. 62/748,946, filed October 22, 2018, which are incorporated herein by reference in their entirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under grant number R01 GM086374 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[0003] Deconstructive functionalization, which entails a C-C bond cleavage event followed by bond construction on at least one of the constituent carbons, can provide access to molecules that would otherwise not be readily accessible. For example, ozonolysis (7) and olefin metathesis (2,3) have shifted paradigms in organic chemistry wherein each carbon in Csp ² -Csp ² double bonds is now viewed as a functional group. Despite the significant advances in deconstructive functionalizations involving scission of Csp ² -Csp ² double bonds, there are very few methods that achieve Csp ³ -Csp ³ single bond cleavage/ftmctionalization, especially in unstrained cyclic systems. Disclosed herein, inter alia, are solutions to these and other problems in the art.

BRIEF SUMMARY

[0004] In an aspect is provided a method of making a haloalkyl amine including reacting a saturated cyclic amine with a halogenating agent in the presence of an oxidizing agent and a metal source, wherein the haloalkyl amine includes a covalently attached halogen, wherein the halogen is -Cl, -Br, or -I. [0005] In an aspect is provided a compound having the formula: wherein X ^a , R ² , R ³ , R ⁴ , R ⁶ , and z2 are as described herein.

[0006] In an aspect is provided a compound having the formula: wherein X ^a , R ² , R ⁴ , and R ⁶ are as described herein.

[0007] In an aspect is provided a compound having the formula:

wherein R ^a , R ² , R ³ , R ⁴ , R ⁶ , F, and z2 are as described herein.

[0008] In an aspect is provided a compound having the formula: (lid), wherein R ^a , R ² , R ⁴ , and R ⁶ are as described herein. . [0009] In an aspect is provided a compound made by a method as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGS. 1A-1C. Development of a deconstructive halogenation of cyclic amines. FIG. 1A. Representative bioactive molecules containing saturated nitrogen heterocycles. FIG. 1B.

Deconstructive halogenation enables diversification of saturated nitrogen heterocycles. FIG. 1C. proposed mechanism for silver-mediated deconstructive halogenation. FG, functional group; Nu, nucleophile; Piv, pivaloyl; NCS, N-chlorosuccinimide; NBS, N-bromosuccinimide; HAT, hydrogen-atom transfer; SET, single electron transfer.

[0011] FIG. 2. Deconstructive halogenation: cyclic amine scope. Only isolated yields are shown. Reaction conditions: 1 (0.1 mmol), NXS (4 equiv), (NH ₄ ) ₂ S ₂ 0 ₈ (4 equiv), acetone: ¾0 (1 :9), room temperature, 0.5 h. Boc, tert- butoxycarbonyl; Bz, benzoyl; BRSM, based on recovered starting material. *5,6-dihydro-4H-l,3-oxazine was obtained.

[0012] FIGS. 3A-3B. Applications of deconstructive halogenation. FIG. 3A. Skeletal remodeling of cyclic amines. FIG. 3B. Dehomologation of cyclic amines. *Yields in bracket represent the average yield per step. Ns, 2-nitrobenzenesulfonamide; DBU, l,8-diazabicyclo(5.4.0)undec-7-ene; DMF, N,N-dimethylformamide.

[0013] FIGS. 4A-4D. Diversification of L-proline-containing tripeptide 20 through deconstructive chlorination. RSM, recovered starting material. FIG. 4A. Diversification of L-proline-containing tripeptide 21 through deconstructive chlorination. FIG. 4B. The tolerance for oxidizable amino acid residues. FIG. 4C. Deconstructive chlorination of L-phenylalanine-containing tripeptide 30. FIG.

4D. Deconstructive fluorination of tripeptide 21. RSM, recovered starting material; Tf,

trifluoromethanesulfonyl.

[0014] FIG. 5. Cyclic voltammograms of la (lmM) and Ar background in 0.10 M NBu ₄ PF ₆ in acetonitrile. Data was collected with a scan rate of lOOmV/s. The top curve corresponds to Vs SCE and the bottom curve corresponds to Ar Bkg.

[0015] FIG. 6. The structure of compounds 5b and 6b and the HSQC spectrum of the product mixture containing both compounds.

DETAILED DESCRIPTION

I. Definitions

[0016] 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.

[0017] 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-.

[0018] 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). 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-(l ,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 (-0-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.

[0019] 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.

[0020] 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., 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- 0-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH ₃ )-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(0)-CH ₃ , - CH ₂ -CH ₂ -S(0)2-CH3, -CH=CH-0-CH ₃ , -SI(CH ₃ )3, -CH ₂ -CH=N-0CH3, -CH=CH-N(CH ₃ )-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 -CH ₂ -0-Si(CH ₃ ) 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.

[0021] 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(0) ₂ R'- represents both -C(0) ₂ R'- and - R'C(0) 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(0)R', -C(0)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.

[0022] 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, l-(l,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.

[0023] 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 (CIBj _w , where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.l . l]heptane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3. l]nonane, and bicyclo[4.2.l]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-l -yl, and

perhydrophenoxazin- 1 -yl.

[0024] 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 alkyl ene 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.

[0025] 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, l,3-dioxanyl, 1 ,3 -dioxolanyl, l,3-dithiolanyl, l ,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-l-yl, indolin-2-yl, indolin-3-yl, 2,3- dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-lH-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 lOH-phenothiazin-lO-yl, 9,l0-dihydroacridin-9-yl, 9,l0-dihydroacridin-l0-yl, l OH-phenoxazin-lO-yl, l0,l l -dihydro-5H- dibenzo[b,f]azepin-5-yl, l,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, l2H-benzo[b]phenoxazin- l2-yl, and dodecahydro-lH-carbazol-9-yl.

[0026] The term“cyclic amine” means, unless otherwise stated, a heterocycloalkyl group including one ring nitrogen atom. Examples of cyclic amines include, but are not limited to, aziridine, azetidine, pyrrolidine, 2,3-dihydro- 1 //-pyrrole, piperidine, l ,2,3,4-tetrahydropyridine, azepane, 2,3,4,5-tetrahydro- l //-azepine, azocane, (Z)-l ,2,3,4,5,6-hexahydroazocine, azonane, azecane, azacycloundecane, azacyclododecane, and the like. In embodiments, the cyclic amine is a saturated (i.e. non aromatic cyclic amine). In embodiments, a cyclic amine refers to a monocyclic or a multicyclic (e.g., bicyclic) heterocycloalkyl ring system including one ring nitrogen, wherein the base ring of the multicyclic system is the cyclic amine. In embodiments, a monocyclic amine is a cyclic hydrocarbon group including from 3 to 8 carbon atoms and only one nitrogen atom, where such group can be saturated or unsaturated, but not aromatic. In embodiments, cyclic amine groups are fully saturated. Examples of monocyclic cyclic amines include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, azonane, azecane, azacycloundecane, and azacyclododecane. Bicyclic cyclic amine ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, fused bicyclic heterocycloalkyl ring systems contain a monocyclic heterocycloalkyl ring fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. In embodiments, the bridged or fused bicyclic heterocycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic heterocycloalkyl ring. In embodiments, heterocycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cyclic amine is a C3-C6 monocyclic cyclic amine ring fused to either a C5-C6 monocyclic cycloalkyl, a C5-C6 monocyclic cycloalkenyl, or a C4-C6 monocyclic heterocyclyl, wherein the fused bicyclic cyclic amine is optionally substituted by one or two groups which are independently oxo or thia.

[0027] The term“protected cyclic amine,” by itself or as part of another substituent, means, unless otherwise state, a“cyclic amine” wherein the nitrogen of the amine is bonded to an amine protecting group. An amine protecting group is a protecting group that is attached to the nitrogen of an amine. Examples of amine protecting groups for a cyclic amine include, but are not limited to,

carbobenzyloxy (Cbz), tert- butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl ether (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), pivaloyl (Piv), and tosyl (Ts). For additional examples of amine protecting groups, See Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis. 3 ^rd Edition. John Wiley and Sons Chapter 7, pp 494-615, which is incorporated herein by reference in its entirety for all purposes.

[0028] The term“acyclic amine” means, unless otherwise stated, a noncyclic moiety (e.g., substituted alkyl, substituted or unsubstituted heteroalkyl, or -NH2) containing at least one nitrogen atom. Examples of acyclic amines include, but are not limited to, propylamine, butylamine, pentylamine, hexylamine, heptyamine, and the like.

[0029] 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(Ci- C ₄ )alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like. In embodiments, the term“fluoroalkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, fluoropropyl, fluorobutyl, fluoropenytl, and the like.

[0030] A“haloalkyl amine” is a compound that includes at least one halogen atom, at least one carbon atom, and at least one nitrogen atom (e.g., an amine, -NH ₂ ). In embodiments, the haloalkyl amine is a substituted alkyl (e.g. C1-C20 alkyl, C3-C8 alkyl, etc.) substituted with one or more halogen atoms and a nitrogen containing moiety, a substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl) substituted with one or more halogen atoms and a nitrogen containing moiety, a substituted cycloalkyl (e.g., C3-C8 cycloalkyl) substituted with one or more halogen atoms and a nitrogen containing moiety, a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl) substituted with one or more halogen atoms and a nitrogen containing moiety, a substituted aryl (e.g., Ce-Cio aryl) substituted with one or more halogen atoms and a nitrogen containing moiety, or a substituted amine (e.g. -NR R ), wherein R’ or R” includes one or more halogen atoms. In embodiments, the haloalkyl amine may optionally be substituted with additional chemical moieties (e.g. a substituent, size-limited substituent or lower substituent). The haloalkyl amine may be fully saturated, mono- or polyunsaturated. In embodiments, the halogen is -Cl, -Br, or -I. In embodiments, the haloalkyl amine contains one halogen atom (e.g., -Cl, -Br, or -I).

[0031] The term“acyl” means, unless otherwise stated, -C(0)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.

[0032] 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. 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). A 5,6-fused ring heteroaryl ene 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, benzoxazoyl 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.

[0033] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring

heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring

heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be

unsubstituted or substituted with one or more of the substituents described herein.

[0034] 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). Spirocylic 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.

[0035] The symbol ·” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0036] The term“oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. The term“thia,” as used herein, means a sulfur that is double bonded to a carbon atom.

[0037] The term“alkylsulfonyl,” as used herein, means a moiety having the formula -S(0 ₂ )-R', where R' is a substituted or unsubstituted alkyl group as defined above. R may have a specified number of carbons (e.g.,“C ₁ -C ₄ alkylsulfonyl”).

[0038] 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:

[0039] 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, -CCI3, -CBr ₃ ,

CI ₃ , -CN, -C(0)H, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₂ CH ₃ -S0 ₃ H, -OS0 ₃ H,

S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0040] Each of the above terms (e.g.,“alkyl,”“heteroalkyl,”“cycloalkyl,”“hete rocycloalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0041] 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', =0, =NR', =N-OR', -NR'R", -SR, halogen, -SiR'R'R'", -OC(0)R', -C(0)R', - C(0)OR, -C(0)NR'R", -OC(0)NR'R", -NR"C(0)R, -NR'-C(0)NR"R"', -NR"C(0) ₂ R', -NR- C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(0)R', -S(0) ₂ R', -S(0) ₂ NR'R", -NRS0 ₂ R,

-NR'NR'R'", -ONR'R", -NR'C(0)NR"NR"'R"", -CN, -N0 ₂ , -NR'S0 ₂ R", -NR'C(0)R", -NR'C(O)- OR", -NR'OR", in a number ranging from zero to (2m'+l), 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, l-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 -CIFCF3) and acyl (e.g., -C(0)CH ₃ , -C(0)CF ₃ , -C(0)CH ₂ 0CH ₃ , and the like).

[0042] 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(0)R', -C(0)R, -C0 ₂ R, -CONR'R", -OC(0)NR'R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR"C(0) ₂ R, -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(0)R, -S(0) ₂ R, -S(0) ₂ NR'R", - NRS0 ₂ R, -NR'NR"R"', -ONRR", -NR'C(0)NR"NR"R"", -CN, -N0 ₂ , -R', -N ₃ , -CH(Ph) ₂ , fluoro(Ci-C ₄ )alkoxy, and fluoro(Ci-C ₄ )alkyl, -NR'S0 ₂ R", -NR'C(0)R", -NR'C(0)-0R", -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 ¹ ", 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 ¹ ", and R"" groups when more than one of these groups is present.

[0043] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl ene, 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. [0044] In embodiments, when there are multiple substituents connected to an atom, it is understood that the substituents bond to the atom according to the standard rules of chemical

R ^G

R ^G

valency known in the chemical arts. For example, for a compound having the structure ,<y wherein each R° may independently be a substituent selected from the group halogen or oxo, it is understood that both R ^a may each independently be a halogen substituent, O ' BG or both R G ¹ together form an oxo substituent, . In embodiments, for a compound having the structure wherein each R° may independently be a substituent selected from the group halogen or oxo, it is understood that each R° may independently be halogen, or one R° may independently be an oxo and the other R ^u will be absent, y° . Thus, in embodiments, both R , together with

the atom they are connected to, form

[0045] 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. [0046] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') _q -U-, wherein T and U are independently -NR-, -0-, - CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2) _r -B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O) -S(0) ₂ -, -

S(0) ₂ NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') _s -X'- (C"R"R"') _d -, where s and d are independently integers of from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(0) ₂ -, or -S(0) ₂ NR-. The substituents 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.

[0047] As used herein, the terms“heteroatom” or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0048] A‘‘substituent group,” as used herein, means a group selected from the following moieties:

(A) oxo, halogen, -CCl ₃ , -CBr ₃ , -CF ₃ , -CI ₃ , CHCl ₂ , -CHBr ₂ , -CHF ₂ , -CHI ₂ , -

CH ₂ Cl, -CH ₂ Br, -CH2F, -CH2I, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -S0 ₃ H, - S0 ₄ H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H,

-NHC(0)H, -NHC(0)OH, -NHOH, -OCCl ₃ , -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr ₂ , -O Cffl ₂ , -OCHF2, -OCH2CI, -OCH ₂ Br, -OCH2I, -OCH2F, -N ₃ , unsubstituted alkyl (e g., Ci-Cg alkyl, Ci-C ₆ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ 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., Ce-Cio 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

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(1) oxo, halogen, -CCl ₃ , -CBr ₃ , -CF ₃ , -CI ₃ , CHCl ₂ , -CHBr ₂ , -CHF ₂ , -CHI ₂ , -

CH2CI, -CH ₂ Br, -CH2F, -CH2I, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -S0 ₃ H,

-SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2,-NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCCl ₃ , -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr ₂ , - OCffl ₂ , -OCHF ₂ , -OCH ₂ Cl, -OCH ₂ Br, -OCH ₂ I, -OCH ₂ F, -N ₃ , unsubstituted alkyl (e g., Ci- C ₈ alkyl, Ci-C ₆ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ 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., Ce-Cio 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

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(a) oxo, halogen, -CCl ₃ , -CBr ₃ , -CF ₃ , -CI ₃ , CHCl ₂ , -CHBr ₂ , -CHF ₂ , -CHI ₂ , - CH ₂ Cl, -CH ₂ Br, -CH ₂ F, -CH ₂ I, -CN, -OH, -NH _¾ -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,-NHC(0)NH ₂ ,

-NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCl ₃ , -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , -OCH ₂ Cl, -OCH ₂ Br, -OCH ₂ I, -OCH ₂ F, -N ₃ , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-Cr, 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ 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., Ce-Cio 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

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CCl ₃ , -CBr ₃ , -CF ₃ , -CI ₃ ,

CHCh, -CHBr ₂ , -CHF ₂ , -CHI ₂ , -

CH ₂ Cl, -CH ₂ Br, -CH ₂ F, -CH ₂ I, -CN, -OH, -NH _¾ -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCl ₃ , -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , -OCH ₂ Cl, -OCH ₂ Br, -OCH ₂ I, -OCH ₂ F, -N ₃ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ 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., Ce-Cio 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).

[0049] 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 Ce-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0050] 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 Ci-Cs 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 Ce-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0051] 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.

[0052] 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 Ce-Cio 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 heteroalkyl ene 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 Ce-Cio aryl ene, and/or each substituted or unsubstituted heteroaryl ene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0053] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs 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 Ce-Cio 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 Ci-Cs 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 Ce-Cio arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0054] 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).

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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. [0059] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (i?)-or (5)- 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 (5)-, 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.

[0060] 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. [0061] 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.

[0062] 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. [0063] 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.

[0064] 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 ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this disclosure. [0065] 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 (¾), iodine-l25 ( ¹²⁵ I), or carbon-l4 ( ¹⁴ C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0066] 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.

[0067] As used herein, the terms“bioconjugate” and“bioconjugate linker” refers to the resulting association between atoms or molecules of“bioconjugate reactive groups” or“bioconjugate reactive moieties”. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., -NFF, -C(0)OH, -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).

[0068] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example:

(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;

(b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.

(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;

(d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups;

(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;

(f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides;

(g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides;

(h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc;

(j) epoxides, which can react with, for example, amines and hydroxyl compounds;

(k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis;

(l) metal silicon oxide bonding; and

(m) metal bonding to reactive phosphorus groups (e.g. phosphines) to form, for example, phosphate diester bonds.

(n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry.

(o) biotin conjugate can react with avidin or strepavidin to form an avidin-biotin complex or streptavidin-biotin complex.

[0069] 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.

[0070] “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.

[0071] 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.

[0072] 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 R ¹³ substituents are present, each R ¹³ 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 R ¹³ and optionally differently.

[0073] “Oxidizing agent” is used in accordance with its ordinary plain meaning within chemistry and biology and refers to a substance that has the ability to oxidize other substances (i.e. removes electrons from the substance). The term“oxidizing agent” is a substance that, in the course of a chemical redox reaction, removes one or more electrons from a substance (e.g., the reactant), wherein the oxidizing agent gains one or more electrons from the substrate. In embodiments, an oxidizing agent is a chemical species that transfers electronegative atoms to another substrate (e.g., a reactant). In embodiments, the oxidizing agent is analogous to the term“electron acceptor” and may be used herein interchangeably. Non-limiting examples of oxidizing agents include oxygen (O2), ozone (O3), hydrogen peroxide (H2O2), nitric acid (HNO3), sulfuric acid (H2SO4), hexavalent chromium, pyridinium chlorochromate (PCC), A'-methylmorpholine-A'-oxide (NMO), chromium trioxide (CrCb, Jones reagent), potassium permanganate (K ₂ Mn0 ₄ ), potassium nitrate (KNO3), Dess-Martin periodinane (DMP), 2-iodoxybenzoic acid (P3C), 2,2,6,6-tetramethylpiperidinyloxy (TEMPO), and Selectfluor ^® (F-TEDA-BF4, chloromethyl-4-fluoro-l ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), potassium perchlorate, or ammonium persulfate.

[0074] The term“halogenating agent” is used in accordance with its ordinary plain meaning within chemistry and refers to a substance (e.g., compound or composition) that has the ability to incorporate one or more halogen atoms (e.g. bromination, dibromination, tribromination, chlorination, dichlorination, trichlorination, iodination, diiodination, triiodination, fluorination, difluorination, trifluorination, etc.) into another substance (e.g., compound or composition).

Halogenating agents include chlorinating agents, brominating agents, iodinating agents and fluorinating agents, wherein a chlorinating agent incorporates a chlorine atom, a brominating agent incorporates a bromine atom, an iodinating agent incorporates an iodine atom, or a fluorinating agent incorporates a fluorine atom. Brominating agents include, but are not limited to, N- bromosuccinimide (NBS), dibromoisocyanuric acid (DBI), bromine, bromotrichloromethane, 1,2- dibromo-l ,l ,2,2-tetrachloroethane, carbon tetrabromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide perbromide, 1 -butyl-3 -methybmidazolium tribromide, l,8-diazabicyclo[5.4.0]-7-undecene, hydrogen tribromide, L'-bromophthalimide, N- bromosaccharin, A'-bromoacetamide, 2 - b ro m o -2 - cy an o - A', A'- d i m eth y 1 acetam i de , l,3-dibromo-5,5- dimethylhydantoin, monosodium bromoisocyanurate hydrate, boron tribromide, phosphorus tribromide, bromodimethylsulfonium bromide, 5,5-dibromomeldrum's acid, 2,4,4,6-tetrabromo-2,5- cyclohexadienone, or bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate. Chlorinating agents include, but are not limited to, N- ch 1 o ro s ucci n i m i de (NCS), thionyl chloride,

methanesulfonyl chloride, trichloromethanesulfonyl chloride, /er/-butyl hypochlorite, chloromethyl methyl ether, dichloromethyl methyl ether, methoxyacetyl chloride, oxalyl chloride, cyanuric chloride, A'-chlorophthalimide, sodium dichloroisocyanurate, trichloroisocyanuric acid, chloramine B hydrate, o-chloramine T dihydrate, chloramine T trihydrate, dichloramine B, dichloramine T, benzyltrimethylammonium, tetrachloroiodate. Iodinating agents include, but are not limited to, N- iodosuccinimide (NIS), l ,3-diodo-5,5'-dimethylhidantoin (DIH), iodine, hydriodic acid,

diiodomethane, 1 -chloro-2-iodoethane, carbon tetraiodide, tetramethylammonium dichloroiodate, benzyltrimethylammonium dichloroiodate, pyridine iodine monochloride, A',A'-dimethyl-A'- (methylsulfanylmethylene)-ammonium iodide, A'-iodosaccharin, trimethylsilyl iodide,

bis(pyridine)iodonium tetrafluoroborate, bis(2,4,6-trimethylpyridine)-iodonium

hexafluorophosphate. In embodiments, the halogenating agent is not a fluorinating agent.

[0075] A‘‘metal source” is used in accordance with its ordinary plain meaning within chemistry and biology and refers to a compound, salt or complex that includes a transition metal (e.g., as found in the periodic table of the elements). In embodiments, the metal source is a transition metal element (i.e., an element whose atom has a partially filled d sub-shell, or which can give rise to cations with an incomplete d sub-shell). The metal source may be a compound, salt, or complex and may contain one or more transition metals. In one embodiment, the metal source can be a“silver source”, wherein the transition metal is silver. Non-limiting examples of a silver source include silver(I) tetrafluoroborate (AgBF ₄ ), silver(I) nitrate (AgNO,), silver(II) fluoride (AgF ₂ ), silver(I) fluoride (AgF), silver trifluoromethanesulfonate (AgOTf), silver bis(trifluoromethanesulfonyl)imide (AgNTfz), silver carbonate (Ag ₂ CO,), silver(I) oxide (Ag ₂ 0), silver(I) acetate (AgOAc), silver(I) sulfate (Ag ₂ S0 ₄ ), silver methanesulfonate (AgOMs), silver hexafluoroantimonate(V) (AgSbFe), silver / oluenesulfonate (AgOTs), silver(I) trifluoromethanethiolate (AgSCF-,), and silver(I) bromide (AgBr). In one embodiment, the metal source can be a“copper source”, wherein the transition metal is copper. Non-limiting examples of a copper source include copper(II) sulfate (CuS0 ₄ ). In one embodiment, the metal source can be an“iron source”, wherin the transition metal is iron. Non-limiting examples of an iron source include iron(III) chloride (FeCl·,) and iron(I) nitrate (FeNCb) In one embodiment, the metal source can be a“manganese source”, wherin the transition metal is manganese. Non-limiting examples of a manganese source include manganese(II) chloride (MnCl ₂ ), manganese(III) acetate (Mn(OAc)-,), manganese(III) acetylacetonate (Mn(acac) ₃ ), and manganese(III) 2-pyridinecarboxylate (Mn(pic) ₃ ). See, Chem. Lett. 2017, 46, 1692, which is incorporated herein by reference in its entirety.

[0076] A‘‘detectable agent” or“detectable moiety” is a substance (e.g., compound) or composition detectable by appropriate means such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, useful detectable agents include ¹⁸ F, ³² P, ³³ P, ⁴⁵ Ti, ⁴⁷ Sc, ⁵² Fe, ⁵⁹ Fe, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ⁶⁷ Ga, ⁶⁸ Ga,

Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, ³² P, fluorophore (e.g. fluorescent dyes), electron- dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO")

nanoparticles, SPIO nanoparticle aggregates, monocrystalline iron oxide nanoparticles,

monocrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g. carbon-l l , nitrogen-l3, oxygen-l 5, fluorine-l 8, rubidium-82), fluorodeoxyglucose (e.g.

fluorine-l 8 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g. including microbubble shells including albumin, galactose, lipid, and/or polymers; microbubble gas core including air, heavy gas(es), perfluorocarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g. iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. A detectable moiety is a monovalent detectable agent or a detectable agent capable of forming a bond with another compound or composition.

[0077] Radioactive substances (e.g., radioisotopes) that may be used as imaging and/or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to, ¹⁸ F, ³² P,

2 ²³ Ra and ²²⁵ Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g. metals having atomic numbers of 21 -29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.

[0078] Descriptions of 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.

[0079] The term“leaving group” is used in accordance with its ordinary meaning in chemistry and refers to a moiety (e.g., atom, functional group, molecule) that separates from the molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, 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, organotin moieties (e.g., organotin heteroalkyl), halogen (e.g., Br), perfluoroalkylsulfonates (e.g. triflate), tosylates, mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, boronic acid, boronate esters, and alkoxides. In embodiments, two molecules with leaving groups are allowed to contact, and upon a reaction and/or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, Stille reaction) the leaving groups separates from their respective molecule. In embodiments, a leaving group is a bioconjugate reactive moiety. In embodiments, at least two leaving groups (e.g., R ¹ and R ¹³ ) are allowed to contact such that the leaving groups are sufficiently proximal to react, interact or physically touch.

In embodiments, the leaving group is designed to facilitate the reaction.

[0080] 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 to prevent reactivity of the heteroatom during one or more chemical reactions performed prior to removal of the protecting group. In embodiments, the protecting group is covalently bound to a heteroatom that is part of a heteroalkyl, heterocycloalkyl or heteroaryl moiety. Typically a protecting group is bound to a heteroatom (e.g., O) during a part of a multistep synthesis wherein it is not desired to have the heteroatom react (e.g., a chemical reduction) with a 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., trimethyls ilyl (TMS), / /V-butyl dimethylsilyl (TBS)). In embodiments the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), /7-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p- methoxybenzyl ether (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), pivaloyl (Piv), tosyl (Ts), and phthalimide. [0081] 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 fdled, 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 -CH ₃ ). Likewise, for a linker variable (e.g., L ¹ , L ² , or L ³ 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).

[0082] The term“exogenous” refers to a molecule or substance (e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism. For example, an "exogenous promoter" as referred to herein is a promoter that does not originate from the plant it is expressed by. Conversely, the term "endogenous" or "endogenous promoter" refers to a molecule or substance that is native to, or originates within, a given cell or organism.

[0083] The term“lipid moiety” is used in accordance with its ordinary meaning in chemistry and refers to a hydrophobic molecule which is typically characterized by an aliphatic hydrocarbon chain. In embodiments, the lipid moiety includes a carbon chain of 3 to 100 carbons. In

embodiments, the lipid moiety includes a carbon chain of 5 to 50 carbons. In embodiments, the lipid moiety includes a carbon chain of 5 to 25 carbons. In embodiments, the lipid moiety includes a carbon chain of 8 to 25 carbons. Lipid moieties may include saturated or unsaturated carbon chains, and may be optionally substituted. In embodiments, the lipid moiety is optionally substituted with a charged moiety at the terminal end. In embodiments, the lipid moiety is an alkyl or heteroalkyl optionally substituted with a carboxylic acid moiety at the terminal end. [0084] A charged moiety refers to a functional group possessing an abundance of electron density (i.e. electronegative) or is deficient in electron density (i.e. electropositive). Non-limiting examples of a charged moiety includes carboxylic acid, alcohol, phosphate, aldehyde, and sulfonamide. In embodiments, a charged moiety is capable of forming hydrogen bonds.

[0085] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, g-carboxyglutamate, and O- phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms“non-naturally occurring amino acid” and“unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0086] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0087] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments 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 polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety. [0088] As may be used herein, the terms“nucleic acid,”“nucleic acid molecule,”“nucleic acid oligomer,”“oligonucleotide,”“nucleic acid sequence,”“nucleic acid fragment” and

“polynucleotide” are used interchangeably and are intended to include, but are not limited to, a polymeric form of nucleotides covalently linked together that may have various lengths, either deoxyribonucleotides or ribonucleotides, or analogs, derivatives or modifications thereof. Different polynucleotides may have different three-dimensional structures, and may perform various functions, known or unknown. Non-limiting examples of polynucleotides include a gene, a gene fragment, an exon, an intron, intergenic DNA (including, without limitation, heterochromatic DNA), messenger RNA (mRNA), transfer RNA, ribosomal RNA, a ribozyme, cDNA, a recombinant polynucleotide, a branched polynucleotide, a plasmid, a vector, isolated DNA of a sequence, isolated RNA of a sequence, a nucleic acid probe, and a primer. Polynucleotides useful in the methods of the disclosure may include natural nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or a combination of such sequences.

[0089] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term“polynucleotide sequence” is the alphabetical

representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and/or modified nucleotides.

[0090] “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) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, 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 protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. [0091] An amino acid moiety refers to a monovalent amino acid (

[0092] A“protein moiety” or“polypeptide moiety” refers to a monovalent protein, monovalent

polypeptide, or polymer of amino acid residues

embodiments the polypeptide moiety contains less than 50 amino acid residues. In embodiments the protein moiety contains more than 50 amino acid residues.

[0093] A“therapeutic agent” or“drug agent” as used herein refers to an agent (e.g., compound or composition) that when administered to a subject will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms or the intended therapeutic effect, e.g., treatment or amelioration of an injury, disease, pathology or condition, or their symptoms including any objective or subjective parameter of treatment such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient’s physical or mental well-being. A drug moiety is a monovalent drug. A therapeutic moiety is a monovalent therapeutic agent.

[0001] The term“nucleophilic reaction product” as used herein is the product of the reaction between the haloalkyl amine with the nucleophilic agent (e.g., a monovalent nucleophilic agent).

[0129] The term“nucleophilic agent” is used in accordance with its plain ordinary chemical meaning and refers to a chemical group (e.g., monovalent chemical group) that is nucleophilic. A nucleophilic agent may be an ion. A nucleophilic agent may be monovalent. A nucleophilic agent may be a moiety (e.g., -OH) attached to the remainder of a compound (e.g., a compound such as methanol, wherein the remainder is -CH3). A nucleophilic agent donates an electron pair to a substance (e.g., an electrophile), which results in the formation of a covalent bond between the nucleophilic agent and the electrophile. Compounds or ions with a free pair of electrons or at least one pi bond can act as a nucleophilic agent. Quantifying relative nucleophilic strength have been devised, referred to as nucleophilicity, via various methods (e.g., the Swain-Scott equation, the Ritchie equation, the Mayr-Patz equation, or the Unified equation). In embodiments, wherein multiple nucleophilic agents are present in the reaction (e.g., -OH or -SH) the nucleophilic agent that participates in the reaction (i.e. the reaction between the haloalkyl amine with the nucleophilic agent) is the stronger nucleophile as determined by one of the methods known in the art (e.g., the Swain-Scott equation, the Ritchie equation, the Mayr-Patz equation, or the Unified equation). In embodiments, the nucleophilic agent includes an enol. In embodiments, the nucleophilic agent is - OH, alcohol, alkoxide anion, hydrogen peroxide, or a carboxylate anion. In embodiments, the nucleophilic agent is hydrogen sulfide, thiols (-SH), thiolate anions, anions of thiolcarboxylic acids (-C(O)-S-), anions of dithiocarbonates (-O-C(S)-S-) or dithiocarbamates (-N-C(S)-S-). In embodiments, the nucleophilic agent is ammonia, azide, amines, nitrites, hydroxylamine, hydrazine, carbazide, phenylhydrazine, semicarbazide, or an amide. In embodiments, the nucleophilic agent includes ammonia, azide, amines, nitrites, hydroxylamine, hydrazine, carbazide, phenylhydrazine, semicarbazide, or an amide. In embodiments, the nucleophilic agent includes -OH, alcohol, alkoxide anion, hydrogen peroxide, or a carboxylate anion. In embodiments, the nucleophilic agent includes hydrogen sulfide, thiols (-SH), thiolate anions, anions of thiolcarboxylic acids (-C(O)-S-), anions of dithiocarbonates (-O-C(S)-S-) or dithiocarbamates (-N-C(S)-S-). In embodiments, the nucleophilic agent is a halo-ester. II. Methods of making compounds

[0094] In an aspect is provided a method of making a haloalkyl amine including reacting a saturated cyclic amine with a halogenating agent in the presence of an oxidizing agent and a metal source, wherein the haloalkyl amine includes a covalently attached halogen, wherein the halogen is -Cl, -Br, or -I.

[0095] In an aspect is provided a method of making a haloalkyl amine including reacting a saturated cyclic amine with a halogenating agent in the presence of an oxidizing agent and a metal source, wherein the haloalkyl amine includes a covalently attached halogen.

[0096] In embodiments, the saturated cyclic amine has the structure of formula (I)

ly -L'-R ¹ , wherein each R ⁵ is optionally different. L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R ⁸ is independently

hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or

heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. R ² is independently

hydrogen, -CX ² ₃ , -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety. R ² and one R ⁵ may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R ² and one R ⁶ may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R ³ is independently hydrogen, -Cl, -Br,

-I, -CN, -SOnsR ³⁰ , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B ,

-C(0)R ^3C , -C(0)-OR ^3C , -C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -N R ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero cycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. X ¹ , X ² , and X ⁸ are independently - F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently hydrogen, -CX ₃ , -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently - F, -Cl, -Br, or -I. nl and n3 are independently an integer from 0 to 4. ml , m3, vl, and v3 are independently 1 or 2. z2 is an integer from 0 to 18. R ⁴ is hydrogen or -C(0)H. R ⁶ is independently - L'-R ¹ , wherein each R ⁶ is optionally different.

[0097] In embodiments, X ^a is independently -Cl, -Br, or -I. R ⁵ is independently -L'-R ¹ , wherein each R ⁵ is optionally different. L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R ⁸ is independently

hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -OCH ₂ X ⁸ , -OCHX ⁸ ₂ ,

-CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or

unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety. R ³ is independently hydrogen, -Cl, -Br, -I, -CN, -SO„ ₃ R ^D -SO _v3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B ,

-N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , -C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. nl and n3 are independently an integer from 0 to 4. ml , m3, vl , and v3 are independently 1 or 2. z2 is an integer from 0 to 18. R ⁴ is hydrogen or -C(0)H. R ⁶ is independently -L^R ¹ , wherein each R ⁶ is optionally different.

[0098] In embodiments the saturated cyclic amine has the structure of formula (Iz):

wherein R ² , R ³ , and z2 are as described herein, including in embodiments. R ^{5 1} , R ^{5 2} , R ⁵ and R ^{5 4} are each independently a value of R ⁵ (e.g., embodiments of R ⁵ ). In embodiments, R ^{5 1} or R ^{5 2} are combined with R ² in formula Iz to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R ⁵ is combined with R ² to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0099] In embodiments the haloalkyl amine has the structure of formula (Pz):

wherein R ² , R ³ , R ⁴ , X ^a , and z2 are as described herein, including in embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} _, andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ). In embodiments, R ^{6 1} or R ^{6 2} are combined with R ² in formula IIz to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R ⁶ is combined with R ² to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0100] In embodiments, the saturated cyclic amine has the structure of formula (I)

wherein R ² , R ³ , R ⁵ and z ² have any of the values described herein. ts, the saturated cyclic amine has the structure of formula (la):

herein R ² and R ⁵ have any of the values described herein. [0102] In embodiments, the haloalkyl amine has the structure of formula (II):

wherein X ^a , R ² , R , R ⁴ , R and z ² have any of the values described herein.

[0103] In embodiments, the haloalkyl amine has the structure of formula:

(Ha), wherein X ^a , R ² , R ⁴ , and R ⁶ are as described herein.

[0104] In embodiments, the nucleophilic reaction product has the structure of formula:

(lib), wherein R ^a , R ² , R ³ , R ⁴ , R ⁶ , and z2 are as described herein.

[0105] In embodiments, the nucleophilic reaction product has the structure of formula (Ilbz):

(Ilbz), wherein R ² , R ³ , R ⁴ , R ^a , and z2 are as described herein, including in embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} _, andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0106] In embodiments, the nucleophilic reaction product has the structure of formula:

embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} _. andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0108] In embodiments, the nucleophilic reaction product has the structure of formula:

, , , , , g embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} _. andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0110] In embodiments, the nucleophilic reaction product has the structure of formula:

(nie), wherein R ³ , R ⁶ , L, and z2 are as described herein.

[0111] In embodiments, the nucleophilic reaction product has the structure of formula:

, , [0112] In embodiments, the nucleophilic reaction product has the structure of formula:

, , , , bodiments. R ^{6 2} , R ^{6 3} _. andR ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0114] In embodiments, the nucleophilic reaction product has the structure of formula:

wherein R ² , R ³ , R ⁴ , R ⁶ , and z2 are as described herein. the nucleophilic reaction product has the structure of formula:

wherein R ² , R ³ , R ⁴ , and z2 are as described herein, including

embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} , andR ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ). [0116] In embodiments, the nucleophilic reaction product has the structure of formula:

in.

[0118] In embodiments, the nucleophilic reaction product has the structure of formula:

wherein R ² , R ³ , R ⁴ , z3, and Ring A are as described herein, including embodiments. R ⁶ · ¹ , R ^{6 2} , andR ^{6 3} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0119] In embodiments, z2 is an integer from 0 to 8.

[0120] In embodiments, z2 is an integer from 1 to 4. In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. In embodiments, z2 is 6. In embodiments, z2 is 7. In embodiments, z2 is 8.

[0121] In embodiments, each R ¹ is independently hydrogen, halogen, -CX , -CHXS, - CH2X ¹ , -OCXS, -OCH2X ¹ , -OCHX ,

oxo, -NHC(0)NR ^1A R ^1B , -N(0)mi, -NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^lc , -NR ^1A C(0)0R ^lc , -NR ^1A OR ^1c , -N ₃ , R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ -substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl; and R ²⁰ is independently oxo, halogen, -CF ₃ , -CHF2, - CH ₂ F, -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF3, -OCHF ₂ , or -OCH ₂ F. In embodiments, each R ¹ is independently hydrogen, halogen, -CX , -CHX^, -Ci X ¹ , -OCXS, -OCH2X ¹ , -OCHX ,

oxo, -NHC(0)NR ^1A R ^1B , -N(0)mi, -NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^lc , -NR ^1A C(0)OR ^lc , -NR ^1A OR ^1c , -N3, R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ -substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl.

[0122] In embodiments, R ²⁰ is independently oxo, halogen, -CF3, -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ ,

-ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0123] In embodiments, each R ¹ is independently hydrogen, -CF3, -CHF ₂ , -CH ₂ F, -OCF3, - OCH ₂ F, -OCHF ₂ , OXO, -NHC(0)NR ^1A R ^1b , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -N3, or R ²⁰ -substituted or unsubstituted C3-8 alkyl; and R ²⁰ is independently oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)OH, -C(0)NH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -OCF3, -OCHF ₂ , or -OCH ₂ F.

[0124] In embodiments, each R ¹ is independently hydrogen, -CF3, -CHF ₂ , -CH ₂ F, -OCF3, - OCH ₂ F, -OCHF ₂ , OXO, -NHC(0)NR ^1A R ^1b , -C(0)R ^1c , -C(0)-0R ^1c , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , or unsubstituted C3-8 alkyl.

[0125] In embodiments, each L ¹ is independently a bond, -S(0) ₂ -, -S(O)- , -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, R ²² -substituted or unsubstituted alkylene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroarylene.

[0126] In embodiments, R ²² is independently oxo, halogen, -CF ₃ , -CHF2, - CH ₂ F, -CN, -OH, -NH2, -C(0)OH,

-C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0127] In embodiments, each L ¹ is independently a bond, -S(0) ₂ -, -S(O)- , -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, R ²² -substituted or unsubstituted alkylene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroarylene.

[0128] In embodiments, R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ ,

-ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0129] In embodiments, each L ¹ is independently a

bond, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or R ²² -substituted or unsubstituted alkylene; and R ²² is independently oxo, halogen, -CF3, -CHF ₂ , - CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0130] In embodiments, each L ¹ is independently a

bond, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or R ²² -substituted or unsubstituted alkylene.

[0131] In embodiments, R ²² is independently oxo, halogen, -CF3, -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ON¾ -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)0H,

-NHOH, -OCF3, -OCHF ₂ , or -OCH ₂ F.

[0132] In embodiments, each L ¹ is independently a

bond, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-C ₈ alkylene.

[0133] In embodiments, two -L'-R ¹ substituents attached to the same carbon atom are independently joined to form a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two -L'-R ¹ substituents attached to the same carbon atom are independently joined to form an R ²⁰ -substituted or unsubstituted C3-C8 cycloalkyl or an R ²⁰ -substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In

embodiments, two -L'-R ¹ substituents attached to the same carbon atom are independently joined to form an R ²² -substituted or unsubstituted C3-C8 cycloalkyl or an R ²² -substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

[0134] In embodiments, two -L'-R ¹ substituents attached to adjacent carbon atoms are independently joined to form a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, a substituted or unsubstituted Ce-Cio aryl or a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, two -L'-R ¹ substituents attached to adjacent carbon atoms are independently joined to form an R ²⁰ -substituted or unsubstituted C3-C8 cycloalkyl, an R ²⁰ -substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, an R ²⁰ -substituted or unsubstituted Ce-Cio aryl or an R ²⁰ -substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, two -L'-R ¹ substituents attached to adjacent carbon atoms are independently joined to form an R ²² -substituted or unsubstituted C3-C8 cycloalkyl, an R ²² -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, an R ²² -substituted or unsubstituted Ce-Cio aryl or an R ²² -substituted or unsubstituted 5 to 10 membered heteroaryl.

[0135] In embodiments, each R ⁸ is hydrogen.

[0136] In embodiments, each R ⁴ is hydrogen.

[0137] In embodiments, R ² is substituted or unsubstituted alkyl or an amine protecting group chosen from the list including: carboxybenzyl (CBz), methoxybenzyl carbonyl (Moz), tert- Butyloxycarbonyl (BOC), Fluorenylmethyloxycarbonyl (FMOC), acyl (Ac), benzyl (Bz), benzyl ether (Bn), carbamate, p-methoyxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p- methoxyphenyl (PMP), pivaloyl (PIV), or tosylate (Ts).

[0138] In embodiments, R ² is substituted or unsubstituted alkyl. In embodiments, R ² is amine protecting group. In embodiments, R ² is amine protecting group chosen from the list including: carboxybenzyl (CBz), methoxybenzyl carbonyl (Moz), tert-Butyloxycarbonyl (BOC),

Fluorenylmethyloxycarbonyl (FMOC), acyl (Ac), benzyl (Bz), benzyl ether (Bn), carbamate, p- methoyxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), pivaloyl (PIV), or tosylate (Ts).

[0139] In embodiments, the saturated cyclic amine has the structure of formula (la):

tly -L'-R ¹ ; L ¹ is independently a -C(O)- or -C(0)0-; R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHXN, -

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; R ² is independently hydrogen, -CX ² ₃ , -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety; X ¹ and X ² are independently -F, -Cl, -Br, or -I; R ^1A , R ^1B , R ^1C , and R ^1D are independently hydrogen, -CX3, -CHX ₂ , -CFFX, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2; R ⁴ is hydrogen or -C(0)H; and R ⁶ is independently -I^-R ¹ . [0140] In embodiments, X ^a is independently -Cl, -Br, or -I; R ⁵ is independently -L' -R ¹ ; L ¹ is independently a -C(O)- or -C(0)0-; R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and R ² is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0141] In embodiments, X ^a is independently -Cl, -Br, or -I. [0142] In embodiments, R ⁵ is independently -I^-R ¹ . In embodiments, L ¹ is independently a -C(O)- or -C(0)0-.

[0143] In embodiments, R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0144] In embodiments, R ² is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0145] In embodiments, the method further includes reacting the haloalkyl amine with a nucleophilic agent, wherein the nucleophilic agent displaces the covalently attached halogen with a covalently attached substituent, thereby forming a nucleophilic reaction product. [0146] In embodiments, the method further includes reacting the haloalkyl amine, e.g.,

nucleophilic agent (e.g., Nuc), wherein the nucleophilic agent displaces the covalently attached halogen (selected from -Br, -Cl or -I) with a covalently attached

substituent, thereby forming a nucleophilic reaction product, e.g,

[0147] In embodiments, the method further includes reacting the haloalkyl amine, e.g.,

nucleophilic agent (e.g., Nuc), wherein the nucleophilic agent displaces the covalently attached halogen (selected from -Br, -Cl or -I) with a covalently attached

substituent, thereby forming a nucleophilic reaction product, wherein

X ^a , R ² , R ³ , R ⁴ , and z2, are as described herein, including embodiments. R ⁶ · ¹ , R ^{6 2} , andR ^{6 3} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ). [0148] In embodiments, the nucleophilic agent

includes -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, -NHC(O)- OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety.

[0149] In embodiments, the nucleophilic agent

is -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, -NHC(O)- OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety. In embodiments, the nucleophilic agent is -CF ₃ . In embodiments, the nucleophilic agent is -CN. In embodiments, the nucleophilic agent is -OH. In embodiments, the nucleophilic agent is -NH ₂ . In embodiments, the nucleophilic agent is -COOH. In embodiments, the nucleophilic agent is -CONH ₂ . In embodiments, the nucleophilic agent is -N0 ₂ . In embodiments, the nucleophilic agent is -SH. In embodiments, the nucleophilic agent is -S0 ₂ Cl. In embodiments, the nucleophilic agent is -S0 ₃ H. In embodiments, the nucleophilic agent is -SO4H In embodiments, the nucleophilic agent is -S0 ₂ NH ₂ . In embodiments, the nucleophilic agent is -NHNH ₂ . In embodiments, the nucleophilic agent is -ONH ₂ . In embodiments, the nucleophilic agent is -NHC=(0)NHNH ₂ . In embodiments, the nucleophilic agent is -NHC=(0) NH ₂ . In embodiments, the nucleophilic agent is -NHSO2H. In embodiments, the nucleophilic agent is -NHC= (O)H. In embodiments, the nucleophilic agent is -NHC(0)-OH. In embodiments, the nucleophilic agent is -NHOH. In embodiments, the nucleophilic agent is -OCF ₃ .

In embodiments, the nucleophilic agent is -OCHF ₂ . In embodiments, the nucleophilic agent is -N ₃ .

In embodiments, the nucleophilic agent is substituted or unsubstituted alkyl. In embodiments, the nucleophilic agent is substituted or unsubstituted heteroalkyl. In embodiments, the nucleophilic agent is substituted or unsubstituted cycloalkyl. In embodiments, the nucleophilic agent is substituted or unsubstituted heterocycloalkyl. In embodiments, the nucleophilic agent is substituted or unsubstituted aryl. In embodiments, the nucleophilic agent is substituted or unsubstituted heteroaryl. In embodiments, the nucleophilic agent is detectable moiety. In embodiments, the nucleophilic agent is therapeutic moiety. In embodiments, the nucleophilic agent is a drug moiety. In embodiments, the nucleophilic agent is a protein moiety. In embodiments, the nucleophilic agent is a bioconjugate reactive moiety.

[0150] In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, -S0 ₄ H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, - NHC(0)-OH, -NHOH, -OCF3, -OCHF ₂ , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety.

[0151] In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) includes -CF ₃ , -CN, -OH, -N¾, -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -SO3H, -S0 ₄ H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, - NHC(0)-OH, -NHOH, -OCF3, -OCHF ₂ , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety.

[0152] In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -SH, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -CF3. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -CN. In embodiments, the covalently attached substituent

(e.g., -(Nuc) of a nucleophilic reaction product) is -OH. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NH ₂ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -COOH. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -CONH ₂ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NO ₂ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -SH. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -SO ₂ CI. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -SO ₃ H. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -SO ₄ H. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -SO ₂ NH ₂ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHNH ₂ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -ONH ₂ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHC=(0)NHNH2. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHC=(0) NH ₂ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHSO ₂ H. In embodiments, the covalently attached substituent is -NHC= (O)H. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHC(0)-OH. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHOH. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -OCF3. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -OCHF ₂ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -N ₃ . In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is substituted or unsubstituted alkyl. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is substituted or unsubstituted heteroalkyl. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is substituted or unsubstituted cycloalkyl. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is substituted or unsubstituted heterocycloalkyl. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is substituted or unsubstituted aryl. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is substituted or unsubstituted heteroaryl. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is detectable moiety. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is a therapeutic moiety. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is a drug moiety. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is a protein moiety. In embodiments, the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is a bioconjugate reactive moiety.

[0153] In embodiments, X ^a is -Cl.

[0154] In embodiments, X ^a is -Br.

[0155] In embodiments, X ^a is -I.

[0156] In embodiments, the reaction between the haloalkyl amine and the nucleophilic agent is an intramolecular reaction.

[0157] In embodiments, the intramolecular reaction is a cyclization reaction.

[0158] In embodiments, the nucleophilic reaction product has the formula:

, and L are described herein.

[0159] In embodiments, the nucleophilic reaction product has the formula:

, , , , , , , , and L are described herein, including embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} _, andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments ofR ⁶ ). [0160] R ^a is hydrogen,

halogen, -CX ^b ₃ , -CHX ^b ₂ , -CH ₂ X ^b , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, - S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCX ^b ₃ , -OCHX ^b ₂ , -OCH ₂ X ^b , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety. X ^b is F, Cl, Br, or I.

[0161] In embodiments, R ^a is hydrogen,

halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -COMB, -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, -NHC(O)-

OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety. [0162] L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. [0163] L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(O)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0164] In embodiments, R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CkbX ⁸ , -OCX ⁸ ₃ , - OCH2X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0165] In embodiments, R ¹ is independently hydrogen, halogen, -CXN, -CHXN, -CH2X ¹ , -OCX ¹ ,,

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or

unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0166] In embodiments, R ² is independently hydrogen, -CX ² ₃ , -CHX ² 2, - CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0167] In embodiments, R ³ is independently hydrogen, -Cl, -Br, -

I, -CN, -SOn3R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , -

C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0168] In embodiments, X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I. [0169] In embodiments, R ^1A , R ^1B , R ^1C , R ^1D , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently hydrogen, -CX3, -CHX2, -CFFX, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0170] In embodiments, X is independently -F, -Cl, -Br, or -I.

[0171] In embodiments, nl and n3 are independently an integer from 0 to 4.

[0172] In embodiments, ml, m3, vl , and v3 are independently 1 or 2.

[0173] In embodiments, z2 is an integer from 0 to 18. In embodiments, z2 is an integer from 1 to 6

[0174] In embodiments, R ⁴ is hydrogen or -C(0)H.

[0175] In embodiments, L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

[0176] In embodiments, R ⁶ is independently -I^-R ¹ , wherein each R ⁶ is optionally different; [0177] In embodiments, the nucleophilic reaction product has the formula:

) wherein one R ⁶ is combined with the carbon adjacent to R ³ in formula He to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0178] In embodiments, the nucleophilic reaction product has the formula:

, R _, orR is combined with the carbon adjacent to R ³ in formula IIcz to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ² , R ³ , R ⁴ , and z2 are as described herein, including in embodiments. R ^{6· 1} , R ^{6 2} , R ^{6 3} _. andR ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ). [0179] In embodiments, the nucleophilic reaction product has the formula:

wherein R ^{6 3} or R ^{6 4} are combined with the carbon adjacent to R ³ in formula IIcz to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ² , R ³ , R ⁴ , and z2 are as described herein, including in embodiments. R ⁶ · ¹ , R ^{6 2} , R ^{6 3} _, andR ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0180] In embodiments, the nucleophilic reaction product has the formula:

Ring A are as described herein. [0181] Ring A is a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). The symbol z3 is an integer from 0 to 17. In embodiments, z3 is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17.

[0182] In embodiments, the halogenating agent is A'-chlorosuccininiide, A'-bromosuccinimide, N- iodosuccinimide, or dibromohydantoin. In embodiments, the halogenating agent is aluminum bromide. In embodiments, the halogenating agent is aluminum chloride. In embodiments, the halogenating agent is bromo phthalimide. In embodiments, the halogenating agent is chloro phthalimide. In embodiments, the halogenating agent is trityl chloride.

[0183] In embodiments, the method of making the haloalkyl amine is performed under mild conditions that do not degrade the starting material (e.g., other than by making the haloalkyl amine). In embodiments, the reaction occurs under conditions suitable for stabilizing a protein. [0184] In embodiments, the conditions includes: an aqueous environment, an aerobic environment and a reaction temperature ranging from 15°C to 30°C.

[0185] In embodiments, the reacting temperature ranges from 20°C to 25°C.

[0186] In embodiments, the reacting temperature ranges from 22°C to 23°C. [0187] In embodiments, the oxidizing agent is ammonium persulfate.

[0188] In embodiments, X ^a is independently -Cl, -Br, or -I. In embodiments, X ^a is independently -Cl or -Br. In embodiments, X ^a is independently -Cl. In embodiments, X ^a is independently -Br. In embodiments, X ^a is independently -I.

[0189] In embodiments, L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0190] In embodiments, R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -OCX ⁸ 3, -CN, -SOnxR ^XD , -SO _V8 NR ^8A R ^8B , -NHC(0)NR ^8A R ^8B ,

-N(0) _m8 , -NR ^8A R ^8B , -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , -NR ^8A S0 ₂ R ^8D , -NR ^8A C(0)R ^8C , -NR ^8A C(0)0R ^8C , -NR ^8A OR ^8C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or

unsubstituted amino acid moiety, a substituted or unsubstituted peptide moiety, a substituted or unsubstituted nucleoside, a substituted or unsubstituted nucleotide, a substituted or unsubstituted nucleic acid moiety, a bioconjugate moiety, or a lipid moiety.

[0192] In embodiments, R ¹ is independently hydrogen, halogen, -CX^, -CHX' ₂ , -CH ₂ X', -OCX ¹ ,,

-NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted amino acid moiety, a substituted or unsubstituted peptide moiety, a substituted or unsubstituted nucleoside, a substituted or unsubstituted nucleotide, a substituted or unsubstituted nucleic acid moiety, a bioconjugate moiety, or a lipid moiety.

[0193] In embodiments, R ¹ is independently hydrogen, halogen, -CX ¹ -,, -CHXN, -CH2X ¹ , -OCX ¹ -,, -OCH2X ¹ , -OCHX^, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1b ,

-N(0)mi, -NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0194] In embodiments, two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl. In embodiments, two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0195] In embodiments, R ² is independently hydrogen, -CX ² ₃ , -CHX ² 2, - CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0196] In embodiments, R ² is independently hydrogen, -CX ² ₃ , -CHX ² 2, - CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0197] In embodiments, R ² is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0198] In embodiments, R ² is independently hydrogen or an amine protecting group.

[0199] In embodiments, R ² is an amine protecting group. [0200] In embodiments, R ² is substituted or unsubstituted alkyl, CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts.

[0201] In embodiments, R ³ is independently hydrogen, -Cl, -Br,-

I, -CN, -SO _n3 R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , - C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0202] In embodiments, R ³ is independently hydrogen.

[0203] In embodiments, X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I.

[0204] In embodiments, R ^1A , R ^1B , R ^1C , R ^1D , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0205] In embodiments, R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0206] In embodiments, X is independently -F, -Cl, -Br, or -I.

[0207] In embodiments, the symbol nl and n8 are independently an integer from 0 to 4.

[0208] In embodiments, the symbols ml, vl, m8 and v8 are independently 1 or 2.

[0209] In embodiments, the symbol z2 is an integer from 0 to 18.

[0210] In embodiments, R ⁴ is hydrogen or -C(0)H. [0211] In embodiments, z2 is an integer from 0 to 8.

[0212] In embodiments, z2 is an integer from 1 to 4.

[0213] In embodiments, R ¹ is independently hydrogen, -CF ₃ , -CHF2, -CFFF, -OCF3, - OCH2F, -OCHF2,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0 )OR ^lc , or unsubstituted C3-8 alkyl.

[0214] In embodiments, R ¹ is independently an amino acid moiety, a polypeptide moiety, or a protein moiety. In embodiments, R ² is independently an amino acid moiety, a polypeptide moiety, or a protein moiety. In embodiments, R ⁶ is independently an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0215] In embodiments, L ¹ is independently a

bond, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or R ²² -substituted or unsubstituted alkylene.

[0216] In embodiments, L ¹ is independently a

bond, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-C ₈ alkylene.

[0217] In embodiments, L ¹ is independently -C(O)- or -C(0)0-.

[0218] In embodiments, two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

[0219] In embodiments, two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, a substituted or unsubstituted Ce-Cio aryl or a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0220] In embodiments, R ⁸ is hydrogen.

[0221] In embodiments, R ⁴ is hydrogen. [0222] In embodiments, R ¹ is independently hydrogen, halogen, -CX ¹ -,, -CHXN, -CH2X ¹ , -OCX ¹ -,,

substituted or unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C ₁ -C ₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0223] In embodiments, R ¹ is independently hydrogen,

halogen, -CX , -CHX^, -CH2X ¹ , -OCXS, -OCHXS, -OCH2X ¹ , oxo, -CN, -OH, -NH ₂ , -C(0)OH, - C(0)OCH ₃ , -C(0)H, -C(0)NH ₂ , -NO2, substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently halogen, -CX , oxo, -CN, -OH, -C(0)OH, -C(0)OCH ₃ , -C(0)H, -C(0)NH ₂ , unsubstituted C ₁ -C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted butyl. In embodiments, R ¹ is independently unsubstituted methyl. In embodiments, R ¹ is independently unsubstituted ethyl. In embodiments, R ¹ is independently unsubstituted propyl. In embodiments, R ¹ is independently unsubstituted n-propyl. In embodiments, R ¹ is independently unsubstituted isopropyl. In embodiments, R ¹ is independently unsubstituted butyl. In embodiments, R ¹ is independently unsubstituted n-butyl. In embodiments, R ¹ is independently unsubstituted isobutyl.

In embodiments, R ¹ is independently unsubstituted tert-butyl. In embodiments, R ¹ is independently unsubstituted pentyl. In embodiments, R ¹ is independently unsubstituted hexyl. In embodiments,

R ¹ is independently halogen. In embodiments, R ¹ is independently -F. In embodiments, R ¹ is independently -Cl. In embodiments, R ¹ is independently -Br. In embodiments, R ¹ is

independently -I. In embodiments, R ¹ is independently unsubstituted methoxy. In embodiments, R ¹ is independently unsubstituted ethoxy. In embodiments, R ¹ is independently -CF ₃ . In embodiments, R ¹ is independently -CCh.

[0224] In embodiments, R ¹ is independently hydrogen. In embodiments, R ¹ is independently halogen. In embodiments, R ¹ is independently -CXV In embodiments, R ¹ is independently - CHX ' T. In embodiments, R ¹ is independently -CH2X ¹ . In embodiments, R ¹ is

independently -OCX ¹ -,. In embodiments, R ¹ is independently -OCH2X ¹ . In embodiments, R ¹ is independently -OCHXN. In embodiments, R ¹ is independently oxo. In embodiments, R ¹ is independently -CN. In embodiments, R ¹ is independently -NHC(0)NR ^1A R ^1B . In embodiments, R ¹ is independently -N(0) _mi . In embodiments, R ¹ is independently -NR ^1A R ^1B . In embodiments, R ¹ is independently -C(0)R ^lc . In embodiments, R ¹ is independently -C(0)-OR ^lc . In embodiments, R ¹ is independently -C(0)NR ^1A R ^1B . In embodiments, R ¹ is independently -OR ^1D . In embodiments, R ¹ is independently -NR ^1A S0 ₂ R ^1D . In embodiments, R ¹ is independently -NR ^1A C(0)R ^lc . In

embodiments, R ¹ is independently -NR ^1A C(0)OR ^lc . In embodiments, R ¹ is independently -OH. In embodiments, R ¹ is independently -NH2. In embodiments, R ¹ is independently -C(0)OH. In embodiments, R ¹ is independently -C(0)OCH ₃ . In embodiments, R ¹ is independently -C(0)H. In embodiments, R ¹ is independently -C(0)NH ₂ . In embodiments, R ¹ is independently -NO2. In embodiments, R ¹ is independently -SH.

[0225] In embodiments, R ¹ is independently a substituted or unsubstituted amino acid moiety. In embodiments, R ¹ is independently a substituted or unsubstituted peptide moiety. In embodiments, R ¹ is independently a substituted or unsubstituted polypeptide moiety. In embodiments, R ¹ is independently a substituted or unsubstituted protein moiety. In embodiments, R ¹ is independently a substituted or unsubstituted nucleoside. In embodiments, R ¹ is independently a substituted or unsubstituted nucleotide. In embodiments, R ¹ is independently a substituted or unsubstituted nucleic acid moiety. In embodiments, R ¹ is independently a bioconjugate moiety. In embodiments, R ¹ is independently a substituted or unsubstituted lipid moiety.

[0226] In embodiments, R ¹ is independently an R ²⁰ -substituted or unsubstituted amino acid moiety. In embodiments, R ¹ is independently an R ²⁰ -substituted or unsubstituted peptide moiety. In embodiments, R ¹ is independently an R ²⁰ -substituted or unsubstituted polypeptide moiety. In embodiments, R ¹ is independently an R ²⁰ -substituted or unsubstituted protein moiety. In

embodiments, R ¹ is independently an R ²⁰ -substituted or unsubstituted nucleoside. In embodiments, R ¹ is independently an R ²⁰ -substituted or unsubstituted nucleotide. In embodiments, R ¹ is independently an R ²⁰ -substituted or unsubstituted nucleic acid moiety. In embodiments, R ¹ is independently a bioconjugate moiety. In embodiments, R ¹ is independently an R ²⁰ -substituted or unsubstituted lipid moiety.

[0227] In embodiments, R ¹ is independently an unsubstituted amino acid moiety. In

embodiments, R ¹ is independently an unsubstituted peptide moiety. In embodiments, R ¹ is independently an unsubstituted polypeptide moiety. In embodiments, R ¹ is independently an unsubstituted protein moiety. In embodiments, R ¹ is independently an unsubstituted nucleoside. In embodiments, R ¹ is independently an unsubstituted nucleotide. In embodiments, R ¹ is

independently an unsubstituted nucleic acid moiety. In embodiments, R ¹ is independently a bioconjugate moiety. In embodiments, R ¹ is independently an unsubstituted lipid moiety.

[0228] In embodiments, R ¹ is independently -C(0)NR ^1A R ^1B . In embodiments, R ^1A and R ^1B are independently hydrogen, -CX3, -CHX2, -CFbX, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R ^1A and R ^1B are independently hydrogen, -CX3, -CHX2, -CH2X, or substituted or unsubstituted alkyl. In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I.

[0229] In embodiments, R ¹ is independently substituted or unsubstituted alkyl. In embodiments, R ¹ is independently substituted or unsubstituted heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted cycloalkyl. In embodiments, R ¹ is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted aryl. In embodiments, R ¹ is independently substituted or unsubstituted heteroaryl. In embodiments, R ¹ is independently substituted alkyl. In embodiments, R ¹ is independently substituted heteroalkyl. In embodiments, R ¹ is independently substituted cycloalkyl. In embodiments, R ¹ is independently, substituted heterocycloalkyl. In embodiments, R ¹ is independently substituted aryl. In

embodiments, R ¹ is independently substituted heteroaryl. In embodiments, R ¹ is independently unsubstituted alkyl. In embodiments, R ¹ is independently unsubstituted heteroalkyl. In

embodiments, R ¹ is independently unsubstituted cycloalkyl. In embodiments, R ¹ is independently, unsubstituted heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted aryl. In embodiments, R ¹ is independently unsubstituted heteroaryl. In embodiments, R ¹ is independently substituted or unsubstituted Ci-C ₈ alkyl. In embodiments, R ¹ is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R ¹ is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C ₆ -Cio aryl. In embodiments, R ¹ is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently substituted Ci-Cs alkyl. In embodiments, R ¹ is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently substituted C3-C8 cycloalkyl. In embodiments, R ¹ is independently, substituted 3 to 8 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted Ce-Cio aryl. In embodiments, R ¹ is independently substituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted Ci-Cs alkyl. In embodiments, R ¹ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted C ₃ -C ₈ cycloalkyl. In embodiments, R ¹ is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted Ce-Cio aryl. In embodiments, R ¹ is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently substituted or unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ¹ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C ₃ -C ₆ cycloalkyl. In embodiments, R ¹ is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

In embodiments, R ¹ is independently substituted or unsubstituted phenyl. In embodiments, R ¹ is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ¹ is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently substituted C ₃ -C ₆ cycloalkyl. In embodiments, R ¹ is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted phenyl. In embodiments, R ¹ is independently substituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ¹ is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted C ₃ -C ₆ cycloalkyl. In embodiments, R ¹ is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted phenyl. In embodiments, R ¹ is independently unsubstituted 5 to 6 membered heteroaryl. [0230] In embodiments, R ¹ is independently hydrogen,

halogen, -CXS, -CHXS, -CH2X ¹ , -OCXS, -OCH2X ¹ , -OCHXS,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)OR ^lc , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , R ²⁰ - substituted or unsubstituted alkyl, R ²⁰ -substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl. In embodiments, R ¹ is

independently hydrogen, halogen, -CXS, -CHX , -CH2X ¹ ,

oxo, -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH ₂ , -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCXS, -OCH2X ¹ , -OCHXS, -OCXS, R ²⁰ -substituted or unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁰ - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁰ - substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ¹ is independently hydrogen,

halogen, -CXS, -CHXS, -CH2X ¹ ,

oxo, -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH ₂ , -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCXS, -OCH2X ¹ , -OCHXS, -OCXS, unsubstituted alkyl (e.g., Ci-Cg alkyl, Ci-C ₆ alkyl, or Ci-C ₄ 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., Ce-Cio 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). X ¹ is - F, -Cl, -Br, or -I. In embodiments, R ¹ is independently hydrogen. In embodiments, R ¹ is independently methyl. In embodiments, R ¹ is independently ethyl. In embodiments, R ¹ is independently oxo. In embodiments, R ¹ is independently -OH. In embodiments, R ¹ is independently -C(0)OH. In embodiments, R ¹ is independently -C(0)OCH ₃ . In embodiments, R ¹ is independently -C(0)H. In embodiments, R ¹ is independently -C(0)NH ₂ .

[0231] R ²⁰ is independently oxo, halogen, -CX ²⁰ ₃ , -CHX ²⁰ 2, -

CH ₂ X ²⁰ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX ²⁰ ₃ , -OCHX ²⁰ 2, -OCH2X ²⁰ , R ²¹ -substituted or unsubstituted alkyl, R ²¹ -substituted or unsubstituted heteroalkyl, R ²¹ -substituted or unsubstituted cycloalkyl, R ²¹ -substituted or

unsubstituted heterocycloalkyl, R ²¹ -substituted or unsubstituted aryl, or R ²¹ -substituted or unsubstituted heteroaryl. X ²⁰ is -F, -Cl, -Br, or -I. In embodiments, R ²⁰ is independently oxo, halogen, -CX ²⁰ ₃ , -CHX ²⁰ ₂ , -

CH2X ²⁰ , -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH ₂ , -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX ²⁰ 3, -OCHX ²⁰ ₂ , -OCH ₂ X ²⁰ , R ²¹ -substituted or unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), R ²¹ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²¹ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²¹ - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²¹ -substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or R ²¹ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ²⁰ is independently oxo, halogen, -CX ²⁰ 3, -CHX ²⁰ ₂ , -

CH2X ²⁰ , -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH ₂ , -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX ²⁰ ₃ , -OCHX ²⁰ 2, -OCH2X ²⁰ , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, C i-Cr, alkyl, or Ci- C ₄ 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-C ₈ 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., Ce-Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0232] In embodiments, R ²⁰ is independently oxo, halogen, -CF ₃ , -CHF2, -

CH ₂ F, -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ ,

-ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0233] In embodiments, R ²⁰ is oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)OH, -C(0)NH ₂ , - NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -OCF3, -OCHF ₂ , or - OCH ₂ F.

[0234] R ²¹ is independently oxo,

halogen, -CX ²¹ ₃ , -CHX ²¹ ₂ , -CH ₂ X ^{2 1} ,-CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²¹ ₃ , -OCHX ²¹ ₂ , -OCH ₂ X ²¹ , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ 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., Ce-Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ²¹ is -F, -Cl, -Br, or -I.

[0235] In embodiments, R ¹ is independently hydrogen, halogen, -CX^, -CHX' ₂ , - CH ₂ X\ -OCX^, -OCH ₂ X ¹ , -OCHX^,

oxo, -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^lc , -NR ^1A C(0)OR ^lc , -NR ^1A OR ^1c , -N3, R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ -substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl. In embodiments, R ²⁰ is independently oxo, halogen, -CF3, -CHF ₂ , - CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ON¾ -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0236] In embodiments, R ¹ is independently hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -

OCH ₂ F, -OCHF ₂ ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0 )OR ^lc , -N3, or R ²⁰ -substituted or unsubstituted C3-8 alkyl. In embodiments, R ²⁰ is independently oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)OH, -C(0)NH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -OCF3, -OCHF ₂ , or -OCH ₂ F.

[0237] In embodiments, L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , substituted or unsubstituted alkylene (e.g., Ci-C ₈ alkylene, Ci-Cr, alkylene, or C1-C4 alkylene), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkyl ene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkyl ene, 3 to 6 membered

heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), substituted or unsubstituted arylene (e.g., C ₆ -Cio arylene, C10 arylene, or phenylene), or substituted or unsubstituted heteroarylene (e.g.,

5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered

heteroarylene).

[0238] In embodiments, L ¹ is independently a

bond, -NH-, -0-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, substituted or unsubstituted Ci-Cs alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted Ce-Cio arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, L ¹ is independently a

bond, -NH-, -0-, -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)0-, -OC(O)-, unsubstituted C1-C4 alkylene, unsubstituted 2 to 4 membered heteroalkylene, unsubstituted C3-C6 cycloalkylene, unsubstituted 3 to

6 membered heterocycloalkylene, unsubstituted phenylene, or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L ¹ is independently unsubstituted methylene, unsubstituted ethylene, unsubstituted propylene, or unsubstituted butylene. In embodiments, L ¹ is independently unsubstituted methylene. In embodiments, L ¹ is independently unsubstituted ethylene. In embodiments, L ¹ is independently unsubstituted propylene. In embodiments, L ¹ is independently unsubstituted n-propylene. In embodiments, L ¹ is independently unsubstituted isopropylene. In embodiments, L ¹ is independently unsubstituted butylene. In embodiments, L ¹ is independently unsubstituted n-butylene. In embodiments, L ¹ is independently unsubstituted isobutylene.

[0239] In embodiments, L ¹ is independently a bond, -NH- or -0-. In embodiments, L ¹ is independently -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)0- or -OC(O)-. In embodiments, L ¹ is independently a bond, -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)0-, -OC(O)-, or substituted or unsubstituted Ci-C ₈ alkylene. In embodiments, L ¹ is independently a

bond, -C(O)-, -C(0)NH-, -C(0)0-, or substituted or unsubstituted Ci-Cr, alkylene. In embodiments, L ¹ is independently a bond. In embodiments, L ¹ is independently -NH-. In embodiments, L ¹ is independently -0-. In embodiments, L ¹ is independently -C(O)-. In embodiments, L ¹ is

independently -C(0)NH-. In embodiments, L ¹ is independently -NHC(O)-. In embodiments, L ¹ is independently -C(0)0-. In embodiments, L ¹ is independently -OC(O)-.

[0240] In embodiments, L ¹ is independently substituted or unsubstituted alkyl. In embodiments, L ¹ is independently substituted or unsubstituted heteroalkyl. In embodiments, L ¹ is independently substituted or unsubstituted cycloalkyl. In embodiments, L ¹ is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, L ¹ is independently substituted or unsubstituted aryl. In embodiments, L ¹ is independently substituted or unsubstituted heteroaryl. In embodiments, L ¹ is independently substituted alkyl. In embodiments, L ¹ is independently substituted heteroalkyl. In embodiments, L ¹ is independently substituted cycloalkyl. In embodiments, L ¹ is independently, substituted heterocycloalkyl. In embodiments, L ¹ is independently substituted aryl. In

embodiments, L ¹ is independently substituted heteroaryl. In embodiments, L ¹ is independently unsubstituted alkyl. In embodiments, L ¹ is independently unsubstituted heteroalkyl. In

embodiments, L ¹ is independently unsubstituted cycloalkyl. In embodiments, L ¹ is independently, unsubstituted heterocycloalkyl. In embodiments, L ¹ is independently unsubstituted aryl. In embodiments, L ¹ is independently unsubstituted heteroaryl. In embodiments, L ¹ is independently substituted or unsubstituted Ci-C ₈ alkyl. In embodiments, L ¹ is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, L ¹ is independently substituted Ci-C ₈ alkyl. In embodiments, L ¹ is independently substituted 2 to 8 membered heteroalkyl. In embodiments, L ¹ is independently unsubstituted Ci-C ₈ alkyl. In embodiments, L ¹ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, L ¹ is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, L ¹ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, L ¹ is independently substituted C1-C4 alkyl. In

embodiments, L ¹ is independently substituted 2 to 4 membered heteroalkyl. In embodiments, L ¹ is independently unsubstituted C1-C4 alkyl. In embodiments, L ¹ is independently unsubstituted 2 to 4 membered heteroalkyl.

[0241] In embodiments L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , R ²² -substituted or unsubstituted alkylene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroarylene. In embodiments, L ¹ is independently a

bond, -S(0) ₂ -, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0 -, -OC(O)-, R ²² -substituted or unsubstituted alkylene (e.g., Ci-Cs alkylene, Ci-Cr, alkylene, or C ₁ -C ₄ alkylene), R ²² -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R ²² -substituted or unsubstituted cycloalkylene (e.g., C ₃ -C ₈ cycloalkylene, C ₃ -C ₆ cycloalkylene, or C ₅ -C ₆ cycloalkylene), R ²² - substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), R ²² -substituted or unsubstituted arylene (e.g., C e-Cio arylene, C ₁₀ arylene, or phenylene), or R ²² -substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L ¹ is independently a

bond, -S(0) ₂ -, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0 -, -OC(O)-, unsubstituted alkylene (e.g., Ci-C ₈ alkylene, Ci-C ₆ alkylene, or C ₁ -C ₄ alkylene), unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered

heteroalkylene, or 2 to 4 membered heteroalkylene), unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C ₃ -C ₆ cycloalkylene, or C ₅ -C ₆ cycloalkylene), unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), unsubstituted arylene (e.g., Ce-Cio arylene, C ₁₀ arylene, or phenyl ene), or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroaryl ene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).

[0242] R ²² is independently oxo, halogen, -CX ²² ₃ , -CHX ²² ₂ , -

CH ₂ X ²² , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX ²² 3, -OCHX ²² ₂ , -OCH ₂ X ²² , R ²³ -substituted or unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), R ²³ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²³ -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R ²³ - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²³ -substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or R ²³ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ²² is independently oxo, halogen, -CX ²² ₃ , -CHX ²² ₂ , -

CH ₂ X ²² , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX ²² ₃ , -OCHX ²² ₂ , -OCH ₂ X ²² , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or Ci- C ₄ 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., Ce-Cio 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). X ²² is - F, -Cl, -Br, or -I.

[0243] In embodiments, R ²² is independently oxo, halogen, -CF3, -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ ,

-ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F. [0244] In embodiments, R ²² is independently oxo, halogen, -CF ₃ , -CHF2, - CH ₂ F, -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHC(0)H, -NHC(0)OH, -OCF3, -OCHF ₂ , or -OCH ₂ F.

[0245] R ²³ is independently oxo, halogen, -CX ²³ ₃ , -CHX ²³ ₂ , -

CH ₂ X ²³ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²³ ₃ , -OCHX ²³ ₂ , -OCH ₂ X ²³ , unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-Cr, 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., Ce-Cio 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). X ²³ is -F, -Cl, -Br, or -I.

[0246] In embodiments, L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, R ²² -substituted or unsubstituted alkylene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroarylene. In embodiments, R ²² is independently oxo, halogen, -CF3, -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCF3, -OCHF ₂ , or -OCH ₂ F.

[0247] In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted aryl. In embodiments, two adjacent -L ¹ - R ¹ substituents may optionally be joined to form a substituted heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted Ce-Cio aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted C3-C8 cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent -L ¹ - R ¹ substituents may optionally be joined to form a substituted Ce-Cio aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted 5 to 10 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted C3-C8 cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted Ce-Cio aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted phenyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted C3-C6 cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted phenyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted 5 to 6 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted C3-C6 cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted phenyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted 5 to 6 membered heteroaryl.

[0248] In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a R ²⁰ - substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ - substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a R ²⁰ -substituted or unsubstituted C3-C8 cycloalkyl, R ²⁰ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁰ -substituted or unsubstituted phenyl, or R ²⁰ -substituted or unsubstituted 5 to 6 membered heteroaryl.

[0249] In embodiments, R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH2X ⁸ , -OCX ⁸ ₃ , - OCH2X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5- Ce cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or substituted or

unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0250] In embodiments, R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ 2, -CH2X ⁸ , -OCX ⁸ ₃ , - OCH2X ⁸ , -OCHX ⁸ 2, -CN, -C(0)CH ₃ , -C(0)-OH, -C(0)H, -C(0)NH ₂ , -OH, substituted or unsubstituted Ci-Cs alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -

CH ₂ X ⁸ , -CN, -C(0)CH ₃ , -C(0)-OH, -C(0)H, -C(0)NH ₂ , -OH, unsubstituted Ci-C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0251] In embodiments, R ⁸ is independently hydrogen. In embodiments, R ⁸ is

independently -CF ₃ . In embodiments, R ⁸ is independently -CHF ₂ . In embodiments, R ⁸ is independently -CH ₂ F. In embodiments, R ⁸ is independently -C(0)CH3. In embodiments, R ⁸ is independently -C(0)NH ₂ . In embodiments, R ⁸ is independently -OH. In embodiments, R ⁸ is independently C1-C4 alkyl. In embodiments, R ⁸ is independently methyl. In embodiments, R ⁸ is independently ethyl. In embodiments, R ⁸ is independently propyl. In embodiments, R ⁸ is independently butyl.

[0252] In embodiments, R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -SO„ _X R ^xd , -SO _V8 NR ^8A R ^8B , -NHC(0)NR ^8A R ^8B ,

-N(0)m8, -NR ^8A R ^8B , -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , -NR ^8A S0 ₂ R ^8D , -NR ^8A C(0)R ^8C , -NR ^8A C(0)0R ^8C , -NR ^8A OR ^8C , R ²⁴ -substituted or unsubstituted alkyl, R ²⁴ -substituted or

unsubstituted heteroalkyl, R ²⁴ -substituted or unsubstituted cycloalkyl, R ²⁴ -substituted or

unsubstituted heterocycloalkyl, R ²⁴ -substituted or unsubstituted aryl, or R ²⁴ -substituted or unsubstituted heteroaryl. In embodiments, R ⁸ is independently hydrogen,

halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -

NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ⁸ ₃ , -OCH ₂ X ⁸ , -OCHX ⁸ ₂ , R ²⁴ - substituted or unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁴ -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), R ²⁴ -substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCX ⁸ ₃ , -OCH2X ⁸ , -OCHX ⁸ ₂ , unsubstituted alkyl (e g., Ci-Cg alkyl, Ci-C ₆ 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., Ce-Cio 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). X ⁸ is - F, -Cl, -Br, or -I. In embodiments, R ⁸ is independently hydrogen. In embodiments, R ⁸ is independently methyl. In embodiments, R ⁸ is independently ethyl.

[0253] R ²⁴ is independently oxo, halogen, -CX ²⁴ ₃ , -CHX ²⁴ 2, -

CH2X ²⁴ , -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH ₂ , -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX ²⁴ 3, -OCHX ²⁴ ₂ , -OCH ₂ X ²⁴ , R ²⁵ -substituted or unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C ₁ -C ₄ alkyl), R ²⁵ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁵ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁵ - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁵ -substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or R ²⁵ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ²⁴ is independently oxo, halogen, -CX ²⁴ 3, -CHX ²⁴ ₂ , -

CH2X ²⁴ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX ²⁴ ₃ , -OCHX ²⁴ 2, -OCH2X ²⁴ , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, C i-Cr, alkyl, or Ci- 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), R unsubstituted aryl (e.g., Ce-Cio 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). X ²⁴ is - F, -Cl, -Br, or -I.

[0254] R ²⁵ is independently oxo, halogen, -CX ²⁵ ₃ , -CHX ²⁵ ₂ , -

CH ₂ X ²⁵ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX ²⁵ 3, -OCHX ²⁵ ₂ , -OCH ₂ X ²⁵ , unsubstituted alkyl (e.g., Ci-Cx alkyl, C i-Ce alkyl, or Ci- C ₄ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ²⁵ is - F, -Cl, -Br, or -I.

[0255] In embodiments, X ¹ is independently -F. In embodiments, X ¹ is independently -Cl. In embodiments, X ¹ is independently -Br. In embodiments, X ¹ is independently -I.

[0256] In embodiments, X ² is independently -F. In embodiments, X ² is independently -Cl. In embodiments, X ² is independently -Br. In embodiments, X ² is independently -I.

[0257] In embodiments, X ⁸ is independently -F. In embodiments, X ⁸ is independently -Cl. In embodiments, X ⁸ is independently -Br. In embodiments, X ⁸ is independently -I.

[0258] In embodiments, R ^1A , R ^1B , R ^1C , R ^1D , R ^3A , R ^3B , R ^3C , R ^3D R ^8A , R ^8B , R ^8C , and R ^8D are independently hydrogen, -CX3, -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0259] In embodiments, R ^1A is independently

hydrogen, -CX3, -CHX2, -CFFX, -CN, -C(0)0H, -C(0)NH ₂ , R ²⁰ -substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ alkyl _, or C1-C4 alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁰ - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁰ - substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^1A is independently

hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH2, unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-C ₆ 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., Ce-Cio 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). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^1A is independently unsubstituted methyl. In embodiments, R ^1A is independently unsubstituted ethyl. In embodiments, R ^1A is independently unsubstituted propyl. In embodiments, R ^1A is independently unsubstituted isopropyl. In embodiments, R ^1A is independently unsubstituted tert-butyl.

[0260] In embodiments, R ^1B is independently

hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁰ -substituted or unsubstituted alkyl (e.g. C1-C8 alkyl, Ci-C ₆ alkyl _, or C1-C4 alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁰ - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁰ - substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^1B is independently hydrogen, -CX3, -CHX2, -CFFX, -CN, -C(0)0H, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ 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., Ce-Cio 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). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^1B is independently unsubstituted methyl. In embodiments, R ^1B is independently unsubstituted ethyl. In embodiments, R ^1B is independently unsubstituted propyl. In embodiments, R ^1B is independently unsubstituted isopropyl. In embodiments, R ^1B is independently unsubstituted tert-butyl.

[0261] In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form an R ²⁰ -substituted or unsubstituted heterocycloalkyl or R ²⁰ -substituted or unsubstituted heteroaryl.

[0262] In embodiments, R ^1C is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁰ -substituted or unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁰ - substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁰ - substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^1C is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-C io aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^1C is independently unsubstituted methyl. In embodiments, R ^1C is independently unsubstituted ethyl. In embodiments, R ^1C is independently unsubstituted propyl. In embodiments, R ^1C is independently unsubstituted isopropyl. In embodiments, R ^1C is independently unsubstituted tert-butyl.

[0263] In embodiments, R ^1D is independently

hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH2, R ²⁰ -substituted or unsubstituted alkyl (e.g. Ci-C _x alkyl, Ci-Cr, alkyl _, or C1-C4 alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁰ - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁰ - substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^1D is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^1D is independently unsubstituted methyl. In embodiments, R ^1D is independently unsubstituted ethyl. In embodiments, R ^1D is independently unsubstituted propyl. In embodiments, R ^1D is independently unsubstituted isopropyl. In embodiments, R ^1D is independently unsubstituted tert-butyl.

[0264] In embodiments, R ^3A is independently

hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl (e.g. C1-C8 alkyl, Ci-Cr, alkyl _. or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., Ce- C ₁₀ aryl, C ₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^3A is independently hydrogen, -CX ₃ , -CHX ₂ , -CkbX, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C ₁ -C ₄ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio 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). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^3A is independently unsubstituted methyl. In embodiments, R ^3A is independently unsubstituted ethyl. In embodiments, R ^3A is independently unsubstituted propyl. In embodiments, R ^3A is independently unsubstituted isopropyl. In embodiments, R ^3A is independently unsubstituted tert-butyl.

[0265] In embodiments, R ^3B is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C ₁ -C ₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., Ce- C ₁₀ aryl, C ₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^3B is independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Ce alkyl or C ₁ -C ₄ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^3B is independently unsubstituted methyl. In embodiments, R ^3B is independently unsubstituted ethyl. In embodiments, R ^3B is independently unsubstituted propyl. In embodiments, R ^3B is independently unsubstituted isopropyl. In embodiments, R ^3B is independently unsubstituted tert-butyl.

[0266] In embodiments, R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0267] In embodiments, R ^3C is independently

hydrogen, -CX3, -CHX2, -CFFX, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., Ce- C10 aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^3C is independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, 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., C ₃ -C ₈ 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., Ce-Cio 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). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^3C is independently unsubstituted methyl. In embodiments, R ^3C is independently unsubstituted ethyl. In embodiments, R ^3C is independently unsubstituted propyl. In embodiments, R ^3C is independently unsubstituted isopropyl. In embodiments, R ^3C is independently unsubstituted tert-butyl. [0268] In embodiments, R ^3D is independently

hydrogen, -CX3, -CHX2, -CFFX, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., Ce- C10 aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^3D is independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH2, unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-Cr, 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., Ce-Cio 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). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^3D is independently unsubstituted methyl. In embodiments, R ^3D is independently unsubstituted ethyl. In embodiments, R ^3D is independently unsubstituted propyl. In embodiments, R ^3D is independently unsubstituted isopropyl. In embodiments, R ^3D is independently unsubstituted tert-butyl.

[0269] In embodiments, R ^3A is independently

hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-Cr, alkyl _. or C1-C4 alkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), or substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^3A is independently hydrogen, -CX3, -CHX2, -CFbX, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, 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., Ce-Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^3A is independently unsubstituted methyl. In embodiments, R ^3A is independently unsubstituted ethyl. In embodiments, R ^3A is independently unsubstituted propyl. In embodiments, R ^3A is independently unsubstituted isopropyl. In embodiments, R ^3A is independently unsubstituted tert-butyl.

[0270] In embodiments, R ^3B is independently

hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH2, substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-Cr, alkyl _. or C1-C4 alkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), or substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^3B is independently hydrogen, -CX3, -CHX2, -CFFX, -CN, -C(0)0H, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, 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., Ce-Cio 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). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^3B is independently unsubstituted methyl. In embodiments, R ^3B is independently unsubstituted ethyl. In embodiments, R ^3B is independently unsubstituted propyl. In embodiments, R ^3B is independently unsubstituted isopropyl. In embodiments, R ^3B is independently unsubstituted tert- butyl.

[0271] In embodiments, R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0272] In embodiments, R ^3C is independently

hydrogen, -CX3, -CHX ₂ , -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-Cr, alkyl _. or C1-C4 alkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), or substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In

embodiments, R ^3C is independently hydrogen, -CX ₃ , -CHX ₂ , -CFFX, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C ₁ -C ₄ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^3C is independently unsubstituted methyl. In embodiments, R ^3C is independently unsubstituted ethyl. In embodiments, R ^3C is independently unsubstituted propyl. In embodiments, R ^3C is independently unsubstituted isopropyl. In embodiments, R ^3C is independently unsubstituted tert- butyl.

[0273] In embodiments, R ^3D is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C ₁ -C ₄ alkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), or substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In

embodiments, R ^3D is independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C ₁ -C ₄ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^3D is independently unsubstituted methyl. In embodiments, R ^3D is independently unsubstituted ethyl. In embodiments, R ^3D is independently unsubstituted propyl. In embodiments, R ^3D is independently unsubstituted isopropyl. In embodiments, R ^3D is independently unsubstituted tert- butyl.

[0274] In embodiments, R ^8A is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁴ -substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _, or C1-C4 alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁴ - substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁴ - substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8A is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ 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, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8A is independently unsubstituted methyl. In embodiments, R ^8A is independently unsubstituted ethyl. In embodiments, R ^8A is independently unsubstituted propyl. In embodiments, R ^8A is independently unsubstituted isopropyl. In embodiments, R ^8A is independently unsubstituted tert-butyl. X is independently -F, -Cl, -Br, or -I.

[0275] In embodiments, R ^8B is independently

hydrogen, -CX ₃ , -CHX ₂ , -CFFX, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁴ -substituted or unsubstituted alkyl (e.g. C1-C8 alkyl, C i-Cr, alkyl _, or C1-C4 alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁴ - substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁴ - substituted or unsubstituted aryl (e.g., Ce-C io aryl, C ₁₀ aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8B is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ 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, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-C io aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8B is independently unsubstituted methyl. In embodiments, R ^8B is independently unsubstituted ethyl. In embodiments, R ^8B is independently unsubstituted propyl. In embodiments, R ^8B is independently unsubstituted isopropyl. In embodiments, R ^8B is independently unsubstituted tert-butyl. X is independently -F, -Cl, -Br, or -I.

[0276] In embodiments, R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form an R ²⁴ -substituted or unsubstituted heterocycloalkyl or R ²⁴ -substituted or unsubstituted heteroaryl.

[0277] In embodiments, R ^8C is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁴ -substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ alkyl _, or C1-C4 alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁴ - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁴ - substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8C is independently

hydrogen, -CX3, -CHX2, -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-C ₆ 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., Ce-Cio 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). In embodiments, R ^8C is independently unsubstituted methyl. In embodiments, R ^8C is independently unsubstituted ethyl. In embodiments, R ^8C is independently unsubstituted propyl. In embodiments, R ^8C is independently unsubstituted isopropyl. In embodiments, R ^8C is independently unsubstituted tert-butyl. X is independently -F, -Cl, -Br, or -I.

[0278] In embodiments, R ^8D is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁴ -substituted or unsubstituted alkyl (e.g. C ₁ -C ₈ alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁴ - substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁴ - substituted or unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8D is independently

hydrogen, -CX3, -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cs alkyl,

Ci-C ₆ 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, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8D is independently unsubstituted methyl. In embodiments, R ^8D is independently unsubstituted ethyl. In embodiments, R ^8D is independently unsubstituted propyl. In embodiments, R ^8D is independently unsubstituted isopropyl. In embodiments, R ^8D is independently unsubstituted tert-butyl. X is independently -F, -Cl, -Br, or -I.

[0279] In embodiments, R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , - CH ₂ X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C ₁ -C ₄ alkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-C io aryl, C ₁₀ aryl, or phenyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety. In embodiments, R ² is

independently hydrogen, -CX ² 3, -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl or C ₁ -C ₄ 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ 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., Ce-Cio aryl, Cio aryl, or phenyl), unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0280] In embodiments, R ³ is independently hydrogen, -Cl, -Br, -

I, -CN, -SO _n3 R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , - C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _, or C1-C4 alkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ³ is independently hydrogen, -Cl, -Br, - I, -CN, -SO _n3 R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , - C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, 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., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ 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., Ce-Cio aryl, Cio aryl, or phenyl), unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0281] In embodiments, R ^a is hydrogen, halogen, -CCh, -CBr ₃ , -CF ₃ , -CI ₃ ,

CHCh, -CHBr ₂ , -CHF2, -CHI ₂ , -

CH ₂ Cl, -CH ₂ Br, -CH ₂ F, -CH ₂ I, -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -SO3H, - S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC=

(O)H, -NHC(O)-

OH, -NHOH, -OCCh, -OCF3, -OCBr ₃ , -OCl3,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , -OCH ₂ Cl, -OC H ₂ Br, -OCH ₂ I, -OCH ₂ F, -N3, substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ alkyl), substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-C io aryl, C ₁₀ aryl, or phenyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety. In embodiments, R ^a is hydrogen, halogen, -CCb, -CBr ₃ , -CF3, -CI3, CHCh, -CHBr ₂ , -CHF ₂ , -CHI ₂ , - CH ₂ Cl, -CH ₂ Br, -CH ₂ F, -CH ₂ I, -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -SO3H, - S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHSO2H, -NHC=

(O)H, -NHC(O)-

OH, -NHOH, -OCCh, -OCF3, -OCBr ₃ , -OCh,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , -OCH ₂ Cl, -OC H ₂ Br, -OCH ₂ I, -OCH ₂ F, -N3, unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-Cr, 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., Ce-Cio aryl, Cio aryl, or phenyl), unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety.

[0282] In embodiments, L is substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkylene (e.g. Ci- C ₈ alkylene, C i-Ce alkylene _. or C1-C4 alkylene) or substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkyl ene, 2 to 6 membered heteroalkyl ene, or 2 to 4 membered heteroalkylene). In embodiments, L is unsubstituted alkylene (e.g. Ci-C ₈ alkylene, Ci-Cr, alkylene _, or C1-C4 alkylene) or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L is -CH2-. In embodiments, L is =CH-. In embodiments, L is =CR ^c -0-. R ^c is substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl _. or C1-C4 alkyl). In embodiments, R ^c is

unsubstituted alkyl. In embodiments, R ^c is unsubstituted C1-C4 alkyl.

[0283] In embodiments Ring A is a substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), or substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments Ring A is unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -Ce 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., Ce-Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0284] In embodiment, the nucleophilic agent is a -CCh, -CBn, -CF3, -CI3,

CHCh, -CHBr ₂ , -CHF2, -CHI ₂ , -

CH ₂ Cl, -CH ₂ Br, -CH ₂ F, -CH ₂ I, -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, - NHC(O)-

OH, -NHOH, -OCCI3, -OCF3, -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , -OCH ₂ Cl, -OC H ₂ Br, -OCH ₂ I, -OCH ₂ F, -N3, substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ alkyl _, or C1-C4 alkyl), substituted (e.g., substituted with one or more substituent groups, size- limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-C io aryl, Cio aryl, or phenyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety. In embodiment, the nucleophilic agent is a -CCI3, -CBR, -CF3, -CI3, CHCh, -CHBr ₂ , -CHF ₂ , -CHI ₂ , - CH ₂ Cl, -CH ₂ Br, -CH ₂ F, -CH ₂ I, -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHSOzH, -NHC= (0)H, - NHC(O)-

OH, -NHOH, -OCCI ₃ , -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , -OCH ₂ Cl, -OC H ₂ Br, -OCH ₂ I, -OCH ₂ F, -N ₃ , unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, alkyl or C ₁ -C ₄ 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., Ce-Cio aryl, C10 aryl, or phenyl), unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety.

[0285] In embodiments, the covalently attached substituent is a -CCb, -CBn, -CF3, -CI3,

CHCh, -CHBr ₂ , -CHF ₂ , -CHI ₂ , -

CH ₂ Cl, -CH ₂ Br, -CH ₂ F, -CH ₂ I, -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, - NHC(O)-

OH, -NHOH, -OCCh, -OCF3, -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , -OCH ₂ Cl, -OC H ₂ Br, -OCH ₂ I, or -OCH ₂ F, -N3, substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted alkyl (e.g. Ci-Cx alkyl, C 1 -Ce alkyl _, or C ₁ -C ₄ alkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted aryl (e.g., Ce-C io aryl, C ₁₀ aryl, or phenyl), substituted (e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety. In embodiments, the covalently attached substituent is a -CCI3, -CBR, -CF3, -CI3,

CHCh, -CHBr ₂ , -CHF ₂ , -CHI ₂ , - SO2NH2, -NHNH2, -0NH2, -NHC=(0)NHNH ₂ , -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, - NHC(O)-

OH, -NHOH, -OCCh, -OCF3, -OCBr ₃ , -OCl3,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , -OCH2CI, -OC FbBr, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-Cr, 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., Ce-Cio aryl, C10 aryl, or phenyl), unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety.

[0286] In embodiments, X is -F. In embodiments, X is -Cl. In embodiments, X is -Br. In embodiments, X is -I.

[0287] In embodiments, z2 is an integer from 0 to 18. In embodiments, z2 is an integer from 0 to 12. In embodiments, z2 is an integer from 0 to 8. In embodiments, z2 is an integer from 1 to 4. In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. In embodiments, z2 is 6.

[0288] In embodiments, R ² is substituted or unsubstituted alkyl, CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts. In embodiments, R ² is substituted or unsubstituted alkyl. In embodiments, R ² is CBz. In embodiments, R ² is BOC. In embodiments, R ² is Ac. In embodiments, R ² is Bz. In embodiments, R ² is Bn. In embodiments, R ² is PMB. In embodiments, R ² is PIV. In embodiments, R ² is Ts. In embodiments, R ² is substituted or unsubstituted Ci-C ₈ alky. In embodiments, R ² is substituted or unsubstituted Ci-C ₆ alkyl. In embodiments, R ² is substituted or unsubstituted Ci-C ₄ alky. In embodiments, R ² is independently unsubstituted methyl. In

embodiments, R ² is independently unsubstituted ethyl. In embodiments, R ² is independently unsubstituted propyl. In embodiments, R ² is independently unsubstituted isopropyl. In

embodiments, R ² is independently unsubstituted tert-butyl.

[0289] In embodiments, R ² is an amino acid moiety, a polypeptide moiety, or a protein moiety. [0290] In embodiments, R ⁴ is hydrogen or -C(0)H. In embodiments, R ⁴ is hydrogen. In embodiments, R ⁴ is -C(0)H.

[0291] In embodiments, R ⁵ is independently -I^-R ¹ , wherein each R ⁵ is optionally different. In embodiments, R ⁵ is independently -I^-R ¹ . In embodiments, R ⁵ is independently -L'-R ¹ , wherein -R ¹ is hydrogen. In embodiments, R ⁵ is independently -L^R ¹ , wherein -L ¹ is a bond and -R ¹ is hydrogen.

[0292] In embodiments, R ⁶ is independently -I^-R ¹ , wherein each R ⁶ is optionally different. In embodiments, R ⁶ is independently -I^-R ¹ . In embodiments, R ⁶ is independently -L'-R ¹ , wherein -R ¹ is hydrogen. In embodiments, R ⁶ is independently -L^R ¹ , wherein -L ¹ is a bond and -R ¹ is hydrogen.

[0293] In embodiments, the nucleophilic agent includes

a -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, -NHC(O)-

OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety.

[0294] In embodiments, the covalently attached substituent is

a -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, -NHC(O)-

OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety.

[0295] In embodiments, R ^a is hydrogen, -CF ₃ , -CN, -OH, -NH _¾ -COOH, -CONH ₂ , -N0 ₂ , -SH, - S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety.

[0296] In embodiments, R ¹ is independently hydrogen, -CX ¹ -,, -CHXN, -CH2X ¹ , -OCX ¹ -,, - OCH2X ¹ , -OCHX^,

oxo,

c, -C

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or

unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0297] In embodiments, the saturated cyclic amine is part of a substituted or unsubstituted amino acid. In embodiments, the saturated cyclic amine is part of a substituted or unsubstituted peptide. In embodiments, the saturated cyclic amine is part of a substituted or unsubstituted polypeptide. In embodiments, the saturated cyclic amine is part of a substituted or unsubstituted protein. In embodiments, the saturated cyclic amine is part of a substituted or unsubstituted nucleic acid. In embodiments, the saturated cyclic amine is part of a bioconjugate. In embodiments, the saturated cyclic amine is part of a lipid.

[0298] In embodiments, the saturated cyclic amine is part of a polypeptide. In embodiments, the saturated cyclic amine is part of a peptide containing 2 to 20 amino acids. In embodiments, the saturated cyclic amine is part of a peptide containing 2 to 10 amino acids. In embodiments, the saturated cyclic amine is part of a peptide containing 2 to 5 amino acids. In embodiments, the saturated cyclic amine is part of a peptide containing 2 to 3 amino acids. In embodiments, the saturated cyclic amine is part of a pentapeptide. In embodiments, the saturated cyclic amine is part of a tetrapeptide. In embodiments, the saturated cyclic amine is part of a tripeptide. In

embodiments, the saturated cyclic amine is part of a dipeptide. In embodiments, at least one of the amino acids of the peptide is proline. In embodiments, at least one of the amino acids of the peptide is pipecolic acid. In embodiments, at least one of the amino acids of the peptide is alanine. In embodiments, at least one of the amino acids of the peptide is valine.

[0299] In embodiments, the metal source is a silver source. In embodiments, the metal source is a silver(I) source. In embodiments, the metal source is a silver (II) source. In embodiments, the metal source is a copper source. In embodiments, the metal source is a copper(II) source. In

embodiments, the metal source is an iron source. In embodiments, the metal source is an iron(I) source. In embodiments, the metal source is an iron(III) source. In embodiments, the metal source is a manganese source. In embodiments, the metal source is a manganese(II) source. In

embodiments, the metal source is a manganese(III) source.

[0300] In embodiments, the metal source is silver(I) tetrafluoroborate (AgBF ₄ ), silver(I) nitrate (AgNO,), silver(II) fluoride (AgF ₂ ), silver(I) fluoride (AgF), silver trifluoromethanesulfonate (AgOTf), silver bis(trifluoromethanesulfonyl)imide (AgNTf ₂ ), silver carbonate (Ag ₂ CO,), silver(I) oxide (Ag ₂ 0), silver(I) acetate (AgOAc), silver(I) sulfate (Ag ₂ S0 ₄ ), silver methanesulfonate (AgOMs), silver hexafluoroantimonate(V) (AgSbFe), silver / oluenesulfonate (AgOTs), silver(I) trifluoromethanethiolate (AgSCF-,), or silver(I) bromide (AgBr). In embodiments, the metal source is silver(I) tetrafluoroborate (AgBF ₄ ). In embodiments, the metal source is copper(II) sulfate (CuS0 ₄ ). In embodiments, the metal source is iron(III) chloride (FeCl·,). In embodiments, the metal source is iron(I) nitrate (FeNCb). In embodiments, the metal source is manganese(II) chloride (MnCl ₂ ). In embodiments, the metal source is manganese(III) acetate (Mh(OA ). In

embodiments, the metal source is manganese(M) acetylacetonate (Mn(acac) ₃ ). In embodiments, the metal source is manganese(III) 2-pyridinecarboxylate (Mn(pic) ₃ ).

[0301] In embodiments, an excess (e.g. a greater amount than necessary to react completely with the limiting reactant) of the metal source is used in the reaction. In embodiments, 1.1 to 10 equivalents (e.g. as compared to the amount of the limiting reactant, wherein the limiting reactant may be the cyclic amine) of the metal source are used in the reaction. In embodiments, 2 to 8 equivalents of the metal source are used in the reaction. In embodiments, 3 to 5 equivalents of the metal source are used in the reaction. In embodiments, 4 equivalents of the metal source are used in the reaction. In embodiments, sub-stoichiometric amounts of the metal source are used in the reaction. In embodiments, 0.1 to 0.9 equivalents of the metal source are used in the reaction. In embodiments, 0.4 to 0.6 equivalents of the metal source are used in the reaction. In embodiments, 0 equivalents of the metal source are used in the reaction. In embodiments, an excess of the silver source is used in the reaction. In embodiments, 1.1 to 10 equivalents of the silver source are used in the reaction. In embodiments, 2 to 8 equivalents of the silver source are used in the reaction. In embodiments, 3 to 5 equivalents of the silver source are used in the reaction. In embodiments, 4 equivalents of the silver source are used in the reaction. In embodiments, sub-stoichiometric amounts of the silver source are used in the reaction. In embodiments, 0.1 to 0.9 equivalents of the silver source are used in the reaction. In embodiments, 0.4 to 0.6 equivalents of the silver source are used in the reaction. In embodiments, an excess of AgBF ₄ is used in the reaction. In embodiments, 1.1 to 10 equivalents of AgBF ₄ are used in the reaction. In embodiments, 2 to 8 equivalents of AgBF ₄ are used in the reaction. In embodiments, 3 to 5 equivalents of AgBF ₄ are used in the reaction. In embodiments, 4 equivalents of AgBF ₄ are used in the reaction. In embodiments, sub- stoichiometric amounts of AgBF ₄ are used in the reaction. In embodiments, 0.1 to 0.9 equivalents of AgBF ₄ are used in the reaction. In embodiments, 0.4 to 0.6 equivalents of AgBF ₄ are used in the reaction. In embodiments, an excess of AgNO, is used in the reaction. In embodiments, 1.1 to 10 equivalents of AgNO-, are used in the reaction. In embodiments, 2 to 8 equivalents of AgNO-, are used in the reaction. In embodiments, 3 to 5 equivalents of AgNO-, are used in the reaction. In embodiments, 4 equivalents of AgNO-, are used in the reaction. In embodiments, at least 0.1 equivalents of the silver source are used in the reaction. In embodiments, at least 0.5 equivalents of the silver source are used in the reaction.

[0302] In embodiments, the halogenating agent is a nucleophilic halogenating agent or an electrophilic halogenating agent. In embodiments, the halogenating agent is a brominating agent. In embodiments, the brominating agent is A'-bromosuccinimide (NBS), dibromoisocyanuric acid (DBI), bromine, bromotrichloromethane, l,2-dibromo-l,l,2,2-tetrachloroethane, carbon

tetrabromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide,

benzyltrimethylammonium tribromide, pyridinium bromide perbromide, 4- dimethylaminopyridinium bromide perbromide, 1 -butyl-3 -methybmidazobum tribromide, 1,8- diazabicyclo[5.4.0]-7-undecene, hydrogen tribromide, L'-bromophthalimide, A'-bromosaccharin, N- bromoacetamide, 2-bromo-2-cyano-A',A'-dimethylacetamide, 1 ,3-dibromo-5,5-dimethylhydantoin, monosodium bromoisocyanurate hydrate, boron tribromide, phosphorus tribromide,

bromodimethylsulfonium bromide, 5,5-dibromomeldrum's acid, 2,4,4,6-tetrabromo-2,5- cyclohexadienone, or bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate. In embodiments, the halogenating agent is a chlorinating agent. In embodiments, the chlorinating agent is A'-chlorosuccinimide (NCS), thionyl chloride, methanesulfonyl chloride,

trichloromethanesulfonyl chloride, /er/-butyl hypochlorite, chloromethyl methyl ether,

dichloromethyl methyl ether, methoxyacetyl chloride, oxalyl chloride, cyanuric chloride, N- chlorophthalimide, sodium dichloroisocyanurate, trichloroisocyanuric acid, chloramine B hydrate, o- chloramine T dihydrate, chloramine T trihydrate, dichloramine B, dichloramine T,

benzyltrimethylammonium, tetrachloroiodate. In embodiments, the halogenating agent is an iodinating agent. In embodiments, the iodinating agent is A'-iodosuccinimide (NIS), l,3-diodo-5,5 - dimethylhidantoin (DIH), iodine, hydriodic acid, diiodomethane, 1 -chloro-2-iodoethane, carbon tetraiodide, tetramethylammonium dichloroiodate, benzyltrimethylammonium dichloroiodate, pyridine iodine monochloride, A',A'-dimethyl-A'-(methylsulfanylmethylene)-ammonium iodide, N- iodosaccharin, trimethyls ilyl iodide, bis(pyridine)iodonium tetrafluoroborate, bis(2,4,6- trimethylpyridine)-iodonium hexafluorophosphate.

[0303] In embodiments, the solvent for the reaction is a mixture of H ₂ 0 and an organic solvent.

In embodiments, the solvent for the reaction is a mixture of H ₂ 0 and acetone, acetonitrile, toluene, ethyl acetate, dimethyl sulfoxide (DMSO), A', A'- d i m e th y 1 fo rm a m i d e (DMF), methanol, ethanol, 2- propanol, dichloromethane, benzene, tetrahydrofuran, 2-methyltetrahydrofuran (2-Me-THF), chloroform, diethylether, or dioxane. In embodiments, the solvent for the reaction is a mixture of H ₂ 0/organic solvent ranging from a 10:1 (v/v) mixture to 1 :l (v/v) mixture. In embodiments, the solvent for the reaction is a mixture of H ₂ 0/organic solvent ranging from a 10:1 (v/v) mixture to 4:1 (v/v) mixture. In embodiments, the solvent for the reaction is a 9:1 (v/v) mixture of H ₂ 0/organic solvent. In embodiments, the solvent for the reaction is a 4:1 (v/v) mixture of H ₂ 0/organic solvent.

In embodiments, the solvent for the reaction is a 7:3 (v/v) mixture of H ₂ 0/organic solvent. In embodiments, the solvent for the reaction is a 3:2 (v/v) mixture of H ₂ 0/organic solvent. In embodiments, the solvent for the reaction is a 1 : 1 (v/v) mixture of H ₂ 0/organic solvent. In embodiments, the solvent for the reaction is a mixture of H ₂ 0 and acetone. In embodiments, the solvent for the reaction is a mixture of H ₂ 0 and acetonitrile. In embodiments, the solvent for the reaction is a mixture of H ₂ 0 and dichloromethane. In embodiments, the solvent for the reaction is a 9:1 (v/v) mixture of H ₂ 0/acetone. In embodiments, the solvent for the reaction is a 4:1 (v/v) mixture of H ₂ 0/acetone. In embodiments, the solvent for the reaction is a 7:3 (v/v) mixture of H ₂ 0/acetone.

In embodiments, the solvent for the reaction is a 3:2 (v/v) mixture of H ₂ 0/acetone. In embodiments, the solvent for the reaction is a 1 : 1 (v/v) mixture of H ₂ 0/acetone. In embodiments, the solvent for the reaction is a 9:1 (v/v) mixture of H ₂ 0/acetonitrile. In embodiments, the solvent for the reaction is H ₂ 0. In embodiments, the solvent for the reaction is acetone. In embodiments, the solvent for the reaction is acetonitrile. In embodiments, the solvent for the reaction includes at least 10% (v/v) of H ₂ 0. In embodiments, the solvent for the reaction includes at least 50% (v/v) of H ₂ 0.

[0304] In embodiments, the aqueous solution includes from 1:1 to 1:100 organic solvent (e.g., acetone): H ₂ 0 (e.g., 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33,

1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50,

1:51, 1:52, 1:53, 1:54, 1:55, 1:56, 1:57, 1:58, 1:59, 1:60, 1:61, 1:62, 1:63, 1:64, 1:65, 1:66, 1:67,

1:68, 1:69, 1:70, 1:71, 1:72, 1:73, 1:74, 1:75, 1:76, 1:77, 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84,

1:85, 1:86, 1:87, 1:88, 1:89, 1:90, 1:91, 1:92, 1:93, 1:94, 1:95, 1:96, 1:97, 1:98, 1:99, or 1:100 organic solvent vol:H ₂ 0 vol).

[0305] In embodiments, the temperature for the reaction ranges from 15 °C to 80°C. In embodiments, the temperature for the reaction ranges from room temperature to 80°C. In embodiments, the temperature for the reaction ranges from room temperature to 60°C. In embodiments, the temperature for the reaction ranges from room temperature to 40°C. In embodiments, the temperature for the reaction ranges from 15°C to 30°C. In embodiments, the temperature for the reaction ranges from room temperature to 30°C. In embodiments, the temperature for the reaction ranges from 20°C to 25°C. In embodiments, the temperature for the reaction is room temperature.

[0306] In embodiments, the yield for the reaction ranges from 0 to 100%. In embodiments, the yield for the reaction ranges from 1 to 100%. In embodiments, the yield for the reaction ranges from 20 to 100%. In embodiments, the yield for the reaction ranges from 40 to 95%. In embodiments, the yield for the reaction ranges from 60 to 90%. In embodiments, the yield for the reaction ranges from 50 to 85%. In embodiments, the yield for the reaction is 80 to 90%. In embodiments, the yield for the reaction ranges from 1 to 10%. In embodiments, the yield for the reaction ranges from 10 to 20%. In embodiments, the yield for the reaction ranges from 20 to 30%. In embodiments, the yield for the reaction ranges from 30 to 40%. In embodiments, the yield for the reaction ranges from 40 to 50%. In embodiments, the yield for the reaction ranges from 50 to 60%. In embodiments, the yield for the reaction ranges from 60 to 70%. In embodiments, the yield for the reaction ranges from 70 to 80%. In embodiments, the yield for the reaction ranges from 80 to 90%. In embodiments, the yield for the reaction ranges from 90 to 100%.

[0307] In embodiments, the method is a method as described herein, including embodiments. In embodiments the method is a method described herein (e.g., in the example section).

IP. Compounds

[0308] In an aspect is provided a compound having the formula:

independently -Cl, -Br, or -I. L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R ⁸ is independently

hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX , -CHX' ₂ , -CH ₂ X', -OCX's, - OCIBX ¹ , -OCHX^,

oxo, -CN, -SOniR ^1D , -SOviNR ^1A R ^1B , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-OR ^{1 c} , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety. Two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl. Two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R ² is independently hydrogen, -CX ² ₃ , -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety. R ³ is independently hydrogen, -Cl, -Br, -

I, -CN, -SO _n3 R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , - C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently - F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4. ml, m3, vl, and v3 are independently 1 or 2. z2 is an integer from 0 to 18. R ⁴ is hydrogen or -C(0)H. R ⁶ is independently - I^-R ¹ , wherein each R ⁶ is optionally different.

[0309] In embodiments the compound has the structure of formula (Pz): wherein R ² , R ³ , R ⁴ , X ^a , and z2 are as described herein, including in embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} _, andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0310] In an aspect is provided a compound having the formula:

independently -Cl, -Br, or -I. L ¹ is independently a -C(O)- or -C(0)0-. R ¹ is independently

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety. R ² is independently hydrogen, -CX ² ₃ , -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety. X ¹ and X ² are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , and R ^1D are independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. nl is independently an integer from 0 to 4. ml and vl are independently 1 or 2. R ⁴ is hydrogen or -C(0)H. R ⁶ is independently -I^-R ¹ .

[0311] In embodiments, X ^a is independently -Cl, -Br, or -I; L ¹ is independently

a -C(O)- or -C(0)0-; R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and R ² is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0312] In embodiments, X ^a is independently -Cl, -Br, or -I.

[0313] In embodiments, L ¹ is independently a -C(O)- or -C(0)0-. [0314] In embodiments, R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0315] In embodiments, R ² is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0316] In an aspect is provided a compound having the formula:

halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -COMB, -N0 ₂ , -SH, -S0 ₂ Cl, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ ,

-NHNH2, -0NH2, -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, -NHC(O)-

OH, -NHOH, -OCF3, -OCHF ₂ , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety. L ¹ is

independently a bond, -S(0) ₂ -,-S(0)-, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-,

-NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -0C(0)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or

unsubstituted heteroarylene. R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX , -CHX' ₂ , -CH ₂ X', -OCX ¹ ,, - , -CN, -SO _ni R ^1D , -SO _vi NR ^1A R ^1B , -NHC(0)NR ^1A R ^1B , -N(0) _mi ,

(0)-0R ^1c , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C( 3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. R ² is independently

hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety. R ³ is independently hydrogen, -Cl, -Br, -I, -CN, -SO _n 3R ^3D , -SO _V 3NR ^3A R ^3B ,

-NHC(0)NR ^3A R ^3B , -N(0)m3, -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-0R ^3C , -C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A SO ₂ R 3D, -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently hydrogen, -CX3, -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. nl and n3 are independently an integer from 0 to 4. ml , m3, vl , and v3 are independently 1 or 2. z2 is an integer from 0 to 18. R ⁴ is hydrogen or -C(0)H. L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. R ⁶ is independently -L^R ¹ , wherein each R ⁶ is optionally different; or a compound having the formula:

) wherein one R ⁶ is combined with the carbon adjacent to R ³ in formula He to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R ⁶ is independently -L^R ¹ , wherein each R ⁶ is optionally different.

[0317] In embodiments, the compound has the formula:

, , , , , , , L are described herein, including embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} _, andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments ofR ⁶ ).

[0318] In embodiments, a compound having the formula: wherein one

R ^{6 1} , J^ ⁶ 2 p^ ^6. ^ _anc j R ^6.4 j _{s com} bined with the carbon adjacent to R ³ in formula IIcz to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ² , R ³ , R ⁴ , and z2 are as described herein, including embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} , andR ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ). [0319] In embodiments, a compound having the formula: wherein R ^{6 3} or R ^{6 4} are combined with the carbon adjacent to R ³ in formula IIcz to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ² , R ³ , R ⁴ , and z2 are as described herein, including embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} , andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0320] In an aspect is provide a compound having the formula: (lid). R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, -SO4H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, - NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety. L ¹ is independently a -C(O)- or -C(0)0-; R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHX' ₂ , - CH ₂ X\ -OCX^, -OCH2X ¹ , -OCHX^,

oxo, -CN, -SOniR ^1D , -SOviNR ^1A R ^1B , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -CCOj-OR ^{1 c} , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety. R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety. X ¹ and X ² are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , and R ^1D are independently hydrogen, -CX3, -CHX ₂ , -CFFX, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or

unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. nl is independently an integer from 0 to 4. ml and vl are independently 1 or 2. R ⁴ is hydrogen or -C(0)H. R ⁶ is

independently -L^R ¹ .

[0321] In embodiments, R ^a is hydrogen,

halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -COMB, -NO2, -SH, -SO2CI, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH ₂ , -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)- OH, -NHOH, -OCF3, -OCHF2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety; L ¹ is

independently a -C(O)- or -C(0)0-; R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and R ² is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0322] In embodiments, the nucleophilic agent includes

a -CF ₃ , -CN, -OH, -MB, -COOH, -COMB, -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHMB, -OMB, -NHC=(0)NHMB, -NHC=(0) MB, -NHSO ₂ H, -NHC= (O)H, -NHC(O)-

OH, -NHOH, -OCF3, -OCHF2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety. [0323] In embodiments, the covalently attached substituent is

a -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, -NHC(O)-

OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety.

[0324] In embodiments, R ^a is hydrogen, -CF ₃ , -CN, -OH, -NH _¾ -COOH, -CONH ₂ , -N0 ₂ , -SH, - S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive group moiety.

[0325] In embodiments, R ¹ is independently hydrogen, -CX' ₃ , -CHX' ₂ , -CFFX ¹ , -OCX's, -

heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0326] In an aspect is provided a compound made by a method as described herein, including embodiments. [0327] In embodiments, the compound has the formula: wherein X ^a ,

R ² , R ³ , R ⁴ , R ⁶ , and z2 are as described herein.

[0328] In embodiments, the compound has the formula: (Pz), wherein X ^a ,

R ² , R ³ , R ⁴ , and z2 are as described herein, including in embodiments. R ⁶ · ¹ , R ^{6 2} , R ^{6 3} _, andR ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0329] In embodiments, the compound has the formula: wherein X ^a , R ² , R ⁴ , and R ⁶ are as described herein.

[0330] In embodiments, the compound has the formula: (lib), wherein R ^a ,

R ² , R ³ , R ⁴ , R ⁶ , and z2 are as described herein. [0331] In embodiments, the compound has the structure of formula (Ilbz):

(Ilbz), wherein R ² , R ³ , R ⁴ , R ^a , and z2 are as described herein, including in embodiments. R ^6·1 , R ^{6 2} , R ^{6 3} _, andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0332] In embodiments, the compound has the formula: wherein R R ³ , R ⁶ , and z2 are as described herein.

[0333] In embodiments, the compound has the structure of formula:

(Mcz), wherein R ² , R ³ , and z2 are as described herein, including embodiments. R ⁶ · ¹ , R ^{6 2} , R6'’.3 _\ and

R ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ). [0334] In embodiments, the compound has the formula: (ind), wherein R R ⁴ , R ⁶ , L, and z2 are as described herein.

are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0336] In embodiments, the compound has the formula: (Ille), wherein R ³ , R ⁶ , L, and z2 are as described herein.

[0337] In embodiments, the compound has the structure of formula: (niez), wherein R ³ , L, and z2 are as described herein, including embodiments. R ⁶ · ¹ , R ^{6 2} , R ^{6 3} _. and R ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ). [0338] In embodiments, the compound has the formula: wherein R ³ ,

R ⁶ , L, and z2 are as described herein.

[0339] In embodiments, the compound has the structure of formula: (Illfz), wherein R ³ , L, and z2 are as described herein, including embodiments. R ⁶² , R ^{6 3} _. andR ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0340] In embodiments, the compound has the formula: (lie), wherein R ² , R ³ ,

R ⁴ , R ⁶ , and z2 are as described herein.

[0341] In embodiments, the compound has the structure of formula:

wherein R ² , R ³ , R ⁴ , and z2 are as described herein, including embodiments. R ⁶ · ¹ , R ^{6 2} , R ^{6 3} , andR ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ). [0342] In embodiments, the compound has the formula: (lid), wherein R ^a , R ² , R ⁴ , and R ⁶ are as described herein.

[0343] In embodiments, the compound has the formula: wherein R ² ,

R ³ , R ⁴ , R ⁶ , z3, and Ring A are as described herein.

[0344] In embodiments, the compound has the structure of formula:

wherein R ² , R ³ , R ⁴ , z3, and Ring A are as described herein, including embodiments. R ^{6· 1} , R ^{6 2} , and

R ^{6 3} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0345] In embodiments, the compound is a compound as described herein, including

embodiments. In embodiments the compound is a compound described herein (e.g., in the example section, in the figures, in the claims, or in the appendix).

IV. Embodiments

[0346] Embodiment Pl . A method of making a haloalkyl amine comprising reacting a saturated cyclic amine with a halogenating agent in the presence of an oxidizing agent and a metal source, wherein the haloalkyl amine comprises a covalently attached halogen, wherein the halogen is -Cl, -Br, or -I. [0347] Embodiment P2. The method of embodiment Pl , wherein said saturated cyclic amine has the structure of formula (I):

and said haloalkyl amine has the structure of formula (II):

wherein,

X ^a is independently -Cl, -Br, or -I;

R ⁵ is independently -L'-R ¹ , wherein each R ⁵ is optionally different;

L ¹ is independently a bond, -S(0) ₂ -,-S(0)- , -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(O)-

, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ 3, -CHX ⁸ ₂ , -CFbX ⁸ , -OCX ⁸ 3, - OCH ₂ X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHXN, -CH2X ¹ , -OCXS, -OCH2X ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-OR ^{1 c} , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

R ² is independently hydrogen, -CX ² 3, -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ³ is independently hydrogen, -Cl, -Br, -

I, -CN, -SO _n3 R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , - C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4; ml, m3, vl, and v3 are independently 1 or 2; z2 is an integer from 0 to 18;

R ⁴ is hydrogen or -C(0)H; and

R ⁶ is independently -L^R ¹ , wherein each R ⁶ is optionally different.

[0348] Embodiment P3. The method of embodiment P2, wherein z2 is an integer from 0 to 8.

[0349] Embodiment P4. The method of one of embodiments P2 or P3, wherein z2 is an integer from 1 to 4.

[0350] Embodiment P5. The method of one of embodiments P2-P4, wherein each R ¹ is independently hydrogen, halogen, -CX , -CHXN, -CH2X ¹ , -OCX ¹ -,, -OCH2X ¹ , -OCHX , oxo, -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^lc , -NR ^1A C(0)OR ^lc , -NR ^1A OR ^1c , -N ₃ , R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ -substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl; and

R ²⁰ is independently oxo, halogen, -CF3, -CHF2, -

CH ₂ F, -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF3, -OCHF2, or -OCH2F. [0351] Embodiment P6. The method of one of embodiments P2-P4, wherein each R ¹ is independently hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCH ₂ F, -OCHF ₂ ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0 )OR ^lc , -N ₃ , or R ²⁰ -substituted or unsubstituted C _3-8 alkyl; and

R ²⁰ is independently oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)OH, -C(0)NH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0352] Embodiment P7. The method of one of embodiments P2-P4, wherein each R ¹ is independently hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCH ₂ F, -OCHF ₂ ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-0R ^1c , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0 )0R ^1C , or unsubstituted C _3-8 alkyl.

[0353] Embodiment P8. The method of one of embodiments P2-P7, wherein each L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, R ²² -substituted or unsubstituted alkylene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroarylene; and

R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)0H, -C(0)NH ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)0H,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0354] Embodiment P9. The method of one of embodiments P2-P7, wherein each L ¹ is independently a

bond, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or R ²² -substituted or unsubstituted alkylene; and

R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)0H, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)0H,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F. [0355] Embodiment P10. The method of one of embodiments P2-P7, wherein each L ¹ is independently a

bond, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-C ₈ alkylene. [0356] Embodiment Pl l . The method of one of embodiments P2-P10, wherein two -LkR ¹ substituents attached to the same carbon atom are independently joined to form a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

[0357] Embodiment P12. The method of one of embodiments P2-P10, wherein two -L'-R ¹ substituents attached to adjacent carbon atoms are independently joined to form a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, a substituted or unsubstituted Ce-C io aryl or a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0358] Embodiment P13. The method of one of embodiments P2-P12, wherein each R ⁸ is hydrogen. [0359] Embodiment Pl 4. The method of one of embodiments P2-P 13, wherein each R ⁴ is hydrogen.

[0360] Embodiment Pl 5. The method of one of embodiments P2-P14, wherein R ² is substituted or unsubstituted alkyl or an amine protecting group chosen from the list comprising: CBz, Moz,

BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts.

[0361] Embodiment Pl 6. A method of embodiment Pl , wherein said saturated cyclic amine has the structure of formula (la):

and said haloalkyl amine has the structure of formula (Ila):

wherein,

X ^a is independently -Cl, -Br, or -I;

R ⁵ is independently -L'-R ¹ ; L ¹ is independently a -C(O)- or -C(0)0-;

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ² is independently hydrogen, -CXS, -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

X ¹ and X ² are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , and R ^1D are independently

hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2;

R ⁴ is hydrogen or -C(0)H; and R ⁶ is independently -I^-R ¹ .

[0362] Embodiment Pl 7. The method of embodiment Pl 6, wherein X ^a is independently -Cl, -Br, or -I;

R ⁵ is independently -L^R ¹ ;

L ¹ is independently a -C(O)- or -C(0)0-;

R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and

R ² is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0363] Embodiment Pl 8. The method of one of embodiments Pl -Pl 7, further comprising reacting the haloalkyl amine with a nucleophilic agent, wherein the nucleophilic agent displaces said covalently attached halogen with a covalently attached substituent, thereby forming a nucleophilic reaction product.

[0364] Embodiment Pl 9. The method of embodiment Pl 8, wherein the nucleophilic agent comprises a -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -COMB, -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, -S0 ₄ H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) B, -NHSO ₂ H, -NHC= (0)H, - MTC(0)-OH, -MTOH, -OCF ₃ , -OCHF ₂ , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety.

[0365] Embodiment P20. The method of embodiment Pl 8, wherein said covalently attached substituent is a -CF ₃ , -CN, -OH, -MB, -COOH, -COMB, -MB, -SH, -S0 ₂ Cl, -SO3H, -SO4H, - S0 ₂ MB, -NHMB, -OMB, -NHC=(0)NHMB, -NHC=(0) MB, -NHSO2H, -NHC= (O)H, - NHC(0)-0H, -NHOH, -OCF3, -OCHF2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety. [0366] Embodiment P21. The method of one of embodiments P2 to P20, wherein X ^a is -Cl.

[0367] Embodiment P22. The compound of one of embodiments P2 to P29, wherein X ^a is -Br.

[0368] Embodiment P23. The method of embodiment Pl 8, wherein the reaction between the haloalkyl amine and the nucleophilic agent is an intramolecular reaction.

[0369] Embodiment P24. The method of embodiment P23, wherein the intramolecular reaction is a cyclization reaction.

[0370] Embodiment P25. The method of embodiment Pl 8 wherein the nucleophilic reaction product has the formula:

wherein,

R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO2, -SH, -SO2CI, -SO3H,

SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -0NH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety;

L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ 3, -CHX ⁸ ₂ , -CkbX ⁸ , -OCX ⁸ 3, - OCH ₂ X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or

unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

R ² is independently hydrogen, -CX ² 3, -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety; R ³ is independently hydrogen, -Cl, -Br, -

I, -CN, -SO _n3 R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-0R ^3C , - C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4; ml, m3, vl, and v3 are independently 1 or 2; z2 is an integer from 0 to 18;

R ⁴ is hydrogen or -C(0)H;

L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; and R ⁶ is independently -I^-R ¹ , wherein each R ⁶ is optionally different; or a compound having the formula :

(lie) wherein one R ⁶ is combined with the carbon adjacent to R ³ in formula lie to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0371] Embodiment P26. The method of embodiments Pl to P25 wherein the halogenating agent is A'-chlorosuccinimide, N- b ro m o s ucci n i m i de , A'-iodosuccinimide, or dibromohydantoin.

[0372] Embodiment P27. The method of embodiments Pl to P26, wherein the method of making the haloalkyl amine is perfomed under mild conditions that do not degrade the starting material .

[0373] Embodiment P28. The method of embodiments Pl to P27, wherein the conditions comprise: an aqueous environment, an aerobic environment and a reaction temperature ranging from 15 to 30 °C.

[0374] Embodiment P29. The method of embodiment P28, wherein the reacting temperature ranges from 20 to 25 °C.

[0375] Embodiment P30. The method of embodiments Pl to P29, wherein the oxidizing agent is ammonium persulfate.

[0376] Embodiment P31. A compound having the formula:

wherein,

X ^a is independently -Cl, -Br, or -I;

L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(O)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ 3, -CHX ⁸ 2, -CH2X ⁸ , -OCX ⁸ 3, - OCH2X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or

unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

R ² is independently hydrogen, -CX ² ₃ , -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety; R ³ is independently hydrogen, -Cl, -Br, -I, -CN, -SO _n3 R ^3D , -SO _V 3NR ^3A R ^3B ,

-NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-0R ^3C , -C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A SO ₂ R ^3D -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX3, -CHX2, -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4; ml, m3, vl, and v3 are independently 1 or 2; z2 is an integer from 0 to 18;

R ⁴ is hydrogen or -C(0)H; and

R ⁶ is independently -I^-R ¹ , wherein each R ⁶ is optionally different.

[0377] Embodiment P32. A compound having the formula:

wherein,

X ^a is independently -Cl, -Br, or -I;

L ¹ is independently a -C(O)- or -C(0)0-; R ¹ is independently hydrogen, halogen, -CX^, -CHX^, -CH2X ¹ , -OCXS, -OCH2X ¹ , -OCHXS, oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0R ^{1 c} , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ² is independently hydrogen, -CXS, -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

X ¹ and X ² are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , and R ^1D are independently

hydrogen, -CX3, -CHX2, -CH2X, -CN, -C(0)OH, -C(0)NH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2;

R ⁴ is hydrogen or -C(0)H; and R ⁶ is independently -I^-R ¹ . [0378] Embodiment P33. The compound of one of embodiments P31 to P32, wherein

X ^a is independently -Cl, -Br, or -I;

L ¹ is independently a -C(O)- or -C(0)0-;

R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and

R ² is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety, [0379] Embodiment P34. A compound having the formula:

wherein,

R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -COME, -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, - S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC=

(O)H, -MTC(0)-OH, -MTOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety;

L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ 3, -CHX ⁸ ₂ , -CkbX ⁸ , -OCX ⁸ 3, - OCH ₂ X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

0)0R ^1C , -NR ^1A OR ^lc , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

R ² is independently hydrogen, -CX ² ₃ , -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety; R ³ is independently hydrogen, -Cl, -Br, -I, -CN, -SO _n3 R ^3D , -SO _V3 NR ^3A R ^3B ,

-NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-0R ^3C , -C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A SO ₂ R ^3D -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX3, -CHX2, -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4; ml, m3, vl, and v3 are independently 1 or 2; z2 is an integer from 0 to 18;

R ⁴ is hydrogen or -C(0)H;

L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; and R ⁶ is independently -I^-R ¹ , wherein each R ⁶ is optionally different; or a compound having the formula :

(lie) wherein one R ⁶ is combined with the carbon adjacent to R ³ in formula lie to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0380] Embodiment P35. A compound having the formula:

wherein,

R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, -

S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC=

(O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety;

L ¹ is independently a -C(O)- or -C(0)0-;

R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHX' ₂ , -CH ₂ X', -OCXS, -OCH ₂ X ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _vi NR ^1A R ^1B , -NHC(0)NR ^1A R ^1B , -N(0) _mi ,

-NR ^1A R ^1B , -C(0)R ^1c , -C(0)-0R ^1c , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C( 0)0R ^1C , -NR ^1A OR ^lc , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

X ¹ and X ² are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , and R ^1D are independently

hydrogen, -CX3, -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2;

R ⁴ is hydrogen or -C(0)H; and

R ⁶ is independently -L^R ¹ .

[0381] Embodiment P36. The compound of one of embodiments P34 to P35, wherein

R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -SO3H, - S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC=

(O)H, -NHC(0)-OH, -NHOH, -OCF3, -OCHF ₂ , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety;

L ¹ is independently a -C(O)- or -C(0)0-; R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and R ² is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety. [0382] Embodiment P37. A compound made by a method of one of embodiments Pl to P23.

V. Additional Embodiments

[0383] Embodiment 1. A method of making a haloalkyl amine comprising reacting a saturated cyclic amine with a halogenating agent in the presence of an oxidizing agent and a metal source, wherein the haloalkyl amine comprises a covalently attached halogen, wherein the halogen is -Cl, -Br, or -I.

[0384] Embodiment 2. The method of embodiment 1, wherein said saturated cyclic amine has the structure of formula (I):

and said haloalkyl amine has the structure of formula (II):

wherein, X ^a is independently -Cl, -Br, or -I;

R ⁵ is independently -L^R ¹ , wherein each R ⁵ is optionally different; L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -0C(0)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ¹ is independently hydrogen, halogen, -CX^, -CHX' ₂ , -CH ₂ X', -OCXS, -OCH ₂ X', -OCHXS, oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0R ^{1 c} , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or

unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ³ is independently hydrogen, -Cl, -Br, -

I, -CN, -SOn3R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-0R ^3C , -

C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX3, -CHX2, -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4; ml, m3, vl, and v3 are independently 1 or 2; z2 is an integer from 0 to 18;

R ⁴ is hydrogen or -C(0)H; and

R ⁶ is independently -I^-R ¹ , wherein each R ⁶ is optionally different.

[0385] Embodiment 3. The method of embodiment 2, wherein z2 is an integer from 0 to 8.

[0386] Embodiment 4. The method of one of embodiments 2 to 3, wherein z2 is an integer from 1 to 4.

[0387] Embodiment 5. The method of one of embodiments 2 to 4, wherein each R ¹ is independently hydrogen, halogen, -CX , -CHX' ₂ , -CFEX ¹ , -OCX ¹ -,, -OCFEX ¹ , -OCHX' ₂ , oxo, -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^lc , -NR ^1A C(0)OR ^lc , -NR ^1A OR ^1c , -N ₃ , R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ -substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl; and

R ²⁰ is independently oxo, halogen, -CF ₃ , -CHF2, -

CH ₂ F, -CN, -OH, -NH2, -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0388] Embodiment 6. The method of one of embodiments 2 to 4, wherein each R ¹ is independently hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCH ₂ F, -OCHF ₂ ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0 )OR ^lc , -N3, or R ²⁰ -substituted or unsubstituted CNxalkyl; and

R ²⁰ is independently oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)OH, -C(0)NH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH, -OCF3, -OCHF ₂ , or -OCH ₂ F.

[0389] Embodiment 7. The method of one of embodiments 2 to 4, wherein each R ¹ is independently hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCH ₂ F, -OCHF ₂ ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0 )OR ^lc , or unsubstituted C3-8alkyl.

[0390] Embodiment 8. The method of one of embodiments 2 to 7, wherein each L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, R ²² -substituted or unsubstituted alkylene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroarylene; and

R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0391] Embodiment 9. The method of one of embodiments 2 to 7, wherein each L ¹ is independently a bond, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or R ²² -substituted or unsubstituted alkylene; and

R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH2, -C(0)0H, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)0H,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0392] Embodiment 10. The method of one of embodiments 2 to 7, wherein each L ¹ is independently a

bond, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-C ₈ alkylene.

[0393] Embodiment 11. The method of one of embodiments 2 to 10, wherein two -L'-R ¹ substituents attached to the same carbon atom are independently joined to form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl or a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

[0394] Embodiment 12. The method of one of embodiments 2 to 10, wherein two -L'-R ¹ substituents attached to adjacent carbon atoms are independently joined to form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl, a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, a substituted or unsubstituted Ce-C io aryl or a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0395] Embodiment 13. The method of one of embodiments 2 to 12, wherein each R ⁸ is hydrogen.

[0396] Embodiment 14. The method of one of embodiments 2 to 13, wherein each R ⁴ is hydrogen.

[0397] Embodiment 15. The method of one of embodiments 2 to 14, wherein R ² is substituted or unsubstituted alkyl or an amine protecting group chosen from the list comprising: CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts.

[0398] Embodiment 16. The method of embodiment 1, wherein said saturated cyclic amine has the structure of formula (la):

and said haloalkyl amine has the structure of formula (Ila):

wherein, X ^a is independently -Cl, -Br, or -I;

R ⁵ is independently -I^-R ¹ ;

L ¹ is independently a -C(O)- or -C(0)0-;

R ¹ is independently hydrogen, halogen, -CX^, -CHXN, -CH2X ¹ , -OCXS, -OCH2X ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0R ^{1 c} , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; R ² is independently hydrogen, -CXS, -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety; X ¹ and X ² are independently -F, -Cl, -Br, or -I; R ^1A , R ^1b , R ^1C , and R ^1D are independently

hydrogen, -CX3, -CHX2, -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2;

R ⁴ is hydrogen or -C(0)H; and

R ⁶ is independently -L^-R ¹ .

[0399] Embodiment 17. The method of embodiment 16, wherein X ^a is independently -Cl, -Br, or -I;

R ⁵ is independently -L^R ¹ ;

L ¹ is independently a -C(O)- or -C(0)0-;

R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and

R ² is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0400] Embodiment 18. The method of one of embodiments 1 to 17, further comprising reacting the haloalkyl amine with a nucleophilic agent, wherein the nucleophilic agent displaces said covalently attached halogen with a covalently attached substituent, thereby forming a nucleophilic reaction product.

[0401] Embodiment 19. The method of embodiment 18, wherein the nucleophilic agent comprises a -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -COMB, -N0 ₂ , -SH, -S0 ₂ Cl, -SO3H, -S0 ₄ H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (0)H, - NHC(0)-OH, -NHOH, -OCF3, -OCHF ₂ , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety.

[0402] Embodiment 20. The method of embodiment 18, wherein said covalently attached substituent is a -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -COME, -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, -SO4H, - S0 ₂ NH ₂ , -NHNH _Z , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHSO ₂ H, -NHC= (0)H, - MTC(0)-OH, -MTOH, -OCF3, -OCHF ₂ , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety.

[0403] Embodiment 21. The method of one of embodiments 2 to 20, wherein X ^a is -Cl.

[0404] Embodiment 22. The method of one of embodiments 2 to 20, wherein X ^a is -Br.

[0405] Embodiment 23. The method of embodiment 18, wherein the reaction between the haloalkyl amine and the nucleophilic agent is an intramolecular reaction. [0406] Embodiment 24. The method of embodiment 23 , wherein the intramolecular reaction is a cyclization reaction.

[0407] Embodiment 25. The method of embodiment 18, wherein the nucleophilic reaction product has the formula:

wherein,

R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO2, -SH, -SO2CI, -SO3H, - S0 ₄ H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH ₂ , -NHC=(0) NH2, -NHSO2H, -NHC=

(O)H, -NHC(0)-0H, -NHOH, -OCF3, -OCHF2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety; L ¹ is independently a bond, -S(0)2-,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(O)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R ⁸ is independently hydrogen, -CX ⁸ 3, -CHX ⁸ 2, -CH2X ⁸ , -OCX ⁸ 3, -

OCH2X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHX' ₂ , -CH ₂ X', -OCXS, -OCFFX ¹ , -OCHXS, oxo, -CN, -SOniR ^1D , -SOviNR ^1A R ^1B , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -CCOj-OR ^{1 c} , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ³ is independently hydrogen, -Cl, -Br, -

I, -CN, -SO _n3 R ^3D , -SO _V3 NR ^3A R ^3B , -NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-0R ^3C , - C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A S0 ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4; ml, m3, vl, and v3 are independently 1 or 2; z2 is an integer from 0 to 18;

R ⁴ is hydrogen or -C(0)H;

L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; and R ⁶ is independently -L'-R ¹ , wherein each R ⁶ is optionally different; or a compound having the formula :

) wherein one R ⁶ is combined with the carbon adjacent to R ³ in formula He to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0408] Embodiment 26. The method of one of embodiments 1 to 25, wherein the halogenating agent is A'-chlorosuccinimide, N- b ro m o s ucci n i m i de , A'-iodosuccinimide, or dibromohydantoin.

[0409] Embodiment 27. The method of one of embodiments 1 to 26, wherein the method of making the haloalkyl amine is perfomed under mild conditions that do not degrade the starting material . [0410] Embodiment 28. The method of one of embodiments 1 to 27, wherein the conditions comprise: an aqueous environment, an aerobic environment and a reaction temperature ranging from 15 to 30 °C.

[0411] Embodiment 29. The method of embodiment 28, wherein the reacting temperature ranges from 20 to 25 °C.

[0412] Embodiment 30. The method of one of embodiments 1 to 29, wherein the oxidizing agent is ammonium persulfate.

[0413] Embodiment 31. A compound having the formula:

wherein,

X ^a is independently -Cl, -Br, or -I;

L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(0)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ 3, -CHX ⁸ ₂ , -CH2X ⁸ , -OCX ⁸ 3, - OCH2X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHX' ₂ , -CH2X ¹ , -OCXS, -OCFbX ¹ , -OCHXS, oxo, -CN, -SOniR ^1D , -SOviNR ^1A R ^1B , -NHC(0)NR ^1A R ^1b , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -CCOj-OR ^{1 c} , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L ¹ - R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ³ is independently hydrogen, -Cl, -Br, -I, -CN, -SO„ ₃ R ^,D , -SO _v3 NR ^3A R ^3B ,

-NHC(0)NR ^3A R ^3B , -N(0) _m3 , -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , -C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A SO ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX3, -CHX2, -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4; ml, m3, vl, and v3 are independently 1 or 2; z2 is an integer from 0 to 18;

R ⁴ is hydrogen or -C(0)H; and

R ⁶ is independently -L'-R ¹ , wherein each R ⁶ is optionally different.

[0414] Embodiment 32. A compound having the formula:

wherein,

X ^a is independently -Cl, -Br, or -I;

L ¹ is independently a -C(O)- or -C(0)0-;

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ² is independently hydrogen, -CXS, -CHX ² 2, -CH2X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

X ¹ and X ² are independently -F, -Cl, -Br, or -I; R ^1A , R ^1b , R ^1C , and R ^1D are independently

hydrogen, -CX3, -CHX2, -CFFX, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2;

R ⁴ is hydrogen or -C(0)H; and R ⁶ is independently -L^R ¹ .

[0415] Embodiment 33. The compound of one of embodiments 31 to 32, wherein X ^a is independently -Cl, -Br, or -I;

L ¹ is independently a -C(O)- or -C(0)0-;

R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and R ² is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.

[0416] Embodiment 34. A compound having the formula:

wherein,

R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO2, -SH, -SO2CI, -SO3H, - S0 ₄ H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH ₂ , -NHC=(0) NH2, -NHSO2H, -NHC=

(O)H, -NHC(0)-0H, -NHOH, -OCF3, -OCHF2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety; L ¹ is independently a bond, -S(0)2-,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(O)- , substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R ⁸ is independently hydrogen, -CX ⁸ 3, -CHX ⁸ 2, -CH2X ⁸ , -OCX ⁸ 3, -

OCH2X ⁸ , -OCHX ⁸ 2, -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or

unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ¹ is independently hydrogen, halogen, -CX ¹ -,, -CHX' ₂ , -CH2X ¹ , -OCXS, -OCFbX ¹ , -OCHXS, oxo, -CN, -SOniR ^1D , -SOviNR ^1A R ^1B , -NHC(0)NR ^1A R ^1b , -N(0) _mi ,

-NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C( 0)0R ^1C , -NR ^1A OR ^lc , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ³ is independently hydrogen, -Cl, -Br, -I, -CN, -SO _n 3R ^3D , -SO _V 3NR ^3A R ^3B ,

-NHC(0)NR ^3A R ^3B , -N(0)m3, -NR ^3A R ^3B , -C(0)R ^3C , -C(0)-OR ^3C , -C(0)NR ^3A R ^3B , -OR ^3D , -NR ^3A SO ₂ R ^3D , -NR ^3A C(0)R ^3C , -NR ^3A C(0)0R ^3C , -NR ^3A OR ^3C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X ¹ , X ² , and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^3A , R ^3B , R ^3C , R ^3D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX3, -CHX2, -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^3A and R ^3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl and n3 are independently an integer from 0 to 4; ml, m3, vl, and v3 are independently 1 or 2; z2 is an integer from 0 to 18;

R ⁴ is hydrogen or -C(0)H;

L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; and R ⁶ is independently -L'-R ¹ , wherein each R ⁶ is optionally different; or a compound having the formula :

) wherein one R ⁶ is combined with the carbon adjacent to R ³ in formula He to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0417] Embodiment 35. A compound having the formula:

wherein,

R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, - S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC=

(O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety;

L ¹ is independently a -C(O)- or -C(0)0-;

R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHX' ₂ , -CFFX ¹ , -OCXS, -OCH ₂ X ¹ , -OCHXS, oxo, -CN, -SOniR ^1D , -SOviNR ^1A R ^1B , -NHC(0)NR ^1A R ^1b , -N(0) _mi ,

-NR ^1A R ^1B , -C(0)R ^1c , -C(0)-0R ^1c , -C(0)NR ^1A R ^1b , -OR ^1d , -NR ^1A S0 ₂ R ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C( 0)0R ^1C , -NR ^1A OR ^lc , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amino acid moiety, a polypeptide moiety, or a protein moiety;

R ² is independently hydrogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety;

X ¹ and X ² are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , and R ^1D are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2;

R ⁴ is hydrogen or -C(0)H; and R ⁶ is independently -I^-R ¹ .

[0418] Embodiment 36. The compound of one of embodiments 34 to 35, wherein

R ^a is hydrogen, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ Cl, -S0 ₃ H, - S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC=

(O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, detectable moiety, therapeutic moiety, drug moiety, protein moiety, or bioconjugate reactive moiety;

F ¹ is independently a -C(O)- or -C(0)0-;

R ¹ is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety; and R ² is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety. [0419] Embodiment 37. A compound made by the method of one of embodiments 1 to 30.

EXAMPFES

Example 1. Deconstructive Diversification of Cyclic Amines

[0420] Deconstructive functionalization, which entails a C-C bond cleavage event followed by bond construction on at least one of the constituent carbons, can provide access to molecules that would otherwise not be readily accessible. For example, ozonolysis (7) and olefin metathesis (2, 3) have shifted paradigms in organic chemistry wherein each carbon in Csp ² -Csp ² double bonds is now viewed as a functional group. Despite the significant advances in deconstructive functionalizations involving scission of Csp ² -Csp ² double bonds, there are very few methods that achieve Csp ³ -Csp ³ single bond cleavage/functionabzation, especially in unstrained cyclic systems. Here, we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines into halogen-containing acyclic amine derivatives through sequential Csp ³ -N/Csp ³ - Csp ³ single bond cleavage followed by Csp ³ -halogen bond formation. The resulting acyclic haloamines serve as versatile intermediates that are expediently transformed into a variety of structural motifs through substitution reactions. In this way, skeletal remodeling of cyclic amines, which constitutes a scaffold hop, can be achieved. The value of this deconstructive strategy has been demonstrated through the late-stage diversification of proline-containing peptides.

[0421] Bioactive molecules such as natural products and pharmaceutical agents often possess saturated nitrogen heterocycles (FIG. 1A) (4,5). Consequently, the development of technologies that enable the late-stage diversification of these molecules is of great importance to access under explored chemical space (6). Over the past two decades, significant effort has been dedicated to the development of methods to functionalize C-H bonds at a late stage, which has enabled the fine- tuning of substituents on nitrogen heterocycles, enhancing their functional group diversity (FIG. 1B) (7,5). In the medicinal chemistry community, there is growing demand for methods that modify not only the periphery (as in C-H functionalization) but also, the core framework of molecules (i.e., achieve skeletal diversity), a concept referred to as Scaffold Hopping (9,10). Bond cleavage in the core framework of a molecule and subsequent derivatization of the now activated carbon atoms (deconstructive functionalization) would provide a disruptive approach to achieving maximal skeletal diversification. However, few methods are known that achieve ring-opening and attendant functionalization of unstrained cyclic amines (11-14). An exception is the recently reported elegant sequence wherein a generated aldehyde intermediate can be further transformed to install C-O, C- C, and C-N bonds (15). We recognized that a more versatile deconstructive functionalization method that could also convert the cyclic scaffold of one molecule to another (e.g., by excising carbon atoms and transforming, for example, a six-membered piperidine ring to a five-membered pyrrolidine; a cyclic scaffold hop) would provide a powerful alternative to most current strategies that begin the synthesis of each framework with the target scaffold as a part of the starting material.

[0422] In this context, ring-opening chlorination/bromination would generate a versatile intermediate en route to diverse cyclic amines, given the widespread utility of alkyl chlorides and bromides as electrophiles (FIG. 1B). The haloamines that result from ring opening could be coupled with a variety of nucleophiles. For example, pendant nucleophiles could engage the newly formed alkyl halide in an overall skeletal remodeling process. Alternatively, intramolecular nucleophilic substitution would result in a ring contraction of the starting cyclic amine, providing, formally, the realization of a ring-contractive methylene extrusion process. Furthermore, deconstructive halogenation of proline-containing peptides would furnish versatile intermediates for the late-stage diversification of these medicinally important entities (16). Although ring-opening chlorination of cyclic amines is known, the existing methods to effect this transformation are limited to 3-5- membered, N-alkyl substituted, cyclic amines because of competing N-dealkylation in larger (> 5- membered) rings (17). Recently, our laboratory introduced a silver-mediated deconstructive strategy to transform cyclic amine derivatives into fluorine-containing acyclic amine derivatives using Selectfluor ^® via homo lytic ring-opening of hemiaminal intermediates (18). We questioned whether it would be possible to access acyclic chloro/bromoamines from cyclic amines using our

deconstructive strategy. Upon examination of existing reports on silver-catalyzed halogenation reactions, we recognized that simple replacement of Selectfluor ^® with N-halo-reagents such as N- chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) would be unproductive presumably due to their lower oxidation potential (19). Therefore, a distinct approach would be required to oxidize Ag(I) to Ag(II) in order to achieve deconstructive bromination/chlorination.

[0423] A detailed mechanistic proposal for our envisioned, highly orchestrated, reaction sequence is depicted in FIG. 1C. We theorized that consistent with existing precedent (20), in the presence of persulfate anion, Ag(I) will be oxidized to Ag(II) with concomitant disproportionation of the persulfate anion into sulfate dianion and sulfate radical anion. N-acylated cyclic amines (1) would then undergo a hydrogen-atom transfer (HAT) with the resulting sulfate radical anion to give an a- amino radical (21). Subsequent oxidation by Ag(II) via single electron transfer (SET) would lead to iminium ion A. An alternative pathway wherein a Ag(II) species [E° (Ag ²⁺ /Ag ⁺ ) = +1.98 V vs SCE] (22) oxidizes N-acylated cyclic amines (e.g., la: \E _pa = +2.02 V vs saturated calomel electrode (SCE)]) (FIG. 5) to the radical cation via SET followed by hydrogen atom abstraction by the sulfate radical anion to generate the same iminium ion, A, is also possible. The resulting iminium ion (A) would then be trapped by FFO to give hemi-aminal B. The heterolytic cleavage of the C-N bond would then occur through an equilibrium between hemi-aminal B and aldehyde C, the latter being subsequently oxidized to carboxylic acid D (23), setting the stage for a silver-catalyzed

decarboxylative halogenation (19,24). This strategy would represent a general method for deconstructive diversification as the electrophile is independent of the initial redox cycle.

[0424] We commenced our investigations of the proposed deconstructive halogenation by evaluating a broad range of silver salts, halogenating reagents, and solvent combinations. After extensive screening, we identified the optimized conditions shown in FIG. 1 C that employs cheap and commercially available AgNO„ (NFLfiS^Ox, and NCS in a 1 :9 (v/v) mixture of acetone/FLO at room temperature. Upon subjecting N-pivaloyl piperidine (la) to the optimized conditions, we obtained 81% yield of the desired acyclic chlorinated product 2a. Likewise, a bromine-atom could be readily incorporated to afford 4a in 54% yield by switching the electrophilic halogenating reagent to NBS. It is worth noting that this method can be performed without the strict exclusion of air. Control experiments established the importance of both silver and persulfate, as no formation of the desired chlorinated product was observed in the absence of the silver salt or persulfate additive. The optimized conditions employ 4 equivalents of AgNO„ whereas lower amounts led to diminished yields presumably due to substrate/product inhibition by binding to the silver salt. For example, when 1 equivalent of AgNO, was used, 2a was obtained in only 26% yield.

[0425] With the optimized conditions in hand, we proceeded to investigate the scope of the deconstructive halogenation process (FIG. 2). The nature of the acyl groups on nitrogen was first examined. An N-substituted piperidine derivative bearing a t v-butoxycarbonyl group (Boc, lb), gave the desired chlorinated products in a combined 52% yield of 2b, along with formimide product 3 b, which results from ho mo lytic C-C bond cleavage of hemi-aminal B (16). Unlike the bulky pivaloyl group which favors linear aldehyde C over hemiaminal B in the equilibration of the two species, the less sterically congested Boc group favors B (see Fig. 1C). Bromination using NBS led to a mixture of mono and dibrominated products 5b and 6b in 65% combined yield. Upon switching the group on nitrogen to benzoyl (Bz, 1 c), the secondary amide products 2c and 4c were obtained as the major products along with formimide products 3c and 5c. In all cases, the secondary amide product and corresponding formimide are easily separated. Overall, the pivaloyl (Piv) group emerged as the superior acyl substituent on nitrogen. A variety of saturated heterocycles were then examined. For example, pyrrolidine derivative ld underwent chlorination in 77% yield, whereas the analogous deconstructive bromination of ld using NBS led to 5,6-dihydro-4H-l,3-oxazine through autocyclization of the desired alkyl bromide 4d. Both the deconstructive chlorination and bromination protocols function well for other saturated heterocycles such as azepane le, and azocane lf, providing acyclic halogenated building blocks of various chain lengths. 2-Substituted piperidines were also good substrates, giving, for example, 2g and 4g in modest yield from lg. 4- Substituted piperidines were also competent substrates and chlorinated and brominated products 2h and 4h were obtained in 80% and 55% yields, respectively. Ester substituents were well tolerated, leading to 2i and 4i in 73% and 59% yields, respectively. This skeletal cleavage/halogenation method is not limited to monocyclic amines. Polycyclic compounds such as lj are also readily functionalized, paving the way for late-stage derivatization in more complex polycyclic frameworks. 5 -Halo-no rvaline derivatives (2k and 4k) are accessed in 3 steps from L-pipecolic acid. Notably, chlorinated amino acid 21, which may serve as a versatile intermediate to other unnatural amino acids, is obtained in two steps from L-proline methyl ester.

[0426] Next, the skeletal remodeling of piperidine scaffolds bearing other reactive groups was examined (FIG. 3 A). Piperidines bearing pendant nucleophiles were successfully remodeled to a variety of ring systems bearing new functional groups. For example, ring-opening of 7 and engaging the pendant 2-nitrobenzenesulfonamide (NsNH) nucleophile with the incipient aldehyde group in 8 ultimately yielded the corresponding lactam 9. The choice of halogenating reagent led to divergence in the products that were formed. For example, when carboxylic acid 10 was subjected to the deconstructive chlorination conditions, dichloro compound 11 was obtained through decarboxylative (19) and deconstructive chlorination, and was directly transformed to azetidine 12 via double nucleophilic displacement with NsNFF. Alternatively, when NBS was used as the halogenating agent, in situ generated alkyl bromide 13 was engaged by the carboxylic acid group to form the corresponding lactone 14 in 44% yield.

[0427] Given the aforementioned importance of scaffold hopping in cyclic systems (9,10), we have also pursued the ring contraction of piperidines (FIG. 3B). Few reports exist that detail the ring contraction of piperidines to pyrrolidines (26-29). The majority of the existing methods, which rely on nucleophilic substitution/ring contraction of bicyclic aziridinium intermediates (26), require very specific leaving groups and substitution patterns on the piperidine ring. Our approach now obviates the need for these restrictive requirements. Deconstructive bromination ofN-benzoyl piperidine (l c) with dibromohydantoin followed by cyclization of the resulting bromoamine with NaO'Bu furnished N-benzoyl pyrrolidine (15) in 89% (94% average yield per step) in just two steps with only one chromatographic purification step. Notably, this process can also be conducted in one-pot, albeit in lower yield (unoptimized) due to the competing displacement of the newly installed halogen group by the imide byproduct from the halogenating reagent. Piperidines possessing various substitution patterns are also readily dehomologated. For example, 4-methyl and 2-methyl derivatives 16 and 18 underwent ring contraction to provide 17 and 19 in 55% yield (74% average yield per step) and 60% yield (77 % average yield per step), respectively. Moreover, cyclic amines with different ring-sizes such as azepane 20 were also found to be amenable to this dehomologation process. These results demonstrate a powerfully direct approach to achieving deep-seated structural modifications.

[0428] The virtue of this methodology is evident in the deconstructive

functionalization/diversification of peptides (30). Notably, this method allows for proline-containing peptides to be ring opened as opposed to their oxidation to the pyroglutamic acid derivatives observed in the deconstructive fluorination method (18). L-Proline-containing tripeptide 21 underwent ring-opening chlorination in 41% yield along with 15% recovered starting material (RSM) (FIG. 4A). Importantly, chlorinated peptide 22 is easily transformed into a variety of products. For example, treatment of 22 with sodium methylthiolate afforded 23 in 91% yield, constituting the conversion of a proline residue into the corresponding methionine residue in only two steps. Alternatively, C-N bond formation can be achieved by treatment of 22 with sodium azide and in this way convert a proline residue or polypeptides bearing a cyclic amine (e.g., L-pipecolic acid) into a site for azide-based biorthogonal click chemistry (31). In a demonstration of this tactic, 22 was azidated and then subjected to copper-catalyzed azide-alkyne cycloaddition to afford triazole

24 in 72% yield over the two steps. In addition, C-0 bond formation is also easily achieved by displacement of the halogen group with the appropriate oxygen nucleophile. For example, benzoate

25 was obtained in 51% yield upon treatment of 22 with benzoic acid and K2CO3 in DMF.

Treatment of 22 with NaCN in DMF led to nitrile 26 as the major product along with 5,6-dihydro- 4H-l,3-oxazine 27 in 36% yield, demonstrating the feasibility of carbon-carbon bond formation. Cyclized product 27 is obtained as the sole product when 22 is treated with DBU. Overall, the newly generated alkyl chloride side chain in peptides such as 22 can be leveraged in a host of nucleophilic substitution reactions. The ability to effect this deconstructive chlorination protocol under aqueous, aerobic, and ambient temperature conditions sets the stage for application to the derivatization of a range of proline-containing bioactive peptides having a high content of alkyl residues, such as the peptaibols (32).

[0429] Additionally, we evaluated the functional group tolerance of the deconstructive chlorination process with various peptides that bear potentially oxidizable amino acid residues (e.g., benzylic groups; see FIG. 4B). When OTf-tyrosine-containing dipeptide 28a was subjected to our reaction conditions, deconstructive chlorination proceeded to afford dipeptide 29a in 29% yield along with 52% recovered starting material. Longer reaction times did not lead to higher yields of the product, presumably due to over-oxidation and attendant decomposition of the product.

Dipeptide 28b, bearing a phenylalanine residue, underwent deconstructive chlorination to provide 29b in 19% yield along with 46% of recovered starting material. Aspartic acid derivative 29c and glutamic acid derivative 29d underwent ring opening chlorination in modest yields (44% and 37%, respectively) with significant recovery of starting material (40% and 45%, respectively) providing excellent mass balance. Dipeptides bearing serine and threonine residues (29e, 29f) were also viable substrates, giving modest yields of the deconstructive halogenation products. Notably, the proline residue can be preferentially oxidized over the C-H bonds of the activated aliphatic side-chains bearing oxygen heteroatoms. A dipeptide bearing a methionine residue underwent deconstructive chlorination with oxidation of the thioether to the corresponding sulfone (see 29g). Therefore, like many other oxidative processes (33-35), deconstructive halogenation leads to competing reaction with the sulfur group of methionine.

[0430] Deconstructive chlorination of the challenging tripeptide substrate 30 proceeded to furnish 16% yield of the ring-opened product (31) along with 62% of recovered starting material (FIG. 4C).

In these cases, the decreased yields likely result from competing oxidation of the benzylic positions. Despite the lower yields obtained in the presence of these challenging residues, the deconstructive chlorination protocol provides an expedient approach to a novel range of peptides without the need for their de novo synthesis. Previously, a limitation in applying deconstructive functionalization to peptide diversification was the over oxidation of proline residues to the corresponding pyroglutamic acid (18). Given the mechanistic change in the current methodology to a heterolytic C-N cleavage (B®C, FIG. 1 C), over-oxidation of the hemiaminal intermediate is generally avoided as evidenced by the ring opening fluorination of 21 to give fluorinated tripeptide 32 (FIG. 4D) using the newly developed strategy. [0431] Saturated heterocycles remain a prevalent structural motif that is found in a large percentage of bioactive organic molecules such as pharmaceuticals. The operationally simple method that we have described here harnesses a highly orchestrated cascade sequence to efficiently generate skeletal diversity from saturated cyclic amines via their halogenated ring-opened derivatives. We anticipate that deconstructive functionalization strategies of this type that transform cyclic amines into myriad scaffolds will provide access to wide-ranging structural diversity at a late stage in the preparation of pharmaceuticals, agrochemicals, and other complex molecules. a. Solvents and Reagents

[0432] Tetrahydrofuran (THF) and triethylamine (Et ₃ N) were sparged with argon and dried by passing through alumina columns using argon in a Glass Contour solvent purification system.

Dichloromethane (CH2CI2) was freshly distilled over calcium hydride under a N2 atmosphere prior to each use. DMF was purchased in Aldrich Sure/Seal™ bottles. A'-Boc-piperidine (lb) was obtained from commercial vendors and used as received. Reagents for the fluorination reaction were purchased from commercial vendors as follows: Silver nitrate (AgNO,, >99%) was purchased from Sigma- Aldrich. Ammonium persulfate ((NH ₄ ) ₂ S ₂ 0 ₈ , ACS Reagent) was purchased from J. T. Baker Chemicals. A'-Chlorosuccini ide (NCS, 97%) was purchased from Acros Organics. N- Bromosuccinimide (NBS, 99%) was purchased from Aldrich. Acetone (HPLC) and water (HPLC) were purchased from Fisher Scientific. b. Experimental Procedures [0433] Unless otherwise noted in the experimental procedures, reactions were carried out in flame or oven-dried glassware under a positive pressure of N2 in anhydrous solvents using standard Schlenk techniques. Reaction temperatures above room temperature (22-23 °C) were controlled by an IKA® temperature modulator and monitored using liquid-in-glass thermometers. Reaction progress was monitored using a combination of LC/MS analysis (using a Shimadzu LCMS-2020 (UFLC) equipped with the LC-20AD solvent delivery system, a SPD-20AV prominence UV/Vis detector (SPD-M20A Photo Diode Array), and a Thermo Scientific Hypersil GOLD HPLC column (5 pm particle size, 4.6 x 50 mm)), and thin-layer chromatography (TLC) on SiliCycle Silicaplates (glass backed, extra hard layer, 60 A, 250 pm thickness, F254 indicator). Flash column

chromatography was performed with either glass columns using Silicycle silica gel (40-63 pm particle size) or with a Yamazen Smart Flash EPCLC W-Prep 2XY (dual channel) automated flash chromatography system on prefilled, premium, universal columns using ACS grade solvents.

Preparative thin layer chromatography was performed on SiliCycle Siliaplates (glass backed, extra hard layer, 60 A, 250 pm thickness, F254 indicator). c. Analytical Instrumentation

[0434] ¾ NMR and ¹³ C NMR data were recorded on Bruker AVQ-400, AVB-400, RDX-500,

AV-600 and AV-700 spectrometers using CDCh as solvents, typically at 20-23 °C. Chemical shifts (d) are reported in ppm relative to the residual solvent signal (d 7.26 for 'H NMR, d 77.16 for ¹³ C NMR in CDCh). The ¹⁹ F NMR spectra were acquired on an AVQ-400 spectrometer and internally referenced to CFCF, (d 0.00). Data for 'H and ¹³ C spectroscopy are reported as follows; chemical shift (d ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, hept = heptet, m = multiplet, br = broad), coupling constant (Hz), integration. Melting points were determined using a MEL-TEMP™ apparatus and are uncorrected. Optical rotations were measured on a Perkin-Elmer 241 polarimeter. High-resolution mass spectra (HRMS) were obtained from the Catalysis Facility of the Lawrence Berkeley National Laboratory (supported by the Director, Office of Science, of the US Department of Energy under contract no. DE-AC02-05CH11231) using a PerkinElmer AxION 2 TOF-MS.

Example 2. Experimental Procedures for Preparation of Starting Materials d. Preparation of N-Protected Cyclic Amines

[0435] A 50 mL round-bottomed flask was charged with a solution of piperidine (426 mg, 5.00 mmol) and Et ₃ N (0.91 mL, 6.5 mmol) in CH2CI2 (20 mL) and cooled to 0 °C. Pivaloyl chloride (0.67 mL, 5.5 mmol) was added dropwise over 5 min and the resulting mixture was warmed to room temperature. After 12 h, the reaction mixture was quenched with 1 M HC1 aq. (5.0 mL) and the phases were separated. The aqueous phase was extracted with CH2CI2 (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (S1O2, 25%

EtO Ac/hexanes) to provide 2,2-dimethyl-l-(piperidin-l-yl)propan-l -one (la) (753 mg, 89%). Spectral data were in full agreement with the reported literature values (36).

[0436] Phenyl(piperidin-l-yl)methanone (lc) was prepared according to a published procedure (37). Spectral data were in full agreement with the reported literature values.

Piv [0437] 2,2-Dimethyl- l-(pyrrolidin-l -yl)propan-l -one (ld) was prepared from pyrrolidine using a procedure analogous to that for the preparation of la. Spectral data were in full agreement with the reported literature values (38).

Piv

[0438] 1 -(Azepan-l -yl)-2,2-dimethylpropan-l -one (1 e) was prepared from azepane using a procedure analogous to that for the preparation of 1 a. The title compound was obtained as a colorless oil (742 mg, 81%). ¾ NMR (600 MHz, CDCh): 6 3.52 (br, 4H), 1.71 (br, 4H), 1.56-1.53 (m, 4H), 1.27 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 177.0, 48.5, 39.2, 28.7, 27.8 (assigned by HSQC), 27.0 (assigned by HSQC); HRMS (ESI): Calc’d for CnH _2i NONa [M+Na] ⁺ : 206.1515, found: 206.1517.

[0439] 1 -(Azocan- 1 -yl)-2,2-dimethylpropan-l -one (1 f) was prepared from azocane using a procedure analogous to that for the preparation of 1 a. The title compound was obtained as a white waxy solid (485 mg, 82%).Meltmg Point: 33-35 °C; Ή NMR (600 MHz, CDCh): d 3.44 (br, 4H), 1.72 (br, 4H), 1.50 (br, 6H), 1.26 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 176.8, 49.3, 39.1 , 28.6, 27.3, 26.6, 24.3; HRMS (ESI): Calc’d for C12H24NO [M+H] ⁺ : 198.1852, found: 198.1860.

Piv

[0440] 2,2-Dimethyl- 1 -(2-methylpiperidin-l -yl)propan-l -one (1 g) was prepared from 2- methylpiperidine using a procedure analogous to that for the preparation of la. The title compound was obtained as a yellow oil (788 mg, 86%). ¾ NMR (600 MHz, CDCh): d 4.70 (br, 1H), 4.10 (br, 1H), 2.91 (br, 1H), 1.67-1.57 (m, 4H), 1.49 (d, = 10.9 Hz, 1H), 1.40-1.33 (m, 1H), 1.25 (s, 9H),

1.17 (br, 3H); ¹³ C NMR (l 5l MHz, CDCh): d 176.3, 39.0, 30.3, 28.6, 26.2, 19.1, 16.0 (Two ¹³ C signals are missing due to peak broadening), HRMS (ESI): Calc’d for C11H22NO [M+H] ⁺ :

184.1696, found: 184.1698.

Piv

[0441] 2,2-Dimethyl- l-(4-methylpiperidin-l-yl)propan-l -one (lh) was prepared from 4- methylpiperidine using a procedure analogous to that for the preparation of la. The title compound was obtained as a colorless oil (632 mg, 69%). ¾ NMR (600 MHz, CDCh): d 4.36 (d, J = 11.7 Hz, 2H), 2.74 (d, J= 11.7 Hz, 2H), 1.65 (d, J= 13.5 Hz, 2H), 1.62-1.55 (m, 1H), 1.25 (s, 9H), 1.08 (dq, J= 13.5, 3.8 Hz, 2H), 0.93 (d, J= 6.5 Hz, 3H); ¹³ C NMR (151 MHz, CDCh): d 176.2, 45.6, 38.8, 34.5, 31.4, 28.6, 21.9; HRMS (ESI): Calc’d for C11H22NO [M+H] ⁺ : 184.1696, found: 184.1698.

Piv

[0442] Ethyl l-Pivaloylpiperidine-4-carboxylate (l i) was prepared from ethyl piperidine-4- carboxylate using a procedure analogous to that for the preparation of la. Spectral data were in full agreement with the reported literature values (39).

[0443] /ra«.v-2, 2-Dimethyl- 1 -octahydroquinolin- 1 (2//)-yl)propan- l -one (lj) was prepared from

//r .s-decahydroquinoline using a procedure analogous to that for the preparation of la. The title compound was obtained as a pale yellow oil (1.53 g, 95%). ³ H NMR (600 MHz, CDCh): d 3.63 (dt, J= 12.8, 6.0 Hz, 1H), 3.29 (t, J= 10.8 Hz, 1H), 3.12 (td, J= 13.5, 5.8 Hz, 1H), 1.93 (dt, J= 12.7,

3.4 Hz, 1H), 1.69-1.60 (m, 1H), 1.58-1.50 (m, 4H), 1.48-1.34 (m, 2H), 1.27 (ddd, = 17.3, 11.2,

4.1 Hz, 1H), 1.17-1.11 (m, 1H), 1.10-1.09 (m, 9H), 1.02-0.86 (m, 3H); ¹³ C NMR (l 5l MHz, CDCh): d 176.6, 61.6, 39.5, 38.5, 37.6, 33.0, 29.7, 28.2, 26.2, 25.5, 25.3, 23.3; HRMS (ESI): Calc’d for C14H26NO [M+H] ⁺ : 224.2009, found: 224.2007.

[0444] Methyl (L')- 1 -Pivaloylpiperidine-2-carboxylate (lk) was prepared from fV)-piperidine-2- carboxylic acid methyl ester hydrochloride using a procedure analogous to that for the preparation of la. The title compound was obtained as a pale yellow oil (1.62 g, 79%). Optical Rotation: [a] ²² _D = -62 (c 0.81, CHCh); ¾ NMR (600 MHz, CDCh): d 5.35 (br, 1H), 4.13 (br, 1H), 3.71 (s, 3H), 3.17 (br, 1H), 2.24 (d, = 13.0 Hz, 1H), 1.70 (d, J= 13.0 Hz, 1H), 1.66-1.60 (m, 2H), 1.47-1.33 (m,

2H), 1.28 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): d 177.7, 172.2, 53.4, 52.2, 44.7, 38.8, 28.3, 26.9, 25.4, 21.3; HRMS (ESI): Calc’d for C12H22NO3 [M+H] ⁺ : 228.1594, found: 228.1596.

Piv

[0445] Methyl Pivaloyl-E-prolinate (11) was prepared from /.-Proline methyl ester hydrochloride using a procedure analogous to that for the preparation of 1 a. Spectral data were in full agreement with reported literature values {40).

[0446] 2-Nitro-A'-(( l -pivaloylpiperidin-4-yl)methyl)benzenesulfonamide (7): A 50 mL round- bottomed flask containing a solution of l-(4-(hydroxymethyl)piperidin-l-yl)-2,2-dimethylpropan-l- one (41) (399 mg, 2.00 mmol), tert- butyl ((2-nitrophenyl)sulfonyl (carbamate (42) (665 mg, 2.20 mmol), Ph ₃ P (577 mg, 2.20 mmol) in THF (10 mL) was cooled to 0 °C. To this solution was added diisopropyl azodicarboxylate (DIAD: 0.43 mL, 2.2 mmol) dropwise over 3 min and the resulting mixture was warmed to room temperature. After 12 h, the solvent was removed under reduced pressure to afford a yellow, sticky oil. To a solution of the residue in CH2CI2 (8.0 mL) was added trifluoroacetic acid (TFA: 4.0 mL) at 0 °C and the resulting mixture was warmed to room temperature. After 6 h, the reaction mixture was quenched with sat. NaHCO, aq. (20 mL) and the phases were separated. The aqueous phase was extracted with CH2CI2 (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (S1O2, 30% to 60% EtOAc/ hexanes) to provide the title compound (567 mg, 76% over 2 step) as an off white solid. Melting Point: 174-177 °C; ¾ NMR (600 MHz, CDCL): d 8.09 (brs, 1H), 7.83 (brs, 1H), 7.73 (brs, 2H), 5.53 (brs, 1H), 4.39 (d, J= 11.0 Hz, 2H), 2.95 (brs, 2H), 2.71 (brs, 2H), 1.76 (brs, 2H), 1.74 (brs, 1H), 1.123 (s, 9H), 1.08 (d, J= 11.0 Hz, 2H); ¹³ C NMR (l 5l MHz, CDCL): d 176.3, 148.1, 133.8, 133.6, 132.9, 131.0, 125.4, 49.0, 44.9, 38.8, 36.8, 30.0, 28.5; HRMS (ESI): Calc’d for Ci ₇ H ₂₅ N ₃ Na0 ₅ S [M+Na] ⁺ : 406.1407, found: 406.1411.

[0447] 2-(l-Pivaloylpiperidin-4-yl)acetic acid (10): A 100 mL round-bottomed flask was charged with a solution of methyl 2-(piperidin-4-yl)acetate hydrochloride (1.94 g, 10.0 mmol) and Et ₃ N (4.18 mL, 30.0 mmol) in CH2CI2 (50 mL) and cooled to 0 °C. Pivaloyl chloride (1.35 mL, 11.0 mmol) was added dropwise over 5 min and the resulting mixture was warmed to room temperature. After 12 h, the reaction mixture was quenched with 1 M HC1 aq. (20 mL) and the phases were separated. The aqueous phase was extracted with CH2CI2 (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford a pale yellow oil. To a 250 mL round-bottomed flask containing a solution of the crude methyl ester in 3:1 THP: H2O (40 mL) was added LiOHHhO (2.10 g, 50.0 mmol) at 0 °C and the resulting mixture was warmed to room temperature. After 15 h, the reaction mixture was cooled to 0 °C and acidified with 1 M HC1 aq. (50 mL) to pH <2. The solution was then diluted with EtOAc (20 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (10 mL x 3) and the combined organic layers were washed with brine (10 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The title compound was obtained as a white solid by recrystallization from EtOAc/Et ₂ 0 (1.39 g, 61 % yield over 2 steps). Melting Point: 156-159 °C; 'H NMR (600 MHz, CDCh): d 10.8 (br, 1H), 4.38 (d, J= 12.0 Hz, 2H), 2.78 (brs, 2H), 2.25 (d, J= 7.0 Hz, 2H), 2.06-1.98 (m, 1H), 1.78 (d, J= 12.8 Hz, 2H), 1.24 (s, 9H), 1.16 (qd, J = 12.8, 3.4 Hz, 2H); ¹³ C NMR (151 MHz, CDCh): d 177.0, 176.6, 45.4, 40.8, 38.8, 33.1 , 32.2, 28.4; HRMS (ESI): Calc’d for C12H22NO3 [M+H] ⁺ : 228.1594, found: 228.1594.

[0448] (4-Methylpiperidin-l-yl)(phenyl)methanone (16) was prepared from 4-methylpiperidine and benzoyl chloride using a procedure analogous to that used for the synthesis of la. Spectral data were in full agreement with the reported literature values (43).

[0449] (2-Methylpiperidin-l -yl)(phenyl)methanone (18) was prepared from 2-methylpiperidine and benzoyl chloride using a procedure analogous to that used for the synthesis of la. Spectral data were in full agreement with the reported literature values (44).

[0450] Azepan-l-yl(phenyl)methanone (20) was prepared from azepane and benzoyl chloride using a procedure analogous to that used for the synthesis of la. Spectral data were in full agreement with the reported literature values (45). e. Preparation of Proline-Containing Peptides

S1

[0451] Methyl P i va 1 o y 1 - va 1 i n at e (Sl): A 250 mL round-bottomed flask was charged with a solution of pivaloyl-T-proline (46) (3.05 g, 15.3 mmol), /.-valine methyl ester hydrochloride

(2.82 g, 16.8 mmol) and hydroxybenzotriazole (HOBt: 2.07 g, 15.3 mmol) in CH2CI2 (150 mL) and cooled to 0 °C. To this solution was added zP^NEt (2.93 mL, 16.8 mmol) dropwise over 5 min and the resulting mixture was stirred at 0 °C for 10 min. To this solution was added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC: 3.23 g, 16.8 mmol) and the resulting mixture was warmed to room temperature. After 16 h, the reaction mixture was cooled to 0

°C and quenched with 1 M HC1 aq. (30 mL). The phases were separated and the aqueous phase was extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over MgS0 ₄ , fdtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (S1O2, 20% to 40% EtOAc/ hexanes) to provide the title compound

(4.61 g, 96%) as a pale yellow, sticky oil. Optical Rotation: [a] ²² _D = -85 (c 1.3, CHCL); ¾ NMR

(700 MHz, CDCL): d 7.19 (br, 1H), 4.67 (dd, J= 8.3, 3.2 Hz, 1H), 4.41 (dd, = 8.6, 4.4 Hz, 1H),

3.70-3.67 (m, 1H), 3.67 (s, 3H), 3.62 (ddd, J= 10.2, 8.0, 4.5 Hz, 1H), 2.22 (dquint, J= 11.8, 4.5 Hz,

1H), 2.11 (ddt, J = 13.0, 7.0, 4.5 Hz, 1H), 2.08-2.02 (m, 1H), 1.89 (dddd, J= 11.8, 7.0, 4.5, 2.5 Hz, 1H), 1.82 (dq, J= 13.0, 8.0 Hz, 1H), 1.23 (s, 9H), 0.85 (d, = 6.9 Hz, 3H), 0.84 (d, = 6.9 Hz, 3H); ¹³ C NMR (176 MHz, CDCh): d 177.8, 172.2, 171.8, 61.5, 57.2, 52.1 , 48.3, 39.3, 31.1 , 27.5, 26.4, 25.9, 19.1, 17.6; HRMS (ESI): Calc’d for Ci ₆ H ₂₈ N ₂ Na0 ₄ [M+Na] ⁺ : 335.1941 , found: 335.1942.

[0452] Methyl Pivaloyl-F-prolyl-F-valyl-F-alaninate (21): A 250 mL round-bottomed flask was charged with a solution of Sl (4.61 g, 14.8 mmol) in 3:1 THF: ¾0 (120 mL) and cooled to 0 °C. LiOFPFhO (3.09 g, 73.8 mmol) was added and the resulting mixture was warmed to room temperature. After 5 h, the reaction mixture was cooled to 0 °C and acidified with 1 M HC1 aq. (100 mL) to pH <2. The solution was then diluted with EtOAc (50 mL) and the aqueous layer was extracted with EtOAc (30 mL x 4). The combined organic layers were washed with brine (30 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford the corresponding carboxylic acid, which was used in the next step without further purification.

[0453] A 250 mL round-bottomed flask was charged with a solution of the crude carboxylic acid generated from Sl, L-alanine methyl ester hydrochloride (2.27 g, 16.2 mmol) and

hy dr oxybenzo triazole (HOBt: 1.99 g, 14.8 mmol) in CH2CI2 (150 mL) and cooled to 0 °C. /RbNEΐ (2.83 mL, 16.2 mmol) was added dropwise over 5 min and the resulting mixture was stirred at 0 °C for 10 min. To this solution was added l -(3-dimethylaminopropyl)-3-ethylcarbodiimide

hydrochloride (EDC: 3.11 g, 16.2 mmol) and the resulting mixture was warmed to room

temperature. After 14 h, the reaction mixture was cooled to 0 °C and quenched with 1 M HC1 aq.

(50 mL). The phases were separated and the aqueous phase was extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (S1O2, 20% to 50% EtOAc/ hexanes) to provide the title compound (21, 5.55 g, 98%) as a white amorphous solid. Optical Rotation: [a] ²² _D = -86.1 ( c 1.08, CHCh); ¾ NMR (600 MHz, CDCh): 7.02 (d, = 8.7 Hz, 1H), 6.81 (d, = 8.0 Hz, 1H), 4.67 (dd, J= 8.0, 3.8 Hz, 1H), 4.51 (quint, J= 12 Hz, 1H), 4.27 (dd, = 8.7, 5.4 Hz, 1H), 3.75-3.67 (m, 2H), 3.71 (s, 3H), 2.26 (dq, J= 13.4, 6.8 Hz, 1H), 2.21-2.17 (m, 1H), 2.09-2.02 (m, 1H), 1.98-1.91 (m, 2H), 1.39 (d, J= 12 Hz, 3H), 1.26 (s, 9H), 0.90 (d, J= 6.8 Hz, 3H), 0.86 (d, J= 6.8 Hz, 3H); ¹³ C NMR (151 MHz, CDCh): d 178.2, 173.2, 172.2, 170.8, 62.1, 58.3, 52.5, 48.6, 48.2, 39.4, 30.3, 27.63, 27.56, 27.2, 19.4, 18.2, 17.4; HRMS (ESI): Calc’d for Ci^NsNaOs [M+Na] ⁺ : 406.2312, found: 406.2322.

[0454] Methyl (S)-2- Amino-3 -(4-(trifluoromethylsulfonyloxy)phenyl)propanoate hydrochloride (S2): To a 250 mL round-bottomed flask containing a solution of HC1 in dioxane (4.0 M, 77 mL) was added methyl (6')-2-((/ -butoxycarbonyl)amino)-3-(4- ((trifluoromethyl)sulfonyloxy)phenyl)propanoate (47) ( 1.64 g, 3.84 mmol) in one portion at 0 °C and the resulting mixture was warmed to room temperature. After 1 h, the reaction mixture was concentrated under reduced pressure. The crude residue was then washed with Et ₂ 0 and collected by filtration to afford S2, which was used in the next step without further purification.

[0455] Methyl ( S)-2-((S)-l -Pivaloylpyrrolidine-2-carboxamido)-3-(4- (trifluoromethylsulfonyloxy)phenyl)propanoate (28a) was prepared from pivaloyl-T-proline and S2 using a procedure analogous to that used for the synthesis of Sl . The title compound was obtained as a white solid (295 mg, 58%). Melting Point: 94-95 °C; Optical Rotation: [a] ²² D = -14 ( c 0.55, CHCh); ¾ NMR (600 MHz, CDCh): d 7.27-7.24 (m, 2H), 7.20-7.16 (m, 2H), 6.98 (d, J= 7.5 Hz, 1H), 4.81 (q, J= 6.8 Hz, 1H), 4.58-4.56 (m, 1H), 3.71 (s, 3H), 3.68-3.64 (m, 1H), 3.59-3.52 (m, 1H), 3.22 (dd, J= 14.1, 5.6 Hz, 1H), 3.06 (dd, J= 14.1, 6.7 Hz, 1H), 2.14-2.07 (m, 1H), 1.93-1.84

(m, 3H), 1.23 (s, 9H); ¹³ C NMR (l 76 MHz, CDCh): d 178.0, 172.0, 171.7, 148.7, 137.1, 131.3, 121.4, 118.9 (q, J= 320.9 Hz), 62.0, 53.1, 52.6, 48.5, 39.2, 37.4, 27.5, 27.1, 25.9; ¹⁹ F NMR (376 MHz, CDCh): d -72.1 ; HRMS (ESI): Calc’d for C21H28F3N2O7S [M+H] ⁺ : 509.1564, found:

509.1547.

[0456] Methyl Pivaloyl-E-prolyl-E-phenylalaninate (28b) was prepared from pivaloyl-E-proline and E-phenylalanine methyl ester hydrochloride using a procedure analogous to that used for the synthesis of Sl . The title compound was obtained as a white solid (1.13 g, 63%). Melting Point: 80-82 °C; Optical Rotation: [a] ²² o = -27 (c 0.55, CHCh); ¾ NMR (700 MHz, CDCI3): d 7.26 (t, J = 7.3 Hz, 2H), 7.21 (t, J= 7.3 Hz, 1H), 7.12 (d, J= 7.3 Hz, 2H), 6.90 (br, 1H), 4.79 (q, J= 6.8 Hz, 1H), 4.60 (dd, J= 7.9, 3.1 Hz, 1H), 3.69 (s, 3H), 3.66-3.62 (m, 1H), 3.53 (br, 1H), 3.15 (dd, J =

14.0, 5.7 Hz, 1H), 3.03 (dd, = l4.0, 6.7 Hz, 1H), 2.15-2.13 (m, 1H), 1.88-1.83 (m, 3H), 1.20 (s, 9H); ¹³ C NMR (176 MHz, CDCI3): d 177.8, 172.0, 171.8, 136.2, 129.3, 128.6, 127.1, 61.9, 53.3, 52.4, 48.4, 39.2, 38.0, 27.5, 27.1, 25.6; HRMS (ESI): Calc’d for C20H29N2O4 [M+H] ⁺ : 361.2122, found: 361.2123.

[0457] Dimethyl Pivaloyl-E-prolyl-E-aspartate (28c) was prepared from pivaloyl-E-proline and E- aspartic acid dimethyl ester hydrochloride using a procedure analogous to that used for the synthesis of Sl . The title compound was obtained as a colorless oil (745 mg, 62%). Optical Rotation: [a] ²² _D =

- 24 (c 0.80, CHCh); ¾ NMR (600 MHz, CDCh): d 7.13 (d, J= 8.0 Hz, 1H), 4.80 (dt, J= 9.0, 4.6 Hz, 1H), 4.55 (dd, J= 8.0, 3.6 Hz, 1H), 3.73 (s, 3H), 3.72-3.68 (m, 2H), 3.67 (s, 3H), 2.97 (dd, J = 17.0, 4.6 Hz, 1H), 2.84 (dd, = l7.0, 4.6 Hz, 1H), 2.16-1.88 (m, 4H), 1.26 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): d 177.7, 172.2, 171.4, 171.2, 62.0, 52.8, 52.1, 48.6, 48.5, 39.2, 36.2, 27.5 ( Two ^I3 C signal is overlapping with others), HRMS (ESI): Calc’d for Ci ₆ H ₂₆ N ₂ Na0 ₆ [M+Na] ⁺ : 365.1683, found: 365.1680.

28e

[0459] Methyl C-(/ /v-Butyl)-A'-(pivaloyl-E-prolyl)-E-serinate (28e) was prepared from pivaloyl- E-proline and (9-/er/-butyl-E-serine methyl ester hydrochloride using a procedure analogous to that used for the synthesis of Sl . The title compound was obtained as a colorless oil (493 mg, 69%).

Optical Rotation: [a] ²² o = - 37 (c 0.84, CHCh); ¾ NMR (700 MHz, CDCb): d 6.88 (d, J= 8.9 Hz,

1H), 4.64 (dt, = 8.0, 3.1 Hz, 1H), 4.60 (dd, J= 8.9, 3.2 Hz, 1H), 3.76 (dd, J= 8.9, 3.2 Hz, 1H), 3.74- 3.67 (m, 2H), 3.70 (s, 3H), 3.55 (dd, J= 8.9, 3.2 Hz, 1H), 2.18-2.10 (m, 1H), 2.09-2.01 (m, 1H), 2.02-1.89 (m, 2H), 1.27 (s, 9H), 1.11 (s, 9H); ¹³ C NMR (176 MHz, CDCb): d 177.6, 172.2, 171.1, 73.4, 62.0, 61.9, 53.0, 52.4, 48.5, 39.2, 27.6, 27.4 ( Two ¹³ C signal is overlapping with others), HRMS (ESI): Calc’d for Ci ₈ H ₃₂ N ₂ Na0 ₄ [M+Na] ⁺ : 379.2203, found: 379.2216.

[0460] Methyl C-(/ -butyl)-A'-(pivaloyl-E-prolyl)-E-threoninate (28f) was prepared from pivaloyl-E-proline and (9-/er/-butyl-E-threonine methyl ester hydrochloride using a procedure analogous to that used for the synthesis of S 1. The title compound was obtained as a white solid (925 mg, 71%). Melting Point: 56-58 °C; Optical Rotation: [a] ²² _D = ^— 51 (c 0.95, CHCh); ¾

NMR (600 MHz, CDCh): d 6.86 (d, J= 9.0 Hz, 1H), 4.67 (dd, J = 8.2, 3.0 Hz, 1H), 4.45 (dd, J = 9.0, 1.7 Hz, 1H), 4.17 (qd, J= 6.3, 1.7 Hz, 1H), 3.71-3.69 (m, 2H), 3.66 (s, 3H), 2.16 (ddd, J = 10.9, 6.7, 3.0 Hz, 1H), 2.04 (dt, J= 15.8, 7.5 Hz, 1H), 1.99-1.87 (m, 2H), 1.26 (s, 9H), 1.12 (d, = 6.3 Hz, 3H), 1.07 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 177.4, 172.6, 171.3, 74.0, 67.6, 61.9, 57.8, 52.1, 48.4, 39.2, 28.4, 27.6, 20.9 (Two ¹³ C signal is overlapping with others), HRMS (ESI): Calc’d for C19H35N2O5 [M+H] ⁺ : 371.2540, found: 371.2543.

[0461] Methyl pivaloyl-E-prolyl-E-methioninate (28g) was prepared from pivaloyl-E-proline and E-methionine methyl ester hydrochloride using a procedure analogous to that used for the synthesis of S 1. The title compound was obtained as a clear oil (1.18 g, 69%). Optical Rotation: [a] ²² _D = ^— 43

(c 1.3, CHCh); ¾ NMR (400 MHz, CDCh): d 7.09 (d, = 7.4 Hz, 1H), 4.66-4.55 (m, 2H), 3.72 (s, 3H), 3.70-3.62 (m, 2H), 2.47 (dd, J= 8.1, 7.1 Hz, 2H), 2.21-2.08 (m, 3H), 2.06 (s, 3H), 2.02-1.85 (m, 3H), 1.25 (s, 9H); ¹³ C NMR (l 0l MHz, CDCh): d 177.9, 172.4, 172.0, 61.8, 52.5, 51.5, 48.5, 39.2, 31.8, 29.9, 27.6, 15.5 (Two ^I3 C signal is overlapping with others), HRMS (ESI): Calc’d for Ci ₆ H ₂₈ N ₂ Na0 ₄ S[M+Na] ⁺ : 367.1662, found: 367.1677.

[0462] Methyl Pivaloyl-T-prolyl-T-valyl-T-phenylalaninate (30) was prepared from Sl and L- phenylalanine methyl ester hydrochloride using a procedure analogous to that used for the synthesis of 21. The title compound was obtained as a white solid (2.75 g, 94% over 2 steps). Melting Point: 123-125 °C; Optical Rotation: [a] ²² _D = -38 (c 1.2, CHCb); ¾ NMR (700 MHz, CDCb): d 7.28 (t,

J= 7.5 Hz, 2H), 7.22 (t, = 7.5 Hz, 1H), 7.13 (d, = 7.5 Hz, 2H), 7.09 (d, = 7.l Hz, 1H), 6.53 (d, J= 7.4 Hz, 1H), 4.85 (dt, J= 7.9, 6.2 Hz, 1H), 4.66 (dd, J= 8.3, 3.3 Hz, 1H), 4.20 (dd, J= 8.5, 5.5 Hz, 1H), 3.75-3.72 (m, 1H), 3.69 (s, 3H), 3.68-3.65 (m, 1H), 3.14 (dd, J= 13.9, 5.9 Hz, 1H), 3.08 (dd, J= 13.9, 6.6 Hz, 1H), 2.25-2.19 (m, 2H), 2.1 1-2.05 (m, 1H), 1.97-1.92 (m, 1H), 1.91-1.86 (m, 1H), 1.28 (s, 9H), 0.86 (d, J= 6.8 Hz, 3H), 0.80 (d, J= 6.8 Hz, 3H); ¹³ C NMR (176 MHz, CDCb): d

178.2, 172.1 , 171.8, 170.8, 136.0, 129.4, 128.7, 127.2, 61.9, 58.5, 53.2, 52.4, 48.5, 39.4, 38.0, 30.1 , 27.6, 23.3, 19.5, 17.4 ( One ¹³ C signal is overlapping with others), HRMS (ESI): Calc’d for

C25H38N3O5 [M+H] ⁺ : 460.2806, found: 460.2803.

Example 3. Experimental Procedures for the Silver-Mediated Halogenation

[0463] Table Sl . Optimization Details

AgN0 ₃

(NH ₄ ) ₂ S ₂ 0 ₈

NCS (4 equiv.)

- ►

acetone: H ₂ 0 (1 :9)

RT, 30 min

1 a

AgN0 ₃ (equiv.) (NH ₄ ) ₂ S ₂ 0 ₈ (equiv.) yield (%)*

f. Representative Procedure for Deconstructive Chlorination

[0464] To a l -dram vial was added sequentially la (33.9 mg, 0.200 mmol), AgNCh (136 mg,

0.800 mmol), ammonium persulfate (183 mg, 0.800 mmol), /V-chlorosuccinimide (NCS: 107 mg, 0.800 mmol) and 1.0 mL of a 1 :9 acetone: H ₂ 0 solution. The resulting mixture was allowed to stir at room temperature. After 30 min, the reaction mixture was partitioned with EtOAc (0.5 mL) and FLO (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (1.5 mL x 3) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (33% EtO Ac/hexanes) to provide A-(4- chlorobutyl)pivalamide (2a) (47.3 mg, 81%) as a colorless oil. ¾ NMR (600 MHz, CDCh): d 5.76 (br, 1H), 3.54 (t, J= 6.5 Hz, 2H), 3.26 (q, J= 6.5 Hz, 2H), 1.78 (quint, J= 6.5 Hz, 2H), 1.65 (quint, J= 6.5 Hz, 2H), 1.17 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 178.8, 44.7, 38.84, 38.77, 29.9, 27.7, 27.1 ; HRMS (ESI): Calc’d for C9H19CINO [M+H] ⁺ : 192.1150, found: 192.1146.

[0465] tv - Butyl (4-chlorobutyl)carbamate (2b) and tert- butyl (4-chlorobutyl)(formyl)carbamate

(3b): The title compounds were prepared according to the representative procedure using lb.

Purification by preparative thin-layer chromatography (10% EtO Ac/hexanes) provided 2b (4.8 mg, 12%) as a colorless oil and 3b (19.0 mg, 40%) as a colorless oil.

[0466] tert- Butyl (4-chlorobutyl)carbamate (2b): 'H NMR (600 MHz, CDCh): d 4.56 (br, 1H), 3.55 (t, = 7.0 Hz, 2H), 3.15 (q, J= 7.0 Hz, 2H), 1.80 (quint, J= 7.0 Hz, 2H), 1.63 (quint, = 7.0

Hz, 2H), 1.43 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): d 156.1, 79.4, 44.7, 39.9, 29.9, 28.5, 27.7; HRMS (ESI): Calc’d for C9H19CINO2 [M+H] ⁺ : 208.1099, found: 208.1099. [0467] /7- Butyl (4-chlorobutyl)(formyl)carbamate (3b): 'H NMR (500 MHz, CDCh): d 9.17 (s,

1H), 3.61 (t, = 7.0 Hz, 2H), 3.54 (t, J= 6.3 Hz, 2H), 1.79-1.73 (m, 2H), 1.71-1.66 (m, 2H), 1.54 (s, 9H); ¹³ C NMR (126 MHz, CDCh): d 163.2, 152.5, 84.2, 44.5, 39.8, 29.8, 28.2, 25.8; HRMS (ESI): Calc’d for CioHisClNNaC [M+Na] ⁺ : 258.0867, found: 258.0863.

[0468] N-(4-Chlorobutyl)benzamide (2c) and N-(4-chlorobutyl)-N-formylbenzamide (3c): The title compounds were prepared according to the representative procedure using lc. Purification by preparative thin-layer chromatography (10% EtO Ac/hexanes) provided N-(4-chlorobutyl)benzamide (2c) (19.8 mg, 47%) as a white solid and N-(4-chlorobutyl)-N-formylbenzamide (3c) (9.6 mg, 20%) as a pale yellow oil.

[0469] A-(4-chlorobutyl)benzamide (2c): Melting Point: 47-49 °C; 'H NMR (600 MHz, CDCh): d 7.76 (d, J= 7.4 Hz, 2H), 7.47 (d, J= 7.4 Hz, 1H), 7.39 (d, J= 7.4 Hz, 2H), 6.56 (br, 1H), 3.55 (t, J = 6.9 Hz, 2H), 3.45 (q, = 6.9 Hz, 2H), 1.83 (quint, J= 6.9 Hz, 2H), 1.75 (quint, J= 6.9 Hz, 2H);

¹³ C NMR (151 MHz, CDCh): d 167.8, 134.6, 131.5, 128.6, 127.0, 44.7, 39.3, 30.0, 27.1 ; HRMS (ESI): Calc’d for C11H15CINO [M+H] ⁺ : 212.0837, found: 212.0837.

[0470] A-(4-chlorobutyl)-A-formylbenzamide (3c): ¾ NMR (600 MHz, CDCh): d 8.93 (s, 1H), 7.57 (t, = 7.2 Hz, 1H), 7.53-7.48 (m, 4H), 3.91 (t, = 7.0 Hz, 2H), 3.58 (t, = 6.2 Hz, 2H), 1.87- 1.79 (m, 4H); ¹³ C NMR (l 5l MHz, CDCh): d 172.4, 164.3, 133.6, 132.4, 129.1 , 128.9, 44.5, 39.8, 30.1, 25.6; HRMS (ESI): Calc’d for C12H15CINO2 [M+H] ⁺ : 240.0786, found: 240.0787.

[0471] /V-(3-Chloropropyl)pivalamide (2d): The title compound was prepared according to the representative procedure using ld. Purification by preparative thin-layer chromatography (20% EtO Ac/hexanes) provided the title compound (27.4 mg, 77%) a colorless oil. 'H NMR (500 MHz, CDCh): d 6.10 (br, 1H), 3.54 (t, J = 6.6 Hz, 2H), 3.36 (q, J = 6.6 Hz, 2H), 1.96 (quint, J = 6.6 Hz, 2H), 1.15 (s, 9H); ¹³ C NMR (126 MHz, CDCh): d 179.2, 42.8, 38.7, 37.4, 32.0, 27.6; HRMS (ESI): Calc’d for CsHieClNNaO [M+Na] ⁺ : 200.0813, found: 200.0809.

Cl

ran

Piv [0472] L'- ( 5 - C h 1 o ro p en ty 1 ) p i va 1 a 111 i de (2e): The title compound was prepared according to the representative procedure using le. Purification by preparative thin-layer chromatography (20%

EtO Ac/hexanes) provided the title compound (22.6 mg, 55%) as a colorless oil. 'H NMR (500 MHz,

CDCh): d 5.72 (br, 1H), 3.52 (t , J= 6.6 Hz, 2H), 3.23 (q, J= 6.3 Hz, 2H), 1.77 (quint, J= 6.6 Hz, 2H), 1.54-1.41 (m, 4H), 1.17 (s, 9H); ¹³ C NMR (126 MHz, CDCh): d 178.6, 45.0, 39.3, 38.7, 32.1, 28.9, 27.7, 24.1 ; HRMS (ESI): Calc’d for CioH ₂₀ ClNaNO [M+Na] ⁺ : 228.1126, found: 228.1126.

Piv Piv

2f 3f

[0473] A'-(6-Chlorohexyl)pivalamide (2f) and A'-(6-chlorohexyl)-A'-forniylpivalaniide (3f): The title compounds were prepared according to the representative procedure using lf. Purification by preparative thin-layer chromatography (20% EtO Ac/hexanes) provided 2f (13.3 mg, 30%) as a colorless oil and 3f (10.7 mg, 22%) as a colorless oil.

[0474] A-(6-Chlorohexyl)pivalamide (2f): ¾ NMR (600 MHz, CDCh): d 5.66 (br, 1H), 3.51 (t, J = 6.7 Hz, 2H), 3.21 (t, J= 6.7 Hz, 2H), 1.75 (quint, J= 6.7 Hz, 2H), 1.49 (quint, J= 6.7 Hz, 2H), 1.44 (quint, J= 6.7 Hz, 2H), 1.32 (quint, J= 6.7 Hz, 2H), 1.17 (s, 9H); ¹³ C NMR (l 5l MHz,

CDCh): d 178.5, 45.1, 39.5, 38.7, 32.5, 29.6, 27.7, 26.6, 26.2; HRMS (ESI): Calc’d for

CnH ₂₂ ClNNaO [M+Na] ⁺ : 242.1282, found: 242.1285.

[0475] M-(6-chlorohexyl)-M-formylpivalamide (3f): ¾ NMR (600 MHz, CDCh): d 9.37 (s, 1H), 3.70 (t, J= 7.6 Hz, 2H), 3.52 (t, J= 6.8 Hz, 2H), 1.76 (quint, J = 6.8 Hz, 2H), 1.50 (quint, J= 7.6 Hz, 2H), 1.45 (quint, J= 7.6 Hz, 2H), 1.37 (s, 9H), 1.34-1.27 (m, 2H); ¹³ C NMR (151 MHz, CDCh): d 179.3, 163.2, 45.1, 41.2, 40.8, 32.6, 28.8, 28.0, 26.6, 26.3; HRMS (ESI): Calc’d for Ci ₂ H ₂₂ ClNNa0 ₂ [M+Na] ⁺ : 270.1231, found: 270.1232.

Piv

[0476] N-(5-Chloropentan-2-yl)pivalamide (2g): The title compound was prepared according to the representative procedure using lg. Purification by preparative thin-layer chromatography (20% EtO Ac/hexanes) provided the title compound (30.4 mg, 74%) as a colorless oil. 'H NMR (500 MHz, CDCh): d 5.36 (br, 1H), 4.01 (hept, J= 6.5 Hz, 1H), 3.55 (t, J= 6.5 Hz, 2H), 1.83-1.73 (m, 2H), 1.66-1.59 (m, 1H), 1.56-1.50 (m, 1H), 1.18 (s, 9H), 1.14 (d, J= 6.5 Hz, 3H); ¹³ C NMR (l 5l MHz, CDCh): d 178.6, 45.0, 44.7, 38.7, 34.2, 29.3, 27.6, 21.2; HRMS (ESI): Calc’d for Ci ₀ H ₂₀ ClNNaO [M+Na] ⁺ : 228.1126, found: 228.1121.

Piv

[0477] N-(4-Chloro-3-methylbutyl)pivalamide (2h): The title compound was prepared according to the representative procedure using lh. Purification by preparative thin-layer chromatography (20% EtO Ac/hexanes) provided the title compound (32.9 mg, 80%) as a colorless oil. 'H NMR (600 MHz, CDCh): d 5.82 (br, 1H), 3.45 (dd, J= 10.8, 5.5 Hz, 1H), 3.42 (dd, J= 10.8, 5.5 Hz, 1H),

3.29 (dq, = 13.6, 6.4 Hz, 1H), 3.21 (dq, = l3.6, 6.4 Hz, 1H), 1.87-1.80 (m, 1H), 1.67 (dq, = 13.8, 6.4 Hz, 1H), 1.40 (dq, J= 13.8, 6.4 Hz, 1H), 1.15 (s, 9H), 1.00 (d, J= 6.7 Hz, 3H); ¹³ C NMR (151 MHz, CDCh): d 178.8, 50.8, 38.7, 37.4, 33.7, 33.5, 27.6, 17.8; HRMS (ESI): Calc’d for CioH ₂ oClNNaO [M+Na] ⁺ : 228.1126, found: 228.1118.

[0478] Ethyl 2-(Chloromethyl)-4-pivalamidobutanoate (2i): The title compound was prepared according to the representative procedure using li. Purification by preparative thin-layer

chromatography (30% EtO Ac/hexanes) provided the title compound (38.5 mg, 73%) as a colorless oil. ¾ NMR (600 MHz, CDCh): d 5.97 (br, 1H), 4.22-4.14 (m, 2H), 3.73 (dd, J= 11.0, 6.2 Hz, 1H), 3.66 (dd, J= 11.0, 6.2 Hz, 1H), 3.33 (dq, J= 13.0, 6.6 Hz, 1H), 3.23 (dq, J= 13.0, 6.6 Hz, 1H),

2.74 (quint, J= 6.2 Hz, 1H), 1.92-1.83 (m, 2H), 1.26 (t, = 7.1 Hz, 3H), 1.16 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 178.9, 172.7, 61.3, 45.8, 44.7, 38.8, 37.4, 29.4, 27.6, 14.3; HRMS (ESI): Calc’d for Ci ₂ H ₂₂ ClNNa0 ₃ [M+Na] ⁺ : 286.1180, found: 286.1172.

Piv [0479] trans-N-(2-(2-Chloroethyl)cyclohexyl)pivalamide (2j): The title compound was prepared according to the representative procedure using lj. Purification by preparative thin-layer

chromatography (50% EtO Ac/hexanes) provided the title compound (18.4 mg, 38%) as a white solid. Melting Point: 95-98 °C; ¾ NMR (600 MHz, CDCh): d 5.41 (d, J= 9.1 Hz, 1H), 3.61 (qd, J = 11.0, 4.0 Hz, 1H), 3.56-3.52 (m, 1H), 3.37 (td, J= 10.0, 5.3 Hz, 1H), 2.06-1.98 (m, 1H), 1.95- 1.82 (m, 2H), 1.77-1.62 (m, 3H), 1.46-1.27 (m, 2H), 1.23-1.18 (m, 1H), 1.20 (s, 9H), 1.13-0.98 (m,

2H); ¹³ C NMR (176 MHz, CDCh): d 178.1, 51.6, 41.6, 38.9, 35.9, 34.1, 32.8, 30.9, 27.8, 25.6, 25.3; HRMS (ESI): Calc’d for Ci ₃ H ₂₅ ClNO [M+H] ⁺ : 246.1619, found: 246.1613.

[0480] Methyl (S)-5-Chloro-2-pivalamidopentanoate (2k): The title compound was prepared according to the representative procedure using lk. Purification by preparative thin-layer chromatography (30% EtO Ac/hexanes) provided the title compound (21.5 mg, 43%) as a colorless oil along with recovered lk (13.2 mg, 29%). Optical Rotation: [a] ²² _D = +12 ( c 0.51 , CHCh); ¾ NMR (600 MHz, CDCh): d 6.22 (d, J= 7.3 Hz, 1H), 4.60 (dt, J= 7.3, 5.1 Hz, 1H), 3.75 (s, 3H), 3.54 (t, J= 6.0 Hz, 2H), 2.05-2.00 (m, 1H), 1.86-1.71 (m, 3H), 1.20 (s, 9H); ¹³ C NMR (151 MHz, CDCb): d 178.6, 173.0, 52.6, 51.5, 44.3, 38.9, 30.0, 28.5, 27.5; HRMS (ESI): Calc’d for

CnH ₂ oClNNa0 ₃ [M+Na] ⁺ : 272.1024, found: 272.1027.

Piv

[0481] Methyl (A)-4-Chloro-2-pivalamidobutanoate (21): The title compound was prepared according to the representative procedure using 11. Purification by preparative thin-layer chromatography (30% EtO Ac/hexanes) provided the title compound (25.0 mg, 53%) as a white solid along with recovered 11 (10.7 mg, 25%). Melting Point: 51-54 °C; Optical Rotation: [a] ²² _D = +22 ( c 0.70, CHCb); ¾ NMR (600 MHz, CDCb): d 6.34 (d, J= 6.0 Hz, 1H), 4.68 (dt, J= 6.7, 6.0 Hz,

1H), 3.76 (s, 3H), 3.56 (dt, J= 11.1, 6.7 Hz, 1H), 3.53 (dt, J= 11.1, 6.7 Hz, 1H), 2.38 (dq, J= 13.0, 6.7 Hz, 1H), 2.19 (dq, J= 13.0, 6.7 Hz, 1H), 1.21 (s, 9H); ¹³ C NMR (151 MHz, CDCb): d 178.6,

172.5, 52.8, 50.5, 40.8, 38.9, 35.1, 27.5; HRMS (ESI): Calc’d for CioH ₁₈ ClNNa0 ₃ [M+Na] ⁺ :

258.0867, found: 258.0873. g· Representative Procedure for Deconstructive Bromination

1a 4a [0482] A'- (4 -b ro o b uty 1 ) p i val a i de (4a): To a l-dram vial was added sequentially la (36.7 mg,

0.200 mmol), AgN0 ₃ (135 mg, 0.800 mmol), ammonium persulfate (182 mg, 0.800 mmol), N- bromosuccinimide (NBS: 142 mg, 0.800 mmol) and 1.0 mL of a 1 :9 acetone: H ₂ 0 solution. The resulting mixture was allowed to stir at room temperature. After 30 min, the reaction mixture was partitioned with EtO Ac (0.5 mL) and fbO (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtO Ac (1.5 mL x 3) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (33% EtO Ac/hexanes) to provide A'-(4-broniobutyl)benzamide (4a) (25.4 mg, 54%) as a yellow waxy solid. ¾ NMR (400 MHz, CDCb): d 5.67 (s, 1H), 3.43 (t, J= 7.0 Hz, 2H), 3.27 (q, J= 7.0 Hz, 2H), 1.88 (quint, J= 7.0 Hz, 2H), 1.66 (quint, J= 7.0 Hz, 2H), 1.19 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh) d 178.7, 38.8, 38.7, 33.5, 30.2, 28.5, 27.8; HRMS (ESI): Calc’d for CsHisBrNNaO [M+Na] ⁺ : 258.0464, found: 258.0459.

Boc Boc

5b 6b [0483] tert-Butyl (4-bromobutyl)carbamate (5b) and tert-butyl (4,4- dibromobutyl)(formyl)carbamate (6b): The title compounds were prepared according to the representative procedure using lb. Purification by preparative thin-layer chromatography (10%

EtO Ac/hexanes) provided 5b (29%) and 6 (36%) as a colorless oil (42.0 mg) consisting of 4:5 inseparable mixture. [0484] terf-Butyl (4-bromobutyl)carbamate (5b): ¾ NMR (600 MHz, CDCh): d 9.17 (s, 1H), 3.61

(t, J= 7.3 Hz, 2H), 3.41 (t, J= 7.3 Hz, 2H), 1.82 (quint, J= 7.3 Hz, 2H), 1.69 (quint, J= 7.3 Hz, 2H), 1.55 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 163.1, 152.6, 84.3, 39.7, 33.1, 28.1, 27.1, 26.9; HRMS (ESI): Calc’d for CioH ₁₈ BrNNa0 ₃ [M+Na] ⁺ : 302.0362, found: 302.0375.

[0485] tert- butyl (4,4-dibromobutyl)(formyl)carbamate (6b): 'H NMR (600 MHz, CDCh): d 9.17 (s, 1H), 5.75 (t, J= 6.1 Hz, 1H), 3.64 (t, J= 7.0 Hz, 2H), 2.38-2.35 (m, 2H), 1.83 (quint, J= 7.0 Hz,

2H), 1.55 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): 163.1, 152.4, 84.5, 45.1, 42.4, 39.0, 30.0, 28.2; HRMS (ESI): Calc’d for CioH ₁₇ Br ₂ NNa0 ₃ [M+Na] ⁺ : 379.9467, found: 379.9477.

[0486] A'-(4-Broniobutyl)benzamide (4c) and A'-(4-broniobutyl)-A'-forniylbenzaniide (5c): The title compounds were prepared according to the representative procedure using lc. Purification by preparative thin-layer chromatography (25% EtO Ac/hexanes) provided 4c (21.9 mg, 43%) as a pale yellow waxy solid and 5c (4.5 mg, 8%) as a white waxy solid. [0487] A-(4-Bromobutyl)benzamide (4c): ¾ NMR (700 MHz, CDCh): d 7.76 (d, J= 7.0 Hz, 2H), 7.50 (t, J= 7.0 Hz, 1H), 7.43 (t, J= 7.0 Hz, 2H), 6.22 (s, 1H), 3.50 (q, = 7.0 Hz, 2H), 3.46 (t, J = 7.0 Hz, 2H), 1.96 (quint, J= 7.0 Hz, 2H), 1.79 (quint, J= 7.0 Hz, 2H); ¹³ C NMR (176 MHz,

CDCh): d 167.8, 134.7, 131.6, 128.7, 127.0, 39.3, 33.5, 30.2, 28.5; HRMS (ESI): Calc’d for CiiHisBrNO [M+H] ⁺ : 256.0332, found: 256.0321.

[0488] A-(4-Bromobutyl)-/V-formylbenzamide (5c): ¾ NMR (600 MHz, CDCh): d 8.93 (s, 1H), 7.58 (t, J= 12 Hz, 1H), 7.54 (d, J= 12 Hz, 2H), 7.50 (t, J= 12 Hz, 2H), 3.91 (t, J= 12 Hz, 2H), 3.45 (t, = 6.6 Hz, 2H), 1.98-1.79 (m, 4H); ¹³ C NMR (l5l MHz, CDCh): d 172.5, 164.4, 133.7, 132.4, 129.2, 129.0, 39.7, 33.0, 30.2, 26.9; HRMS (ESI): Calc’d for Ci ₂ Hi ₄ BrNNa0 ₂ [M+Na] ⁺ : 306.0100, found: 306.0115.

1d 4d S2a

[0489] 2-(tert-butyl)-5,6-dihydro-4H-l,3-oxazin-3-ium bromide (S2a): The title compound was prepared according to the representative procedure using ld. Yield was determined by 'H NMR integration using PtyCH as an internal standard. The characterization data for S2a (30 % NMR yield) was in full agreement with reported literature values.

Piv

[0490] L'- ( 5 - B ro m o pen ty l ) p i va l am i de (4e): The title compound was prepared according to the representative procedure using le. Purification by preparative thin-layer chromatography (25%

EtO Ac/hexanes) provided the title compound (34.0 mg, 68%) as a colorless oil. 'H NMR (400 MHz, CDCh): d 5.66 (s, 1H), 3.40 (t, J= 6.7 Hz, 2H), 3.24 (q, J= 6.7 Hz, 2H), 1.87 (quint, J= 6.7 Hz, 2H), 1.55-1.42 (m, 4H), 1.18 (s, 9H); ¹³ C NMR (101 MHz, CDCh): d 178.6, 39.3, 38.8, 33.8, 32.3, 28.9, 27.8, 25.4; HRMS (ESI): Calc’d for CioH _2i FBrNO [M+H] ⁺ : 250.0801 , found: 250.0805.

Piv

[0491] A'- (6 - B ro m o h ex y 1 )p i va 1 am i de (4f): The title compound was prepared according to the representative procedure using lf. Purification by preparative thin-layer chromatography (25%

EtO Ac/hexanes) provided the title compound (34.3 mg, 65%) as a colorless oil. 'H NMR (700 MHz, CDCh): 5 5.61 (s, 1H), 3.40 (t, J= 6.8 Hz, 2H), 3.25-3.22 (m, 2H), 1.86 (quint, J= 6.8 Hz, 2H), 1.51 (quint, J= 7.5 Hz, 2H), 1.46 (quint, = 7.5 Hz, 2H), 1.37-1.31 (m, 2H), 1.19 (s, 9H); ¹³ C NMR (176 MHz, CDCh): 5 178.5, 39.5, 38.8, 33.9, 32.7, 29.7, 27.9, 27.8, 26.2; HRMS (ESI): Calc’d for CnH ₂₃ BrNO [M+H] ⁺ : 264.0958, found: 264.0952.

l

Piv [0492] N-(5-Bromopentan-2-yl)pivalamide (4g): The title compound was prepared according to the representative procedure using lg. Purification by preparative thin-layer chromatography (25% EtO Ac/hexanes) provided the title compound (26.5 mg, 53%) as a white waxy solid. 'H NMR (400 MHz, CDCh): 5 5.36 (s, 1H), 4.00 (hept, J= 6.6 Hz, 1H), 3.42 (t, J= 6.5 Hz, 2H), 1.92-1.78 (m, 2H), 1.72-1.45 (m, 2H), 1.17 (s, 9H) 1.13 (d, = 6.6 Hz, 3H); ¹³ C NMR (l0l MHz, CDCh): 5 178.0, 44.3, 38.7, 35.7, 33.9, 29.5, 27.7, 21.3; HRMS (ESI): Calc’d for CioH ₂₀ BrNNaO [M+Na] ⁺ :

272.0620, found: 272.0608.

Piv

[0493] N-(4-Bromo-3-methylbutyl)pivalamide (4h): The title compound was prepared according to the representative procedure using lh. Purification by preparative thin-layer chromatography (25% EtO Ac/hexanes) provided the title compound (27.5 mg, 55%) as a colorless oil. 'H NMR

(700 MHz, CDCh): 5 5.63 (s, 1H), 3.43-3.35 (m, 2H), 3.32 (m, 1H), 3.27-3.21 (m, 1H), 1.85 (m, 1H), 1.72-1.68 (m, 1H), 1.45 (dq, J= 13.7, 7.0, 1H) 1.23 (s, 9H), 1.05 (d, = 6.6 Hz, 3H); ^l3 C NMR (176 MHz, CDCb): d 178.6, 41.1, 38.8, 37.4, 34.8, 33.3, 27.7, 19.0; HRMS (ESI): Calc’d for CioH _2i BrNO [M+H] ⁺ : 250.0801, found: 250.0806.

Piv

[0494] Ethyl 2-(Bromomethyl)-4-pivalamidobutanoate (4i): The title compound was prepared according to the representative procedure using li. Purification by preparative thin-layer

chromatography (50% EtO Ac/hexanes) provided the title compound (36.3 mg, 59%) as a colorless oil. ¾ NMR (600 MHz, CDCb): d 5.89 (s, 1H), 4.26-4.16 (m, 2H), 3.60 (dd, J= 10.2, 5.3 Hz, 1H), 3.53 (dd, J= 10.2, 5.3 Hz, 1H), 3.36 (dq, J= 13.2, 5.3 Hz, 1H), 3.24 (dq, J= 13.2, 5.3, 1H), 2.81 (quint, = 5.3 Hz, 1H), 1.97-1.83 (m, 2H), 1.28 (t, = 7.l Hz, 3H), 1.18 (s, 9H); ¹³ C NMR (l 5l

MHz, CDCb): d 178.8, 172.7, 61.4, 45.7, 38.8, 37.4, 32.7, 30.7, 27.7, 14.4; HRMS (ESI): Calc’d for Ci ₂ H ₂₃ BrN0 ₃ [M+H] ⁺ : 308.0856, found: 308.0867.

Piv

[0495] trans-N-(2-(2-Bromoethyl)cyclohexyl)pivalamide (4j): The title compound was prepared according to the representative procedure using lj. Purification by preparative thin-layer

chromatography (50% EtO Ac/hexanes) provided the title compound (18.6 mg, 32%) as a white amorphous solid. ¾ NMR (400 MHz, CDCb): d 5.39 (d, J= 9.5 Hz, 1H), 3.62 (tq, J= 9.5, 3.7 Hz, 1H), 3.54 (dt, J= 10.3, 5.3 Hz, 1H), 3.37 (td, J= 10.3, 5.3 Hz, 1H), 2.11-1.97 (m, 1H), 1.98-1.84 (m, 2H), 1.78-1.59 (m, 3H), 1.49-1.23 (m, 3H), 1.20 (s, 9H), 1.21-0.93 (m, 2H); ¹³ C NMR (l0l MHz, CDCb): d 178.0, 51.7, 41.7, 38.9, 35.9, 34.1, 32.8, 30.9, 27.8, 25.6, 25.4; HRMS (ESI):

Calc’d for Ci ₃ H ₂₄ BrNaO [M+Na] ⁺ : 312.0933, found: 312.0931.

Piv

[0496] Methyl (S)-5-Bromo-2-pivalamidopentanoate (4k): The title compound was prepared according to the representative procedure using lk. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (14.7 mg, 25%) as a colorless oil. Optical Rotation: [a] ²² o = +19 (c 0.58, CHCh); ¾ NMR (700 MHz, CDCh): d 6.18 (d, J= 7.3 Hz, 1H), 4.62 (td, J= 7.3, 5.2 Hz, 1H), 3.77 (s, 3H), 3.42 (t, J= 6.4 Hz, 2H), 2.07-2.02 (m, 1H), 1.96-1.76 (m, 3H), 1.22 (s, 9H); ¹³ C NMR (176 MHz, CDCh): d 178.5, 173.1 , 52.7, 51.4, 38.9, 33.0, 31.4, 28.7, 27.6; HRMS (ESI): Calc’d for CnH ₂ oBrNNa0 ₃ [M+Na] ⁺ : 316.0519, found:

316.0519. h. Skeletal Remodeling of Cyclic Amines

Piv Piv

7 9

[0497] N-(2-( \ -((2-Nitrophenyl)sulfonyl)-5-oxopyrrolidin-3-yl)ethyl)pivala mide (9): The title compound was prepared according to the representative procedure for chlorination using 7 with the following modifications: AcetoneftO (1 :1) was used as solvent. Purification by preparative thin- layer chromatography (50% EtO Ac/hexanes) provided the title compound (16.7 mg, 43% yield) as an off-white solid. Melting Point: 139-141 °C; ¾ NMR (600 MHz, CDCh): d 8.46-8.43 (m, 1H), 7.81-7.76 (m, 2H), 7.76-7.73 (m, 1H), 5.77 (brs, 1H), 4.18 (dd, J= 10.0, 7.7 Hz, 1H), 3.69 (dd, J = 10.0, 7.7 Hz, 1H), 3.34-3.26 (m, 2H), 2.67 (dd, J= 17.2, 7.7 Hz, 1H), 2.54 (hept, J= 7.7 Hz, 1H), 2.27 (dd, J= 17.2, 7.7 Hz, 1H), 1.79-1.69 (m, 2H), 1.19 (s, 9H); ¹³ C NMR (l5l MHz, CDCh): d 178.9, 172.9, 148.1, 135.1, 134.7, 132.2, 131.6, 124.4, 52.5, 38.8, 38.6, 37.6, 33.9, 30.7, 27.7;

HRMS (ESI): Calc’d for CnHasNsNaOeS [M+Na] ⁺ : 420.1200, found: 420.1198.

[0498] N-(4-Chloro-3-(chloromethyl)butyl)pivalamide (11): The title compound was prepared according to the representative procedure for chlorination using 10. Purification by preparative thin- layer chromatography (30% EtO Ac/hexanes) provided the title compound (23.5 mg, 49%) as a colorless oil. ¾ NMR (600 MHz, CDCb): d 5.69 (br, 1H), 3.69 (dd, J= 11.3, 6.5 Hz, 2H), 3.66 (dd, J= 11.3, 6.5 Hz, 2H), 3.34 (q, J= 6.5 Hz, 2H), 2.10 (hept, = 6.5 Hz, 1H), 1.69 (q, = 6.5 Hz, 2H), 1.20 (s, 9H); ¹³ C NMR (151 MHz, CDCb): d 178.8, 45.5, 40.6, 38.9, 37.0, 29.9, 27.7; HRMS (ESI): Calc’d for CioHi hNNaO [M+Na] ⁺ : 262.0736, found: 262.0736.

[0499] A'-(2-( l -((2-Nitrophenyl)sulfonyl)azetidin-3-yl)ethyl)pivalamide (12): To a l-dram vial containing a solution of 10 (23.5 mg, 0.0978 mmol) and 2-nitrobenzenesulfonamide (21.8 mg, 0.108 mmol) in DMF (0.5 mL) was added DBU (0.037 mL, 0.25 mmol) at room temperature. The resulting mixture was then heated to 80 °C and held at this temperature. After 15 h, the reaction mixture was cooled to room temperature and was partitioned with EtO Ac (1.0 mL) and FbO (1.0 mL), and the aqueous phase was extracted with EtO Ac (1.0 mL x 4). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by preparative thin- layer chromatography (35% EtO Ac/hexanes) to provide the title compound (18.8 mg, 52%) as pale yellow solid. Melting Point: 151-154 °C; ¾ NMR (600 MHz, CDCb): d 8.03-8.01 (m, 1H), 7.73- 7.70 (m, 2H), 7.69-7.67 (m, 1H), 5.65 (brs, 1H), 4.17 (t, J= 8.0 Hz, 2H), 3.77 (dd, J= 8.0, 6.0 Hz, 2H), 3.21 (q, = 7.0 Hz, 2H), 2.60-2.53 (m, 1H), 1.79 (q, = 7.0 Hz, 2H), 1.18 (s, 9H); ¹³ C NMR (151 MHz, CDCb): 178.8, 148.5, 133.8, 132.0 (2), 130.9, 124.3, 57.0, 38.8, 37.3, 34.1, 27.7, 26.5;

HRMS (ESI): Calc’d for C16H24N3O5S [M+H] ⁺ : 370.1431, found: 370.1421.

[0500] N-(2-(5-oxotetrahydrofuran-3-yl)ethyl)pivalamide (14): The title compound was prepared according to the representative procedure for bromination using 10. Purification by preparative thin- layer chromatography (5% MeOH/CthCh) provided the title compound (18.6 mg, 44% yield) as a white amorphous solid. ¾ NMR (600 MHz, CDCh): d 5.73 (s, 1H), 4.45 (dd, = 9. l, 7.3 Hz, 1H), 3.97 (dd, = 9.l, 7.3 Hz, 1H), 3.38-3.22 (m, 2H), 2.67 (dd, J= 17.3, 8.4 Hz, 1H), 2.57 (hept, J= 7.5 Hz, 1H), 2.22 (dd, J= 17.3, 8.4 Hz, 1H), 1.82-1.55 (m, 2H), 1.19 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): d 178.9, 176.8, 73.1, 38.9, 37.7, 34.6, 33.7, 33.6, 27.7; HRMS (ESI): Calc’d for

CiiHi ₉ NNa0 ₃ [M+Na] ⁺ : 236.1257, found: 236.1256. i. Representative Procedure for Dehomologation of N-Bz Piperidines

1) AgN0 ₃

dibromohydantoin

(NH ₄ ) ₂ S ₂ 0 ₈ .

15

[0501] Phenyl(pyrrolidin-l -yl)methanone (15): To a l-dram vial was added sequentially lc (18.9 mg, 0.100 mmol), AgNCb (67 mg, 0.400 mmol), ammonium persulfate (91.3 mg, 0.400 mmol), 1,3- dibromo-5,5-dimethylhydantoin (dibromohydantoin; 57.1 mg, 0.200 mmol) and a solution of 1 :9 acetone: FbO (0.5 mL) and the resulting mixture was stirred at room temperature. After 2 h, the aqueous phase was extracted with CH2CI2 (3.0 ml x 5). The combined organic layer was dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. The crude residue was triturated with CH2CI2 (3.0 mL) and the precipitated hydantoin was removed by filtration. The filtrate was concentrated under reduced pressure. To the l -dram vial containing the crude alkyl bromide was added sequentially NaO'Bu (28.8 mg, 0.300 mmol) and DMF (0.5 ml). The resulting mixture was stirred at room temperature. After 1.5 h, the reaction mixture was diluted with H2O (0.5 ml) and extracted with CH2CI2 (3.0 ml x 3). The combined organic layer was dried over Na ₂ S0 _4. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (15.6 mg, 89% yield over 2 steps). Spectral data were in full agreement with the reported literature values (38). [0502] One pot procedure: To a l-dram vial was added sequentially lc (18.9 mg, 0.100 mmol),

AgN0 ₃ (67 mg, 0.400 mmol), ammonium persulfate (91.3 mg, 0.400 mmol), l,3-Dibromo-5,5- dimethylhydantoin (dibromohydantoin: 57.1 mg, 0.200 mmol) and 1 :9 acetone: ThO (0.5 mL) and the resulting mixture was stirred vigorously at room temperature. After 2 h, CS ₂ CO ₃ (162 mg, 0.500 mmol) was added. The resulting mixture was heated to 60 °C and stirred for 16 h. The mixture was cooled to room temperature and extracted with CH ₂ CI ₂ (5.0 ml x 3). The combined organic layer was dried over Na ₂ S0 _4. Purification by preparative thin-layer chromatography (50%

EtO Ac/hexanes) provided 15 (2.8 mg, 16% yield).

1) AgNOj

[0503] (3-Methylpyrrolidin-l-yl)(phenyl)methanone (17): The title compound was prepared according to the representative procedure for ring contraction using 16. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (10.4 mg, 44% yield over 2 steps). Spectral data were in full agreement with the reported literature values {48).

1) AgN0 ₃

dibromohydantoin

[0504] (2-Methylpyrrolidin-l-yl)(phenyl)methanone (19): The title compound was prepared according to the representative procedure for ring contraction using 18. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (11.3 mg, 60% yield over 2 steps). Spectral data were in full agreement with the reported literature values (49).

1) AgN0 ₃

dibromohydantoin

[0505] Phenyl(piperidin-l-yl)methanone (lc): The title compound was prepared according to the representative procedure for ring contraction using 20. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (6.6 mg, 35% yield over 2 steps). Spectral data were in full agreement with the reported literature values (37). j. Diversification of Proline-Containing Peptides

[0506] Methyl (fY)-4-Chloro-2-pivalamidobutanoyl)-/.-valyl-/.-alaninate (22): The title compound was prepared according to the representative procedure for chlorination using 21. Purification by column chromatography (S1O2, 25% to 75% EtO Ac/ hexanes) provided the title compound (33.3 mg, 41%) as a white amorphous solid along with recovered 21 (11.5 mg, 15%). Optical Rotation: [a] ²² _D = -49 (c 0.61, CHCh);‘H NMR (700 MHz, CDCh): d 6.97 (d, J= 8.5 Hz, 1H), 6.62 (d, J = 7.4 Hz, 1H), 6.47 (d, = 7.7 Hz, 1H), 4.71 (q, = 7.l Hz, 1H), 4.57 (quint, J= 12 Hz, lH), 4.3l-

4.27 (m, 1H), 3.74 (s, 3 H), 3.67-3.60 (m, 2H), 2.34-2.26 (m, 1H), 2.24-2.14 (m, 2H), 1.41 (d, J = 12 Hz, 3H), 1.21 (s, 9H), 0.95 (d, J= 6.7 Hz, 3H), 0.92 (d, J= 6.7 Hz, 3H); ¹³ C NMR (176 MHz, CDCb): d 179.1 , 173.2, 171.2, 170.4, 58.7, 52.6, 51.4, 48.2, 41.5, 38.9, 34.6, 31.0, 27.6, 19.3, 18.4, 17.9; HRMS (ESI): Calc’d for Ci ₈ H ₃₂ ClN ₃ Na0 ₅ [M+Na] ⁺ : 428.1923, found: 428.1938.

[0507] Methyl Pivaloyl-E-methionyl-E-valyl-E-alaninate (23): To a l-dram vial was added sequentially 22 (40.5 mg, 0.100 mmol), NaSMe (14.0 mg, 0.200 mmol) and DMF (0.4 mL). The resulting mixture was stirred at room temperature. After 2 h, the reaction mixture was diluted with H2O (2.0 ml). The aqueous phase was extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (50% EtO Ac/hexanes) to provide the title compound (38.1 mg, 91%) as a white foam. Optical Rotation: [a] ²² _D = -43 ( c 0.2.8, CHCh); ¾ NMR (600 MHz, CDCh): d 7.10 (d, J= 8.7 Hz, 1H), 6.87 (d, J= 7.4 Hz, 1H), 6.71 (d, J= 7.7 Hz, 1H), 4.67 (q, = 7.1 Hz, 1H), 4.56 (quint, J= 12 Hz, 1H), 4.33 (dd, J= 8.7, 6.4 Hz, 1H), 2.60-2.50

(m, 2H), 2.17-2.11 (m, 1H), 2.10 (s, 3H), 2.08-1.96 (m, 2H), 1.39 (d, J= 12 Hz, 3H), 1.20 (s, 9H), 0.94 (d, J= 6.9 Hz, 3H), 0.91 (d, J= 6.9 Hz, 3H); ¹³ C NMR (151 MHz, CDCh): d 178.9, 173.2, 171.7, 170.5, 58.6, 52.5, 52.5, 48.2, 38.9, 31.1, 31.0, 30.4, 27.6, 19.3, 18.3, 18.0, 15.4; HRMS (ESI): Calc’d for CwHssNsNaOsS [M+Na] ⁺ : 440.2190, found: 440.2183.

[0508] Methyl ((S)-4-(4-Phenyl-lEEl ,2,3-triazol-l -yl)-2-pivalamidobutanoyl)-E-valyl-E-alaninate (24): To a l-dram vial was added sequentially 22 (40.5 mg, 0.100 mmol), NaN3 (13.5 mg, 0.200 mmol) and DMF (0.4 mL). The resulting mixture was heated and held at 70 °C. After 2 h, the reaction mixture was cooled and diluted with H ₂ 0 (2.0 ml). The aqueous phase was extracted with EtOAc (3.0 mL x 3) and the combined organic layers were concentrated under reduced pressure. The crude mixture was directly used for the next reaction. The crude azide and phenyl acetylene (20.2 mg, 0.200 mmol) were suspended in ThiOH/fhO (2:1 v/v, 0.6 ml). CuS0 ₄ (3.18 mg, 0.0200 mmol) and sodium ascorbate (7.92 mg, 0.0400 mmol) were added at room temperature and the reaction mixture was stirred for 5 h. The reaction mixture was diluted with FbO (2.0 ml) and extracted with CH2CI2 (5.0 mL x 3). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (50% EtO Ac/hexanes) to provide the title compound (37.1 mg, 72% over two steps) as a white solid. Optical Rotation: [a] ²² _D = -9.1 ( c 1.2, CHCh); Melting Point: 1 18-120 °C; ¾ NMR (700 MHz, CDCh): d 8.00 (s, 1H), 7.80 (d, = 7.4 Hz, 2H), 7.60 (d, = 8.5 Hz, 1H), 7.39 (t, = 7.4 Hz, 2H), 7.31 (t, = 7.4 Hz, 1H), 7.19 (d, J= 7.4 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 4.70 (q, J= 7.3 Hz, 1H), 4.63 (dt, J= 14.4, 7.3 Hz, 1H), 4.58 (quint, J= 7.3 Hz, 1H), 4.46 (dt, J= 13.8, 6.5 Hz, 1H), 4.41 (dd, J= 8.4, 6.5 Hz, 1H), 3.69 (s, 3H), 2.55-2.37 (m, 2H), 2.22-2.13 (m, 1H),

1.41 (d, J= 7.3 Hz, 3H), 1.20 (s, 9H), 0.98 (d, J= 6.8 Hz, 3H), 0.96 (d, J= 6.8 Hz, 3H); ¹³ C NMR (176 MHz, CDCh): d 179.1, 173.3, 171.3, 170.8, 148.0, 130.5, 128.9, 128.3, 125.9, 120.8, 59.0, 52.5, 50.7, 48.2, 47.2, 38.9, 33.1, 31.0, 27.5, 19.2, 18.2, 18.1 ; HRMS (ESI): Calc’d for

C ₂₆ H ₃₈ N ₆ Na0 ₅ [M+Na] ⁺ : 537.2796, found: 537.2781.

[0509] (L')-4-(((L')- 1 -( ((/>') - 1 -Methoxy-l -oxopropan-2-yl)amino)-3 -methyl- 1 -oxobutan-2- yl)amino)-4-oxo-3-pivalamidobutyl benzoate (25): To a l-dram vial was added sequentially 22 (40.5 mg, 0.100 mmol), benzoic acid (61.0 mg, 0.500 mmol), K2CO3 (34.6 mg, 0.250 mmol) and DMF (0.5 mL). The resulting mixture was heated and held at 90 °C. After 4 h, the reaction mixture was cooled to room temperature and diluted with H ₂ 0 (2.0 ml). The aqueous phase was extracted with EtO Ac (5.0 mL x 3). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (50% EtO Ac/hexanes) to provide the title compound as an amorphous solid. Optical Rotation: [a] ²² _D = -29 (c 0.52, CHCb); ¾ NMR (700 MHz, CDCb): d 8.06 (d, J= 7.4 Hz, 2H), 7.59 (t, J= 7.4 Hz, 1H), 7.47 (t, J= 7.4 Hz, 2H), 7.16 (d, = 8.5 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 6.52 (d, J= 7.5 Hz, 1H), 4.65 (q, J= 7.1 Hz, 1H), 4.62-4.54 (m, 2H), 4.38 (dt, J= 11.7, 5.9 Hz, 1H), 4.33 (dd, J= 8.6, 5.8 Hz, 1H), 3.74 (s, 3H), 2.37-2.29 (m, 1H), 2.28-2.20 (m, 2H), 1.42 (d, J= 12 Hz, 3H), 1.22 (s, 9H), 0.97 (d, = 6.9 Hz, 1H), 0.95 (d, = 6.9 Hz, 1H); ¹³ C NMR (176 MHz, CDCb): d 179.2,

173.3, 171.4, 170.5, 167.1, 133.4, 129.9, 129.9, 128.6, 61.6, 58.8, 52.6, 50.80, 48.2, 38.9, 31.4, 30.8, 27.6, 19.3, 18.3, 17.7; HRMS (ESI): Calc’d for C25H37N3O7 [M+Na] ⁺ : 514.2524, found: 514.2531.

[0510] Methyl (fY)-4-Cyano-2-pivalamidobutanoyl)-T-valyl-T-alaninate (26) and methyl ((S)-2- (/er/-butyl)-5,6-dihydro-4i7-l ,3-oxazine-4-carbonyl)-E-valyl-E-alaninate (27): To a 1 -dram vial containing a solution of 22 (40.5 mg, 0.100 mmol) in DMF (0.5 mL) was add NaCN (19.6 mg,

0.400 mmol) at room temperature. The resulting mixture was stirred at 40 °C. After 15 h, the reaction mixture was cooled to room temperature and diluted with FbO (1.0 ml). The aqueous phase was extracted with EtOAc (1.0 mL x 4). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by preparative thin-layer chromatography (5% MeOH/CH ₂ Cl ₂ ) to provide 26 (16.3 mg, 41%) as a white amorphous solid and 27 (13.3 mg, 36%) as a white amorphous solid.

[0511] Methyl (fY)-4-Cyano-2-pivalamidobutanoyl)-T-valyl-T-alaninate (26): Optical Rotation: [a] ²² D = -42 (c 0.46, CHCb); ¾ NMR (600 MHz, CDCb): d 7.03 (d, J= 8.3 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 6.53 (d, J= 7.6 Hz, 1H), 4.68-4.64 (m, 1H), 4.60-4.54 (m, 1H), 4.30 (dd, J= 8.4, 6.2 Hz, 1H), 3.75 (s, 3H), 2.49-2.39 (m, 2H), 2.24 (dq, J= 13.9, 7.1 Hz, 1H), 2.13 (dq, J= 13.9, 6.8 Hz, 1H), 2.06-2.00 (m, 1H), 1.42 (d, = 7.2 Hz, 1H), 1.22 (s, 9H), 0.95 (d, J= 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H); ¹³ C NMR (151 MHz, CDCI3): d 179.3, 173.2, 170.7, 170.3, 100.1, 58.8, 52.7, 52.1 , 48.2, 39.0, 31.3, 28.2, 27.5, 19.2, 18.4, 18.0, 13.9; HRMS (ESI): Calc’d for Ci^NiNaOs

[M+Na] ⁺ : 419.2265, found: 419.2251. [0512] Methyl ((S)-2-(/er/-Butyl)-5,6-dihydro-4i7-l,3-oxazine-4-carbonyl)- E-valyl-E-alaninate

(27): Optical Rotation: [a ] ²² _D = -82 (c 0.68, CHCl ₃ ); ¾ NMR (600 MHz, CDCh): d 6.64 (d, J= 6.9 Hz, 1H), 6.23 (d, = 4.4 Hz, 1H), 4.49 (quint., J= 12 Hz, 1H), 4.32 (ddd, J= 10.0, 8.6, 5.3 Hz,

1H), 4.11 (d, J= 10.8 Hz, 1H), 3.73 (s, 3H), 3.70 (t, J= 9.5 Hz, 1H), 3.35 (dt, J= 10.0, 6.7 Hz, 1H), 2.68 (ddd, J= 13.3, 8.6, 5.3 Hz, 1H), 2.30 (ddt, J= 13.3, 10.8, 6.7 Hz, 1H), 1.81-1.75 (m ,lH), 1.41 (d, = 7.2 Hz, 3H), 1.21 (s, 9H), 1.00 (d, J= 6.7 Hz, 3H), 0.87 (d, J= 6.7 Hz, 3H); ¹³ C NMR (l 5l

MHz, CDCh): d 179.3, 173.4, 173.0, 169.2, 62.4, 52.5, 51.9, 48.3, 42.0, 38.8, 28.1, 27.6, 27.4, 19.5, 19.2, 17.9; HRMS (ESI): Calc’d for C18H32N3O5 [M+H] ⁺ : 370.2336, found: 370.2331.

[0513] (fV)-2-(/t/7-Butyl)-5,6-dihydro-4//-l ,3-oxazine-4-carbonyl)-T-valyl-T-alaninate (27): To a l-dram vial containing a solution of 22 (40.5 mg, 0.100 mmol) in DMF (0.5 mL) was add DBU

(0.0045 ml, 0.30 mmol) at room temperature. The resulting mixture was stirred at 40 °C. After 13 h, the reaction mixture was cooled to room temperature and diluted with H ₂ 0 (1.0 ml). The aqueous phase was extracted with EtOAc (1.0 mL x 4). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by preparative thin-layer chromatography (5% MeOH/CHiCh) to provide the title compound (15.9 mg, 43%) as a white amorphous solid. The spectroscopic data were in agreement with those reported above. OTf

[0514] Methyl (S)-2-((5)-4-Chloro-2-pivalamidobutanamido)-3-(4-

(trifluoromethylsulfonyloxy)phenyl)propanoate (29a): The title compound was prepared according to the representative procedure for chlorination using 28a. Purification by column chromatography (SiC , 25% to 75% EtOAc/ hexanes) provided the title compound (7.7 mg, 29%) as a white amorphous solid along with recovered 28a (13.2 mg, 52%). Optical Rotation: [a] o = -4.3 (c 0.15, 7.23 (d, J= 8.7 Hz, 2H), 7.20 (d, J= 8.7 Hz, 2H), 6.75 (d, J = 7.6 Hz, 1H), 6.28 (d, = 7.8 Hz, 1H), 4.81 (q, = 7.l Hz, 1H), 4.60 (q, = 6.9 Hz, 1H), 3.72 (s, 3H), 3.65-3.58 (m, 2H), 3.19 (dd, =l4.l , 5.7 Hz, 1H), 3.09 (dd, J= 14.1 , 6.9 Hz, 1H), 2.27-2.21 (m, 1H), 2.18-2.13 (m, 1H), 1.18 (s, 9H); ¹³ C NMR (176 MHz, CDCh): d 179.1, 171.2, 170.8,

148.8, 136.6, 131.2, 121.7, 118.9 (q, J= 320.8 Hz), 53.3, 52.8, 51.3, 41.5, 38.9, 37.3, 34.6, 27.5; ¹⁹ F NMR (376 MHz, CDCh): d -72.1 ; HRMS (ESI): Calc’d for C ₂₀ H ₂₇ CIF ₃ N ₂ O ₇ S [M+H] ⁺ : 531.1174, found: 531.1162.

[0515] Methyl ((S -4-Chloro-2-pivalamidobutanoyl)-E-phenylalaninate (29b): The title compound was prepared according to the representative procedure for chlorination using 28b. Purification by column chromatography (S1O2, 25% to 75% EtOAc/ hexanes) provided the title compound (7.2 mg, 19%) as a white amorphous solid along with recovered 28b (16.7 mg, 46%). Optical Rotation:

[a] ²² _D = +6.6 (c 0.41, CHCh); ¾ NMR (600 MHz, CDCI3): d 7.31-7.28 (m, 2H), 7.25-7.23 (m, 1H), 7.12-7.10 (m, 2H), 6.52 (d, = 7.7 Hz, 1H), 6.31 (d, = 7.7 Hz, 1H), 4.82-4.79 (m, 1H), 4.60

(q, J= 6.9 Hz, 1H), 3.74 (s, 3H), 3.64-3.58 (m, 2H), 3.16 (dd, J= 14.0, 5.6 Hz, 1H), 3.07 (dd, J = 14.0, 6.7 Hz, 1H), 2.25-2.20 (m, 1H), 2.17-2.12 (m, 1H), 1.18 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): d 178.7, 171.6, 170.6, 135.6, 129.3, 128.9, 127.5, 53.5, 52.6, 51.2, 41.5, 38.9, 37.8, 35.2, 27.6; HRMS (ESI): Calc’d for Ci ₉ H ₂₇ ClN ₂ Na0 ₄ [M+Na] ⁺ : 405.1552, found: 405.1551.

[0516] Dimethyl ((5)-4-Chloro-2-pivalamidobutanoyl)-E-aspartate (29c): The title compound was prepared according to the representative procedure for chlorination using 28c. Purification by column chromatography (Si0 ₂ , 25% to 75% EtOAc/ hexanes) provided the title compound (15.9 mg, 44%) as a colorless oil along with recovered 28c (13.6 mg, 40%). Optical Rotation: [a] ²² D = +8.9 (c 1.6, CHCh); ¾ NMR (600 MHz, CDCh): d 7.07 (d, J= 8.2 Hz, 1H), 6.40 (d, J= 7.6 Hz, 1H), 4.85 (dt, J= 8.2, 4.5 Hz, 1H), 4.66 (q, J= 12 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.66 (t, J =

6.8 Hz, 2H), 3.05 (dd, J= 17.3, 4.5 Hz, 1H), 2.81 (dd, J= 17.3, 4.5 Hz, 1H), 2.34-2.27 (m, 1H), 2.19 (dq, = 13.9, 6.8 Hz, 1H), 1.21 (s, 9H). ¹³ C NMR (l5l MHz, CDCh): d 178.8, 171.3, 171.0, 170.8, 53.1, 52.3, 51.2, 48.6, 41.3, 38.9, 36.0, 35.4, 27.6; HRMS (ESI): Calc’d for Ci ₅ H ₂₅ ClN ₂ Na0 ₆ [M+Na] ⁺ : 387.1293, found: 387.1283.

[0517] Dimethyl (fY)-4-Chloro-2-pivalamidobutanoyl)-/.-glutamate (29d): The title compound was prepared according to the representative procedure for chlorination using 28d. Purification by column chromatography (Si0 ₂ , 25% to 75% EtOAc/ hexanes) provided the title compound (13.8 mg, 37%) as a colorless oil along with recovered 28d (15.9 mg, 45%). Optical Rotation: [a] ²² _D = ^— 16 (c 1.3, CHCh); ¾ NMR (600 MHz, CDCh): d 7.00 (d, = 7.7 Hz, 1H), 6.39 (d, = 7.7 Hz, 1H), 4.66 (q, J= 7.0 Hz, 1H), 4.56 (td, J= 7.7, 5.0 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 3.67-3.59 (m, 2H), 2.45-2.34 (m, 2H), 2.33-2.12 (m, 3H), 2.08-1.96 (m, 1H), 1.22 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): d 179.0, 173.3, 171.8, 171.1 , 52.7, 52.1 , 52.0, 51.2, 41.3, 38.9, 35.1 , 30.1 , 27.5, 26.9;

HRMS (ESI): Calc’d for Ci ₆ H ₂₇ ClN ₂ Na0 ₆ [M+Na] ⁺ : 401.1450, found: 401.1448.

Cl

[0518] Methyl 0-(/er/-Butyl)-/V-((6 -4-chloro-2-pivalamidobutanoyl)-E-serinate (29e): The title compound was prepared according to the representative procedure for chlorination using 28e.

Purification by column chromatography (Si0 ₂ , 25% to 75% EtOAc/ hexanes) provided the title compound (12.1 mg, 32%) as a white amorphous solid along with recovered 28e (9.1 mg, 26%). Optical Rotation: [a] ²² o = +6.7 (c 1.3, CHCh); ¾ NMR (600 MHz, CDCh): d 6.76 (d, J= 8.2 Hz, 1H), 6.46 (d, = 7.7 Hz, 1H), 4.72 (dt, = 7.7, 6.6 Hz, 1H), 4.64 (dt, J= 8.2, 3.1 Hz, 1H), 3.84 (dd, J= 9.0, 2.9 Hz, 1H), 3.78-3.71 (m, 1H), 3.75 (s, 3H), 3.70 (dt, J = 11.3, 6.3 Hz, 1H), 3.56 (dd, J = 9.0, 3.3 Hz, 1H), 2.31-2.17 (m, 2H), 1.21 (s, 9H), 1.14 (s, 9H); ¹³ C NMR (l 5l MHz, CDCb): d 178.5, 170.9, 170.6, 73.8, 61.5, 53.1, 52.6, 51.0, 41.5, 38.9, 35.9, 27.6, 27.4; HRMS (ESI): Calc’d for Ci ₇ H _3i ClN ₂ Na0 ₅ [M+Na] ⁺ : 401.1814, found: 401.1823.

, m n

28f 29f

[0519] Methyl (9-(/er/-Butyl)-/V-((5)-4-chloro-2-pivalamidobutanoyl)-E-thr eoninate (29f): The title compound was prepared according to the representative procedure for chlorination using 28f.

Purification by column chromatography (Si0 ₂ , 25% to 75% EtOAc/ hexanes) provided the title compound (11.1 mg, 28%) as a colorless oil along with recovered 28f (14.5 mg, 39%). Optical

Rotation: [a] ²² o = -3.9 (c 1.4, CHCh); ¾ NMK (600 MHz, CDCh): d 6.73 (d, = 8.9 Hz, 1H), 6.46 (d, = 7.8 Hz, 1H), 4.75 (q, = 7.0 Hz, 1H), 4.41 (dd, = 8.9, 1.6 Hz, 1H), 4.25 (qd, = 6.3, 1.6 Hz, 1H), 3.83-3.74 (m, 1H), 3.72 (s, 3H), 3.72-3.63 (m, 1H), 2.32-2.16 (m, 2H), 1.22 (s, 9H), 1.18 (d, = 6.3 Hz, 3H), 1.1 1 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): d 178.4, 171.5, 171.0, 74.4, 67.1 , 58.3, 52.5, 51.0, 41.5, 38.9, 35.9, 28.5, 27.6, 21.4; HRMS (ESI): Calc’d for CisHssCl^NaOs

[M+Na] ⁺ : 415.1970, found: 415.1968.

[0520] Methyl fV)-2-(fY)-4-Chloro-2-pivalamidobutanamido)-4-(methylsulfony l)butanoate (29g): The title compound was prepared according to the representative procedure for chlorination using 28g. Purification by column chromatography (SiCh, 5% MeOH/ DCM) provided the title compound (10.4 mg, 26%) as a colorless oil. Optical Rotation: [a] ²² _D = -7.2 ( c 1.0, CHCh); ¾ NMR (600

MHz, CDCh): d 7.02 (d, J= 7.9 Hz, 1H), 6.34 (d, J= 7.3 Hz, 1H), 4.69 (td, J = 7.9, 4.9 Hz, 1H), 4.57 (td, J= 7.3, 6.1 Hz, 1H), 3.79 (s, 3H), 3.72-3.58 (m, 2H), 3.19-3.04 (m, 2H), 2.95 (s, 3H), 2.54-2.45 (m, 1H), 2.37-2.31 (m, 1H), 2.25-2.17 (m, 2H), 1.23 (s, 9H); ¹³ C NMR (l 5l MHz, CDCh): d 179.4, 171.2, 171.0, 53.2, 51.8, 51.0, 50.8, 41.4, 41.1, 39.0, 34.3, 27.6, 25.0; HRMS (ESI): Calc’d for Ci5H27ClN ₂ Na0 ₆ S [M+Na] ⁺ : 421.1171, found: 421.1168.

30 31

[0521] Methyl ((S)-4-Chloro-2-pivalamidobutanoyl)-E-valyl-E-phenylalaninat e (31): The title compound was prepared according to the representative procedure for chlorination using 30.

Purification by column chromatography (SiCh, 25% to 75% EtOAc/ hexanes) provided the title compound (7.8 mg, 16%) as a white amorphous solid along with recovered 30 (28.5 mg, 62%).

Optical Rotation: [a] ²² o = -12 (c 0.33, CHCh); ¾ NMR (700 MHz, CDCh): d 7.29 (t, J= 7.4 Hz, 2H), 7.24 (t, = 7.4 Hz, 1H), 7.11 (d, J= 7.4 Hz, 2H), 6.81 (d, = 8.4 Hz, 1H), 6.39 (d, J= 8.9 Hz, 1H), 6.38 (d, J= 8.5 Hz, 1H), 4.88 (dt, J= 8.0, 6.1 Hz, 1H), 4.64 (q, = 7.3 Hz, 1H), 4.23 (dd, J = 8.4, 5.9 Hz, 1H), 3.72 (s, 3H), 3.63 (dt, J= 12.7, 6.3 Hz, 1H), 3.60-3.57 (m, 1H), 3.14 (dd, J= 14.0, 5.8 Hz, 1H), 3.09 (dd, = l4.0, 6.3 Hz, 1H), 2.26 (dq, = l2.7, 6.3 Hz, 1H), 2.17-2.11 (m, 2H), 1.21 (s, 9H), 0.89 (d, J= 6.8 Hz, 3H), 0.84 (d, J= 6.8 Hz, 3H); ¹³ C NMR (176 MHz, CDCF): d

179.1, 171.8, 171.0, 170.4, 135.8, 129.3, 128.8, 127.4, 58.7, 53.2, 52.5, 51.4, 41.5, 38.9, 38.1 , 34.5, 30.8, 27.6, 19.3, 17.7; HRMS (ESI): Calc’d for C ₂₄ H ₃₆ ClN ₃ Na0 ₅ [M+Na] ⁺ : 504.2236, found:

504.2216.

21 32 [0522] Methyl ((S)-4-Fluoro-2-pivalamidobutanoyl)-L-valyl-L-alaninate (37): To a l -dram vial was added sequentially 21 (38.3 mg, 0.100 mmol), AgBF ₄ (77.9 mg, 0.400 mmol), Selectfluor ^® (142 mg, 0.400 mmol) and 1 :9 acetone: FFO (0.5 mL) The resulting mixture was allowed to stir at room temperature. After 60 min, the reaction mixture was partitioned with EtOAc (0.5 mL) and FFO (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (1.5 mL x 3) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (50% EtO Ac/hexanes) to provide the title compound (13.9 mg, 36%) as a clear oil along with recovered 21 (13.3 mg, 35%). Optical Rotation:

[a] ²² _D = - 52 (c 0.62, CHCF); ¾ NMR (400 MHz, CDCF): d 6.99 (d, J= 8.5 Hz, 1H), 6.68 (d, J =

7.4 Hz, 1H), 6.54 (d, = 4.6 Hz, 1H), 4.80-4.47 (m, 4H), 4.29 (dd, = 8.5, 5.9 Hz, 1H), 3.74 (s, 3H), 2.38-2.04 (m, 3H), 1.40 (d, J = 12 Hz, 3H), 1.21 (s, 9H), 0.94 (d, J= 6.8 Hz, 3H), 0.91 (d, J =

6.8 Hz, 3H); ¹³ C NMR (l 5l MHz, CDCF): d 179.4, 173.2, 171.3, 170.4, 82.1 (d, J= 163.4 Hz),

58.7, 52.6, 51.4 (d, J= 2.2 Hz), 48.2, 38.9, 32.3 (d, J= 18.9 Hz), 30.7, 27.5, 19.3, 18.3, 17.8; ¹⁹ F NMR (376 MHz, CDCF): -216.7 - -217.3 (m); HRMS (ESI): Calc’d for C ₁₈ H ₃₃ FN ₃ O ₅ [M+H] ⁺ : 390.2399, found: 390.2397. Example 4. Electrochemical Measurements

[0523] Non-aqueous electrochemical experiments were conducted under an Ar atmosphere in 0.1 M NBU ₄ PF ₆ electrolyte in acetonitrile. Cyclic voltammetry experiments were performed using an Epsilon potentiostat from Bioanalytical Systems, Inc. The working electrode was a 3.0 mm diameter glassy carbon disk (from Bioanalytical Systems, Inc.) and was polished between every scan with 0.05-micron alumina powder on a felt pad. The counter electrode was a platinum wire. A silver wire in a porous Vycor tip glass tube fdled with 0.1 M NBu ₄ PF ₆ in acetonitrile was used as a pseudo reference electrode. At the conclusion of the series of experiments, the pseudo-reference potentials were referenced against ferrocene/ferrocenium as an external standard. The scan rate for all cyclic voltammograms was 100 mV/sec unless otherwise noted. All scans were compensated for internal resistance. Data measured with respect to Fc/Fc ⁺ and reported to SCE.

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[0524] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.