WO2020010228A1 - Procédés et composés de fonctionnalisation déconstructive - Google Patents

Procédés et composés de fonctionnalisation déconstructive Download PDF

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WO2020010228A1
WO2020010228A1 PCT/US2019/040547 US2019040547W WO2020010228A1 WO 2020010228 A1 WO2020010228 A1 WO 2020010228A1 US 2019040547 W US2019040547 W US 2019040547W WO 2020010228 A1 WO2020010228 A1 WO 2020010228A1
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substituted
unsubstituted
independently
nhc
moiety
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PCT/US2019/040547
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Richmond SARPONG
Jose B. ROQUE
Yusuke Kuroda
Lucas GÖTTEMANN
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The Regents Of The University Of California
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/04—Formation or introduction of functional groups containing nitrogen of amino groups

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  • 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.
  • 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.
  • 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.
  • 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.
  • ozonolysis (7) and olefin metathesis (2,3) have shifted paradigms in organic chemistry wherein each carbon in Csp
  • 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.
  • R a , R 2 , R 3 , R 4 , R 6 , F, and z2 are as described herein.
  • FIGS. 1A-1C Development of a deconstructive halogenation of cyclic amines.
  • FIG. 1A Representative bioactive molecules containing saturated nitrogen heterocycles.
  • FIG. 1B Representative bioactive molecules containing 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.
  • 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: 3 ⁇ 40 (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.
  • 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.
  • 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. 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.
  • FIG. 6 The structure of compounds 5b and 6b and the HSQC spectrum of the product mixture containing both compounds.
  • 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-.
  • 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.
  • 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.
  • 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-.
  • 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.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • 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
  • heteroatom(s) e.g., N, S, Si, or P
  • the heteroatom(s) 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.
  • heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms
  • a heteroalkyl moiety may include three optionally different heteroatoms
  • a heteroalkyl moiety may include four optionally different heteroatoms
  • 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.
  • 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.
  • 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-.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • heteroalkyl groups 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.
  • 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.
  • the term“heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • 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.
  • heterocycloalkyl examples 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.
  • cycloalkyl means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system.
  • 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.
  • 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.
  • 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.
  • 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.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • 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.
  • 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.
  • multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • 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.
  • multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-l -yl, and
  • a cycloalkyl is a cycloalkenyl.
  • the term“cycloalkenyl” is used in accordance with its plain ordinary meaning.
  • a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system.
  • 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.
  • bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings.
  • 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).
  • 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.
  • bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl.
  • 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.
  • the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring.
  • cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • 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
  • the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • 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.
  • multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring.
  • 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.
  • 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.
  • 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.
  • the cyclic amine is a saturated (i.e. non aromatic cyclic amine).
  • 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.
  • 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.
  • cyclic amine groups are fully saturated.
  • 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.
  • fused bicyclic heterocycloalkyl ring systems contain a monocyclic heterocycloalkyl ring fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl.
  • the bridged or fused bicyclic heterocycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic heterocycloalkyl ring.
  • heterocycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • 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.
  • 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,
  • 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.
  • acyclic amines include, but are not limited to, propylamine, butylamine, pentylamine, hexylamine, heptyamine, and the like.
  • 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.
  • 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.
  • fluoroalkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, fluoropropyl, fluorobutyl, fluoropenytl, and the like.
  • 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 ).
  • 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.
  • R’ or R includes one or more halogen atoms.
  • 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.
  • the halogen is -Cl, -Br, or -I.
  • the haloalkyl amine contains one halogen atom (e.g., -Cl, -Br, or -I).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-imidazo
  • arylene and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • a fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl.
  • heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.
  • 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
  • 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).
  • 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.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • the term“oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.
  • alkylsulfonyl 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”).
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula:
  • 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 ,
  • 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.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • 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.
  • 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.
  • -NR'R includes, but is not limited to, l-pyrrolidinyl and 4-morpholinyl.
  • 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).
  • haloalkyl e.g., -CF3 and -CIFCF3
  • acyl e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 0CH 3 , and the like.
  • Substituents for rings may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the substituents bond to the atom according to the standard rules of chemical
  • each R° may independently be a substituent selected from the group halogen or oxo
  • both R a may each independently be a halogen substituent, O ' BG or both R G 1 together form an oxo substituent, .
  • each R° may independently be halogen, or one R° may independently be an oxo and the other R u will be absent, y° .
  • both R together with
  • 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.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • 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.
  • 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 -, -
  • heteroatom or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • A‘‘substituent group,” as used herein, means a group selected from the following moieties:
  • 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
  • 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
  • -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
  • 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
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • 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‘‘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
  • 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.
  • 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
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • 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 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
  • 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.
  • 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
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • 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
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • 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).
  • 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 alky
  • 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.
  • 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.
  • 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.
  • each lower substituent group is different.
  • 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.
  • 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.
  • 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
  • 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
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • 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.
  • 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.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3 ⁇ 4), 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.
  • 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.
  • a conjugate between a first bioconjugate reactive group e.g., -NFF, -C(0)OH, -N-hydroxysuccinimide, or -maleimide
  • a second bioconjugate reactive group e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate
  • covalent bond or linker e.g.
  • bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e.
  • 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).
  • nucleophilic substitutions e.g., reactions of amines and alcohols with acyl halides, active esters
  • electrophilic substitutions e.g., enamine reactions
  • additions to carbon-carbon and carbon-heteroatom multiple bonds e.g., Michael reaction, Diels-Alder addition.
  • the first bioconjugate reactive group e.g., maleimide moiety
  • the second bioconjugate reactive group e.g. a sulfhydryl
  • the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g. a sulfhydryl).
  • the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g. a sulfhydryl).
  • the first bioconjugate reactive group e.g., -N-hydroxysuccinimide moiety
  • is covalently attached to the second bioconjugate reactive group (e.g. an amine).
  • the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g. a sulfhydryl).
  • the first bioconjugate reactive group (e.g., -sulfo-N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g. an amine).
  • bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example:
  • 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;
  • a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion
  • dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups;
  • 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;
  • amine or sulfhydryl groups e.g., present in cysteine
  • cysteine amine or sulfhydryl groups
  • alkenes which can undergo, for example, cycloadditions, acylation, Michael addition, etc;
  • biotin conjugate can react with avidin or strepavidin to form an avidin-biotin complex or streptavidin-biotin complex.
  • bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein.
  • a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
  • the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
  • an analog 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.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • 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.
  • R-substituted 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.
  • 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.
  • an oxidizing agent is a chemical species that transfers electronegative atoms to another substrate (e.g., a reactant).
  • 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.
  • oxygen oxygen
  • 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).
  • halogen atoms e.g. bromination, dibromination, tribromination, chlorination, dichlorination, trichlorination, iodination, diiodination, triiodination, fluorination, difluorination, trifluorination, etc.
  • 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
  • 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,
  • the halogenating agent is not a fluorinating agent.
  • 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).
  • 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.
  • 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 (A
  • the metal source can be a“copper source”, wherein the transition metal is copper.
  • a copper source include copper(II) sulfate (CuS0 4 ).
  • the metal source can be an“iron source”, wherin the transition metal is iron.
  • an iron source include iron(III) chloride (FeCl ⁇ ,) and iron(I) nitrate (FeNCb)
  • 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.
  • 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.
  • 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,
  • 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,
  • Gadolinium chelate Gadolinium chelate
  • radioisotopes e.g. carbon-l l , nitrogen-l3, oxygen-l 5, fluorine-l 8, rubidium-82
  • fluorodeoxyglucose e.g.
  • a detectable moiety is a monovalent detectable agent or a detectable agent capable of forming a bond with another compound or composition.
  • Radioactive substances e.g., radioisotopes
  • imaging and/or labeling agents include, but are not limited to, 18 F, 32 P,
  • 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.
  • 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.
  • a chemical reaction e.g., bond formation, reductive elimination, condensation, cross- coupling reaction
  • a complementary reactive moiety i.e. a chemical moiety that reacts with the leaving group reactive moiety
  • 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.
  • 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
  • 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.
  • a leaving group is a bioconjugate reactive moiety.
  • 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.
  • the leaving group is designed to facilitate the reaction.
  • 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.
  • the protecting group is covalently bound to a heteroatom that is part of a heteroalkyl, heterocycloalkyl or heteroaryl moiety.
  • 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).
  • the protecting group is an alcohol protecting group.
  • Alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethyls ilyl (TMS), / /V-butyl dimethylsilyl (TBS)).
  • 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.
  • Cbz carbobenzyloxy
  • Moz or MeOZ p-methoxybenzyl carbonyl
  • BOC /7-butyloxycarbonyl
  • FMOC 9- fluorenylmethyloxycarbonyl
  • acetyl Ac
  • benzoyl (Bz) benzyl (Bn
  • variable e.g., moiety or linker
  • a compound or of a compound genus e.g., a genus described herein
  • the unfilled valence(s) of the variable will be dictated by the context in which the variable is used.
  • variable of a compound as described herein 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 ).
  • 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).
  • exogenous refers to a molecule or substance (e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism.
  • an "exogenous promoter” as referred to herein is a promoter that does not originate from the plant it is expressed by.
  • endogenous or endogenous promoter refers to a molecule or substance that is native to, or originates within, a given cell or organism.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • polypeptide refers 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.
  • nucleic acid 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.
  • 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).
  • A adenine
  • C cytosine
  • G guanine
  • T thymine
  • U uracil
  • T thymine
  • Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and/or modified nucleotides.
  • 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.
  • An amino acid moiety refers to a monovalent amino acid (
  • A“protein moiety” or“polypeptide moiety” refers to a monovalent protein, monovalent
  • polypeptide moiety contains less than 50 amino acid residues. In embodiments the protein moiety contains more than 50 amino acid residues.
  • 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.
  • nucleophilic reaction product is the product of the reaction between the haloalkyl amine with the nucleophilic agent (e.g., a monovalent nucleophilic agent).
  • 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.
  • nucleophilic agent 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).
  • the nucleophilic agent includes an enol.
  • the nucleophilic agent is - OH, alcohol, alkoxide anion, hydrogen peroxide, or a carboxylate anion.
  • 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-).
  • the nucleophilic agent is ammonia, azide, amines, nitrites, hydroxylamine, hydrazine, carbazide, phenylhydrazine, semicarbazide, or an amide.
  • the nucleophilic agent includes ammonia, azide, amines, nitrites, hydroxylamine, hydrazine, carbazide, phenylhydrazine, semicarbazide, or an amide.
  • the nucleophilic agent includes -OH, alcohol, alkoxide anion, hydrogen peroxide, or a carboxylate anion.
  • 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-).
  • the nucleophilic agent is a halo-ester. II. Methods of making compounds
  • 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.
  • 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.
  • the saturated cyclic amine has the structure of formula (I)
  • L 1 is independently a bond, -S(0) 2 -,-S(0)-
  • R 8 is independently
  • 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
  • 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,
  • 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 substituent
  • 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.
  • 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)-
  • R 8 is independently
  • R 1 is
  • 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, -SOrance 3
  • 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
  • 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.
  • the saturated cyclic amine has the structure of formula (Iz):
  • 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 ).
  • 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.
  • R 5 is combined with R 2 to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • the haloalkyl amine has the structure of formula (Pz):
  • 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 ).
  • 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.
  • R 6 is combined with R 2 to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • the saturated cyclic amine has the structure of formula (I)
  • R 2 and R 5 have any of the values described herein.
  • the haloalkyl amine has the structure of formula (II):
  • the haloalkyl amine has the structure of formula:
  • the nucleophilic reaction product has the structure of formula:
  • the nucleophilic reaction product has the structure of formula (Ilbz):
  • 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 ).
  • the nucleophilic reaction product has the structure of formula:
  • 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 ).
  • the nucleophilic reaction product has the structure of formula:
  • 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 ).
  • the nucleophilic reaction product has the structure of formula:
  • the nucleophilic reaction product has the structure of formula:
  • the nucleophilic reaction product has the structure of formula:
  • R 6 2 , R 6 3 . andR 64 are each independently a value of R 6 (e.g., embodiments of R 6 ).
  • the nucleophilic reaction product has the structure of formula:
  • nucleophilic reaction product has the structure of formula:
  • R 2 , R 3 , R 4 , and z2 are as described herein, including
  • 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 ).
  • the nucleophilic reaction product has the structure of formula:
  • the nucleophilic reaction product has the structure of formula:
  • 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 ).
  • z2 is an integer from 0 to 8.
  • 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.
  • each R 1 is independently hydrogen, halogen, -CX , -CHXS, - CH2X 1 , -OCXS, -OCH2X 1 , -OCHX ,
  • R 20 is independently 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
  • each R 1 is independently hydrogen, halogen, -CX , -CHX ⁇ , -Ci X 1 , -OCXS, -OCH2X 1 , -OCHX ,
  • R 20 is independently oxo, halogen, -CF3, -CHF 2 , -
  • 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 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -
  • 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.
  • 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.
  • R 22 is independently oxo, halogen, -CF 3 , -CHF2, - CH 2 F, -CN, -OH, -NH2, -C(0)OH,
  • 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.
  • R 22 is independently oxo, halogen, -CF 3 , -CHF 2 , -
  • each L 1 is independently a
  • 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,
  • each L 1 is independently a
  • R 22 is independently oxo, halogen, -CF3, -CHF 2 , -
  • each L 1 is independently a
  • Ci-C 8 alkylene bonds, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-C 8 alkylene.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • each R 8 is hydrogen.
  • each R 4 is hydrogen.
  • 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).
  • CBz carboxybenzyl
  • Moz methoxybenzyl carbonyl
  • BOC tert- Butyloxycarbonyl
  • FMOC Fluorenylmethyloxycarbonyl
  • acyl Ac
  • benzyl ether Bn
  • carbamate
  • R 2 is substituted or unsubstituted alkyl.
  • R 2 is amine protecting group.
  • 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).
  • the saturated cyclic amine has the structure of formula (la):
  • L 1 is independently a -C(O)- or -C(0)0-;
  • R 1 is independently hydrogen, halogen, -CX' 3 , -CHXN, -
  • 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 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 heterocycl
  • 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;
  • R 2 is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • 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, an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • R 2 is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • 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.
  • the method further includes reacting the haloalkyl amine, e.g.,
  • nucleophilic agent e.g., Nuc
  • nucleophilic agent displaces the covalently attached halogen (selected from -Br, -Cl or -I) with a covalently attached
  • nucleophilic reaction product e.g,
  • the method further includes reacting the haloalkyl amine, e.g.,
  • nucleophilic agent e.g., Nuc
  • nucleophilic agent displaces the covalently attached halogen (selected from -Br, -Cl or -I) with a covalently attached
  • 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 ).
  • the nucleophilic agent is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • 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.
  • the nucleophilic agent is -OCHF 2 . In embodiments, the nucleophilic agent is -N 3 .
  • 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.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent 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.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is -CF3.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is -NH 2 .
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is -COOH.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • is -CONH 2 .
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is -SH.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is -SO 2 CI.
  • 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.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is -SO 2 NH 2 .
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is -NHNH 2 .
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • is -ONH 2 .
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • is -NHC (0)NHNH2.
  • the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHSO 2 H.
  • the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHC(0)-OH.
  • the covalently attached substituent (e.g., -(Nuc) of a nucleophilic reaction product) is -NHOH.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is -OCF3.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • 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.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is substituted or unsubstituted heteroalkyl.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is substituted or unsubstituted aryl.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • is detectable moiety e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is a therapeutic moiety.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent is a drug moiety.
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • the covalently attached substituent e.g., -(Nuc) of a nucleophilic reaction product
  • is a bioconjugate reactive moiety e.g., -(Nuc) of a nucleophilic reaction product
  • X a is -Cl.
  • X a is -Br.
  • X a is -I.
  • the reaction between the haloalkyl amine and the nucleophilic agent is an intramolecular reaction.
  • the intramolecular reaction is a cyclization reaction.
  • the nucleophilic reaction product has the formula:
  • the nucleophilic reaction product has the formula:
  • 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 ).
  • R a is hydrogen
  • R a is hydrogen
  • L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
  • L 1 is independently a bond, -S(0) 2 -,-S(0)-
  • 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
  • R 1 is independently hydrogen, halogen, -CXN, -CHXN, -CH2X 1 , -OCX 1 ,,
  • 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, -
  • 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, -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
  • 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. In embodiments, z2 is an integer from 1 to 6
  • R 4 is hydrogen or -C(0)H.
  • L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
  • R 6 is independently -I ⁇ -R 1 , wherein each R 6 is optionally different;
  • the nucleophilic reaction product has the formula:
  • 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.
  • the nucleophilic reaction product has the formula:
  • R , 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 ).
  • the nucleophilic reaction product has the formula:
  • 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 ).
  • the nucleophilic reaction product has the formula:
  • Ring A are as described herein.
  • 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
  • cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl 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).
  • aryl e.g., Ce-Cio aryl, C10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • 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.
  • the halogenating agent is A'-chlorosuccininiide, A'-bromosuccinimide, N- iodosuccinimide, or dibromohydantoin.
  • the halogenating agent is aluminum bromide.
  • the halogenating agent is aluminum chloride.
  • the halogenating agent is bromo phthalimide.
  • the halogenating agent is chloro phthalimide.
  • the halogenating agent is trityl chloride.
  • 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).
  • the reaction occurs under conditions suitable for stabilizing a protein.
  • the conditions includes: an aqueous environment, an aerobic environment and a reaction temperature ranging from 15°C to 30°C.
  • the reacting temperature ranges from 20°C to 25°C.
  • the reacting temperature ranges from 22°C to 23°C.
  • the oxidizing agent is ammonium persulfate.
  • 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.
  • L 1 is independently a bond, -S(0) 2 -, -S(O)-
  • 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 ,
  • 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.
  • R 1 is independently hydrogen, halogen, -CX ⁇ , -CHX' 2 , -CH 2 X', -OCX 1 ,
  • 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 ,
  • 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 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.
  • R 2 is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • R 2 is independently hydrogen or an amine protecting group.
  • R 2 is an amine protecting group.
  • R 2 is substituted or unsubstituted alkyl, CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts.
  • R 3 is independently hydrogen, -Cl, -Br,-
  • R 3 is independently hydrogen
  • 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 n8 are independently an integer from 0 to 4.
  • the symbols ml, vl, m8 and v8 are independently 1 or 2.
  • the symbol z2 is an integer from 0 to 18.
  • R 4 is hydrogen or -C(0)H.
  • z2 is an integer from 0 to 8.
  • z2 is an integer from 1 to 4.
  • R 1 is independently hydrogen, -CF 3 , -CHF2, -CFFF, -OCF3, - OCH2F, -OCHF2,
  • R 1 is independently an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • R 2 is independently an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • R 6 is independently an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • L 1 is independently a
  • L 1 is independently a
  • Ci-C 8 alkylene bonds, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-C 8 alkylene.
  • L 1 is independently -C(O)- or -C(0)0-.
  • 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.
  • 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.
  • R 8 is hydrogen
  • R 4 is hydrogen.
  • 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).
  • aryl e.g., Ce-Cio aryl, C10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • 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.
  • 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.
  • R 1 is independently unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted butyl.
  • R 1 is independently unsubstituted methyl.
  • R 1 is independently unsubstituted ethyl.
  • 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.
  • 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
  • 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.
  • 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
  • R 1 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 -OR 1D . In embodiment
  • 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.
  • 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.
  • 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
  • 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.
  • R 1 is independently an unsubstituted amino acid moiety.
  • 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
  • R 1 independently an unsubstituted nucleic acid moiety.
  • R 1 is independently a bioconjugate moiety.
  • R 1 is independently an unsubstituted lipid moiety.
  • R 1 is independently -C(0)NR 1A R 1B .
  • 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.
  • R 1A and R 1B are independently hydrogen, -CX3, -CHX2, -CH2X, or substituted or unsubstituted alkyl.
  • 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.
  • 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
  • R 1 is independently substituted heteroaryl. In embodiments, R 1 is independently unsubstituted alkyl. In embodiments, R 1 is independently unsubstituted heteroalkyl. In
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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
  • R 20 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1 is independently hydrogen
  • 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
  • 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.
  • R 1 is independently hydrogen.
  • R 1 is independently methyl.
  • R 1 is independently ethyl.
  • R 1 is independently oxo.
  • 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 .
  • R 20 is independently oxo, halogen, -CX 20 3 , -CHX 20 2, -
  • X 20 is -F, -Cl, -Br, or -I.
  • R 20 is independently oxo, halogen, -CX 20 3 , -CHX 20 2 , -
  • 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 heterocyclo
  • alkyl e.g., Ci-C 8 alkyl, C i-Cr, alkyl, or Ci- C 4 alkyl
  • 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
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 20 is independently oxo, halogen, -CF 3 , -CHF2, -
  • 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.
  • R 21 is independently oxo
  • 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
  • R 1 is independently hydrogen, halogen, -CX ⁇ , -CHX' 2 , - CH 2 X ⁇ -OCX ⁇ , -OCH 2 X 1 , -OCHX ⁇ ,
  • 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 , -ON3 ⁇ 4 -NHC(0)NHNH 2 ,
  • R 1 is independently hydrogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -
  • 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 ,
  • L 1 is independently a bond, -S(0) 2 -, -S(O)-
  • 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.,
  • heterocycloalkylene or 5 to 6 membered heterocycloalkylene
  • substituted or unsubstituted arylene e.g., C 6 -Cio arylene, C10 arylene, or phenylene
  • substituted or unsubstituted heteroarylene e.g.,
  • L 1 is independently a
  • L 1 is independently a
  • 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.
  • 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
  • L 1 is independently a bond, -C(O)-, -C(0)NH-, -C(0)0-, or substituted or unsubstituted Ci-Cr, alkylene.
  • L 1 is independently a bond.
  • L 1 is independently -NH-.
  • L 1 is independently -0-.
  • L 1 is independently -C(O)-.
  • L 1 is
  • 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)-.
  • 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
  • L 1 is independently substituted heteroaryl. In embodiments, L 1 is independently unsubstituted alkyl. In embodiments, L 1 is independently unsubstituted heteroalkyl. In
  • 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.
  • 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
  • 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.
  • L 1 is independently a bond, -S(0) 2 -, -S(O)-
  • L 1 is independently a
  • 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
  • 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
  • unsubstituted heteroarylene e.g., 5 to 10 membered heteroaryl ene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene.
  • R 22 is independently oxo, halogen, -CX 22 3 , -CHX 22 2 , -
  • 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, R 23 -substituted alkyl (e.g., Ci-Cx alkyl, Ci
  • 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
  • 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.
  • R 22 is independently oxo, halogen, -CF3, -CHF 2 , -
  • 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 ,
  • R 23 is independently oxo, halogen, -CX 23 3 , -CHX 23 2 , -
  • 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
  • L 1 is independently a bond, -S(0) 2 -, -S(O)-
  • R 22 is independently oxo, halogen, -CF3, -CHF 2 , -
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • R 8 is independently hydrogen, -CX 8 3 , -CHX 8 2 , -
  • R 8 is independently hydrogen. In embodiments, R 8 is
  • R 8 is independently -CF 3 .
  • R 8 is independently -CHF 2 .
  • R 8 is independently -CH 2 F.
  • R 8 is independently -C(0)CH3.
  • R 8 is independently -C(0)NH 2 .
  • R 8 is independently -OH.
  • R 8 is independently C1-C4 alkyl.
  • R 8 is independently methyl.
  • R 8 is independently ethyl.
  • R 8 is independently propyl.
  • R 8 is independently butyl.
  • 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, -SOmony X R xd , -SO V8 NR 8A R 8B , -NHC(0)NR 8A R 8B ,
  • R 8 is independently hydrogen
  • R 24 -substituted or unsubstituted aryl e.g., Ce-Cio aryl, C10 aryl, or phenyl
  • R 24 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • 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 heteroal
  • 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.
  • X 8 is - F, -Cl, -Br, or -I.
  • R 8 is independently hydrogen.
  • R 8 is independently methyl.
  • R 8 is independently ethyl.
  • 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,
  • 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 hetero
  • 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,
  • 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
  • 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.
  • R 25 is independently oxo, halogen, -CX 25 3 , -CHX 25 2 , -
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • R 1A is independently
  • 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
  • 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).
  • R 1A is independently
  • 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.
  • R 1A is independently unsubstituted methyl.
  • R 1A is independently unsubstituted ethyl.
  • R 1A is independently unsubstituted propyl.
  • R 1A is independently unsubstituted isopropyl.
  • R 1A is independently unsubstituted tert-butyl.
  • R 1B is independently
  • 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
  • R 20 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • 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
  • unsubstituted alkyl e.g
  • 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.
  • R 1B is independently unsubstituted methyl.
  • R 1B is independently unsubstituted ethyl.
  • R 1B is independently unsubstituted propyl.
  • R 1B is independently unsubstituted isopropyl.
  • R 1B is independently unsubstituted tert-butyl.
  • 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.
  • R 1C is independently
  • 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
  • R 20 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1C is independently
  • 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.
  • R 1C is independently unsubstituted methyl.
  • R 1C is independently unsubstituted ethyl.
  • R 1C is independently unsubstituted propyl.
  • R 1C is independently unsubstituted isopropyl.
  • R 1C is independently unsubstituted tert-butyl.
  • R 1D is independently
  • 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
  • R 20 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1D is independently
  • 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.
  • R 1D is independently unsubstituted methyl.
  • R 1D is independently unsubstituted ethyl.
  • R 1D is independently unsubstituted propyl.
  • R 1D is independently unsubstituted isopropyl.
  • R 1D is independently unsubstituted tert-butyl.
  • R 3A is independently
  • 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
  • substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9
  • 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 .
  • 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.,
  • X is independently -F, -Cl, -Br, or -I.
  • R 3A is independently unsubstituted methyl.
  • R 3A is independently unsubstituted ethyl.
  • R 3A is independently unsubstituted propyl.
  • R 3A is independently unsubstituted isopropyl.
  • R 3A is independently unsubstituted tert-butyl.
  • R 3B is independently
  • 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
  • substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to
  • 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.,
  • X is independently -F, -Cl, -Br, or -I.
  • R 3B is independently unsubstituted methyl.
  • R 3B is independently unsubstituted ethyl.
  • R 3B is independently unsubstituted propyl.
  • R 3B is independently unsubstituted isopropyl.
  • R 3B is independently unsubstituted tert-butyl.
  • 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).
  • a 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 heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • R 3C is independently
  • 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
  • substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered
  • 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 .
  • 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.,
  • X is independently -F, -Cl, -Br, or -I.
  • R 3C is independently unsubstituted methyl.
  • R 3C is independently unsubstituted ethyl.
  • 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
  • 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
  • substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered
  • 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 .
  • 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.,
  • X is independently -F, -Cl, -Br, or -I.
  • R 3D is independently unsubstituted methyl.
  • R 3D is independently unsubstituted ethyl.
  • R 3D is independently unsubstituted propyl.
  • R 3D is independently unsubstituted isopropyl.
  • R 3D is independently unsubstituted tert-butyl.
  • R 3A is independently
  • substituted e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups
  • 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
  • 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
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloal
  • 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 .
  • 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.,
  • X is independently -F, -Cl, -Br, or -I.
  • R 3A is independently unsubstituted methyl.
  • R 3A is independently unsubstituted ethyl.
  • R 3A is independently unsubstituted propyl.
  • R 3A is independently unsubstituted isopropyl.
  • R 3A is independently unsubstituted tert-butyl.
  • R 3B is independently
  • substituted e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups
  • 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
  • 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
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloal
  • 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 .
  • 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
  • X is independently -F, -Cl, -Br, or -I.
  • R 3B is independently unsubstituted methyl.
  • R 3B is independently unsubstituted ethyl.
  • R 3B is independently unsubstituted propyl.
  • R 3B is independently unsubstituted isopropyl.
  • R 3B is independently unsubstituted tert- butyl.
  • 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).
  • a substituted e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups
  • unsubstituted heterocycloalkyl e.g., 3
  • R 3C is independently
  • substituted e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups
  • 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
  • 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
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloal
  • 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 .
  • 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 membere
  • X is independently -F, -Cl, -Br, or -I.
  • R 3C is independently unsubstituted methyl.
  • R 3C is independently unsubstituted ethyl.
  • R 3C is independently unsubstituted propyl.
  • R 3C is independently unsubstituted isopropyl.
  • R 3C is independently unsubstituted tert- butyl.
  • R 3D is independently
  • substituted e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups
  • 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
  • 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
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered
  • 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 .
  • 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
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membere
  • X is independently -F, -Cl, -Br, or -I.
  • R 3D is independently unsubstituted methyl.
  • R 3D is independently unsubstituted ethyl.
  • R 3D is independently unsubstituted propyl.
  • R 3D is independently unsubstituted isopropyl.
  • R 3D is independently unsubstituted tert- butyl.
  • R 8A is independently
  • 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
  • R 24 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 8A is independently
  • 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
  • R 8A is independently unsubstituted methyl.
  • R 8A is independently unsubstituted ethyl.
  • R 8A is independently unsubstituted propyl.
  • R 8A is independently unsubstituted isopropyl.
  • R 8A is independently unsubstituted tert-butyl.
  • X is independently -F, -Cl, -Br, or -I.
  • R 8B is independently
  • 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
  • R 24 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 8B is independently
  • 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
  • R 8B is independently unsubstituted methyl.
  • R 8B is independently unsubstituted ethyl.
  • R 8B is independently unsubstituted propyl.
  • R 8B is independently unsubstituted isopropyl.
  • R 8B is independently unsubstituted tert-butyl.
  • X is independently -F, -Cl, -Br, or -I.
  • 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.
  • R 8C is independently
  • 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
  • R 24 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 8C is independently
  • 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
  • R 8C is independently unsubstituted methyl.
  • R 8C is independently unsubstituted ethyl.
  • R 8C is independently unsubstituted propyl.
  • R 8C is independently unsubstituted isopropyl.
  • R 8C is independently unsubstituted tert-butyl.
  • X is independently -F, -Cl, -Br, or -I.
  • R 8D is independently
  • 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
  • R 24 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 8D is independently
  • 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
  • R 8D is independently unsubstituted methyl.
  • R 8D is independently unsubstituted ethyl.
  • R 8D is independently unsubstituted propyl.
  • R 8D is independently unsubstituted isopropyl.
  • R 8D is independently unsubstituted tert-butyl.
  • X is independently -F, -Cl, -Br, or -I.
  • 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 .
  • substituted e.g., substituted with one or more substituent groups, size-limited substituent groups and/or lower substituent groups
  • 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
  • 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
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycl
  • 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.,
  • aryl e.g., Ce-Cio aryl, Cio aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • an amine protecting group e.g., an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • R 3 is independently hydrogen, -Cl, -Br, -
  • 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.
  • 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
  • R a is hydrogen, halogen, -CCh, -CBr 3 , -CF 3 , -CI 3 ,
  • 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.
  • 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
  • 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 membere
  • 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).
  • alkylene e.g. Ci- C 8 alkylene, C i-Ce alkylene . or C1-C4 alkylene
  • substituted heteroalkylene e.g., 2 to 8 membered heteroalkyl ene, 2 to 6 membered heteroalkyl ene, or 2 to 4 membere
  • 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).
  • L is -CH2-.
  • L CH-.
  • L 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).
  • 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.
  • R c is unsubstituted C1-C4 alkyl.
  • 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,
  • aryl
  • 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).
  • cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -Ce cycloalkyl, or C5-C6 cycloalkyl
  • the nucleophilic agent is a -CCh, -CBn, -CF3, -CI3,
  • 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 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.
  • 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
  • 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 member
  • the covalently attached substituent is a -CCb, -CBn, -CF3, -CI3,
  • 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 membere
  • X is -F. In embodiments, X is -Cl. In embodiments, X is -Br. In embodiments, X is -I.
  • 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.
  • R 2 is substituted or unsubstituted alkyl, CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts.
  • R 2 is substituted or unsubstituted alkyl.
  • R 2 is CBz.
  • R 2 is BOC.
  • R 2 is Ac.
  • R 2 is Bz.
  • R 2 is Bn.
  • R 2 is PMB.
  • R 2 is PIV.
  • R 2 is Ts.
  • R 2 is substituted or unsubstituted Ci-C 8 alky.
  • 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.
  • R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently unsubstituted propyl. In embodiments, R 2 is independently unsubstituted isopropyl.
  • R 2 is independently unsubstituted tert-butyl.
  • R 2 is an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • R 4 is hydrogen or -C(0)H. In embodiments, R 4 is hydrogen. In embodiments, R 4 is -C(0)H.
  • 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.
  • 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.
  • the nucleophilic agent includes
  • the covalently attached substituent is
  • R 1 is independently hydrogen, -CX 1 -,, -CHXN, -CH2X 1 , -OCX 1 -,, - OCH2X 1 , -OCHX ⁇ ,
  • 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.
  • 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
  • the saturated cyclic amine is part of a dipeptide.
  • at least one of the amino acids of the peptide is proline.
  • at least one of the amino acids of the peptide is pipecolic acid.
  • at least one of the amino acids of the peptide is alanine.
  • at least one of the amino acids of the peptide is valine.
  • 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
  • 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
  • the metal source is a manganese(III) source.
  • 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
  • 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
  • the metal source is manganese(M) acetylacetonate (Mn(acac) 3 ). In embodiments, the metal source is manganese(III) 2-pyridinecarboxylate (Mn(pic) 3 ).
  • 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.
  • 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.
  • 2 to 8 equivalents of the metal source are used in the reaction.
  • 3 to 5 equivalents of the metal source are used in the reaction.
  • 4 equivalents of the metal source are used in the reaction.
  • sub-stoichiometric amounts of the metal source are used in the reaction.
  • 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.
  • 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.
  • 0.4 to 0.6 equivalents of AgBF 4 are used in the reaction.
  • an excess of AgNO is used in the reaction.
  • 1.1 to 10 equivalents of AgNO- are used in the reaction.
  • 2 to 8 equivalents of AgNO- are used in the reaction.
  • 3 to 5 equivalents of AgNO- are used in the reaction.
  • 4 equivalents of AgNO- are used in the reaction.
  • at least 0.1 equivalents of the silver source are used in the reaction.
  • at least 0.5 equivalents of the silver source are used in the reaction.
  • the halogenating agent is a nucleophilic halogenating agent or an electrophilic halogenating agent.
  • the halogenating agent is a brominating agent.
  • the brominating agent is A'-bromosuccinimide (NBS), dibromoisocyanuric acid (DBI), bromine, bromotrichloromethane, l,2-dibromo-l,l,2,2-tetrachloroethane, carbon
  • 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,
  • the halogenating agent is a chlorinating agent.
  • the chlorinating agent is A'-chlorosuccinimide (NCS), thionyl chloride, methanesulfonyl chloride,
  • 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,
  • the halogenating agent is an iodinating agent.
  • 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 tetra
  • the solvent for the reaction is a mixture of H 2 0 and an organic solvent.
  • 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.
  • DMSO dimethyl sulfoxide
  • methanol ethanol
  • 2- propanol dichloromethane
  • benzene tetrahydrofuran
  • 2-methyltetrahydrofuran 2-methylte
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 1:100 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,
  • 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.
  • 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%.
  • 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%.
  • 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).
  • L 1 is independently a bond, -S(0) 2 -,-S(0)-
  • R 8 is independently
  • R 1 is independently hydrogen, halogen, -CX , -CHX' 2 , -CH 2 X', -OCX's, - OCIBX 1 , -OCHX ⁇ ,
  • 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 heterocycl
  • 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
  • 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.
  • 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 ).
  • L 1 is independently a -C(O)- or -C(0)0-.
  • R 1 is independently
  • 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 .
  • R 1 is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety
  • R 2 is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • 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.
  • R 2 is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • L 1 is
  • 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
  • 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 ,
  • R 3 is independently hydrogen, -Cl, -Br, -I, -CN, -SO n 3R 3D , -SO V 3NR 3A R 3B ,
  • 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
  • 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:
  • R 6 is independently -L ⁇ R 1 , wherein each R 6 is optionally different.
  • the compound has the formula:
  • 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 ).
  • 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 ).
  • 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 ).
  • 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 ⁇ ,
  • 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
  • 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
  • R a is hydrogen
  • R 1 is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety
  • R 2 is independently hydrogen, an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • the nucleophilic agent includes
  • 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;
  • a compound made by a method as described herein including embodiments.
  • the compound has the formula: wherein X a ,
  • R 2 , R 3 , R 4 , R 6 , and z2 are as described herein.
  • 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 ).
  • the compound has the formula: wherein X a , R 2 , R 4 , and R 6 are as described herein.
  • the compound has the formula: (lib), wherein R a ,
  • R 2 , R 3 , R 4 , R 6 , and z2 are as described herein.
  • the compound has the structure of formula (Ilbz):
  • 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 ).
  • the compound has the formula: wherein R R 3 , R 6 , and z2 are as described herein.
  • the compound has the structure of formula:
  • R 6 4 are each independently a value of R 6 (e.g., embodiments of R 6 ).
  • the compound has the formula: (ind), wherein R R 4 , R 6 , L, and z2 are as described herein.
  • R 6 are each independently a value of R 6 (e.g., embodiments of R 6 ).
  • the compound has the formula: (Ille), wherein R 3 , R 6 , L, and z2 are as described herein.
  • 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 ).
  • the compound has the formula: wherein R 3 ,
  • R 6 , L, and z2 are as described herein.
  • 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 ).
  • the compound has the formula: (lie), wherein R 2 , R 3 ,
  • R 4 , R 6 , and z2 are as described herein.
  • the compound has the structure of formula:
  • 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 ).
  • the compound has the formula: (lid), wherein R a , R 2 , R 4 , and R 6 are as described herein.
  • the compound has the formula: wherein R 2 ,
  • R 3 , R 4 , R 6 , z3, and Ring A are as described herein.
  • the compound has the structure of formula:
  • R 2 , R 3 , R 4 , z3, and Ring A are as described herein, including embodiments.
  • R 6 3 are each independently a value of R 6 (e.g., embodiments of R 6 ).
  • the compound is a compound as described herein, including
  • the compound is a compound described herein (e.g., in the example section, in the figures, in the claims, or in the appendix).
  • 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.
  • Embodiment P2 The method of embodiment Pl , wherein said saturated cyclic amine has the structure of formula (I):
  • 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)-
  • 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
  • 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
  • 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, -
  • 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
  • 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
  • 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.
  • Embodiment P3 The method of embodiment P2, wherein z2 is an integer from 0 to 8.
  • Embodiment P4 The method of one of embodiments P2 or P3, wherein z2 is an integer from 1 to 4.
  • 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 cyclo
  • R 20 is independently oxo, halogen, -CF3, -CHF2, -
  • 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 ,
  • 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.
  • 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 ,
  • Embodiment P8 The method of one of embodiments P2-P7, wherein each L 1 is independently a bond, -S(0) 2 -, -S(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 , -
  • Embodiment P9 The method of one of embodiments P2-P7, wherein each L 1 is independently a
  • R 22 is independently oxo, halogen, -CF 3 , -CHF 2 , -
  • Embodiment P10 The method of one of embodiments P2-P7, wherein each L 1 is independently a
  • 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.
  • 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.
  • Embodiment P13 The method of one of embodiments P2-P12, wherein each R 8 is hydrogen.
  • Embodiment Pl 4. The method of one of embodiments P2-P 13, wherein each R 4 is hydrogen.
  • 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,
  • Embodiment Pl 6 A method of embodiment Pl , wherein said saturated cyclic amine has the structure of formula (la):
  • 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 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
  • 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 .
  • 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
  • R 2 is independently hydrogen, an amine protecting group, an amino acid moiety, a polypeptide moiety, or a protein moiety.
  • 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.
  • Embodiment P22 The compound of one of embodiments P2 to P29, wherein X a is -Br.
  • Embodiment P23 The method of embodiment Pl 8, wherein the reaction between the haloalkyl amine and the nucleophilic agent is an intramolecular reaction.
  • Embodiment P24 The method of embodiment P23, wherein the intramolecular reaction is a cyclization reaction.
  • Embodiment P25 The method of embodiment Pl 8 wherein the nucleophilic reaction product has the formula:
  • R a is hydrogen, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO2CI, -SO3H,
  • L 1 is independently a bond, -S(0) 2 -,-S(0)-
  • 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
  • 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, -
  • 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
  • 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 :
  • 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.
  • the halogenating agent is A'-chlorosuccinimide, N- b ro m o s ucci n i m i de , A'-iodosuccinimide, or dibromohydantoin.
  • 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 .
  • 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.
  • Embodiment P29 The method of embodiment P28, wherein the reacting temperature ranges from 20 to 25 °C.
  • Embodiment P30 The method of embodiments Pl to P29, wherein the oxidizing agent is ammonium persulfate.
  • Embodiment P31 A compound having the formula:
  • X a is independently -Cl, -Br, or -I;
  • L 1 is independently a bond, -S(0) 2 -,-S(0)-
  • 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
  • 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 ,
  • 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
  • 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
  • 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.
  • Embodiment P32 A compound having the formula:
  • 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 hetero
  • 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
  • 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;
  • 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

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Abstract

La présente invention concerne, entre autres, des procédés de fonctionnalisation déconstructive et des composés préparés à l'aide de ceux-ci.
PCT/US2019/040547 2018-07-06 2019-07-03 Procédés et composés de fonctionnalisation déconstructive WO2020010228A1 (fr)

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