Cysteine conjugation

Abstract

Provided herein are compounds of Formulae (I'), (I), (IV'), and (IV). Also provided herein are methods of preparation of Formulae (Ill-i), (VI), and (VIII). Further provided herein are methods of functionalizing or sequencing a peptide having at least one free cysteine residue, and methods of enriching a sample comprising one or more peptides.

Description

CYSTEINE CONJUGATION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority of US Provisional Application No. 63 / 552,520, filed February 12, 2024, the entire content of which is incorporated herein by reference. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (R070870175WO00-SEQ-WLC.xml; Size: 61,462 bytes; and Date of Creation: February 12, 2025) are herein incorporated by reference in its entirety. BACKGROUND OF THE INVENTION

[0003] The landscape of residue-specific modification of proteins is dominated by the targeting of lysine side chains with N-hydroxysuccinimide esters (NHS esters) and cysteine side chains with maleimides, due to the nucleophilicities and availabilities of lysine and cysteine in solvent-accessible regions. Lysine is found in high abundance on the surface of proteins, but cysteine is relatively rare and often found in functional sites of proteins. Approaches to protein sequencing and identification often employ lysine conjugation. However, chemoselectivity and regioselectivity can be difficult to control with lysine conjugation, leading to sample heterogeneity. Moreover, lysine is absent in some proteins (e.g., p14ARF tumor suppressor), which cannot be sequenced by those approaches. Expanding conjugation beyond lysine residues would help streamline workflows in protein sequencing and identification. SUMMARY OF THE INVENTION

[0004] The present disclosure provides novel compounds for cysteine conjugation, and methods for cysteine conjugation and peptide characterization.

[0005] Accordingly, in one aspect, provided herein is a compound of Formula (I′):or a salt thereof, wherein X, n, L1, RB, R1, and Z are defined herein; and wherein the substituent moietylocated at a position ortho or para to N.R0708.70175WO00 1 / 180 #13640937v1

[0006] In another aspect, provided herein is a compound of Formula (I):or a salt thereof, wherein X, n, L1, R1, and Z are defined herein.

[0007] In another aspect, provided herein is a compound of Formula (IV′):or a salt thereof, wherein X, n, L1, RB, R1, R2, R3a, and R3bare defined herein.

[0008] In another aspect, provided herein is a compound of Formula (IV):or a salt thereof, wherein X, n, L1, R1, R2, R3a, and R3bare defined herein.

[0009] In another aspect, provided herein is a method of preparing a compound of Formula (III-i):or a salt thereof, comprising contacting a compound of Formula (V):or a salt thereof, with a compound of Formula (II):R0708.70175WO00 2 / 180 #13640937v1or a salt thereof, to obtain the compound of Formula (III-i), or a salt thereof, wherein X, n, L1, R1, RC, and RNare defined herein.

[0010] In another aspect, provided herein is a method of preparing a compound of Formula (VI):or a salt thereof, with a compound of Formula (VII):or a salt thereof, to obtain the compound of Formula (VI), or a salt thereof, wherein L2, RC, and RNare defined herein.

[0011] In another aspect, provided herein is a method of preparing a compound of Formula (VIII):or a salt thereof, comprising contacting a compound of Formula (V):or a salt thereof, with a compound of Formula (IX):R0708.70175WO00 3 / 180 #13640937v1or a salt thereof, to obtain the compound of Formula (VIII), or a salt thereof, wherein L3, R4, RC, RN, and Y are defined herein.

[0012] In another aspect, provided herein is a method of functionalizing a peptide having at least one free cysteine residue, comprising reacting the peptide with a compound of Formula (II):or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:wherein X, n, L1, and R1are defined herein.

[0013] In another aspect, provided herein is a method of sequencing a peptide having at least one free cysteine residue, comprising: reacting the peptide with a compound of Formula (II), Formula (VII), or Formula (IX):or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:performing a peptide sequencing protocol; wherein X, n, L1, R1, L2, L3, and R4are defined herein.

[0014] In another aspect, provided herein is a method of enriching a sample comprising one or more peptides, comprising: reacting a target peptide having at least one free cysteine residue with a compound of Formula (II), Formula (VII), or Formula (IX):R0708.70175WO00 4 / 180 #13640937v1or a salt thereof, to provide an azide-functionalized peptide, such that a sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:contacting the azide-functionalized peptide with a compound comprising a complementary moiety, such that the azide moiety of the azide-functionalized peptide reacts with the complementary moiety via click chemistry to provide a triazole-linked conjugated peptide; immobilizing the triazole-linked conjugated peptide to a surface; and removing any non-immobilized peptides or portions of peptides; wherein X, n, L1, R1, L2, L3, and R4are defined herein.

[0015] In another aspect, provided herein is a method of sequencing a peptide, comprising: reacting the peptide with a vinylpyridinium compound, or a salt thereof, wherein the vinylpyridinium compound comprises an azide moiety, to provide an azide-functionalized peptide, wherein a sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to an ethylenepyridinium moiety; and performing a peptide sequencing protocol.

[0016] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG.1 shows the TOF-LC / MS spectrum of the reaction of Arylpropiolonitrile (APN-N3) (5 eq & 2 eq.) with QP1094 (DDGGGDDDFFC) (SEQ ID NO: 1).

[0018] FIG.2 shows the TOF-LC / MS spectrum of the reaction of vinyl pyridinium (VP-N3) (10 eq & 20 eq.) with QP1094 (DDGGGDDDFFC) (SEQ ID NO: 1). Presence of starting material (QP1094) may indicate less reactivity with VP-N3.

[0019] FIG.3 shows bioactive Tet-20 (KRWRIRVRVIRKC) (SEQ ID NO: 2) as a model system for testing cysteine conjugation with vinyl pyridinium (VP-N3). Tet-20 is an antimicrobial peptide with C- terminal Cys for conjugation. Currently utilized workflow requires Lys-C digestion, diazotransfer, and quenching. Improvements to the library preparation could avoid need to generate C-terminal lysine viaR0708.70175WO00 5 / 180 #13640937v1Lys-C and provide higher peptide coverage.

[0020] FIGs.4A-4B show the TOF-LC / MS spectrum of the reaction of VP-N3 with Tet-20 (FIG.4A), and the structure of the cysteine-conjugated product (FIG.4B), (1) m / z: 1943.1974. Non-specific reactions at K / R not detected.70 pmol of crude material (7 µL) injected on LC-TOF MS Agilent 6230.

[0021] FIGs.5A-5B show on-chip assessment of Cys-conjugation of Tet-20. FIG.5A shows assessment with DK05-81 S67461-14 QP1086 no beads + thiol beads child split 1 (residue). VP-N3 Michael addition followed by click to Q24D complex. The excess VP-N3 was quenched & filtered with thiol beads. FIG. 5B shows a workflow in which Thiol beads were utilized to quench excess VP-N3 via a thiol-ene click reaction.

[0022] FIGs.6A-6B shows VP-N3 conjugation with Rabies virus glycoprotein (RVG): 29 amino acid fragment derived from RVG (YTIWMPENPRPGTPCDIFTNSRGKRASNG) (SEQ ID NO: 3) (Exact Mass: 3268.5848; m / z: 817.3970 (4 charge states)). In the absence of VP-N3, conjugated RVG is not detected. In the presence of 10 eq. VP-N3, RVG Cys conjugated is detected (Exact Mass: 3443.6826).

[0023] FIG.7 shows VP-N3 conjugation with Tau peptide (306-336): 31 amino acid long peptide derived from Repeat 3 domain (VQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQ) (SEQ ID NO: 4) (Exact Mass: 3248.7561). In the presence of 10 eq. VP-N3, Tau cysteine conjugated product is detected (Exact Mass: 3423.8540; 685.1729 (5 charge states)).

[0024] FIG.8 shows LysC digest then APN conjugation. Product of Lys-C digest: ALVLIAFAQYLQQCPFEDHVK (SEQ ID NO: 5).1467.7563 (2); 978.8399 (3); 734.3818 (4).

[0025] FIGs.9A-9B show GluC digest then APN conjugation. Product of Glu-C digest: ALVLIAFAQYLQQCPFEDHVK (SEQ ID NO: 5).1228.1316 (2); 819.0902 (3); 614.5695 (4).

[0026] FIG.10 shows the sequence of human serum albumin.35 cysteine residues lead to 17 disulfide bonds (lines).1 free cysteine (QP300) (arrow).

[0027] FIG.11 shows conjugation to Cys34 of HSA (human serum albumin). Product of Lys-C digest: ALVLIAFAQYLQQCPFEDHVK (SEQ ID NO: 5). HSA fragment (10 µM); 10 eq. of VP-N3; 1X PBS, pH 7.4. Exact mass: 2610.3759; 652.8448 (4 charge states).

[0028] FIG.12 shows direct APN capture of HSA (albumin) from 10-fold diluted human serum.

[0029] FIGs.13A-13B show capture & sequencing of albumin from diluted human serum. FIG.13A shows QL857 (APN). FIG.13B shows QL858 (VPN).

[0030] FIGs.14A-14C show capture & sequencing of albumin from diluted human serum. FIG.14A shows QL857 (APN + TCEP…). FIG.14B shows QL858 (VPN + TCEP…). FIG.14C shows representative QL857 peptide traces.

[0031] FIGs.15A-15C show GFAP conjugation of Cys with APN & VPN. FIG.15A shows GFAP APN (Asp-N digest). DYRRQLQSLTC (SEQ ID NO: 6); 1882.9229 (1); 941.9651 (2); 628.3125 (3). FIG.15B shows GFAP APN (Glu-C digest). DYRRQLQSLTC (SEQ ID NO: 6); 1882.9229 (1); 941.9651 (2); 628.3125 (3). FIG.15C shows GFAP VPN (Asp-N digest). DYRRQLQSLTC (SEQ ID NO: 6); 1556.7751 (1); 778.8912 (2); 519.5966 (3).

[0032] FIGs.16A-15D show Vimentin conjugation of Cys with APN & VPN. FIG.16A showsR0708.70175WO00 6 / 180 #13640937v1Vimentin APN (Glu-C digest). YRRQVQSLTCE (SEQ ID NO: 7); 1882.9229 (1); 941.9651 (2); 628.3125 (3). FIG.16B shows Vimentin APN (Glu-C digest). YRRQVQSLTCE (SEQ ID NO: 7); 1882.9229 (1); 941.9651 (2); 628.3125 (3). FIG.16C shows Vimentin VPN (Glu-C digest). YRRQVQSLTCE (SEQ ID NO: 7); 1556.7751 (1); 778.8912 (2); 519.5966 (3).

[0033] FIGs.17A-17B show conjugation of APN to Vimentin. FIG.17A shows QL859 (TCEP / CAA; APN / Glu-C digest). TCEP may not be needed & may quench APN. Conjugation to Cys & non cys peptides. FIG.17B shows QL754 (SOP: ISA / Lys-C).

[0034] FIG.18 shows conjugation of APN to GFAP (QL861 (APN)).

[0035] FIG.19 shows Vimentin digest w / Glu-C then APN conjugation; 5 µM Vimentin, 25 µM APN (5 eq). No TCEP / CAA.

[0036] FIG.20 shows VIME & APN Conjugation LC-MS and LC-MS / MS demonstrate selective Cys targeting. Chromatogram shows relative abundance of YRRQVQSLTCE (SEQ ID NO: 7) peptide from VIME with APN probe modifier.

[0037] FIGs.21A-21B show VIME-GluC APN conjugation. FIG.21A shows QL888 (APN, no TCEP). FIG.21B shows QL889 (overnight APN, no TCEP).

[0038] FIG 22 shows VIME-GluC APN conjugation. YRRQVQSLTCE (SEQ ID NO: 7) the most abundant on run 2 and second most abundant on run 1.

[0039] FIGs.23A-23B show Vimentin alternative conjugations. FIG.23A shows QL859 – GluC digest, APN. FIG.23B shows representative QL859 traces, YRRQVQSLTCE (SEQ ID NO: 7) appears most abundant which is ~10thfor a typical VIME library (SOP).

[0040] FIGs.24A-24B show GFAP alternative conjugations. FIG.24A shows QL861 – AspN digest, APN. FIG.24B shows representative QL861 traces, same YRRQ peptide appears most abundant.

[0041] FIGs.25A-25B show synthetic peptide Cys conjugation with halogen acetamide (Bromo-PEG3- azide). FIG.25A shows QP1112 (RLAIQFAYPFAQ) (SEQ ID NO: 8). FIG.25B shows QP1149 (RLAIQFAYPACE) (SEQ ID NO: 9). Standard synthetic peptide QP1112 is compared to Cys conjugated QP1149, which lacks a Lys for potential non-specific conjugation.

[0042] FIGs.26A-26B show synthetic peptide Cys conjugation with halogen acetamide (Bromo-PEG3- azide). FIG.26A shows QP1112 (RLAIQFAYPFAQ) (SEQ ID NO: 8). FIG.26B shows QP1149 (RLAIQFAYPACE) (SEQ ID NO: 9).

[0043] FIGs.27A-27B show Cys conjugation to IL1RA protein (PSGRK SSK MQAFRIWDVNQK TFYLRNNQLVAGYLQGPNVNLEEK IDVVPIEPHALFLGIHGGK MCLSCVK SGDETRLQLEAVNITDLSENRK QDK RFAFIRSDSGPTTSFESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTK FYFQEDE) (SEQ ID NO: 10). FIG 27A shows QL833 (Cys), and mostly reads to the Cys peptide RFA. FIG.27B shows QL843 (SOP-Lys), and reads for several peptides present, including some reads to the RFA peptide. DEFINITIONS

[0044] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CASR0708.70175WO00 7 / 180 #13640937v1version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0045] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0046] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0047] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0048] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0049] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbonR0708.70175WO00 8 / 180 #13640937v1atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–12 alkyl (such as unsubstituted C1–6 alkyl, e.g., −CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec- Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).

[0050] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–11alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–7alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1–5alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3alkyl”). In some embodiments, a heteroalkyl group is a saturatedR0708.70175WO00 9 / 180 #13640937v1group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl.

[0051] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C1–4 alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1–6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3ormay be in the (E)- or (Z)-configuration.

[0052] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1-10alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5alkynyl”). In someR0708.70175WO00 10 / 180 #13640937v1embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0053] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic systemR0708.70175WO00 11 / 180 #13640937v1(“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0054] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0055] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance ofR0708.70175WO00 12 / 180 #13640937v1heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0056] In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0057] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzo- thienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydro- pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7- dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-R0708.70175WO00 13 / 180 #13640937v1b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0058] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.

[0059] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ^ electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0060] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom isR0708.70175WO00 14 / 180 #13640937v1independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0061] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0062] The term “unsaturated bond” refers to a double or triple bond.

[0063] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0064] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0065] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalentR0708.70175WO00 15 / 180 #13640937v1moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0066] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0067] Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3−C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa, −SC(=S)SRaa,−OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; whereinR0708.70175WO00 16 / 180 #13640937v1X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; wherein: each instance of Raais, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1– 20 alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; whereinR0708.70175WO00 17 / 180 #13640937v1X−is a counterion; each instance of Reeis, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6 alkyl, −ON(C1–6 alkyl)2, −N(C1–6 alkyl)2, −N(C1–6 alkyl)3+X−, −NH(C1–6 alkyl)2+X−, −NH2(C1–6 alkyl)+X−, −NH3+X−, −N(OC1–6 alkyl)(C1–6 alkyl), −N(OH)(C1–6 alkyl), −NH(OH), −SH, −SC1–6 alkyl, −SS(C1–6 alkyl), −C(=O)(C1–6 alkyl), −CO2H, −CO2(C1–6 alkyl), −OC(=O)(C1– 6 alkyl), −OCO2(C1–6 alkyl), −C(=O)NH2, −C(=O)N(C1–6 alkyl)2, −OC(=O)NH(C1–6 alkyl), −NHC(=O)( C1–6 alkyl), −N(C1–6 alkyl)C(=O)( C1–6 alkyl), −NHCO2(C1–6 alkyl), −NHC(=O)N(C1–6 alkyl)2, −NHC(=O)NH(C1–6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6 alkyl), −OC(=NH)(C1–6 alkyl), −OC(=NH)OC1–6 alkyl, −C(=NH)N(C1–6 alkyl)2, −C(=NH)NH(C1–6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6 alkyl)2, −OC(NH)NH(C1–6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6 alkyl), −SO2N(C1–6 alkyl)2, −SO2NH(C1–6 alkyl), −SO2NH2, −SO2C1–6 alkyl, −SO2OC1–6 alkyl, −OSO2C1–6 alkyl, −SOC1–6 alkyl, −Si(C1–6alkyl)3, −OSi(C1–6alkyl)3−C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, −C(=O)S(C1–6alkyl), −C(=S)SC1–6alkyl, −SC(=S)SC1–6alkyl, −P(=O)(OC1–6alkyl)2, −P(=O)(C1–6alkyl)2, −OP(=O)(C1–6alkyl)2, −OP(=O)(OC1–6alkyl)2, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion.

[0068] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, – NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, −OCO2Raa,R0708.70175WO00 18 / 180 #13640937v1hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3- nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0069] In certain embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0070] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0071] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxy,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −ORaa, −ON(Rbb)2, −OC(=O)SRaa, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −OC(=NRbb)N(Rbb)2, −OS(=O)Raa, −OSO2Raa, −OSi(Raa)3, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, and −OP(=O)(N(Rbb))2, wherein X−, Raa, Rbb, and Rccare as defined herein.

[0072] The term “amino” refers to the group −NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.R0708.70175WO00 19 / 180 #13640937v1

[0073] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0074] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0075] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(Rbb)3 and −N(Rbb)3+X−, wherein Rbband X−are as defined herein.

[0076] The term “acyl” refers to a group having the general formula −C(=O)RX1, −C(=O)ORX1, (RX1)2, and −C(=S)S(RX1),wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0077] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected fromR0708.70175WO00 20 / 180 #13640937v1ketones (–C(=O)Raa), carboxylic acids (–CO2H), aldehydes (–CHO), esters (–CO2Raa, –C(=O)SRaa, – C(=S)SRaa), amides (–C(=O)N(Rbb)2, –C(=O)NRbbSO2Raa, −C(=S)N(Rbb)2), and imines (–C(=NRbb)Raa, – C(=NRbb)ORaa), –C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0078] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0079] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0080] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10alkyl (e.g., aralkyl, heteroaralkyl), C1–20alkenyl, C1–20alkynyl, hetero C1–20alkyl, hetero C1–20alkenyl, hetero C1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0081] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)Raa) isR0708.70175WO00 21 / 180 #13640937v1directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N- acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0082] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10- dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2- haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t- butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p- nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p- acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2- (trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o- nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynylR0708.70175WO00 22 / 180 #13640937v1carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1- methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0083] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0084] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N- 2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3- dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3- pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N- ferrocenylmethylamino (Fcm), N-2-picolylamino N’-oxide, N-1,1-dimethylthiomethyleneamine, N- benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1- cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N- [phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-R0708.70175WO00 23 / 180 #13640937v1nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.

[0085] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0086] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group.

[0087] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0088] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-R0708.70175WO00 24 / 180 #13640937v1ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p- phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4′-dimethoxytrityl (4,4′-dimethoxytriphenylmethyl or DMT), α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p- methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4’- Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4-methoxyphenyl)-1′- pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9- fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4- dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4- methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1- dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4- dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0089] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0090] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independentlyR0708.70175WO00 25 / 180 #13640937v1substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.

[0091] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0092] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0093] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−,HSO4–, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate (triflate), p–toluenesulfonate, benzenesulfonate, 10– camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−,B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.R0708.70175WO00 26 / 180 #13640937v1

[0094] A “leaving group” (LG) is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. In some embodiments, a leaving group is an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501–502). Exemplary leaving groups include, but are not limited to, halo (e.g., fluoro, chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., –OC(=O)SRaa, –OC(=O)Raa, –OCO2Raa, –OC(=O)N(Rbb)2, – OC(=NRbb)Raa, –OC(=NRbb)ORaa, –OC(=NRbb)N(Rbb)2, –OS(=O)Raa, –OSO2Raa, –OP(Rcc)2, –OP(Rcc)3, – OP(=O)2Raa, –OP(=O)(Raa)2, –OP(=O)(ORcc)2, –OP(=O)2N(Rbb)2, and –OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein). Additional examples of suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl- carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, –OTs), methanesulfonate (mesylate, –OMs), p-bromobenzenesulfonyloxy (brosylate, –OBs), – OS(=O)2(CF2)3CF3 (nonaflate, –ONf), or trifluoromethanesulfonate (triflate, –OTf). In some embodiments, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0095] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0096] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0097] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0098] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents.R0708.70175WO00 27 / 180 #13640937v1

[0099] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3– phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0100] As used herein, the term “about X,” or “approximately X,” where X is a number or percentage, refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.

[0101] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence”, and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides. The polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, its hybridization parameters, etc. The antisense oligonuculeotide may comprise a modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4- acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6- isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2- dimethylguanine, 2-methyladenine, 2- methylguanine, 3-methylcytosine, 5- methylcytosine, N6-adenine, 7-methylguanine, 5- methylaminomethyluracil, 5- methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5’-R0708.70175WO00 28 / 180 #13640937v1methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil- 5-oxyacetic acid methylester, uracil-5-oxyacetic acid, 5-methyl-2- thiouracil, 3-(3-amino-3-N-2- carboxypropyl) uracil, a thio-guanine, and 2,6-diaminopurine. A nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or single-stranded genomic and cDNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as “protein nucleic acids” (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrate or lipids. Exemplary DNAs include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA. Exemplary RNAs include single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viral satellite RNA.

[0102] Polynucleotides described herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as those that are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al., Nucl. Acids Res., 16, 3209, (1988), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., Proc. Natl. Acad. Sci. U.S.A.85, 7448-7451, (1988)). A number of methods have been developed for delivering antisense DNA or RNA to cells, e.g., antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systemically. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines. However, it is often difficult to achieve intracellular concentrations of the antisense sufficient to suppress translation of endogenous mRNAs. Therefore a preferred approach utilizes a recombinant DNA construct in which the antisense oligonucleotide is placed under the control of a strong promoter. The use of such a construct toR0708.70175WO00 29 / 180 #13640937v1transfect target cells in the patient will result in the transcription of sufficient amounts of single stranded RNAs that will form complementary base pairs with the endogenous target gene transcripts and thereby prevent translation of the target gene mRNA. For example, a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an antisense RNA. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells. Expression of the sequence encoding the antisense RNA can be by any promoter known in the art to act in mammalian, preferably human, cells. Such promoters can be inducible or constitutive. Any type of plasmid, cosmid, yeast artificial chromosome, or viral vector can be used to prepare the recombinant DNA construct that can be introduced directly into the tissue site.

[0103] The polynucleotides may be flanked by natural regulatory (expression control) sequences or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other ribosome binding site sequences, enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, introns, 5´- and 3´-non-coding regions, and the like. The nucleic acids may also be modified by many means known in the art. Non-limiting examples of such modifications include methylation, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, and internucleotide modifications, such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.). Polynucleotides may contain one or more additional covalently linked moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.), and alkylators. The polynucleotides may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage. Furthermore, the polynucleotides herein may also be modified with a label capable of providing a detectable signal, either directly or indirectly. Exemplary labels include radioisotopes, fluorescent molecules, isotopes (e.g., radioactive isotopes), biotin, and the like.

[0104] A “protein,” “peptide,” or “polypeptide” comprises a polymer of amino acid residues linked together by peptide bonds. The term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein will be at least three amino acids long. A protein may refer to an individual protein or a collection of proteins. Inventive proteins preferably contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and / or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in a protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification. A protein may also be a single molecule or may be a multi- molecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A proteinR0708.70175WO00 30 / 180 #13640937v1may be naturally occurring, recombinant, synthetic, or any combination of these.

[0105] Amino acid residues may be indicated by their corresponding single letter codes, e.g., R (arginine), H (histidine), K (lysine), D (aspartic acid), E (glutamic acid), S (serine), T (threonine), N (asparagine), Q (glutamine), C (cysteine), G (glycine), P (proline), A (alanine), V (valine), I (isoleucine), L (leucine), M (methionine), F (phenylalanine), Y (tyrosine), W (tryptophan).

[0106] A “peptidase,” “protease,” or “proteinase” is an enzyme that catalyzes the hydrolysis of a peptide bond. Peptidases digest polypeptides into shorter fragments and may be generally classified into endopeptidases and exopeptidases, which cleave a polypeptide chain internally and terminally, respectively. An exopeptidase in accordance with the application may be an “aminopeptidase” or a “carboxypeptidase,” which cleaves a single amino acid from an amino- or a carboxy-terminus, respectively. A peptidase (e.g., an aminopeptidase) may also be referred to as a “cutter” or a “cleaving reagent.”

[0107] The term “avidin protein” refers to a biotin-binding protein, generally having a biotin binding site at each of four subunits of the avidin protein. Avidin proteins include, for example, avidin, streptavidin, traptavidin, tamavidin, bradavidin, xenavidin, and homologs and variants thereof. In some cases, the monomeric, dimeric, or tetrameric form of the avidin protein can be used. In some embodiments, the avidin protein of an avidin protein complex is streptavidin in a tetrameric form (e.g., a homotetramer).

[0108] The term “click chemistry” refers to a chemical synthesis technique introduced by K. Barry Sharpless of The Scripps Research Institute, describing chemistry tailored to generate covalent bonds quickly and reliably by joining small units comprising reactive groups together. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition (2001) 40: 2004–2021; Evans, Australian Journal of Chemistry (2007) 60: 384–395). Exemplary coupling reactions (some of which may be classified as “click chemistry”) include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azide–alkyne Huisgen cycloaddition; thiol–yne addition; imine formation; Michael additions (e.g., maleimide addition); and Diels–Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). Exemplary click chemistry reactions include, but are not limited to, azide–alkyne Huisgen cycloaddition; and Diels–Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). In some embodiments, click chemistry reactions are modular, wide in scope, give high chemical yields, generate inoffensive byproducts, are stereospecific, exhibit a large thermodynamic driving force > 84 kJ / mol to favor a reaction with a single reaction product, and / or can be carried out under physiological conditions. In some embodiments, a click chemistry reaction exhibits high atom economy, can be carried out under simple reaction conditions, use readily available starting materials and reagents, uses no toxic solvents or use a solvent that is benign or easily removed (preferably water), and / or provides simple product isolation by non-chromatographic methods (crystallization or distillation).

[0109] The term “click chemistry handle,” as used herein, refers to a reactant, or a reactive group, that can partake in a click chemistry reaction. For example, a strained alkyne, e.g., a cyclooctyne, is a click chemistry handle, since it can partake in a strain-promoted cycloaddition (see, e.g., Table 1). In general,R0708.70175WO00 31 / 180 #13640937v1click chemistry reactions require at least two molecules comprising click chemistry handles that can react with each other. Such click chemistry handle pairs that are reactive with each other are sometimes referred to herein as partner click chemistry handles. For example, an azide is a partner click chemistry handle to a cyclooctyne or any other alkyne. Exemplary click chemistry handles suitable for use according to some aspects of this invention are described herein, for example, in Tables 1 and 2. In some embodiments, click chemistry handles are used that can react to form covalent bonds in the presence of a metal catalyst, e.g., copper (II). In some embodiments, click chemistry handles are used that can react to form covalent bonds in the absence of a metal catalyst. Additional suitable click chemistry handles are well known to those of skill in the art, and such click chemistry handles include, but are not limited to, the click chemistry reaction partners, groups, and handles described in Becer, Hoogenboom, and Schubert, Click Chemistry beyond Metal-Catalyzed Cycloaddition, Angewandte Chemie International Edition (2009) 48: 4900 – 4908 and PCT / US2012 / 044584 and references therein, which references are incorporated herein by reference for click chemistry handles and methodology. Table 1: Exemplary click chemistry handles and reactions.1,3-dipolar cycloaddition terminal alkyne azideTable 2: Exemplary click chemistry handles and reactions (from Becer, Hoogenboom, and Schubert, Click Chemistry Beyond Metal-Catalyzed Cycloaddition, Angewandte Chemie International Edition (2009) 48: 4900 – 4908.). Reagent A Reagent B Mechanism Notes on reaction[a]Reference 0 azide alkyne Cu-catalyzed [3+2] azide- 2 h at 60°C in H2O [9] alkyne cycloaddition (CuAAC)R0708.70175WO00 32 / 180 #13640937v1Reagent A Reagent B Mechanism Notes on reaction[a]Reference 1 azide cyclooctyne strain-promoted [3+2] 1 h at RT [6- azide-alkyne 8,10,11] cycloaddition (SPAAC) 2 azide activated [3+2] Huisgen 4 h at 50°C

[0012] alkyne cycloaddition 3 azide electron- [3+2] cycloaddition 12 h at RT in H2O

[0013] deficient alkyne 4 azide aryne [3+2] cycloaddition 4 h at RT in THF with [14,15] crown ether or 24 h at RT in CH3CN 5 tetrazine alkene Diels-Alder retro-[4+2] 40 min at 25°C (100% [36-38] cycloaddition yield) N2 is the only by- product 6 tetrazole alkene 1,3-dipolar cycloaddition few min UV irradiation [39,40] (photoclick) and then overnight at 4°C 7 dithioester diene hetero-Diels-Alder 10 min at RT

[0043] cycloaddition 8 anthracene maleimide [4+2] Diels-Alder 2 days at reflux in

[0041] reaction toluene 9 thiol alkene radical addition 30 min UV (quantitative [19-23] (thio click) conv.) or 24 h UV irradiation (>96%) 10thiol enone Michael addition 24 h at RT in CH3CN

[0027] 11thiol maleimide Michael addition 1 h at 40°C in THF or [24-26] 16 h at RT in dioxane 12thiol para-fluoro nucleophilic substitution overnight at RT in DMF

[0032] or 60 min at 40°C in DMF 13amine para-fluoro nucleophilic substitution 20 min MW at 95°C in

[0030] NMP as solvent [a ]RT=room temperature, DMF=N,N-dimethylformamide, NMP=N-methylpyrolidone, THF=tetrahydrofuran, CN3CN=acetonitrile DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0110] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.R0708.70175WO00 33 / 180 #13640937v1Compounds

[0111] In another aspect, provided herein is a compound of Formula (I′):or a salt thereof, wherein: is a single bond or a double bond; X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of RBis independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, – C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, or –S(=O)2N(RA)2; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –R0708.70175WO00 34 / 180 #13640937v1Z is absent or is -SR2, wherein R2is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; provided that when is a double bond, Z is absent; and wherein the substituent moietylocated at a position ortho or para to N.

[0112] In some embodiments, the substituent moietylocated at a position ortho to N. In some embodiments, the substituent moietylocated at a position para to N.

[0113] In some embodiments, the compound of Formula (I′) is of Formula (II′):or a salt thereof.

[0114] In some embodiments, the compound of Formula (I′) is of Formula (III′):or a salt thereof.

[0115] In another aspect, provided herein is a compound of Formula (I):or a salt thereof, wherein: is a single bond or a double bond; X−is a counterion;R0708.70175WO00 35 / 180 #13640937v1n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –Z is absent or is -SR2, wherein R2is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; provided that when is a double bond, Z is absent.

[0116] In some embodiments, the compound of Formula (I′) is of Formula (I).

[0117] In some embodiments, the compound of Formula (I) is of Formula (II):or a salt thereof.

[0118] In some embodiments, the compound of Formula (II′) is of Formula (II).R0708.70175WO00 36 / 180 #13640937v1

[0119] In some embodiments, the compound of Formula (I) is of Formula (III):or a salt thereof.

[0120] In some embodiments, the compound of Formula (III′) is of Formula (III).

[0121] In another aspect, provided herein is a compound of Formula (IV′):or a salt thereof, wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of RBis independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, – C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, or –S(=O)2N(RA)2; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –R0708.70175WO00 37 / 180 #13640937v1R2is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0122] In another aspect, provided herein is a compound of Formula (IV):or a salt thereof, wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl,R0708.70175WO00 38 / 180 #13640937v1optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –R2is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0123] In some embodiments, the compound of Formula (IV′) is of Formula (IV). X

[0124] As generally described herein, X−is a counterion.

[0125] In some embodiments, X−is a monovalent counterion, a divalent counterion, or a trivalent counterion. In some embodiments, X−is a monovalent counterion. In some embodiments, X−is a halide ion (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, a sulfonate ion (e.g., methanesulfonate, trifluoromethanesulfonate (triflate), p–toluenesulfonate, benzenesulfonate, 10– camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), a carboxylate ion (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, or a carborane anion (e.g., CB11H12–or (HCB11Me5Br6)–). In some embodiments, X−is CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, a carboxylate anion (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), or a carborane anion.

[0126] In some embodiments, X−is a sulfonate ion (e.g., methanesulfonate, trifluoromethanesulfonate (triflate), p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate) or a halide ion (e.g., F–, Cl–, Br–, I–).R0708.70175WO00 39 / 180 #13640937v1

[0127] In some embodiments, X−is a sulfonate ion. In some embodiments, X−is methanesulfonate, trifluoromethanesulfonate (triflate), p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, or ethan–1–sulfonic acid–2– sulfonate. In some embodiments, X−is methanesulfonate, trifluoromethanesulfonate (triflate), p– toluenesulfonate, or benzenesulfonate. In some embodiments, X−is triflate.

[0128] In some embodiments, X−is a halide ion. In some embodiments, X−is F–, Cl–, Br–, or I–. In some embodiments, X−is Cl–or Br–. In some embodiments, X−is Cl–.

[0129] In some embodiments, X−is triflate or a halide ion. In some embodiments, X−is triflate, F–, Cl–, Br–, or I–. In some embodiments, X−is triflate, Cl–, or Br–. In some embodiments, X−is triflate or Cl–. L1and x

[0130] As generally described herein, L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof.

[0131] In some embodiments, L1comprises optionally substituted alkylene. In some embodiments, L1comprises optionally substituted C1-C12alkylene. In some embodiments, L1comprises optionally substituted C1-C6alkylene. In some embodiments, L1comprises optionally substituted C1-C3alkylene. In some embodiments, L1comprises optionally substituted linear alkylene. In some embodiments, L1comprises optionally substituted linear C1-C12alkylene. In some embodiments, L1comprises optionally substituted linear C1-C6alkylene. In some embodiments, L1comprises optionally substituted linear C1-C3alkylene.

[0132] In some embodiments, L1comprises substituted alkylene. In some embodiments, L1comprises substituted C1-C12alkylene. In some embodiments, L1comprises substituted C1-C6alkylene. In some embodiments, L1comprises substituted C1-C3 alkylene. In some embodiments, L1comprises substituted linear alkylene. In some embodiments, L1comprises substituted linear C1-C12 alkylene. In some embodiments, L1comprises substituted linear C1-C6 alkylene. In some embodiments, L1comprises substituted linear C1-C3 alkylene.

[0133] In some embodiments, L1comprises unsubstituted alkylene. In some embodiments, L1comprises unsubstituted C1-C12 alkylene. In some embodiments, L1comprises unsubstituted C1-C6 alkylene. In some embodiments, L1comprises unsubstituted C1-C3 alkylene. In some embodiments, L1comprises unsubstituted linear alkylene. In some embodiments, L1comprises unsubstituted linear C1-C12 alkylene. In some embodiments, L1comprises unsubstituted linear C1-C6 alkylene. In some embodiments, L1comprises unsubstituted linear C1-C3 alkylene.

[0134] In some embodiments, L1comprises methylene, ethylene, n-propylene, n-butylene, n-pentylene, or n-hexylene. In some embodiments, L1comprises methylene, ethylene, or n-propylene. In some embodiments, L1comprises ethylene.

[0135] In some embodiments, L1is methylene, ethylene, n-propylene, n-butylene, n-pentylene, or n-R0708.70175WO00 40 / 180 #13640937v1hexylene. In some embodiments, L1is methylene, ethylene, or n-propylene. In some embodiments, L1is ethylene.

[0136] In some embodiments, L1comprises optionally substituted alkenylene. In some embodiments, L1comprises optionally substituted C1-C12alkenylene. In some embodiments, L1comprises optionally substituted C1-C6 alkenylene. In some embodiments, L1comprises optionally substituted C1-C3 alkenylene. In some embodiments, L1comprises substituted alkenylene. In some embodiments, L1comprises substituted C1-C12 alkenylene. In some embodiments, L1comprises substituted C1-C6 alkenylene. In some embodiments, L1comprises substituted C1-C3 alkenylene. In some embodiments, L1comprises unsubstituted alkenylene. In some embodiments, L1comprises unsubstituted C1-C12 alkenylene. In some embodiments, L1comprises unsubstituted C1-C6 alkenylene. In some embodiments, L1comprises unsubstituted C1-C3 alkenylene.

[0137] In some embodiments, L1comprises optionally substituted alkynylene. In some embodiments, L1comprises optionally substituted C1-C12 alkynylene. In some embodiments, L1comprises optionally substituted C1-C6 alkynylene. In some embodiments, L1comprises optionally substituted C1-C3 alkynylene. In some embodiments, L1comprises substituted alkynylene. In some embodiments, L1comprises substituted C1-C12 alkynylene. In some embodiments, L1comprises substituted C1-C6 alkynylene. In some embodiments, L1comprises substituted C1-C3 alkynylene. In some embodiments, L1comprises unsubstituted alkynylene. In some embodiments, L1comprises unsubstituted C1-C12 alkynylene. In some embodiments, L1comprises unsubstituted C1-C6 alkynylene. In some embodiments, L1comprises unsubstituted C1-C3 alkynylene.

[0138] In some embodiments, L1comprises optionally substituted heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C12 heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C6 heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C3 heteroalkylene. In some embodiments, L1comprises optionally substituted linear heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C12heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C6heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C3heteroalkylene.

[0139] In some embodiments, L1comprises substituted heteroalkylene. In some embodiments, L1comprises substituted C1-C12heteroalkylene. In some embodiments, L1comprises substituted C1-C6heteroalkylene. In some embodiments, L1comprises substituted C1-C3heteroalkylene. In some embodiments, L1comprises substituted linear heteroalkylene. In some embodiments, L1comprises substituted linear C1-C12heteroalkylene. In some embodiments, L1comprises substituted linear C1-C6heteroalkylene. In some embodiments, L1comprises substituted linear C1-C3heteroalkylene.

[0140] In some embodiments, L1comprises unsubstituted heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C12heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C6heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C3heteroalkylene. In some embodiments, L1comprises unsubstituted linear heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1-C12heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1-R0708.70175WO00 41 / 180 #13640937v1C6heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1-C3heteroalkylene.

[0141] In some embodiments, L1comprises, wherein x is an integer between 1 and 100, inclusive. In some embodiments, L1is or, wherein x is an integer between 1 and 100, inclusive.

[0142] As generally described herein, x is an integer between 1 and 100, inclusive. In some embodiments, x is an integer between 1 and 90, inclusive; between 1 and 80, inclusive; between 1 and 70, inclusive; between 1 and 60, inclusive; between 1 and 50, inclusive; between 1 and 40, inclusive; between 1 and 30, inclusive; between 1 and 20, inclusive; between 1 and 10, inclusive; or between 1 and 5, inclusive. In some embodiments, x is an integer between 1 and 10, inclusive. In some embodiments, x is an integer between 1 and 5, inclusive. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, x is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, x is 1, 2, 3, 4, 5, or 6. In some embodiments, x is 1, 2, 3, 4, or 5. In some embodiments, x is 1, 2, 3, or 4. In some embodiments, x is 1, 2, or 3. In some embodiments, x is 1 or 2. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10.

[0143] In some embodiments, L1comprises or, wherein x is an integer between 1 and 10, inclusive. In some embodiments, L1comprisesorembodiments, L1is, wherein x is an integer between 1 and 5, inclusive.

[0144] In some embodiments, L1comprises optionally substituted heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C12 heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C6 heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C3 heteroalkenylene. In some embodiments, L1comprises substituted heteroalkenylene. InR0708.70175WO00 42 / 180 #13640937v1some embodiments, L1comprises substituted C1-C12heteroalkenylene. In some embodiments, L1comprises substituted C1-C6 heteroalkenylene. In some embodiments, L1comprises substituted C1-C3 heteroalkenylene. In some embodiments, L1comprises unsubstituted heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C12heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C6 heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C3 heteroalkenylene.

[0145] In some embodiments, L1comprises optionally substituted heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C12 heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C6 heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C3 heteroalkynylene. In some embodiments, L1comprises substituted heteroalkynylene. In some embodiments, L1comprises substituted C1-C12 heteroalkynylene. In some embodiments, L1comprises substituted C1-C6 heteroalkynylene. In some embodiments, L1comprises substituted C1-C3 heteroalkynylene. In some embodiments, L1comprises unsubstituted heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C12 heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C6 heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C3 heteroalkynylene.

[0146] In some embodiments, L1comprises optionally substituted carbocyclylene. In some embodiments, L1comprises optionally substituted C3-C10 carbocyclylene. In some embodiments, L1comprises optionally substituted C3-C6 carbocyclylene. In some embodiments, L1comprises substituted carbocyclylene. In some embodiments, L1comprises substituted C3-C10 carbocyclylene. In some embodiments, L1comprises substituted C3-C6 carbocyclylene. In some embodiments, L1comprises unsubstituted carbocyclylene. In some embodiments, L1comprises unsubstituted C3-C10 carbocyclylene. In some embodiments, L1comprises unsubstituted C3-C6 carbocyclylene.

[0147] In some embodiments, L1comprises optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises optionally substituted 3-6 membered heterocyclylene. In some embodiments, L1comprises substituted heterocyclylene. In some embodiments, L1comprises substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises substituted 3-6 membered heterocyclylene. In some embodiments, L1comprises unsubstituted heterocyclylene. In some embodiments, L1comprises unsubstituted 3-10 membered heterocyclylene. In some embodiments, L1comprises unsubstituted 3-6 membered heterocyclylene.

[0148] In some embodiments, L1comprises optionally substituted arylene. In some embodiments, L1comprises optionally substituted phenylene. In some embodiments, L1comprises substituted arylene. In some embodiments, L1comprises substituted phenylene. In some embodiments, L1comprises unsubstituted arylene. In some embodiments, L1comprises unsubstituted phenylene.

[0149] In some embodiments, L1comprises optionally substituted heteroarylene. In some embodiments, L1comprises optionally substituted 5-10 membered heteroarylene. In some embodiments, L1comprises optionally substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L1comprisesR0708.70175WO00 43 / 180 #13640937v1substituted heteroarylene. In some embodiments, L1comprises substituted 5-10 membered heteroarylene. In some embodiments, L1comprises substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L1comprises unsubstituted heteroarylene. In some embodiments, L1comprises unsubstituted 5-10 membered heteroarylene. In some embodiments, L1comprises unsubstituted 5-6 membered monocyclic heteroarylene. R1, RA, and n

[0150] As generally described herein, each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN,

[0151] In some embodiments, at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –some embodiments, at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, –C(=O)RA, – C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA. In someR0708.70175WO00 44 / 180 #13640937v1embodiments, at least one occurrence of R1is halogen. In some embodiments, at least one occurrence of R1is –F, –Cl, or –Br.

[0152] In some embodiments, at least one occurrence of R1is optionally substituted aliphatic. In some embodiments, at least one occurrence of R1is optionally substituted alkyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C12 alkyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C6 alkyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C3 alkyl. In some embodiments, at least one occurrence of R1is optionally substituted linear alkyl. In some embodiments, at least one occurrence of R1is optionally substituted alkenyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C12 alkenyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C6 alkenyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C3 alkenyl. In some embodiments, at least one occurrence of R1is optionally substituted alkynyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C12 alkynyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C6 alkynyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C3 alkynyl.

[0153] In some embodiments, at least one occurrence of R1is optionally substituted heteroaliphatic. In some embodiments, at least one occurrence of R1is optionally substituted heteroalkyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C12 heteroalkyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C6 heteroalkyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C3 heteroalkyl. In some embodiments, at least one occurrence of R1is optionally substituted heteroalkenyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C12 heteroalkenyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C6 heteroalkenyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C3 heteroalkenyl. In some embodiments, at least one occurrence of R1is optionally substituted heteroalkynyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C12heteroalkynyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C6heteroalkynyl. In some embodiments, at least one occurrence of R1is optionally substituted C1-C3heteroalkynyl.

[0154] In some embodiments, at least one occurrence of R1is optionally substituted carbocyclyl. In some embodiments, at least one occurrence of R1is optionally substituted C3-C10carbocyclyl. In some embodiments, at least one occurrence of R1is optionally substituted C3-C6carbocyclyl. In some embodiments, at least one occurrence of R1is optionally substituted heterocyclyl. In some embodiments, at least one occurrence of R1is optionally substituted 3-10 membered heterocyclyl. In some embodiments, at least one occurrence of R1is optionally substituted 3-6 membered heterocyclyl. In some embodiments, at least one occurrence of R1is optionally substituted aryl. In some embodiments, at least one occurrence of R1is optionally substituted phenyl. In some embodiments, at least one occurrence of R1is optionally substituted heteroaryl. In some embodiments, at least one occurrence of R1is optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one occurrence of R1is optionallyR0708.70175WO00 45 / 180 #13640937v1substituted 5-6 membered monocyclic heteroaryl.

[0155] In some embodiments, at least one occurrence of R1is –CN. In some embodiments, at least one occurrence of R1is –ORA. In some embodiments, at least one occurrence of R1is –N(RA)2. In some embodiments, at least one occurrence of R1is –NO2. In some embodiments, at least one occurrence of R1is –C(=O)RA. In some embodiments, at least one occurrence of R1is –C(=O)ORA. In some embodiments, at least one occurrence of R1is –C(=O)N(RA)2. In some embodiments, at least one occurrence of R1is – S(=O)2RA. In some embodiments, at least one occurrence of R1is –S(=O)2ORA. In some embodiments, at least one occurrence of R1is –S(=O)2N(RA)2. In some embodiments, at least one occurrence of R1is – OC(=O)RA.

[0156] In some embodiments, each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, – C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA.

[0157] As generally described herein, each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;

[0158] In some embodiments, at least one occurrence of RAis hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;

[0159] In some embodiments, at least one occurrence of RAis hydrogen.

[0160] In some embodiments, at least one occurrence of RAis optionally substituted aliphatic. In some embodiments, at least one occurrence of RAis optionally substituted alkyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C12alkyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C6alkyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C3alkyl. In some embodiments, at least one occurrence of RAis optionally substituted linear alkyl. In some embodiments, at least one occurrence of RAis optionally substituted alkenyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C12alkenyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C6alkenyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C3alkenyl. In some embodiments, at least one occurrence of RAis optionally substituted alkynyl. In some embodiments, atR0708.70175WO00 46 / 180 #13640937v1least one occurrence of RAis optionally substituted C1-C12alkynyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C6 alkynyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C3 alkynyl.

[0161] In some embodiments, at least one occurrence of RAis optionally substituted heteroaliphatic. In some embodiments, at least one occurrence of RAis optionally substituted heteroalkyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C12 heteroalkyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C6 heteroalkyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C3 heteroalkyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroalkenyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C12 heteroalkenyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C6 heteroalkenyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C3 heteroalkenyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroalkynyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C12 heteroalkynyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C6 heteroalkynyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-C3 heteroalkynyl.

[0162] In some embodiments, at least one occurrence of RAis optionally substituted carbocyclyl. In some embodiments, at least one occurrence of RAis optionally substituted C3-C10 carbocyclyl. In some embodiments, at least one occurrence of RAis optionally substituted C3-C6 carbocyclyl. In some embodiments, at least one occurrence of RAis optionally substituted heterocyclyl. In some embodiments, at least one occurrence of RAis optionally substituted 3-10 membered heterocyclyl. In some embodiments, at least one occurrence of RAis optionally substituted 3-6 membered heterocyclyl. In some embodiments, at least one occurrence of RAis optionally substituted aryl. In some embodiments, at least one occurrence of RAis optionally substituted phenyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroaryl. In some embodiments, at least one occurrence of RAis optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one occurrence of RAis optionally substituted 5-6 membered monocyclic heteroaryl.

[0163] In some embodiments, at least one occurrence of RAis a nitrogen protecting group when attached to a nitrogen atom. In some embodiments, at least one occurrence of RAis an oxygen protecting group when attached to an oxygen atom. In some embodiments, at least one occurrence of RAis a sulfur protecting group when attached to a sulfur atom. In some embodiments, two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring. In some embodiments, two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring. In some embodiments, two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heteroaryl ring.

[0164] As generally described herein, n is 0, 1, 2, 3, or 4.

[0165] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In someR0708.70175WO00 47 / 180 #13640937v1embodiments, n is 0 or 1. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.Z, R2, RC, and RN

[0167] As generally described herein, Z is absent or is -SR2, provided that when is a double bond, Z is absent.

[0168] In some embodiments Z is absent. In some embodiments, is a double bond, and Z is absent.

[0169] In some embodiments, Z is -SR2. In some embodiments, is a single bond, and Z is -SR2.

[0170] As generally described herein, R2is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0171] In some embodiments, R2is optionally substituted aliphatic. In some embodiments, R2isR0708.70175WO00 48 / 180 #13640937v1optionally substituted alkyl. In some embodiments, R2is optionally substituted C1-C12alkyl. In some embodiments, R2is optionally substituted C1-C6 alkyl. In some embodiments, R2is optionally substituted C1-C3 alkyl. In some embodiments, R2is optionally substituted linear alkyl.

[0172] In some embodiments, R2is substituted alkyl. In some embodiments, R2is substituted C1-C12alkyl. In some embodiments, R2is substituted C1-C6 alkyl. In some embodiments, R2is substituted C1-C3 alkyl. In some embodiments, R2is substituted linear alkyl.

[0173] In some embodiments, R2is alkyl substituted with at least 1 substituent selected from –O(RA), – N(RA)2, and =O. In some embodiments, R2is alkyl substituted with 0, 1, 2, 3, 4, or 5 substituents selected from –O(RA), –N(RA)2, and =O. In some embodiments, R2is alkyl substituted with 1, 2, 3, 4, or 5 substituents selected from –O(RA), –N(RA)2, and =O. In some embodiments, R2is alkyl substituted with 3 substituents selected from –O(RA), –N(RA)2, and =O. In some embodiments, R2is alkyl substituted with 1 occurrence of –O(RA), 1 occurrence of –N(RA)2, and 1 occurrence of =O. In some embodiments, R2is alkyl substituted with 2 occurrences of –N(RA)2 and 1 occurrence of =O.

[0174] In some embodiments, R2is alkyl substituted with at least 1 substituent selected from –OH, – NHRA, and =O. In some embodiments, R2is alkyl substituted with 0, 1, 2, 3, 4, or 5 substituents selected from –OH, –NHRA, and =O. In some embodiments, R2is alkyl substituted with 1, 2, 3, 4, or 5 substituents selected from –OH, –NHRA, and =O. In some embodiments, R2is alkyl substituted with 3 substituents selected from –OH, –NHRA, and =O. In some embodiments, R2is alkyl substituted with 1 occurrence of –OH, 1 occurrence of –NHRA, and 1 occurrence of =O. In some embodiments, R2is alkyl substituted with 2 occurrences of –NHRAand 1 occurrence of =O.

[0175] In some embodiments, R2is optionally substituted alkenyl. In some embodiments, R2is optionally substituted C1-C12 alkenyl. In some embodiments, R2is optionally substituted C1-C6 alkenyl. In some embodiments, R2is optionally substituted C1-C3 alkenyl. In some embodiments, R2is optionally substituted alkynyl. In some embodiments, R2is optionally substituted C1-C12 alkynyl. In some embodiments, R2is optionally substituted C1-C6alkynyl. In some embodiments, R2is optionally substituted C1-C3alkynyl.

[0176] In some embodiments, R2is optionally substituted heteroaliphatic. In some embodiments, R2is optionally substituted heteroalkyl. In some embodiments, R2is optionally substituted C1-C12heteroalkyl. In some embodiments, R2is optionally substituted C1-C6heteroalkyl. In some embodiments, R2is optionally substituted C1-C3heteroalkyl.

[0177] In some embodiments, R2is substituted heteroaliphatic. In some embodiments, R2is substituted heteroalkyl. In some embodiments, R2is substituted C1-C12heteroalkyl. In some embodiments, R2is substituted C1-C6heteroalkyl. In some embodiments, R2is substituted C1-C3heteroalkyl.

[0178] In some embodiments, R2 is heteroalkyl substituted with at least 1 substituent selected from – O(RA), –N(RA)2, and =O. In some embodiments, R2 is heteroalkyl substituted with 0, 1, 2, 3, 4, or 5 substituents selected from –O(RA), –N(RA)2, and =O. In some embodiments, R2 is heteroalkyl substituted with 1, 2, 3, 4, or 5 substituents selected from –O(RA), –N(RA)2, and =O. In some embodiments, R2 is heteroalkyl substituted with 2 substituents selected from –O(RA), –N(RA)2, and =O.R0708.70175WO00 49 / 180 #13640937v1In some embodiments, R2 is heteroalkyl substituted with 1 occurrence of –O(RA) and 1 occurrence of =O. In some embodiments, R2 is heteroalkyl substituted with 1 occurrence of –N(RA)2 and 1 occurrence of =O.

[0179] In some embodiments, R2is heteroalkyl substituted with at least 1 substituent selected from –OH, –NHRA, and =O. In some embodiments, R2is heteroalkyl substituted with 0, 1, 2, 3, 4, or 5 substituents selected from –OH, –NHRA, and =O. In some embodiments, R2is heteroalkyl substituted with 1, 2, 3, 4, or 5 substituents selected from –OH, –NHRA, and =O. In some embodiments, R2is heteroalkyl substituted with 2 substituents selected from –OH, –NHRA, and =O. In some embodiments, R2is heteroalkyl substituted with 1 occurrence of –OH and 1 occurrence of =O. In some embodiments, R2is heteroalkyl substituted with 1 occurrence of –NHRAand 1 occurrence of =O.

[0180] In some embodiments, R2is of the formula:or a salt thereof, wherein: RCis -OH, an amino acid moiety, or a peptide; and RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide.

[0181] In some embodiments, R2is of the formula:or a salt thereof.

[0182] As generally described herein, RCis -OH, an amino acid moiety, or a peptide. In some embodiments, RCis -OH. In some embodiments, RCis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety. In some embodiments, RCis a peptide.

[0183] As generally described herein, RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide. In some embodiments, RNis hydrogen. In some embodiments, RNis a nitrogen protecting group. In some embodiments, RNis an amino acid moiety or a peptide. In some embodiments, RNis an amino acid moiety. In some embodiments, RNis a peptide.

[0184] In some embodiments, RCis -OH, and RNis an amino acid moiety or a peptide. In some embodiments, RCis -OH, and RNis an amino acid moiety. In some embodiments, RCis -OH, and RNis a peptide. In some embodiments, RCis an amino acid moiety or a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety, and RNis hydrogen. In some embodiments, RCis a peptide, and RNis hydrogen.

[0185] In some embodiments, RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety; and RNis an amino acid moiety. In someR0708.70175WO00 50 / 180 #13640937v1embodiments, RCis an amino acid moiety; and RNis a peptide. In some embodiments, RCis a peptide; and RNis an amino acid moiety. In some embodiments, RCis a peptide; and RNis a peptide.

[0186] In some embodiments, R2is of the formula:or a salt thereof.

[0187] In some embodiments, R2is of the formula:or a salt thereof.

[0188] In some embodiments, R2is of the formula:(iii), or a salt thereof.

[0189] In some embodiments, R2is of the formula:(iii-a), or a salt thereof.

[0190] In some embodiments, R2is optionally substituted heteroalkenyl. In some embodiments, R2is optionally substituted C1-C12heteroalkenyl. In some embodiments, R2is optionally substituted C1-C6heteroalkenyl. In some embodiments, R2is optionally substituted C1-C3heteroalkenyl. In some embodiments, R2is optionally substituted heteroalkynyl. In some embodiments, R2is optionally substituted C1-C12 heteroalkynyl. In some embodiments, R2is optionally substituted C1-C6 heteroalkynyl. In some embodiments, R2is optionally substituted C1-C3 heteroalkynyl.

[0191] In some embodiments, R2is optionally substituted carbocyclyl. In some embodiments, R2is optionally substituted C3-C10 carbocyclyl. In some embodiments, R2is optionally substituted C3-C6 carbocyclyl. In some embodiments, R2is optionally substituted heterocyclyl. In some embodiments, R2is optionally substituted 3-10 membered heterocyclyl. In some embodiments, R2is optionally substituted 3- 6 membered heterocyclyl. In some embodiments, R2is optionally substituted aryl. In some embodiments, R2is optionally substituted phenyl. In some embodiments, R2is optionally substituted heteroaryl. In someR0708.70175WO00 51 / 180 #13640937v1embodiments, R2is optionally substituted 5-10 membered heteroaryl. In some embodiments, R2is optionally substituted 5-6 membered monocyclic heteroaryl. R3aand R3b

[0192] As generally described herein, each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0193] In some embodiments, at least one of R3aand R3bis hydrogen. In some embodiments, R3ais hydrogen. In some embodiments, R3bis hydrogen.

[0194] In some embodiments, at least one of R3aand R3bis optionally substituted aliphatic. In some embodiments, R3ais optionally substituted aliphatic. In some embodiments, R3bis optionally substituted aliphatic. In some embodiments, at least one of R3aand R3bis substituted aliphatic. In some embodiments, R3ais substituted aliphatic. In some embodiments, R3bis substituted aliphatic.

[0195] In some embodiments, at least one of R3aand R3bis optionally substituted alkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12alkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6alkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3alkyl. In some embodiments, at least one of R3aand R3bis optionally substituted linear alkyl. In some embodiments, at least one of R3aand R3bis substituted alkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12alkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6alkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3alkyl. In some embodiments, at least one of R3aand R3bis substituted linear alkyl. In some embodiments, R3ais optionally substituted alkyl. In some embodiments, R3ais optionally substituted C1-C12alkyl. In some embodiments, R3ais optionally substituted C1-C6alkyl. In some embodiments, R3ais optionally substituted C1-C3 alkyl. In some embodiments, R3ais optionally substituted linear alkyl. In some embodiments, R3ais substituted alkyl. In some embodiments, R3ais substituted C1-C12 alkyl. In some embodiments, R3ais substituted C1-C6 alkyl. In some embodiments, R3ais substituted C1-C3 alkyl. In some embodiments, R3ais substituted linear alkyl. In some embodiments, R3bis optionally substituted alkyl. In some embodiments, R3bis optionally substituted C1-C12 alkyl. In some embodiments, R3bis optionally substituted C1-C6 alkyl. In some embodiments, R3bis optionally substituted C1-C3 alkyl. In some embodiments, R3bis optionally substituted linear alkyl. In some embodiments, R3bis substituted alkyl. In some embodiments, R3bis substituted C1-C12 alkyl. In some embodiments, R3bis substituted C1- C6 alkyl. In some embodiments, R3bis substituted C1-C3 alkyl. In some embodiments, R3bis substituted linear alkyl.

[0196] In some embodiments, at least one of R3aand R3bis optionally substituted alkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12 alkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6 alkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3 alkenyl. In some embodiments, at least one of R3aand R3bisR0708.70175WO00 52 / 180 #13640937v1substituted alkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12alkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6 alkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3 alkenyl. In some embodiments, R3ais optionally substituted alkenyl. In some embodiments, R3ais optionally substituted C1-C12alkenyl. In some embodiments, R3ais optionally substituted C1-C6 alkenyl. In some embodiments, R3ais optionally substituted C1-C3 alkenyl. In some embodiments, R3ais substituted alkenyl. In some embodiments, R3ais substituted C1-C12 alkenyl. In some embodiments, R3ais substituted C1-C6 alkenyl. In some embodiments, R3ais substituted C1-C3 alkenyl. In some embodiments, R3bis optionally substituted alkenyl. In some embodiments, R3bis optionally substituted C1-C12 alkenyl. In some embodiments, R3bis optionally substituted C1-C6 alkenyl. In some embodiments, R3bis optionally substituted C1-C3 alkenyl. In some embodiments, R3bis substituted alkenyl. In some embodiments, R3bis substituted C1-C12 alkenyl. In some embodiments, R3bis substituted C1-C6 alkenyl. In some embodiments, R3bis substituted C1-C3 alkenyl.

[0197] In some embodiments, at least one of R3aand R3bis optionally substituted alkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12 alkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6 alkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3 alkynyl. In some embodiments, at least one of R3aand R3bis substituted alkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12 alkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6 alkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3 alkynyl. In some embodiments, R3ais optionally substituted alkynyl. In some embodiments, R3ais optionally substituted C1-C12 alkynyl. In some embodiments, R3ais optionally substituted C1-C6 alkynyl. In some embodiments, R3ais optionally substituted C1-C3 alkynyl. In some embodiments, R3ais substituted alkynyl. In some embodiments, R3ais substituted C1-C12 alkynyl. In some embodiments, R3ais substituted C1-C6 alkynyl. In some embodiments, R3ais substituted C1-C3 alkynyl. In some embodiments, R3bis optionally substituted alkynyl. In some embodiments, R3bis optionally substituted C1-C12alkynyl. In some embodiments, R3bis optionally substituted C1-C6alkynyl. In some embodiments, R3bis optionally substituted C1-C3alkynyl. In some embodiments, R3bis substituted alkynyl. In some embodiments, R3bis substituted C1-C12alkynyl. In some embodiments, R3bis substituted C1-C6alkynyl. In some embodiments, R3bis substituted C1-C3alkynyl.

[0198] In some embodiments, at least one of R3aand R3bis optionally substituted heteroaliphatic. In some embodiments, R3ais optionally substituted heteroaliphatic. In some embodiments, R3bis optionally substituted heteroaliphatic. In some embodiments, at least one of R3aand R3bis substituted heteroaliphatic. In some embodiments, R3ais substituted heteroaliphatic. In some embodiments, R3bis substituted heteroaliphatic.

[0199] In some embodiments, at least one of R3aand R3bis optionally substituted heteroalkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12heteroalkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6heteroalkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3heteroalkyl. In some embodiments, at least one of R3aand R3bis optionally substituted linear heteroalkyl. In someR0708.70175WO00 53 / 180 #13640937v1embodiments, at least one of R3aand R3bis substituted heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12 heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6 heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3 heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted linear heteroalkyl. In some embodiments, R3ais optionally substituted heteroalkyl. In some embodiments, R3ais optionally substituted C1-C12 heteroalkyl. In some embodiments, R3ais optionally substituted C1-C6 heteroalkyl. In some embodiments, R3ais optionally substituted C1-C3 heteroalkyl. In some embodiments, R3ais optionally substituted linear heteroalkyl. In some embodiments, R3ais substituted heteroalkyl. In some embodiments, R3ais substituted C1-C12 heteroalkyl. In some embodiments, R3ais substituted C1-C6 heteroalkyl. In some embodiments, R3ais substituted C1-C3 heteroalkyl. In some embodiments, R3ais substituted linear heteroalkyl. In some embodiments, R3bis optionally substituted heteroalkyl. In some embodiments, R3bis optionally substituted C1-C12 heteroalkyl. In some embodiments, R3bis optionally substituted C1-C6 heteroalkyl. In some embodiments, R3bis optionally substituted C1-C3 heteroalkyl. In some embodiments, R3bis optionally substituted linear heteroalkyl. In some embodiments, R3bis substituted heteroalkyl. In some embodiments, R3bis substituted C1-C12 heteroalkyl. In some embodiments, R3bis substituted C1-C6 heteroalkyl. In some embodiments, R3bis substituted C1-C3 heteroalkyl. In some embodiments, R3bis substituted linear heteroalkyl.

[0200] In some embodiments, at least one of R3aand R3bis optionally substituted heteroalkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12 heteroalkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6 heteroalkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3 heteroalkenyl. In some embodiments, at least one of R3aand R3bis substituted heteroalkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12 heteroalkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6 heteroalkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3 heteroalkenyl. In some embodiments, R3ais optionally substituted heteroalkenyl. In some embodiments, R3ais optionally substituted C1-C12heteroalkenyl. In some embodiments, R3ais optionally substituted C1- C6heteroalkenyl. In some embodiments, R3ais optionally substituted C1-C3heteroalkenyl. In some embodiments, R3ais substituted heteroalkenyl. In some embodiments, R3ais substituted C1-C12heteroalkenyl. In some embodiments, R3ais substituted C1-C6heteroalkenyl. In some embodiments, R3ais substituted C1-C3heteroalkenyl. In some embodiments, R3bis optionally substituted heteroalkenyl. In some embodiments, R3bis optionally substituted C1-C12heteroalkenyl. In some embodiments, R3bis optionally substituted C1-C6heteroalkenyl. In some embodiments, R3bis optionally substituted C1-C3heteroalkenyl. In some embodiments, R3bis substituted heteroalkenyl. In some embodiments, R3bis substituted C1-C12heteroalkenyl. In some embodiments, R3bis substituted C1-C6heteroalkenyl. In some embodiments, R3bis substituted C1-C3heteroalkenyl.

[0201] In some embodiments, at least one of R3aand R3bis optionally substituted heteroalkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12heteroalkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6heteroalkynyl. In someR0708.70175WO00 54 / 180 #13640937v1embodiments, at least one of R3aand R3bis optionally substituted C1-C3heteroalkynyl. In some embodiments, at least one of R3aand R3bis substituted heteroalkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12 heteroalkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6heteroalkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3heteroalkynyl. In some embodiments, R3ais optionally substituted heteroalkynyl. In some embodiments, R3ais optionally substituted C1-C12 heteroalkynyl. In some embodiments, R3ais optionally substituted C1- C6 heteroalkynyl. In some embodiments, R3ais optionally substituted C1-C3 heteroalkynyl. In some embodiments, R3ais substituted heteroalkynyl. In some embodiments, R3ais substituted C1-C12 heteroalkynyl. In some embodiments, R3ais substituted C1-C6 heteroalkynyl. In some embodiments, R3ais substituted C1-C3 heteroalkynyl. In some embodiments, R3bis optionally substituted heteroalkynyl. In some embodiments, R3bis optionally substituted C1-C12 heteroalkynyl. In some embodiments, R3bis optionally substituted C1-C6 heteroalkynyl. In some embodiments, R3bis optionally substituted C1-C3 heteroalkynyl. In some embodiments, R3bis substituted heteroalkynyl. In some embodiments, R3bis substituted C1-C12 heteroalkynyl. In some embodiments, R3bis substituted C1-C6 heteroalkynyl. In some embodiments, R3bis substituted C1-C3 heteroalkynyl.

[0202] In some embodiments, at least one of R3aand R3bis optionally substituted carbocyclyl. In some embodiments, at least one of R3aand R3bis optionally substituted C3-C10 carbocyclyl. In some embodiments, at least one of R3aand R3bis optionally substituted C3-C6 carbocyclyl. In some embodiments, at least one of R3aand R3bis substituted carbocyclyl. In some embodiments, at least one of R3aand R3bis substituted C3-C10 carbocyclyl. In some embodiments, at least one of R3aand R3bis substituted C3-C6 carbocyclyl. In some embodiments, R3ais optionally substituted carbocyclyl. In some embodiments, R3ais optionally substituted C3-C10 carbocyclyl. In some embodiments, R3ais optionally substituted C3-C6 carbocyclyl. In some embodiments, R3ais substituted carbocyclyl. In some embodiments, R3ais substituted C3-C10 carbocyclyl. In some embodiments, R3ais substituted C3-C6 carbocyclyl. In some embodiments, R3bis optionally substituted carbocyclyl. In some embodiments, R3bis optionally substituted C3-C10carbocyclyl. In some embodiments, R3bis optionally substituted C3-C6carbocyclyl. In some embodiments, R3bis substituted carbocyclyl. In some embodiments, R3bis substituted C3-C10carbocyclyl. In some embodiments, R3bis substituted C3-C6carbocyclyl.

[0203] In some embodiments, at least one of R3aand R3bis optionally substituted heterocyclyl. In some embodiments, at least one of R3aand R3bis optionally substituted 3-10 membered heterocyclyl. In some embodiments, at least one of R3aand R3bis optionally substituted 3-6 membered heterocyclyl. In some embodiments, at least one of R3aand R3bis substituted heterocyclyl. In some embodiments, at least one of R3aand R3bis substituted 3-10 membered heterocyclyl. In some embodiments, at least one of R3aand R3bis substituted 3-6 membered heterocyclyl. In some embodiments, R3ais optionally substituted heterocyclyl. In some embodiments, R3ais optionally substituted 3-10 membered heterocyclyl. In some embodiments, R3ais optionally substituted 3-6 membered heterocyclyl. In some embodiments, R3ais substituted heterocyclyl. In some embodiments, R3ais substituted 3-10 membered heterocyclyl. In some embodiments, R3ais substituted 3-6 membered heterocyclyl. In some embodiments, R3bis optionallyR0708.70175WO00 55 / 180 #13640937v1substituted heterocyclyl. In some embodiments, R3bis optionally substituted 3-10 membered heterocyclyl. In some embodiments, R3bis optionally substituted 3-6 membered heterocyclyl. In some embodiments, R3bis substituted heterocyclyl. In some embodiments, R3bis substituted 3-10 membered heterocyclyl. In some embodiments, R3bis substituted 3-6 membered heterocyclyl.

[0204] In some embodiments, at least one of R3aand R3bis optionally substituted aryl. In some embodiments, at least one of R3aand R3bis optionally substituted phenyl. In some embodiments, at least one of R3aand R3bis substituted aryl. In some embodiments, at least one of R3aand R3bis substituted phenyl. In some embodiments, R3ais optionally substituted aryl. In some embodiments, R3ais optionally substituted phenyl. In some embodiments, R3ais substituted aryl. In some embodiments, R3ais substituted phenyl. In some embodiments, R3bis optionally substituted aryl. In some embodiments, R3bis optionally substituted phenyl. In some embodiments, R3bis substituted aryl. In some embodiments, R3bis substituted phenyl.

[0205] In some embodiments, at least one of R3aand R3bis optionally substituted heteroaryl. In some embodiments, at least one of R3aand R3bis optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one of R3aand R3bis optionally substituted 5-6 membered monocyclic heteroaryl. In some embodiments, at least one of R3aand R3bis substituted heteroaryl. In some embodiments, at least one of R3aand R3bis substituted 5-10 membered heteroaryl. In some embodiments, at least one of R3aand R3bis substituted 5-6 membered monocyclic heteroaryl. In some embodiments, R3ais optionally substituted heteroaryl. In some embodiments, R3ais optionally substituted 5-10 membered heteroaryl. In some embodiments, R3ais optionally substituted 5-6 membered monocyclic heteroaryl. In some embodiments, R3ais substituted heteroaryl. In some embodiments, R3ais substituted 5-10 membered heteroaryl. In some embodiments, R3ais substituted 5-6 membered monocyclic heteroaryl. In some embodiments, R3bis optionally substituted heteroaryl. In some embodiments, R3bis optionally substituted 5-10 membered heteroaryl. In some embodiments, R3bis optionally substituted 5-6 membered monocyclic heteroaryl. In some embodiments, R3bis substituted heteroaryl. In some embodiments, R3bis substituted 5-10 membered heteroaryl. In some embodiments, R3bis substituted 5-6 membered monocyclic heteroaryl.

[0206] In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl.

[0207] In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted C3-C10carbocyclyl. In some embodiments, R3aand R3bR0708.70175WO00 56 / 180 #13640937v1are joined together with their intervening atoms to form optionally substituted unsaturated C3-C10carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted cyclooctenyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted C3-C10 carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted unsaturated C3-C10 carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted cyclooctenyl.

[0208] In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted 3-10 membered heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted unsaturated 3-10 membered heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted unsaturated 3-10 membered heterocyclyl containing 1 ring N atom. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted 3-10 membered heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted unsaturated 3-10 membered heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted unsaturated 3-10 membered heterocyclyl containing 1 ring N atom.

[0209] In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted aryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted phenyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted aryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted phenyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted 5-10 membered heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted 5-10 membered heteroaryl.

[0210] In some embodiments,formula:,R0708.70175WO00 57 / 180 #13640937v1substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or –ORA. In some embodiments, R3Cis optionally substituted aliphatic. In some embodiments, R3Cis optionally substituted heteroaliphatic. In some embodiments, R3Cis optionally substituted carbocyclyl. In some embodiments, R3Cis optionally substituted heterocyclyl. In some embodiments, R3Cis optionally substituted aryl. In some embodiments, R3Cis optionally substituted heteroaryl. In some embodiments, R3Cis –ORA. Additional Subgeneric Embodiments

[0211] In some embodiments, the compound of Formula (I) is of Formula (I-A) or Formula (I-B):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (I-B), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0212] In some embodiments, the compound of Formula (II) is of Formula (II-A) or Formula (II-B):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (II-B), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0213] In some embodiments, the compound of Formula (II) is of Formula (II-C) or Formula (II-D):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (II-D), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.R0708.70175WO00 58 / 180 #13640937v1

[0214] In some embodiments, the compound of Formula (III) is of Formula (III-i):or a salt thereof. In some embodiments of Formula (III-i), RCis an amino acid moiety or a peptide, and RNis an amino acid moiety or a peptide.

[0215] In some embodiments, the compound of Formula (III) is of Formula (III-i-a):or a salt thereof. In some embodiments of Formula (III-i-a), RCis an amino acid moiety or a peptide, and RNis an amino acid moiety or a peptide.

[0216] In some embodiments, the compound of Formula (III) is of Formula (III-A) or Formula (III-B):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-B), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0217] In some embodiments, the compound of Formula (III) is of Formula (III-A-i) or Formula (III-B-R0708.70175WO00 59 / 180 #13640937v1i):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-B-i), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (III-A-i) or Formula (III-B- i), RCis an amino acid moiety or a peptide. In some embodiments of Formula (III-A-i) or Formula (III-B- i), RNis an amino acid moiety or a peptide. In some embodiments of Formula (III-A-i) or Formula (III-B- i), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide.

[0218] In some embodiments, the compound of Formula (III) is of Formula (III-A-i-a) or Formula (III- B-i-a):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-B-i-a), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (III-A-i-a) or Formula (III- B-i-a), RCis an amino acid moiety or a peptide. In some embodiments of Formula (III-A-i-a) or Formula (III-B-i-a), RNis an amino acid moiety or a peptide. In some embodiments of Formula (III-A-i-a) or Formula (III-B-i-a), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide.

[0219] In some embodiments, the compound of Formula (III) is of Formula (III-C) or Formula (III-D):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-D), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0220] In some embodiments, the compound of Formula (III) is of Formula (III-C-i) or Formula (III-D-R0708.70175WO00 60 / 180 #13640937v1i):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-D-i), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0221] In some embodiments, the compound of Formula (III) is of Formula (III-C-i-a) or Formula (III- D-i-a):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-D-i-a), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (III-C-i-a) or Formula (III- D-i-a), RCis an amino acid moiety or a peptide. In some embodiments of Formula (III-C-i-a) or Formula (III-D-i-a), RNis an amino acid moiety or a peptide. In some embodiments of Formula (III-C-i-a) or Formula (III-D-i-a), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide.

[0222] In some embodiments, the compound of Formula (IV) is of Formula (IV-i):or a salt thereof. In some embodiments of Formula (IV-i), RCis an amino acid moiety or a peptide, and RNis an amino acid moiety or a peptide.R0708.70175WO00 61 / 180 #13640937v1

[0223] In some embodiments, the compound of Formula (IV) is of Formula (IV-i-a):or a salt thereof. In some embodiments of Formula (IV-i-a), RCis an amino acid moiety or a peptide, and RNis an amino acid moiety or a peptide.

[0224] In some embodiments, the compound of Formula (IV) is of Formula (IV-A) or Formula (IV-B):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (IV-B), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IV-A) or Formula (IV-B), R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments of Formula (IV-A) or Formula (IV-B), R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl.

[0225] In some embodiments, the compound of Formula (IV) is of Formula (IV-A-i) or Formula (IV-B- i):R0708.70175WO00 62 / 180 #13640937v1or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (IV-B-i), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IV-A-i) or Formula (IV-B- i), RCis an amino acid moiety or a peptide. In some embodiments of Formula (IV-A-i) or Formula (IV-B- i), RNis an amino acid moiety or a peptide. In some embodiments of Formula (IV-A-i) or Formula (IV-B- i), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments of Formula (IV-A-i) or Formula (IV-B-i), R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments of Formula (IV-A-i) or Formula (IV-B-i), R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl. In some embodiments of Formula (IV-A-i) or Formula (IV-B-i), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl.

[0226] In some embodiments, the compound of Formula (IV) is of Formula (IV-A-i-a) or Formula (IV- B-i-a):R0708.70175WO00 63 / 180 #13640937v1or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (IV-B-i-a), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IV-A-i-a) or Formula (IV- B-i-a), RCis an amino acid moiety or a peptide. In some embodiments of Formula (IV-A-i-a) or Formula (IV-B-i-a), RNis an amino acid moiety or a peptide. In some embodiments of Formula (IV-A-i-a) or Formula (IV-B-i-a), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments of Formula (IV-A-i-a) or Formula (IV-B-i-a), R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments of Formula (IV-A-i-a) or Formula (IV-B-i-a), R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl. In some embodiments of Formula (IV-A-i-a) or Formula (IV-B-i-a), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl.

[0227] In some embodiments, the compound of Formula (IV) is of Formula (IV-C) or Formula (IV-D):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (IV-D), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IV-C) or Formula (IV-D), R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments of Formula (IV-C) or Formula (IV-D), R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl.

[0228] In some embodiments, the compound of Formula (IV) is of Formula (IV-C-i) or Formula (IV-D- i):R0708.70175WO00 64 / 180 #13640937v1or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (IV-D-i), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IV-C-i) or Formula (IV-D- i), RCis an amino acid moiety or a peptide. In some embodiments of Formula (IV-C-i) or Formula (IV-D- i), RNis an amino acid moiety or a peptide. In some embodiments of Formula (IV-C-i) or Formula (IV-D- i), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments of Formula (IV-C-i) or Formula (IV-D-i), R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments of Formula (IV-C-i) or Formula (IV-D-i), R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl. In some embodiments of Formula (IV-C-i) or Formula (IV-D-i), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl.

[0229] In some embodiments, the compound of Formula (IV) is of Formula (IV-C-i-a) or Formula (IV- D-i-a):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (IV-D-i-a), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IV-C-i-a) or Formula (IV-R0708.70175WO00 65 / 180 #13640937v1D-i-a), RCis an amino acid moiety or a peptide. In some embodiments of Formula (IV-C-i-a) or Formula (IV-D-i-a), RNis an amino acid moiety or a peptide. In some embodiments of Formula (IV-C-i-a) or Formula (IV-D-i-a), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments of Formula (IV-C-i-a) or Formula (IV-D-i-a), R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments of Formula (IV-C-i-a) or Formula (IV-D-i-a), R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl. In some embodiments of Formula (IV-C-i-a) or Formula (IV-D-i-a), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl.

[0230] In some embodiments, the compound of Formula (I) is of formula:, or a salt thereof. Methods of Preparation Methods of Preparation of Formula (III-i)

[0231] In another aspect, provided herein is a method of preparing a compound of Formula (III-i):or a salt thereof, comprising contacting a compound of Formula (V):or a salt thereof, with a compound of Formula (II):or a salt thereof, to obtain the compound of Formula (III-i), or a salt thereof, wherein:R0708.70175WO00 66 / 180 #13640937v1X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –RCis -OH, an amino acid moiety, or a peptide; and RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide.

[0232] In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 1:1 and about 50:1, about 1:1 and about 45:1, about 1:1 and about 40:1, about 1:1 and about 35:1, about 1:1 and about 30:1, about 1:1 and about 25:1, about 1:1 and about 20:1, about 1:1 and about 15:1, about 1:1 and about 10:1, about 1:1 and about 5:1, about 5:1 and about 30:1, about 5:1 and about 25:1, about 5:1 and about 20:1, about 5:1 and about 15:1, about 5:1 and about 10:1, about 10:1 and about 30:1, about 10:1 and about 25:1, about 10:1 and about 20:1, about 10:1 and about 15:1, about 15:1 and about 30:1, about 15:1 and about 25:1, or about 15:1 and about 20:1. In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 1:1 and about 50:1, about 1:1 and about 30:1,R0708.70175WO00 67 / 180 #13640937v1about 5:1 and about 25:1, about 5:1 and about 20:1, about 5:1 and about 15:1, about 10:1 and about 20:1, about 10:1 and about 25:1, or about 15:1 and about 25:1. In some embodiments, a molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 1:1 and about 50:1. In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 5:1 and about 25:1. In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 5:1 and about 15:1. In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 10:1 and about 20:1. In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is between or about 15:1 and about 25:1.

[0233] In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, or about 25:1. In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is about 5:1. In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is about 10:1. In some embodiments, the molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is about 20:1.

[0234] In some embodiments, X−is a halide ion. In some embodiments, X−is F–, Cl–, Br–, or I–. In some embodiments, X−is Cl–or Br–. In some embodiments, X−is Cl–.

[0235] In some embodiments, X−is triflate or a halide ion. In some embodiments, X−is triflate, F–, Cl–, Br–, or I–. In some embodiments, X−is triflate, Cl–, or Br–. In some embodiments, X−is triflate or Cl–.

[0236] In some embodiments, L1comprises optionally substituted alkylene. In some embodiments, L1comprises optionally substituted C1-C12alkylene. In some embodiments, L1comprises optionally substituted C1-C6alkylene. In some embodiments, L1comprises optionally substituted C1-C3alkylene. In some embodiments, L1comprises optionally substituted linear alkylene. In some embodiments, L1comprises optionally substituted linear C1-C12alkylene. In some embodiments, L1comprises optionally substituted linear C1-C6alkylene. In some embodiments, L1comprises optionally substituted linear C1-C3alkylene.

[0237] In some embodiments, L1comprises substituted alkylene. In some embodiments, L1comprises substituted C1-C12alkylene. In some embodiments, L1comprises substituted C1-C6alkylene. In some embodiments, L1comprises substituted C1-C3alkylene. In some embodiments, L1comprises substituted linear alkylene. In some embodiments, L1comprises substituted linear C1-C12alkylene. In some embodiments, L1comprises substituted linear C1-C6alkylene. In some embodiments, L1comprises substituted linear C1-C3alkylene.

[0238] In some embodiments, L1comprises unsubstituted alkylene. In some embodiments, L1comprisesR0708.70175WO00 68 / 180 #13640937v1unsubstituted C1-C12alkylene. In some embodiments, L1comprises unsubstituted C1-C6alkylene. In some embodiments, L1comprises unsubstituted C1-C3 alkylene. In some embodiments, L1comprises unsubstituted linear alkylene. In some embodiments, L1comprises unsubstituted linear C1-C12 alkylene. In some embodiments, L1comprises unsubstituted linear C1-C6alkylene. In some embodiments, L1comprises unsubstituted linear C1-C3 alkylene.

[0239] In some embodiments, L1comprises methylene, ethylene, n-propylene, n-butylene, n-pentylene, or n-hexylene. In some embodiments, L1comprises methylene, ethylene, or n-propylene. In some embodiments, L1comprises ethylene.

[0240] In some embodiments, L1is methylene, ethylene, n-propylene, n-butylene, n-pentylene, or n- hexylene. In some embodiments, L1is methylene, ethylene, or n-propylene. In some embodiments, L1is ethylene.

[0241] In some embodiments, L1comprises optionally substituted alkenylene. In some embodiments, L1comprises optionally substituted C1-C12 alkenylene. In some embodiments, L1comprises optionally substituted C1-C6 alkenylene. In some embodiments, L1comprises optionally substituted C1-C3 alkenylene. In some embodiments, L1comprises substituted alkenylene. In some embodiments, L1comprises substituted C1-C12 alkenylene. In some embodiments, L1comprises substituted C1-C6 alkenylene. In some embodiments, L1comprises substituted C1-C3 alkenylene. In some embodiments, L1comprises unsubstituted alkenylene. In some embodiments, L1comprises unsubstituted C1-C12 alkenylene. In some embodiments, L1comprises unsubstituted C1-C6 alkenylene. In some embodiments, L1comprises unsubstituted C1-C3 alkenylene.

[0242] In some embodiments, L1comprises optionally substituted alkynylene. In some embodiments, L1comprises optionally substituted C1-C12 alkynylene. In some embodiments, L1comprises optionally substituted C1-C6 alkynylene. In some embodiments, L1comprises optionally substituted C1-C3 alkynylene. In some embodiments, L1comprises substituted alkynylene. In some embodiments, L1comprises substituted C1-C12alkynylene. In some embodiments, L1comprises substituted C1-C6alkynylene. In some embodiments, L1comprises substituted C1-C3alkynylene. In some embodiments, L1comprises unsubstituted alkynylene. In some embodiments, L1comprises unsubstituted C1-C12alkynylene. In some embodiments, L1comprises unsubstituted C1-C6alkynylene. In some embodiments, L1comprises unsubstituted C1-C3alkynylene.

[0243] In some embodiments, L1comprises optionally substituted heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C12heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C6heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C3heteroalkylene. In some embodiments, L1comprises optionally substituted linear heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C12heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C6heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C3heteroalkylene.

[0244] In some embodiments, L1comprises substituted heteroalkylene. In some embodiments, L1comprises substituted C1-C12heteroalkylene. In some embodiments, L1comprises substituted C1-C6R0708.70175WO00 69 / 180 #13640937v1heteroalkylene. In some embodiments, L1comprises substituted C1-C3heteroalkylene. In some embodiments, L1comprises substituted linear heteroalkylene. In some embodiments, L1comprises substituted linear C1-C12 heteroalkylene. In some embodiments, L1comprises substituted linear C1-C6 heteroalkylene. In some embodiments, L1comprises substituted linear C1-C3heteroalkylene.

[0245] In some embodiments, L1comprises unsubstituted heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C12 heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C6 heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C3 heteroalkylene. In some embodiments, L1comprises unsubstituted linear heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1-C12 heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1- C6 heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1-C3 heteroalkylene.

[0246] In some embodiments, L1comprises, wherein x is an integer between 1 and 100, inclusive. In some embodiments, L1is or, wherein x is an integer between 1 and 100, inclusive.

[0247] In some embodiments, x is an integer between 1 and 90, inclusive; between 1 and 80, inclusive; between 1 and 70, inclusive; between 1 and 60, inclusive; between 1 and 50, inclusive; between 1 and 40, inclusive; between 1 and 30, inclusive; between 1 and 20, inclusive; between 1 and 10, inclusive; or between 1 and 5, inclusive. In some embodiments, x is an integer between 1 and 10, inclusive. In some embodiments, x is an integer between 1 and 5, inclusive. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, x is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, x is 1, 2, 3, 4, 5, or 6. In some embodiments, x is 1, 2, 3, 4, or 5. In some embodiments, x is 1, 2, 3, or 4. In some embodiments, x is 1, 2, or 3. In some embodiments, x is 1 or 2. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10.

[0248] In some embodiments, L1comprises, wherein x is an integer between 1 and 10, inclusive. In some embodiments, L1comprisesorR0708.70175WO00 70 / 180 #13640937v1embodiments, L1is or , wherein x is an integer between 1 and 5, inclusive.

[0249] In some embodiments, L1comprises optionally substituted heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C12 heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C6 heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C3 heteroalkenylene. In some embodiments, L1comprises substituted heteroalkenylene. In some embodiments, L1comprises substituted C1-C12heteroalkenylene. In some embodiments, L1comprises substituted C1-C6heteroalkenylene. In some embodiments, L1comprises substituted C1-C3heteroalkenylene. In some embodiments, L1comprises unsubstituted heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C12heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C6heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C3heteroalkenylene.

[0250] In some embodiments, L1comprises optionally substituted heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C12heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C6heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C3heteroalkynylene. In some embodiments, L1comprises substituted heteroalkynylene. In some embodiments, L1comprises substituted C1-C12heteroalkynylene. In some embodiments, L1comprises substituted C1-C6heteroalkynylene. In some embodiments, L1comprises substituted C1-C3heteroalkynylene. In some embodiments, L1comprises unsubstituted heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C12heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C6heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C3heteroalkynylene.

[0251] In some embodiments, L1comprises optionally substituted carbocyclylene. In some embodiments, L1comprises optionally substituted C3-C10 carbocyclylene. In some embodiments, L1comprises optionally substituted C3-C6 carbocyclylene. In some embodiments, L1comprises substituted carbocyclylene. In some embodiments, L1comprises substituted C3-C10 carbocyclylene. In some embodiments, L1comprises substituted C3-C6 carbocyclylene. In some embodiments, L1comprises unsubstituted carbocyclylene. In some embodiments, L1comprises unsubstituted C3-C10 carbocyclylene. In some embodiments, L1comprises unsubstituted C3-C6 carbocyclylene.

[0252] In some embodiments, L1comprises optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises optionally substituted 3-6 membered heterocyclylene. In some embodiments, L1comprises substituted heterocyclylene. In some embodiments, L1comprises substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises substituted 3-6 membered heterocyclylene. In some embodiments, L1comprises unsubstituted heterocyclylene. In some embodiments, L1comprises unsubstituted 3-10 membered heterocyclylene. In some embodiments, L1comprises unsubstituted 3-6 membered heterocyclylene.R0708.70175WO00 71 / 180 #13640937v1

[0253] In some embodiments, L1comprises optionally substituted arylene. In some embodiments, L1comprises optionally substituted phenylene. In some embodiments, L1comprises substituted arylene. In some embodiments, L1comprises substituted phenylene. In some embodiments, L1comprises unsubstituted arylene. In some embodiments, L1comprises unsubstituted phenylene.

[0254] In some embodiments, L1comprises optionally substituted heteroarylene. In some embodiments, L1comprises optionally substituted 5-10 membered heteroarylene. In some embodiments, L1comprises optionally substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L1comprises substituted heteroarylene. In some embodiments, L1comprises substituted 5-10 membered heteroarylene. In some embodiments, L1comprises substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L1comprises unsubstituted heteroarylene. In some embodiments, L1comprises unsubstituted 5-10 membered heteroarylene. In some embodiments, L1comprises unsubstituted 5-6 membered monocyclic heteroarylene.

[0255] In some embodiments, at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –some embodiments, at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, –C(=O)RA, – C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA. In some embodiments, each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, –C(=O)RA, – C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA.

[0256] In some embodiments, at least one occurrence of RAis hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or aR0708.70175WO00 72 / 180 #13640937v1sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;

[0257] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0259] In some embodiments, RCis -OH. In some embodiments, RCis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety. In some embodiments, RCis a peptide. In some embodiments, RNis hydrogen. In some embodiments, RNis a nitrogen protecting group. In some embodiments, RNis an amino acid moiety or a peptide. In some embodiments, RNis an amino acid moiety. In some embodiments, RNis a peptide. In some embodiments, RCis -OH, and RNis an amino acidR0708.70175WO00 73 / 180 #13640937v1moiety or a peptide. In some embodiments, RCis -OH, and RNis an amino acid moiety. In some embodiments, RCis -OH, and RNis a peptide. In some embodiments, RCis an amino acid moiety or a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety, and RNis hydrogen. In some embodiments, RCis a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety; and RNis an amino acid moiety. In some embodiments, RCis an amino acid moiety; and RNis a peptide. In some embodiments, RCis a peptide; and RNis an amino acid moiety. In some embodiments, RCis a peptide; and RNis a peptide.

[0260] In some embodiments, the compound of Formula (II) is of Formula (II-A) or Formula (II-B):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (II-B), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0261] In some embodiments, the compound of Formula (II) is of Formula (II-C) or Formula (II-D):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (II-D), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0262] In some embodiments, the compound of Formula (III-i) is of Formula (III-i-a):or a salt thereof.

[0263] In some embodiments, the compound of Formula (III-i) is of Formula (III-A-i) or Formula (III-B-R0708.70175WO00 74 / 180 #13640937v1i):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-B-i), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (III-A-i) or Formula (III-B- i), RCis an amino acid moiety or a peptide. In some embodiments of Formula (III-A-i) or Formula (III-B- i), RNis an amino acid moiety or a peptide. In some embodiments of Formula (III-A-i) or Formula (III-B- i), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide.

[0264] In some embodiments, the compound of Formula (III-i) is of Formula (III-A-i-a) or Formula (III- B-i-a):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-B-i-a), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (III-A-i-a) or Formula (III- B-i-a), RCis an amino acid moiety or a peptide. In some embodiments of Formula (III-A-i-a) or Formula (III-B-i-a), RNis an amino acid moiety or a peptide. In some embodiments of Formula (III-A-i-a) or Formula (III-B-i-a), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide.

[0265] In some embodiments, the compound of Formula (III-i) is of Formula (III-C-i) or Formula (III-D- i):R0708.70175WO00 75 / 180 #13640937v1or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-D-i), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0266] In some embodiments, the compound of Formula (III-i) is of Formula (III-C-i-a) or Formula (III- D-i-a):or a salt thereof, wherein x is an integer between 1 and 100, inclusive. In some embodiments of Formula (III-D-i-a), x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (III-C-i-a) or Formula (III- D-i-a), RCis an amino acid moiety or a peptide. In some embodiments of Formula (III-C-i-a) or Formula (III-D-i-a), RNis an amino acid moiety or a peptide. In some embodiments of Formula (III-C-i-a) or Formula (III-D-i-a), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. Methods of Preparation of Formula (VI)

[0267] In another aspect, provided herein is a method of preparing a compound of Formula (VI):or a salt thereof, comprising contacting a compound of Formula (V):or a salt thereof, with a compound of Formula (VII):or a salt thereof, to obtain the compound of Formula (VI), or a salt thereof, wherein: L2is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionallyR0708.70175WO00 76 / 180 #13640937v1substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; RCis -OH, an amino acid moiety, or a peptide; and RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide.

[0268] In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 1:1 and about 2:1, about 1:1 and about 3:1, about 1:1 and about 4:1, about 1:1 and about 5:1, about 1:1 and about 6:1, about 1:1 and about 7:1, about 1:1 and about 8:1, about 1:1 and about 9:1, about 1:1 and about 10:1, about 2:1 and about 5:1, about 1.5:1 and about 2.5:1, about 4:1 and about 6:1, or about 4.5:1 and about 5.5:1. In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 1:1 and about 3:1. In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 1:1 and about 10:1. In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 2:1 and about 5:1. In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 1.5:1 and about 2.5:1. In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 4:1 and about 6:1. In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 4.5:1 and about 5.5:1.

[0269] In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 1:1, about 1.5:1, about 2:1, about 2.5:1, about 3:1, about 4:1, about 4.5:1, about 5:1, about 5.5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1. In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 2:1. In some embodiments, the molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is about 5:1.

[0270] As generally described herein, L2is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof.

[0271] In some embodiments, L2comprises optionally substituted alkylene. In some embodiments, L2comprises optionally substituted C1-C12alkylene. In some embodiments, L2comprises optionally substituted C1-C6alkylene. In some embodiments, L2comprises optionally substituted C1-C3alkylene. In some embodiments, L2comprises optionally substituted linear alkylene. In some embodiments, L2comprises optionally substituted linear C1-C12alkylene. In some embodiments, L2comprises optionally substituted linear C1-C6alkylene. In some embodiments, L2comprises optionally substituted linear C1-C3alkylene.R0708.70175WO00 77 / 180 #13640937v1

[0272] In some embodiments, L2comprises substituted alkylene. In some embodiments, L2comprises substituted C1-C12 alkylene. In some embodiments, L2comprises substituted C1-C6 alkylene. In some embodiments, L2comprises substituted C1-C3 alkylene. In some embodiments, L2comprises substituted linear alkylene. In some embodiments, L2comprises substituted linear C1-C12alkylene. In some embodiments, L2comprises substituted linear C1-C6 alkylene. In some embodiments, L2comprises substituted linear C1-C3 alkylene. In some embodiments, L2comprises unsubstituted alkylene. In some embodiments, L2comprises unsubstituted C1-C12 alkylene. In some embodiments, L2comprises unsubstituted C1-C6 alkylene. In some embodiments, L2comprises unsubstituted C1-C3 alkylene. In some embodiments, L2comprises unsubstituted linear alkylene. In some embodiments, L2comprises unsubstituted linear C1-C12 alkylene. In some embodiments, L2comprises unsubstituted linear C1-C6 alkylene. In some embodiments, L2comprises unsubstituted linear C1-C3 alkylene.

[0273] In some embodiments, L2comprises methylene, ethylene, n-propylene, n-butylene, n-pentylene, or n-hexylene. In some embodiments, L2comprises methylene, ethylene, or n-propylene. In some embodiments, L2comprises ethylene. In some embodiments, L2comprises n-propylene.

[0274] In some embodiments, L2comprises optionally substituted alkenylene. In some embodiments, L2comprises optionally substituted C1-C12 alkenylene. In some embodiments, L2comprises optionally substituted C1-C6 alkenylene. In some embodiments, L2comprises optionally substituted C1-C3 alkenylene. In some embodiments, L2comprises substituted alkenylene. In some embodiments, L2comprises substituted C1-C12 alkenylene. In some embodiments, L2comprises substituted C1-C6 alkenylene. In some embodiments, L2comprises substituted C1-C3 alkenylene. In some embodiments, L2comprises unsubstituted alkenylene. In some embodiments, L2comprises unsubstituted C1-C12 alkenylene. In some embodiments, L2comprises unsubstituted C1-C6 alkenylene. In some embodiments, L2comprises unsubstituted C1-C3 alkenylene.

[0275] In some embodiments, L2comprises optionally substituted alkynylene. In some embodiments, L2comprises optionally substituted C1-C12alkynylene. In some embodiments, L2comprises optionally substituted C1-C6alkynylene. In some embodiments, L2comprises optionally substituted C1-C3alkynylene. In some embodiments, L2comprises substituted alkynylene. In some embodiments, L2comprises substituted C1-C12alkynylene. In some embodiments, L2comprises substituted C1-C6alkynylene. In some embodiments, L2comprises substituted C1-C3alkynylene. In some embodiments, L2comprises unsubstituted alkynylene. In some embodiments, L2comprises unsubstituted C1-C12alkynylene. In some embodiments, L2comprises unsubstituted C1-C6alkynylene. In some embodiments, L2comprises unsubstituted C1-C3alkynylene.

[0276] In some embodiments, L2comprises optionally substituted heteroalkylene. In some embodiments, L2comprises optionally substituted C1-C12heteroalkylene. In some embodiments, L2comprises optionally substituted C1-C6heteroalkylene. In some embodiments, L2comprises optionally substituted C1-C3heteroalkylene. In some embodiments, L2comprises optionally substituted linear heteroalkylene. In some embodiments, L2comprises optionally substituted linear C1-C12heteroalkylene. In some embodiments, L2comprises optionally substituted linear C1-C6heteroalkylene. In some embodiments, L2comprisesR0708.70175WO00 78 / 180 #13640937v1optionally substituted linear C1-C3heteroalkylene.

[0277] In some embodiments, L2comprises substituted heteroalkylene. In some embodiments, L2comprises substituted C1-C12 heteroalkylene. In some embodiments, L2comprises substituted C1-C6 heteroalkylene. In some embodiments, L2comprises substituted C1-C3heteroalkylene. In some embodiments, L2comprises substituted linear heteroalkylene. In some embodiments, L2comprises substituted linear C1-C12 heteroalkylene. In some embodiments, L2comprises substituted linear C1-C6 heteroalkylene. In some embodiments, L2comprises substituted linear C1-C3 heteroalkylene.

[0278] In some embodiments, L2comprises unsubstituted heteroalkylene. In some embodiments, L2comprises unsubstituted C1-C12 heteroalkylene. In some embodiments, L2comprises unsubstituted C1-C6 heteroalkylene. In some embodiments, L2comprises unsubstituted C1-C3 heteroalkylene. In some embodiments, L2comprises unsubstituted linear heteroalkylene. In some embodiments, L2comprises unsubstituted linear C1-C12 heteroalkylene. In some embodiments, L2comprises unsubstituted linear C1- C6 heteroalkylene. In some embodiments, L2comprises unsubstituted linear C1-C3 heteroalkylene.

[0279] In some embodiments, L2comprises, wherein y is an integer between 1 and 100, inclusive.

[0280] As generally described herein, y is an integer between 1 and 100, inclusive. In some embodiments, y is an integer between 1 and 90, inclusive; between 1 and 80, inclusive; between 1 and 70, inclusive; between 1 and 60, inclusive; between 1 and 50, inclusive; between 1 and 40, inclusive; between 1 and 30, inclusive; between 1 and 20, inclusive; between 1 and 10, inclusive; or between 1 and 5, inclusive. In some embodiments, y is an integer between 1 and 10, inclusive. In some embodiments, y is an integer between 1 and 5, inclusive. In some embodiments, y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, y is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, y is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, y is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, y is 1, 2, 3, 4, 5, or 6. In some embodiments, y is 1, 2, 3, 4, or 5. In some embodiments, y is 1, 2, 3, or 4. In some embodiments, y is 1, 2, or 3. In some embodiments, y is 1 or 2. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6. In some embodiments, y is 7. In some embodiments, y is 8. In some embodiments, y is 9. In some embodiments, y is 10.

[0281] In some embodiments, L2comprises, wherein y is an integer between 1 and 10, inclusive. In some embodiments, L2comprisesor, wherein y is an integer between 1 and 5, inclusive.

[0282] In some embodiments, L2comprises optionally substituted heteroalkenylene. In some embodiments, L2comprises optionally substituted C1-C12 heteroalkenylene. In some embodiments, L2R0708.70175WO00 79 / 180 #13640937v1comprises optionally substituted C1-C6heteroalkenylene. In some embodiments, L2comprises optionally substituted C1-C3 heteroalkenylene. In some embodiments, L2comprises substituted heteroalkenylene. In some embodiments, L2comprises substituted C1-C12 heteroalkenylene. In some embodiments, L2comprises substituted C1-C6heteroalkenylene. In some embodiments, L2comprises substituted C1-C3heteroalkenylene. In some embodiments, L2comprises unsubstituted heteroalkenylene. In some embodiments, L2comprises unsubstituted C1-C12 heteroalkenylene. In some embodiments, L2comprises unsubstituted C1-C6 heteroalkenylene. In some embodiments, L2comprises unsubstituted C1-C3 heteroalkenylene.

[0283] In some embodiments, L2comprises optionally substituted heteroalkynylene. In some embodiments, L2comprises optionally substituted C1-C12 heteroalkynylene. In some embodiments, L2comprises optionally substituted C1-C6 heteroalkynylene. In some embodiments, L2comprises optionally substituted C1-C3 heteroalkynylene. In some embodiments, L2comprises substituted heteroalkynylene. In some embodiments, L2comprises substituted C1-C12 heteroalkynylene. In some embodiments, L2comprises substituted C1-C6 heteroalkynylene. In some embodiments, L2comprises substituted C1-C3 heteroalkynylene. In some embodiments, L2comprises unsubstituted heteroalkynylene. In some embodiments, L2comprises unsubstituted C1-C12 heteroalkynylene. In some embodiments, L2comprises unsubstituted C1-C6 heteroalkynylene. In some embodiments, L2comprises unsubstituted C1-C3 heteroalkynylene.

[0284] In some embodiments, L2comprises optionally substituted carbocyclylene. In some embodiments, L2comprises optionally substituted C3-C10 carbocyclylene. In some embodiments, L2comprises optionally substituted C3-C6 carbocyclylene. In some embodiments, L2comprises substituted carbocyclylene. In some embodiments, L2comprises substituted C3-C10 carbocyclylene. In some embodiments, L2comprises substituted C3-C6 carbocyclylene. In some embodiments, L2comprises unsubstituted carbocyclylene. In some embodiments, L2comprises unsubstituted C3-C10 carbocyclylene. In some embodiments, L2comprises unsubstituted C3-C6carbocyclylene.

[0285] In some embodiments, L2comprises optionally substituted heterocyclylene. In some embodiments, L2comprises optionally substituted 3-10 membered heterocyclylene. In some embodiments, L2comprises optionally substituted 3-6 membered heterocyclylene. In some embodiments, L2comprises substituted heterocyclylene. In some embodiments, L2comprises substituted 3-10 membered heterocyclylene. In some embodiments, L2comprises substituted 3-6 membered heterocyclylene. In some embodiments, L2comprises unsubstituted heterocyclylene. In some embodiments, L2comprises unsubstituted 3-10 membered heterocyclylene. In some embodiments, L2comprises unsubstituted 3-6 membered heterocyclylene.

[0286] In some embodiments, L2comprises optionally substituted arylene. In some embodiments, L2comprises optionally substituted phenylene. In some embodiments, L2comprises substituted arylene. In some embodiments, L2comprises substituted phenylene. In some embodiments, L2comprises unsubstituted arylene. In some embodiments, L2comprises unsubstituted phenylene.

[0287] In some embodiments, L2comprises optionally substituted heteroarylene. In some embodiments,R0708.70175WO00 80 / 180 #13640937v1L2comprises optionally substituted 5-10 membered heteroarylene. In some embodiments, L2comprises optionally substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L2comprises substituted heteroarylene. In some embodiments, L2comprises substituted 5-10 membered heteroarylene. In some embodiments, L2comprises substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L2comprises unsubstituted heteroarylene. In some embodiments, L2comprises unsubstituted 5-10 membered heteroarylene. In some embodiments, L2comprises unsubstituted 5-6 membered monocyclic heteroarylene.

[0288] In some embodiments, L2comprises,

[0289] In some embodiments, the compound of Formula (VII) is of Formula (VII-A):or a salt thereof, wherein y is an integer between 1 and 100, inclusive. In some embodiments of Formula (VII-A), y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (VII-A), y is 1, 2, 3, 4, or 5. In some embodiments of Formula (VII-A), y is 4.

[0290] In some embodiments, the compound of Formula (VII) is of formula:,R0708.70175WO00 81 / 180 #13640937v1or a salt thereof.

[0291] In some embodiments, RCis -OH. In some embodiments, RCis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety. In some embodiments, RCis a peptide. In some embodiments, RNis hydrogen. In some embodiments, RNis a nitrogen protecting group. In some embodiments, RNis an amino acid moiety or a peptide. In some embodiments, RNis an amino acid moiety. In some embodiments, RNis a peptide. In some embodiments, RCis -OH, and RNis an amino acid moiety or a peptide. In some embodiments, RCis -OH, and RNis an amino acid moiety. In some embodiments, RCis -OH, and RNis a peptide. In some embodiments, RCis an amino acid moiety or a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety, and RNis hydrogen. In some embodiments, RCis a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety; and RNis an amino acid moiety. In some embodiments, RCis an amino acid moiety; and RNis a peptide. In some embodiments, RCis a peptide; and RNis an amino acid moiety. In some embodiments, RCis a peptide; and RNis a peptide.

[0292] In some embodiments, the compound of Formula (VI) is of Formula (VI-A):or a salt thereof, wherein y is an integer between 1 and 100, inclusive. In some embodiments of Formula (VI-A), y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (VI-A), y is 1, 2, 3, 4, or 5. In some embodiments of Formula (VI-A), y is 4. In some embodiments of Formula (VI-A), RCis an amino acid moiety or a peptide. In some embodiments of Formula (VI-A), RNis an amino acid moiety or a peptide. In some embodiments of Formula (VI-A), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments of Formula (VI-A), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (VI-A), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and y is 1, 2, 3, 4, or 5. In some embodiments of Formula (VI-A), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and y is 4. Methods of Preparation of Formula (VIII)

[0293] In another aspect, provided herein is a method of preparing a compound of Formula (VIII):R0708.70175WO00 82 / 180 #13640937v1or a salt thereof, comprising contacting a compound of Formula (V):or a salt thereof, with a compound of Formula (IX):or a salt thereof, to obtain the compound of Formula (VIII), or a salt thereof, wherein: Y is a leaving group; L3is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; and R4is hydrogen, optionally substituted aliphatic, or a nitrogen protecting group; RCis -OH, an amino acid moiety, or a peptide; and RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide.

[0294] As generally described herein, Y is a leaving group.

[0295] In some embodiments, Y is halo (e.g., –F, –Cl, –Br, –I), an activated substituted hydroxyl group (e.g., –OC(=O)SRaa, –OC(=O)Raa, –OCO2Raa, –OC(=O)N(Rbb)2, –OC(=NRbb)Raa, –OC(=NRbb)ORaa, – OC(=NRbb)N(Rbb)2, –OS(=O)Raa, –OSO2Raa, –OP(Rcc)2, –OP(Rcc)3, –OP(=O)2Raa, –OP(=O)(Raa)2, – OP(=O)(ORcc)2, –OP(=O)2N(Rbb)2, –OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein), or a a sulfonic acid ester (e.g., toluenesulfonate (tosylate, –OTs), methanesulfonate (mesylate, –OMs), p- bromobenzenesulfonyloxy (brosylate, –OBs), –OS(=O)2(CF2)3CF3(nonaflate, –ONf), trifluoromethanesulfonate (triflate, –OTf)).

[0296] In some embodiments, Y is halo (e.g., –F, –Cl, –Br, –I). In some embodiments, Y is –Cl, –Br, or –I. In some embodiments, Y is –Cl. In some embodiments, Y is –Br. In some embodiments, Y is –I.

[0297] In some embodiments, the compound of Formula (IX) is of Formula (IX-A):R0708.70175WO00 83 / 180 #13640937v1or a salt thereof.

[0298] As generally described herein, L3is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof.

[0299] In some embodiments, L3comprises optionally substituted alkylene. In some embodiments, L3comprises optionally substituted C1-C12 alkylene. In some embodiments, L3comprises optionally substituted C1-C6 alkylene. In some embodiments, L3comprises optionally substituted C1-C3 alkylene. In some embodiments, L3comprises optionally substituted linear alkylene. In some embodiments, L3comprises optionally substituted linear C1-C12 alkylene. In some embodiments, L3comprises optionally substituted linear C1-C6 alkylene. In some embodiments, L3comprises optionally substituted linear C1-C3 alkylene.

[0300] In some embodiments, L3comprises substituted alkylene. In some embodiments, L3comprises substituted C1-C12 alkylene. In some embodiments, L3comprises substituted C1-C6 alkylene. In some embodiments, L3comprises substituted C1-C3 alkylene. In some embodiments, L3comprises substituted linear alkylene. In some embodiments, L3comprises substituted linear C1-C12 alkylene. In some embodiments, L3comprises substituted linear C1-C6 alkylene. In some embodiments, L3comprises substituted linear C1-C3 alkylene. In some embodiments, L3comprises unsubstituted alkylene. In some embodiments, L3comprises unsubstituted C1-C12 alkylene. In some embodiments, L3comprises unsubstituted C1-C6 alkylene. In some embodiments, L3comprises unsubstituted C1-C3 alkylene. In some embodiments, L3comprises unsubstituted linear alkylene. In some embodiments, L3comprises unsubstituted linear C1-C12 alkylene. In some embodiments, L3comprises unsubstituted linear C1-C6 alkylene. In some embodiments, L3comprises unsubstituted linear C1-C3 alkylene.

[0301] In some embodiments, L3comprises methylene, ethylene, n-propylene, n-butylene, n-pentylene, or n-hexylene. In some embodiments, L3comprises methylene, ethylene, or n-propylene. In some embodiments, L3comprises ethylene. In some embodiments, L3comprises n-propylene.

[0302] In some embodiments, L3comprises optionally substituted alkenylene. In some embodiments, L3comprises optionally substituted C1-C12alkenylene. In some embodiments, L3comprises optionally substituted C1-C6alkenylene. In some embodiments, L3comprises optionally substituted C1-C3alkenylene. In some embodiments, L3comprises substituted alkenylene. In some embodiments, L3comprises substituted C1-C12alkenylene. In some embodiments, L3comprises substituted C1-C6alkenylene. In some embodiments, L3comprises substituted C1-C3alkenylene. In some embodiments, L3comprises unsubstituted alkenylene. In some embodiments, L3comprises unsubstituted C1-C12alkenylene. In some embodiments, L3comprises unsubstituted C1-C6alkenylene. In some embodiments, L3comprises unsubstituted C1-C3alkenylene.

[0303] In some embodiments, L3comprises optionally substituted alkynylene. In some embodiments, L3comprises optionally substituted C1-C12alkynylene. In some embodiments, L3comprises optionallyR0708.70175WO00 84 / 180 #13640937v1substituted C1-C6alkynylene. In some embodiments, L3comprises optionally substituted C1-C3alkynylene. In some embodiments, L3comprises substituted alkynylene. In some embodiments, L3comprises substituted C1-C12 alkynylene. In some embodiments, L3comprises substituted C1-C6 alkynylene. In some embodiments, L3comprises substituted C1-C3alkynylene. In some embodiments, L3comprises unsubstituted alkynylene. In some embodiments, L3comprises unsubstituted C1-C12 alkynylene. In some embodiments, L3comprises unsubstituted C1-C6 alkynylene. In some embodiments, L3comprises unsubstituted C1-C3 alkynylene.

[0304] In some embodiments, L3comprises optionally substituted heteroalkylene. In some embodiments, L3comprises optionally substituted C1-C12 heteroalkylene. In some embodiments, L3comprises optionally substituted C1-C6 heteroalkylene. In some embodiments, L3comprises optionally substituted C1-C3 heteroalkylene. In some embodiments, L3comprises optionally substituted linear heteroalkylene. In some embodiments, L3comprises optionally substituted linear C1-C12 heteroalkylene. In some embodiments, L3comprises optionally substituted linear C1-C6 heteroalkylene. In some embodiments, L3comprises optionally substituted linear C1-C3 heteroalkylene.

[0305] In some embodiments, L3comprises substituted heteroalkylene. In some embodiments, L3comprises substituted C1-C12 heteroalkylene. In some embodiments, L3comprises substituted C1-C6 heteroalkylene. In some embodiments, L3comprises substituted C1-C3 heteroalkylene. In some embodiments, L3comprises substituted linear heteroalkylene. In some embodiments, L3comprises substituted linear C1-C12 heteroalkylene. In some embodiments, L3comprises substituted linear C1-C6 heteroalkylene. In some embodiments, L3comprises substituted linear C1-C3 heteroalkylene.

[0306] In some embodiments, L3comprises unsubstituted heteroalkylene. In some embodiments, L3comprises unsubstituted C1-C12 heteroalkylene. In some embodiments, L3comprises unsubstituted C1-C6 heteroalkylene. In some embodiments, L3comprises unsubstituted C1-C3 heteroalkylene. In some embodiments, L3comprises unsubstituted linear heteroalkylene. In some embodiments, L3comprises unsubstituted linear C1-C12heteroalkylene. In some embodiments, L3comprises unsubstituted linear C1- C6heteroalkylene. In some embodiments, L3comprises unsubstituted linear C1-C3heteroalkylene.

[0307] In some embodiments, L3comprises, wherein z is an integer between 1 and 100, inclusive.

[0308] As generally described herein, z is an integer between 1 and 100, inclusive. In some embodiments, z is an integer between 1 and 90, inclusive; between 1 and 80, inclusive; between 1 and 70, inclusive; between 1 and 60, inclusive; between 1 and 50, inclusive; between 1 and 40, inclusive; between 1 and 30, inclusive; between 1 and 20, inclusive; between 1 and 10, inclusive; or between 1 and 5, inclusive. In some embodiments, z is an integer between 1 and 10, inclusive. In some embodiments, z is an integer between 1 and 5, inclusive. In some embodiments, z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, z is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, z is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, z is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, z is 1, 2, 3, 4, 5, or 6. In some embodiments, z is 1, 2, 3, 4, or 5. In some embodiments, z is 1, 2, 3, or 4. In some embodiments, z is 1, 2,R0708.70175WO00 85 / 180 #13640937v1or 3. In some embodiments, z is 1 or 2. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10.

[0309] In some embodiments, L3comprises, wherein z is an integer between 1 and 10, inclusive. In some embodiments, L3comprises, wherein z is an integer between 1 and 5, inclusive. In some embodiments, L3is , wherein z is an integer between 1 and 10, inclusive. In some embodiments, L3is, wherein z is an integer between 1 and 5, inclusive.

[0310] In some embodiments, L3comprises optionally substituted heteroalkenylene. In some embodiments, L3comprises optionally substituted C1-C12heteroalkenylene. In some embodiments, L3comprises optionally substituted C1-C6heteroalkenylene. In some embodiments, L3comprises optionally substituted C1-C3heteroalkenylene. In some embodiments, L3comprises substituted heteroalkenylene. In some embodiments, L3comprises substituted C1-C12heteroalkenylene. In some embodiments, L3comprises substituted C1-C6heteroalkenylene. In some embodiments, L3comprises substituted C1-C3heteroalkenylene. In some embodiments, L3comprises unsubstituted heteroalkenylene. In some embodiments, L3comprises unsubstituted C1-C12 heteroalkenylene. In some embodiments, L3comprises unsubstituted C1-C6heteroalkenylene. In some embodiments, L3comprises unsubstituted C1-C3heteroalkenylene.

[0311] In some embodiments, L3comprises optionally substituted heteroalkynylene. In some embodiments, L3comprises optionally substituted C1-C12 heteroalkynylene. In some embodiments, L3comprises optionally substituted C1-C6 heteroalkynylene. In some embodiments, L3comprises optionally substituted C1-C3 heteroalkynylene. In some embodiments, L3comprises substituted heteroalkynylene. In some embodiments, L3comprises substituted C1-C12 heteroalkynylene. In some embodiments, L3comprises substituted C1-C6 heteroalkynylene. In some embodiments, L3comprises substituted C1-C3 heteroalkynylene. In some embodiments, L3comprises unsubstituted heteroalkynylene. In some embodiments, L3comprises unsubstituted C1-C12 heteroalkynylene. In some embodiments, L3comprises unsubstituted C1-C6 heteroalkynylene. In some embodiments, L3comprises unsubstituted C1-C3 heteroalkynylene.

[0312] In some embodiments, L3comprises optionally substituted carbocyclylene. In some embodiments, L3comprises optionally substituted C3-C10 carbocyclylene. In some embodiments, L3comprises optionally substituted C3-C6 carbocyclylene. In some embodiments, L3comprises substitutedR0708.70175WO00 86 / 180 #13640937v1carbocyclylene. In some embodiments, L3comprises substituted C3-C10carbocyclylene. In some embodiments, L3comprises substituted C3-C6 carbocyclylene. In some embodiments, L3comprises unsubstituted carbocyclylene. In some embodiments, L3comprises unsubstituted C3-C10 carbocyclylene. In some embodiments, L3comprises unsubstituted C3-C6carbocyclylene.

[0313] In some embodiments, L3comprises optionally substituted heterocyclylene. In some embodiments, L3comprises optionally substituted 3-10 membered heterocyclylene. In some embodiments, L3comprises optionally substituted 3-6 membered heterocyclylene. In some embodiments, L3comprises substituted heterocyclylene. In some embodiments, L3comprises substituted 3-10 membered heterocyclylene. In some embodiments, L3comprises substituted 3-6 membered heterocyclylene. In some embodiments, L3comprises unsubstituted heterocyclylene. In some embodiments, L3comprises unsubstituted 3-10 membered heterocyclylene. In some embodiments, L3comprises unsubstituted 3-6 membered heterocyclylene.

[0314] In some embodiments, L3comprises optionally substituted arylene. In some embodiments, L3comprises optionally substituted phenylene. In some embodiments, L3comprises substituted arylene. In some embodiments, L3comprises substituted phenylene. In some embodiments, L3comprises unsubstituted arylene. In some embodiments, L3comprises unsubstituted phenylene.

[0315] In some embodiments, L3comprises optionally substituted heteroarylene. In some embodiments, L3comprises optionally substituted 5-10 membered heteroarylene. In some embodiments, L3comprises optionally substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L3comprises substituted heteroarylene. In some embodiments, L3comprises substituted 5-10 membered heteroarylene. In some embodiments, L3comprises substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L3comprises unsubstituted heteroarylene. In some embodiments, L3comprises unsubstituted 5-10 membered heteroarylene. In some embodiments, L3comprises unsubstituted 5-6 membered monocyclic heteroarylene.

[0316] In some embodiments, the compound of Formula (IX) is of Formula (IX-B):or a salt thereof, wherein z is an integer between 1 and 100, inclusive. In some embodiments of Formula (IX-B), z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IX-B), z is 1, 2, 3, 4, or 5. In some embodiments of Formula (IX-B), z is 3.

[0317] In some embodiments, the compound of Formula (IX) is of Formula (IX-C):R0708.70175WO00 87 / 180 #13640937v1or a salt thereof, wherein z is an integer between 1 and 100, inclusive. In some embodiments of Formula (IX-C), z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IX-C), z is 1, 2, 3, 4, or 5. In some embodiments of Formula (IX-C), z is 3.

[0318] As generally described herein, R4is hydrogen, optionally substituted aliphatic, or a nitrogen protecting group. In some embodiments, R4is hydrogen. As generally described herein, R4is optionally substituted aliphatic. As generally described herein, R4is optionally substituted alkyl. As generally described herein, R4is optionally substituted C1-12 alkyl. As generally described herein, R4is a nitrogen protecting group.

[0319] In some embodiments, the compound of Formula (IX) is of Formula (IX-D):or a salt thereof, wherein z is an integer between 1 and 100, inclusive. In some embodiments of Formula (IX-D), z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (IX-D), z is 1, 2, 3, 4, or 5. In some embodiments of Formula (IX-D), z is 3.

[0320] In some embodiments, the compound of Formula (IX) is of formula:, or a salt thereof.

[0321] In some embodiments, RCis -OH. In some embodiments, RCis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety. In some embodiments, RCis a peptide. In some embodiments, RNis hydrogen. In some embodiments, RNis a nitrogen protecting group. In some embodiments, RNis an amino acid moiety or a peptide. In some embodiments, RNis an amino acid moiety. In some embodiments, RNis a peptide. In some embodiments, RCis -OH, and RNis an amino acid moiety or a peptide. In some embodiments, RCis -OH, and RNis an amino acid moiety. In some embodiments, RCis -OH, and RNis a peptide. In some embodiments, RCis an amino acid moiety or a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety, and RNis hydrogen. In some embodiments, RCis a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety; and RNis an amino acid moiety. In some embodiments, RCis an amino acid moiety; and RNis a peptide. In some embodiments, RCis a peptide; and RNis an amino acid moiety. In some embodiments, RCis a peptide; and RNis a peptide.

[0322] In some embodiments, the compound of Formula (VIII) is of Formula (VIII-A):R0708.70175WO00 88 / 180 #13640937v1or a salt thereof, wherein z is an integer between 1 and 100, inclusive. In some embodiments of Formula (VIII-A), z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (VIII-A), z is 1, 2, 3, 4, or 5. In some embodiments of Formula (VIII-A), z is 3. In some embodiments of Formula (VIII-A), RCis an amino acid moiety or a peptide. In some embodiments of Formula (VIII-A), RNis an amino acid moiety or a peptide. In some embodiments of Formula (VIII-A), RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments of Formula (VIII-A), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of Formula (VIII-A), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and z is 1, 2, 3, 4, or 5. In some embodiments of Formula (VIII-A), RCis an amino acid moiety or a peptide; RNis an amino acid moiety or a peptide; and z is 3. Additional Embodiments of Methods of Preparation of Formulae (III-i), (VI), and (VIII)

[0323] In some embodiments, the compound of Formula (V), or salt thereof, is a peptide comprising a cysteine residue. In some embodiments, the peptide comprises a C-terminal cysteine residue. In some embodiments, the peptide comprises an internal cysteine residue.

[0324] In some embodiments, the peptide is somatostatin 14 (SST-14), somatostatin 28 (SST-28), hepatitis B virus core antigen protein (HBcAg), vimentin, glial fibrillary acidic protein (GFAP), desmin, human serum albumin (HSA), interleukin-1 receptor antagonist protein (IL1RA), rabies virus glycoprotein (RVG), or Tau peptide (306-336). In some embodiments, the peptide is somatostatin 14 (SST-14). In some embodiments, the peptide is somatostatin 28 (SST-28). In some embodiments, the peptide is hepatitis B virus core antigen protein (HBcAg). In some embodiments, the peptide is vimentin. In some embodiments, the peptide is glial fibrillary acidic protein (GFAP). In some embodiments, the peptide is desmin. In some embodiments, the peptide is human serum albumin (HSA). In some embodiments, the peptide is interleukin-1 receptor antagonist protein (IL1RA). In some embodiments, the peptide is rabies virus glycoprotein (RVG). In some embodiments, the peptide is Tau peptide (306-336).

[0325] In some embodiments, the peptide is QP1094, Tet-20, QP300, QP1112, or QP1149. In some embodiments, the peptide is QP1094. In some embodiments, the peptide is Tet-20. In some embodiments, the peptide is QP300. In some embodiments, the peptide is QP1112. In some embodiments, the peptide is QP1149.

[0326] In some embodiments, the method is performed at a pH of between about 6.0 and about 10.0, about 6.5 and about 9.5, about 6.5 and about 9.0, about 6.5 and about 8.5, about 7.0 and about 9.0, about 7.0 and about 8.5, about 7.0 and about 8.0, or about 7.4 and about 8.0. In some embodiments, the method is performed at a pH of between about 7.0 and about 9.0. In some embodiments, the method is performed at a pH of between about 7.0 and about 8.0. In some embodiments, the method is performed at a pH of between about 7.4 and about 8.0. In some embodiments, the method is performed at a pH of between about 7.0 and about 9.0, preferably wherein the method is performed at a pH of about 7.4 or about 8.0.

[0327] In some embodiments, the method is performed at a pH of about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, or about 8.5. In some embodiments,R0708.70175WO00 89 / 180 #13640937v1the method is performed at a pH of about 7.4 or about 8.0. In some embodiments, the method is performed at a pH of about 7.4. In some embodiments, the method is performed at a pH of about 8.0.

[0328] In some embodiments, the method is performed at a temperature of between about 10 ℃ and about 60 ℃, about 15 ℃ and about 55 ℃, about 20 ℃ and about 50 ℃, about 25 ℃ and about 45 ℃, about 30 ℃ and about 40 ℃, or about 35 ℃ and about 40 ℃. In some embodiments, the method is performed at a temperature of between about 20 ℃ and about 50 ℃. In some embodiments, the method is performed at a temperature of between about 35 ℃ and about 40 ℃. In some embodiments, the method is performed at a temperature of between about 20 ℃ and about 50 ℃, preferably wherein the method is performed at a temperature of about 37 ℃.

[0329] In some embodiments, the method is performed at a temperature of about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 26 ℃, about 27 ℃, about 28 ℃, about 29 ℃, about 30 ℃, about 31 ℃, about 32 ℃, about 33 ℃, about 34 ℃, about 35 ℃, about 36 ℃, about 37 ℃, about 38 ℃, about 39 ℃, about 40 ℃, about 41 ℃, about 42 ℃, about 43 ℃, about 44 ℃, about 45 ℃, about 46 ℃, about 47 ℃, about 48 ℃, about 49 ℃, or about 50 ℃. In some embodiments, the method is performed at a temperature of about 37 ℃.

[0330] In some embodiments, the method further comprises one or more steps selected from: contacting a reaction mixture comprising the product with a polymer particle comprising a thiol group or a dibenzocyclooctynyl group; subjecting the reaction mixture to dialysis; and subjecting the reaction mixture to a desalting column. In some embodiments, the method further comprises contacting a reaction mixture comprising the product with a polymer particle comprising a thiol group or a dibenzocyclooctynyl group. In some embodiments, the method further comprises subjecting the reaction mixture to dialysis. In some embodiments, the method further comprises subjecting the reaction mixture to a desalting column.

[0331] In some embodiments, the method further comprises enzymatic digestion of the peptide or the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof. In some embodiments, enzymatic digestion of the peptide or the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, comprises exposing the peptide or the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, to a polypeptide-cleaving agent. In some embodiments, the method further comprises enzymatic digestion of the peptide or the compound of Formula (III-i), or salt thereof. In some embodiments, enzymatic digestion of the peptide or the compound of Formula (III-i), or salt thereof, comprises exposing the peptide or the compound of Formula (III-i), or salt thereof, to a polypeptide-cleaving agent. In some embodiments, the method further comprises enzymatic digestion of the peptide or the compound of Formula (VI), or salt thereof. In some embodiments, enzymatic digestion of the peptide or the compound of Formula (VI), or salt thereof, comprises exposing the peptide or the compound of Formula (VI), or salt thereof, to a polypeptide- cleaving agent. In some embodiments, the method further comprises enzymatic digestion of the peptide or the compound of Formula (VIII), or salt thereof. In some embodiments, enzymatic digestion of the peptide or the compound of Formula (VIII), or salt thereof, comprises exposing the peptide or theR0708.70175WO00 90 / 180 #13640937v1compound of Formula (VIII), or salt thereof, to a polypeptide-cleaving agent.

[0332] In some embodiments, the polypeptide-cleaving agent comprises a protease. In some embodiments, the protease comprises Arg-C, Lys-C, Glu-C, trypsin, chymotrypsin, and / or Asp-N. In some embodiments, the protease comprises Arg-C. In some embodiments, the protease comprises Lys-C. In some embodiments, the protease comprises Glu-C. In some embodiments, the protease comprises trypsin. In some embodiments, the protease comprises chymotrypsin. In some embodiments, the protease comprises Asp-N. In some embodiments, the protease comprises Lys-C, Glu-C, and / or Asp-N.

[0333] In some embodiments, the peptide is a product of Lys-C digest of HSA, a product of Glu-C digest of HSA, a product of Glu-C digest of GFAP, a product of Asp-N digest of GFAP, or a product of Glu-C digest of vimentin. In some embodiments, the peptide is a product of Lys-C digest of HSA. In some embodiments, the peptide is a product of Glu-C digest of HSA. In some embodiments, the peptide is a product of Glu-C digest of GFAP. In some embodiments, the peptide is a product of Asp-N digest of GFAP. In some embodiments, the peptide is or a product of Glu-C digest of vimentin.

[0334] In some embodiments, the method further comprises contacting the peptide or the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, with tris(2- carboxyethyl)phosphine (TCEP). In some embodiments, the method further comprises contacting the peptide or the compound of Formula (III-i), or salt thereof, with tris(2-carboxyethyl)phosphine (TCEP). In some embodiments, the method further comprises contacting the peptide or the compound of Formula (VI), or salt thereof, with tris(2-carboxyethyl)phosphine (TCEP). In some embodiments, the method further comprises contacting the peptide or the compound of Formula (VIII), or salt thereof, with tris(2- carboxyethyl)phosphine (TCEP).

[0335] In some embodiments, the method further comprises contacting the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, with a compound comprising a complementary moiety, such that the azide moiety of the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, reacts with the complementary moiety via click chemistry to form a triazole-linked conjugated peptide. In some embodiments, the method further comprises contacting the compound of Formula (III-i), or salt thereof, with a compound comprising a complementary moiety, such that the azide moiety of the compound of Formula (III-i), or salt thereof, reacts with the complementary moiety via click chemistry to form a triazole-linked conjugated peptide. In some embodiments, the method further comprises contacting the compound of Formula (VI), or salt thereof, with a compound comprising a complementary moiety, such that the azide moiety of the compound of Formula (VI), or salt thereof, reacts with the complementary moiety via click chemistry to form a triazole-linked conjugated peptide. In some embodiments, the method further comprises contacting the compound of Formula (VIII), or salt thereof, with a compound comprising a complementary moiety, such that the azide moiety of the compound of Formula (VIII), or salt thereof, reacts with the complementary moiety via click chemistry to form a triazole-linked conjugated peptide.

[0336] In some embodiments, the compound comprising a complementary moiety is of Formula (X):R0708.70175WO00 91 / 180 #13640937v1or a salt thereof, wherein: each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0337] In some embodiments, at least one of R3aand R3bis hydrogen. In some embodiments, R3ais hydrogen. In some embodiments, R3bis hydrogen.

[0338] In some embodiments, at least one of R3aand R3bis optionally substituted aliphatic. In some embodiments, R3ais optionally substituted aliphatic. In some embodiments, R3bis optionally substituted aliphatic. In some embodiments, at least one of R3aand R3bis substituted aliphatic. In some embodiments, R3ais substituted aliphatic. In some embodiments, R3bis substituted aliphatic.

[0339] In some embodiments, at least one of R3aand R3bis optionally substituted alkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12 alkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6 alkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3 alkyl. In some embodiments, at least one of R3aand R3bis optionally substituted linear alkyl. In some embodiments, at least one of R3aand R3bis substituted alkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12 alkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6 alkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3 alkyl. In some embodiments, at least one of R3aand R3bis substituted linear alkyl. In some embodiments, R3ais optionally substituted alkyl. In some embodiments, R3bis optionally substituted alkyl.

[0340] In some embodiments, at least one of R3aand R3bis optionally substituted alkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12 alkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6alkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3alkenyl. In some embodiments, at least one of R3aand R3bis substituted alkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12alkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6alkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3alkenyl. In some embodiments, R3ais optionally substituted alkenyl. In some embodiments, R3bis optionally substituted alkenyl.

[0341] In some embodiments, at least one of R3aand R3bis optionally substituted alkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12alkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6alkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3alkynyl. In some embodiments, at least one of R3aand R3bis substituted alkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12alkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6alkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3alkynyl. In some embodiments, R3ais optionally substituted alkynyl. In some embodiments, R3bis optionally substituted alkynyl.R0708.70175WO00 92 / 180 #13640937v1

[0342] In some embodiments, at least one of R3aand R3bis optionally substituted heteroaliphatic. In some embodiments, R3ais optionally substituted heteroaliphatic. In some embodiments, R3bis optionally substituted heteroaliphatic. In some embodiments, at least one of R3aand R3bis substituted heteroaliphatic. In some embodiments, R3ais substituted heteroaliphatic. In some embodiments, R3bis substituted heteroaliphatic.

[0343] In some embodiments, at least one of R3aand R3bis optionally substituted heteroalkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12 heteroalkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6 heteroalkyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3 heteroalkyl. In some embodiments, at least one of R3aand R3bis optionally substituted linear heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12 heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6 heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3 heteroalkyl. In some embodiments, at least one of R3aand R3bis substituted linear heteroalkyl. In some embodiments, R3ais optionally substituted heteroalkyl. In some embodiments, R3bis optionally substituted heteroalkyl.

[0344] In some embodiments, at least one of R3aand R3bis optionally substituted heteroalkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12 heteroalkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6 heteroalkenyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3 heteroalkenyl. In some embodiments, at least one of R3aand R3bis substituted heteroalkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12 heteroalkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6 heteroalkenyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3 heteroalkenyl. In some embodiments, R3ais optionally substituted heteroalkenyl. In some embodiments, R3bis optionally substituted heteroalkenyl.

[0345] In some embodiments, at least one of R3aand R3bis optionally substituted heteroalkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C12heteroalkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C6heteroalkynyl. In some embodiments, at least one of R3aand R3bis optionally substituted C1-C3heteroalkynyl. In some embodiments, at least one of R3aand R3bis substituted heteroalkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C12heteroalkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C6heteroalkynyl. In some embodiments, at least one of R3aand R3bis substituted C1-C3heteroalkynyl. In some embodiments, R3ais optionally substituted heteroalkynyl. In some embodiments, R3bis optionally substituted heteroalkynyl.

[0346] In some embodiments, at least one of R3aand R3bis optionally substituted carbocyclyl. In some embodiments, at least one of R3aand R3bis optionally substituted C3-C10carbocyclyl. In some embodiments, at least one of R3aand R3bis optionally substituted C3-C6carbocyclyl. In some embodiments, at least one of R3aand R3bis substituted carbocyclyl. In some embodiments, at least one ofR0708.70175WO00 93 / 180 #13640937v1R3aand R3bis substituted C3-C10carbocyclyl. In some embodiments, at least one of R3aand R3bis substituted C3-C6 carbocyclyl. In some embodiments, R3ais optionally substituted carbocyclyl. In some embodiments, R3bis optionally substituted carbocyclyl.

[0347] In some embodiments, at least one of R3aand R3bis optionally substituted heterocyclyl. In some embodiments, at least one of R3aand R3bis optionally substituted 3-10 membered heterocyclyl. In some embodiments, at least one of R3aand R3bis optionally substituted 3-6 membered heterocyclyl. In some embodiments, at least one of R3aand R3bis substituted heterocyclyl. In some embodiments, at least one of R3aand R3bis substituted 3-10 membered heterocyclyl. In some embodiments, at least one of R3aand R3bis substituted 3-6 membered heterocyclyl. In some embodiments, R3ais optionally substituted heterocyclyl. In some embodiments, R3bis optionally substituted heterocyclyl.

[0348] In some embodiments, at least one of R3aand R3bis optionally substituted aryl. In some embodiments, at least one of R3aand R3bis optionally substituted phenyl. In some embodiments, at least one of R3aand R3bis substituted aryl. In some embodiments, at least one of R3aand R3bis substituted phenyl. In some embodiments, R3ais optionally substituted aryl. In some embodiments, R3bis optionally substituted aryl.

[0349] In some embodiments, at least one of R3aand R3bis optionally substituted heteroaryl. In some embodiments, at least one of R3aand R3bis optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one of R3aand R3bis optionally substituted 5-6 membered monocyclic heteroaryl. In some embodiments, at least one of R3aand R3bis substituted heteroaryl. In some embodiments, at least one of R3aand R3bis substituted 5-10 membered heteroaryl. In some embodiments, at least one of R3aand R3bis substituted 5-6 membered monocyclic heteroaryl. In some embodiments, R3ais optionally substituted heteroaryl. In some embodiments, R3bis optionally substituted heteroaryl.

[0350] In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl or substituted heterocyclyl.

[0351] In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted C3-C10carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted unsaturated C3-C10carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted cyclooctenyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted C3-C10carbocyclyl. In some embodiments, R3aand R3bR0708.70175WO00 94 / 180 #13640937v1are joined together with their intervening atoms to form substituted unsaturated C3-C10carbocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted cyclooctenyl.

[0352] In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted 3-10 membered heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted unsaturated 3-10 membered heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted unsaturated 3-10 membered heterocyclyl containing 1 ring N atom. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted 3-10 membered heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted unsaturated 3-10 membered heterocyclyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted unsaturated 3-10 membered heterocyclyl containing 1 ring N atom.

[0353] In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted aryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted phenyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted aryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted phenyl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form optionally substituted 5-10 membered heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted heteroaryl. In some embodiments, R3aand R3bare joined together with their intervening atoms to form substituted 5-10 membered heteroaryl.

[0354] In some embodiments, the compound of Formula (X) is of formula:,, wherein R3Cis optionally substituted aliphatic, optionally substituted heteroaliphatic,R0708.70175WO00 95 / 180 #13640937v1optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or –ORA. In some embodiments, R3Cis optionally substituted aliphatic. In some embodiments, R3Cis optionally substituted heteroaliphatic. In some embodiments, R3Cis optionally substituted carbocyclyl. In some embodiments, R3Cis optionally substituted heterocyclyl. In some embodiments, R3Cis optionally substituted aryl. In some embodiments, R3Cis optionally substituted heteroaryl. In some embodiments, R3Cis –ORA.

[0355] In some embodiments, the compound comprising a complementary moiety comprises a strained alkyne. In some embodiments, the compound comprising a complementary moiety comprises a cyclooctyne or an azacyclooctyne. In some embodiments, the compound comprising a complementary moiety comprises a cyclooctyne. In some embodiments, the compound comprising a complementary moiety comprises an azacyclooctyne. In some embodiments, the compound comprising a complementary moiety comprises dibenzoazacyclooctyne (DIBAC or DBCO), biarylazacyclooctynone (BARAC), dibenzocyclooctyne (DIBO), difluorinated cyclooctyne (DIFO), bicyclononyne (BCN), dimethoxyazacyclooctyne (DIMAC), monofluorinated cyclooctyne (MOFO), cyclooctyne (OCT), and / or aryl-less cyclooctyne (ALO). In some embodiments, the compound comprising a complementary moiety comprises dibenzoazacyclooctyne (DIBAC or DBCO). In some embodiments, the compound comprising a complementary moiety comprises biarylazacyclooctynone (BARAC). In some embodiments, the compound comprising a complementary moiety comprises dibenzocyclooctyne (DIBO). In some embodiments, the compound comprising a complementary moiety comprises difluorinated cyclooctyne (DIFO). In some embodiments, the compound comprising a complementary moiety comprises bicyclononyne (BCN). In some embodiments, the compound comprising a complementary moiety comprises dimethoxyazacyclooctyne (DIMAC). In some embodiments, the compound comprising a complementary moiety comprises monofluorinated cyclooctyne (MOFO). In some embodiments, the compound comprising a complementary moiety comprises cyclooctyne (OCT). In some embodiments, the compound comprising a complementary moiety comprises aryl-less cyclooctyne (ALO).

[0356] In some embodiments, the compound comprising a complementary moiety comprises a linking group. In some embodiments, the linking group comprises a polypeptidyl group.

[0357] In some embodiments, the linking group comprises a polypeptidyl group. In certain embodiments, the polypeptidyl group comprises at least 5 amino acid residues, at least 10 amino acid residues, at least 15 amino acid residues, or at least 20 amino acid residues. In certain embodiments, the polypeptidyl group comprises between 5 and 10 amino acid residues, between 5 and 15 amino acid residues, between 5 and 20 amino acid residues, between 10 and 15 amino acid residues, between 10 and 20 amino acid residues, or between 15 and 20 amino acid residues. In some embodiments, the polypeptidyl group comprises between 5 and 15 amino acid residues.

[0358] In some embodiments, the polypeptidyl group has a length of at least about 20 Å, 25 Å, 30 Å, 35 Å, 40 Å, 45 Å, 50 Å, 55 Å, 60 Å, 65 Å, 70 Å, or 75 Å. In certain embodiments, the polypeptidyl group has a length in a range from 20 Å to 30 Å, 20 Å to 35 Å, 20 Å to 40 Å, 20 Å to 45 Å, 20 Å to 50 Å, 20 Å to 55 Å, 20 Å to 60 Å, 20 Å to 65 Å, 20 Å to 70 Å, 20 Å to 75 Å, 30 Å to 40 Å, 30 Å to 45 Å, 30 Å to 50R0708.70175WO00 96 / 180 #13640937v1Å, 30 Å to 55 Å, 30 Å to 60 Å, 30 Å to 65 Å, 30 Å to 70 Å, 30 Å to 75 Å, 40 Å to 50 Å, 40 Å to 55 Å, 40 Å to 60 Å, 40 Å to 65 Å, 40 Å to 70 Å, 40 Å to 75 Å, 50 Å to 60 Å, 50 Å to 65 Å, 50 Å to 70 Å, 50 Å to 75 Å, 60 Å to 70 Å, or 60 Å to 75 Å.

[0359] In some embodiments, the polypeptidyl group comprises at least 1 negatively charged moiety at physiological pH. In certain embodiments, the polypeptidyl group comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises between 1 and 2, 1 and 3, 1 and 4, 1 and 5, 1 and 6, 1 and 7, 1 and 8, 1 and 9, 1 and 10, 1 and 11, 1 and 12, 1 and 13, 1 and 14, 1 and 15, 2 and 3, 2 and 4, 2 and 5, 2 and 6, 2 and 7, 2 and 8, 2 and 9, 2 and 10, 2 and 11, 2 and 12, 2 and 13, 2 and 14, 2 and 15, 3 and 4, 3 and 5, 3 and 6, 3 and 7, 3 and 8, 3 and 9, 3 and 10, 3 and 11, 3 and 12, 3 and 13, 3 and 14, 3 and 15, 4 and 5, 4 and 6, 4 and 7, 4 and 8, 4 and 9, 4 and 10, 4 and 11, 4 and 12, 4 and 13, 4 and 14, 4 and 15, 5 and 6, 5 and 7, 5 and 8, 5 and 9, 5 and 10, 5 and 11, 5 and 12, 5 and 13, 5 and 14, 5 and 15, 6 and 10, 6 and 15, 7 and 10, 7 and 15, 8 and 10, 8 and 15, 9 and 10, 9 and 15, or 10 and 15 negatively charged moieties at physiological pH. In some embodiments, the polypeptidyl group comprises between 1 and 10 negatively charged moieties at physiological pH.

[0360] In some embodiments, the polypeptidyl group comprises at least 1 aspartate residue. In certain embodiments, the polypeptidyl group comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 aspartate residues. In certain embodiments, the polypeptidyl group comprises between 1 and 2, 1 and 3, 1 and 4, 1 and 5, 1 and 6, 1 and 7, 1 and 8, 1 and 9, 1 and 10, 1 and 11, 1 and 12, 1 and 13, 1 and 14, 1 and 15, 2 and 3, 2 and 4, 2 and 5, 2 and 6, 2 and 7, 2 and 8, 2 and 9, 2 and 10, 2 and 11, 2 and 12, 2 and 13, 2 and 14, 2 and 15, 3 and 4, 3 and 5, 3 and 6, 3 and 7, 3 and 8, 3 and 9, 3 and 10, 3 and 11, 3 and 12, 3 and 13, 3 and 14, 3 and 15, 4 and 5, 4 and 6, 4 and 7, 4 and 8, 4 and 9, 4 and 10, 4 and 11, 4 and 12, 4 and 13, 4 and 14, 4 and 15, 5 and 6, 5 and 7, 5 and 8, 5 and 9, 5 and 10, 5 and 11, 5 and 12, 5 and 13, 5 and 14, 5 and 15, 6 and 10, 6 and 15, 7 and 10, 7 and 15, 8 and 10, 8 and 15, 9 and 10, 9 and 15, or 10 and 15 aspartate residues. In some embodiments, the polypeptidyl group comprises between 1 and 10 aspartate residues.

[0361] In some embodiments, the polypeptidyl group comprises at least 1 phenylalanine residue. In certain embodiments, the polypeptidyl group comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 phenylalanine residues. In certain embodiments, the polypeptidyl group comprises between 1 and 2, 1 and 3, 1 and 4, 1 and 5, 1 and 6, 1 and 7, 1 and 8, 1 and 9, 1 and 10, 1 and 11, 1 and 12, 1 and 13, 1 and 14, 1 and 15, 2 and 3, 2 and 4, 2 and 5, 2 and 6, 2 and 7, 2 and 8, 2 and 9, 2 and 10, 2 and 11, 2 and 12, 2 and 13, 2 and 14, 2 and 15, 3 and 4, 3 and 5, 3 and 6, 3 and 7, 3 and 8, 3 and 9, 3 and 10, 3 and 11, 3 and 12, 3 and 13, 3 and 14, 3 and 15, 4 and 5, 4 and 6, 4 and 7, 4 and 8, 4 and 9, 4 and 10, 4 and 11, 4 and 12, 4 and 13, 4 and 14, 4 and 15, 5 and 6, 5 and 7, 5 and 8, 5 and 9, 5 and 10, 5 and 11, 5 and 12, 5 and 13, 5 and 14, 5 and 15, 6 and 10, 6 and 15, 7 and 10, 7 and 15, 8 and 10, 8 and 15, 9 and 10, 9 and 15, orR0708.70175WO00 97 / 180 #13640937v110 and 15 phenylalanine residues.

[0362] In some embodiments, the polypeptidyl group comprises at least 1 glycine residue. In certain embodiments, the polypeptidyl group comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 glycine residues. In certain embodiments, the polypeptidyl group comprises between 1 and 2, 1 and 3, 1 and 4, 1 and 5, 1 and 6, 1 and 7, 1 and 8, 1 and 9, 1 and 10, 1 and 11, 1 and 12, 1 and 13, 1 and 14, 1 and 15, 2 and 3, 2 and 4, 2 and 5, 2 and 6, 2 and 7, 2 and 8, 2 and 9, 2 and 10, 2 and 11, 2 and 12, 2 and 13, 2 and 14, 2 and 15, 3 and 4, 3 and 5, 3 and 6, 3 and 7, 3 and 8, 3 and 9, 3 and 10, 3 and 11, 3 and 12, 3 and 13, 3 and 14, 3 and 15, 4 and 5, 4 and 6, 4 and 7, 4 and 8, 4 and 9, 4 and 10, 4 and 11, 4 and 12, 4 and 13, 4 and 14, 4 and 15, 5 and 6, 5 and 7, 5 and 8, 5 and 9, 5 and 10, 5 and 11, 5 and 12, 5 and 13, 5 and 14, 5 and 15, 6 and 10, 6 and 15, 7 and 10, 7 and 15, 8 and 10, 8 and 15, 9 and 10, 9 and 15, or 10 and 15 glycine residues.

[0363] In some embodiments, the polypeptidyl group comprises at least 1 proline residue. In certain embodiments, the polypeptidyl group comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 proline residues. In certain embodiments, the polypeptidyl group comprises between 1 and 2, 1 and 3, 1 and 4, 1 and 5, 1 and 6, 1 and 7, 1 and 8, 1 and 9, 1 and 10, 1 and 11, 1 and 12, 1 and 13, 1 and 14, 1 and 15, 2 and 3, 2 and 4, 2 and 5, 2 and 6, 2 and 7, 2 and 8, 2 and 9, 2 and 10, 2 and 11, 2 and 12, 2 and 13, 2 and 14, 2 and 15, 3 and 4, 3 and 5, 3 and 6, 3 and 7, 3 and 8, 3 and 9, 3 and 10, 3 and 11, 3 and 12, 3 and 13, 3 and 14, 3 and 15, 4 and 5, 4 and 6, 4 and 7, 4 and 8, 4 and 9, 4 and 10, 4 and 11, 4 and 12, 4 and 13, 4 and 14, 4 and 15, 5 and 6, 5 and 7, 5 and 8, 5 and 9, 5 and 10, 5 and 11, 5 and 12, 5 and 13, 5 and 14, 5 and 15, 6 and 10, 6 and 15, 7 and 10, 7 and 15, 8 and 10, 8 and 15, 9 and 10, 9 and 15, or 10 and 15 proline residues.

[0364] In some embodiments, the polypeptidyl group comprises at least 1 DD repeat, GG repeat, FF repeat, DDD repeat, GGG, and / or FFF repeat. In certain embodiments, the polypeptidyl group comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 DD repeats, GG repeats, FF repeats, DDD repeats, GGG, and / or FFF repeats. In certain embodiments, the polypeptidyl group comprises between 1 and 2, 1 and 3, 1 and 4, 1 and 5, 1 and 6, 1 and 7, 1 and 8, 1 and 9, 1 and 10, 1 and 11, 1 and 12, 1 and 13, 1 and 14, 1 and 15, 2 and 3, 2 and 4, 2 and 5, 2 and 6, 2 and 7, 2 and 8, 2 and 9, 2 and 10, 2 and 11, 2 and 12, 2 and 13, 2 and 14, 2 and 15, 3 and 4, 3 and 5, 3 and 6, 3 and 7, 3 and 8, 3 and 9, 3 and 10, 3 and 11, 3 and 12, 3 and 13, 3 and 14, 3 and 15, 4 and 5, 4 and 6, 4 and 7, 4 and 8, 4 and 9, 4 and 10, 4 and 11, 4 and 12, 4 and 13, 4 and 14, 4 and 15, 5 and 6, 5 and 7, 5 and 8, 5 and 9, 5 and 10, 5 and 11, 5 and 12, 5 and 13, 5 and 14, 5 and 15, 6 and 10, 6 and 15, 7 and 10, 7 and 15, 8 and 10, 8 and 15, 9 and 10, 9 and 15, or 10 and 15 DD repeats, GG repeats, FF repeats, DDD repeats, GGG, and / or FFF repeats.

[0365] In some embodiments, the polypeptidyl group comprises a sequence selected from the group consisting of GPPPPPPPPG (SEQ ID NO: 11), isoEGWRW (SEQ ID NO: 12), DDGGGDDDFF (SEQ ID NO: 13), GGSSSGSGNDEEFQ (SEQ ID NO: 14), GGGGGDPDPDFF (SEQ ID NO: 15),R0708.70175WO00 98 / 180 #13640937v1GDGDGDGDGDFF (SEQ ID NO: 16), NNGGGNNNFF (SEQ ID NO: 17), and DDGGGCyCyCyFF (SEQ ID NO: 18), or a salt thereof, wherein Cy is a cysteic acid. In some embodiments, the polypeptidyl group comprises DDGGGDDDFF (SEQ ID NO: 13).

[0366] In some embodiments, the linking group comprises an oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. In certain embodiments, the oligonucleotide has a length of at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 nucleotides. In certain embodiments, the oligonucleotide has a length in a range from 15 to 20, 15 to 25, 15 to 30, 15 to 35, 15 to 40, 15 to 45, 15 to 50, 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 25 to 30, 25 to 35, 25 to 40, 25 to 45, 25 to 50, 30 to 35, 30 to 40, 30 to 45, 30 to 50, 35 to 40, 35 to 45, 35 to 50, 40 to 45, 40 to 50, or 45 to 50 nucleotides. In some embodiments, the oligonucleotide has a length of at least 25 nucleotides.

[0367] In certain embodiments, at least one strand of the oligonucleotide has a sequence that is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to 5'-CCACGCGTGGAACCCTTGGGATCCA- 3' (SEQ ID NO: 19). In some embodiments, at least one strand of the oligonucleotide has a sequence that is at least 80% identical to 5'-CCACGCGTGGAACCCTTGGGATCCA-3' (SEQ ID NO: 19). In certain embodiments, at least one strand of the oligonucleotide has a sequence that is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to 5'-TGG AGT CAA GGT CCT CTG ATG CCA T-3’ (SEQ ID NO: 20).

[0368] In some embodiments, the linking group further comprises at least one of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted heterocyclylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof.

[0369] In some embodiments, the compound comprising a complementary moiety comprises a binding group. In some embodiments, the binding group comprises a biotin moiety. In some embodiments, the biotin moiety is a bis-biotin moiety.

[0370] In some embodiments, the binding group comprises at least one tag sequence. In certain embodiments, the at least one tag sequence comprises at least one biotin ligase recognition sequence that permits biotinylation of the compound comprising the complementary moiety (e.g., incorporation of one or more biotin moieties, including biotin and bis-biotin moieties). In certain embodiments, the at least one tag sequence comprises two biotin ligase recognition sequences oriented in tandem. In some cases, a biotin ligase recognition sequence refers to an amino acid sequence that is recognized by a biotin ligase, which catalyzes a covalent linkage between the sequence and a biotin molecule. Each biotin ligase recognition sequence of a tag sequence can be covalently linked to a biotin moiety, such that a tag sequence having multiple biotin ligase recognition sequences can be covalently linked to multiple biotinR0708.70175WO00 99 / 180 #13640937v1molecules. A region of a tag sequence having one or more biotin ligase recognition sequences can be generally referred to as a biotinylation tag or a biotinylation sequence. In some embodiments, a bis-biotin or bis-biotin moiety can refer to two biotins bound to two biotin ligase recognition sequences oriented in tandem. In certain embodiments, the binding group comprises at least one biotin ligase recognition sequence having a biotin moiety attached thereto or at least two biotin ligase recognition sequences, each having a biotin moiety attached thereto.

[0371] In some embodiments, the binding group comprises or is conjugated to an avidin protein. In some embodiments, the biotin moiety comprises an avidin protein. In some embodiments, the biotin moiety is conjugated to an avidin protein. The term “avidin protein” refers to a biotin-binding protein, generally having a biotin binding site at each of four subunits of the avidin protein. Non-limiting examples of avidin proteins include avidin, streptavidin, traptavidin, tamavidin, bradavidin, xenavidin, and homologs and variants thereof. In some cases, the avidin protein may have a monomeric, dimeric, or tetrameric form. In certain embodiments, the avidin protein is streptavidin in a tetrameric form (e.g., a homotetramer). In certain embodiments, the streptavidin in a tetrameric form may be bound to one component (e.g., a first component comprising a first mono-biotin moiety or a first bis-biotin moiety), two components (e.g., a first component comprising a first mono-biotin moiety or a first bis-biotin moiety and a second component comprising a second mono-biotin moiety or a second bis-biotin moiety), three components (e.g., a first component comprising a first bis-biotin moiety, a second component comprising a first mono-biotin moiety, and a third component comprising a second mono-biotin moiety), or four components (e.g., four components, each comprising a mono-biotin moiety).

[0372] In some embodiments, the compound comprising a complementary moiety is immobilized to a surface (e.g., a surface of a sample well). In some embodiments, the compound comprising a complementary moiety is immobilized to a surface of a sample well. Methods of Functionalizing or Sequencing a Peptide Having At Least One Free Cysteine Residue, and Methods of Enriching a Sample Comprising One or More Peptides Methods of Functionalizing a Peptide Having At Least One Free Cysteine Residue

[0373] In another aspect, provided herein is a method of functionalizing a peptide having at least one free cysteine residue, comprising reacting the peptide with a compound of Formula (II):or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:R0708.70175WO00 100 / 180 #13640937v1, wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –Methods of Sequencing a Peptide Having At Least One Free Cysteine Residue

[0374] In another aspect, provided herein is a method of sequencing a peptide having at least one free cysteine residue, comprising: reacting the peptide with a compound of Formula (II):R0708.70175WO00 101 / 180 #13640937v1or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:performing a peptide sequencing protocol; wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –#13640937v1

[0375] In some embodiments, X−is a halide ion. In some embodiments, X−is F–, Cl–, Br–, or I–. In some embodiments, X−is Cl–or Br–. In some embodiments, X−is Cl–.

[0376] In some embodiments, X−is triflate or a halide ion. In some embodiments, X−is triflate, F–, Cl–, Br–, or I–. In some embodiments, X−is triflate, Cl–, or Br–. In some embodiments, X−is triflate or Cl–.

[0377] In some embodiments, L1comprises optionally substituted alkylene. In some embodiments, L1comprises optionally substituted C1-C12 alkylene. In some embodiments, L1comprises optionally substituted C1-C6 alkylene. In some embodiments, L1comprises optionally substituted C1-C3 alkylene. In some embodiments, L1comprises optionally substituted linear alkylene. In some embodiments, L1comprises optionally substituted linear C1-C12 alkylene. In some embodiments, L1comprises optionally substituted linear C1-C6 alkylene. In some embodiments, L1comprises optionally substituted linear C1-C3 alkylene.

[0378] In some embodiments, L1comprises substituted alkylene. In some embodiments, L1comprises substituted C1-C12 alkylene. In some embodiments, L1comprises substituted C1-C6 alkylene. In some embodiments, L1comprises substituted C1-C3 alkylene. In some embodiments, L1comprises substituted linear alkylene. In some embodiments, L1comprises substituted linear C1-C12 alkylene. In some embodiments, L1comprises substituted linear C1-C6 alkylene. In some embodiments, L1comprises substituted linear C1-C3 alkylene.

[0379] In some embodiments, L1comprises unsubstituted alkylene. In some embodiments, L1comprises unsubstituted C1-C12 alkylene. In some embodiments, L1comprises unsubstituted C1-C6 alkylene. In some embodiments, L1comprises unsubstituted C1-C3 alkylene. In some embodiments, L1comprises unsubstituted linear alkylene. In some embodiments, L1comprises unsubstituted linear C1-C12 alkylene. In some embodiments, L1comprises unsubstituted linear C1-C6 alkylene. In some embodiments, L1comprises unsubstituted linear C1-C3 alkylene.

[0380] In some embodiments, L1comprises methylene, ethylene, n-propylene, n-butylene, n-pentylene, or n-hexylene. In some embodiments, L1comprises methylene, ethylene, or n-propylene. In some embodiments, L1comprises ethylene.

[0381] In some embodiments, L1is methylene, ethylene, n-propylene, n-butylene, n-pentylene, or n- hexylene. In some embodiments, L1is methylene, ethylene, or n-propylene. In some embodiments, L1is ethylene.

[0382] In some embodiments, L1comprises optionally substituted alkenylene. In some embodiments, L1comprises optionally substituted C1-C12alkenylene. In some embodiments, L1comprises optionally substituted C1-C6alkenylene. In some embodiments, L1comprises optionally substituted C1-C3alkenylene. In some embodiments, L1comprises substituted alkenylene. In some embodiments, L1comprises substituted C1-C12alkenylene. In some embodiments, L1comprises substituted C1-C6alkenylene. In some embodiments, L1comprises substituted C1-C3alkenylene. In some embodiments, L1comprises unsubstituted alkenylene. In some embodiments, L1comprises unsubstituted C1-C12alkenylene. In some embodiments, L1comprises unsubstituted C1-C6alkenylene. In some embodiments, L1comprises unsubstituted C1-C3alkenylene.R0708.70175WO00 103 / 180 #13640937v1

[0383] In some embodiments, L1comprises optionally substituted alkynylene. In some embodiments, L1comprises optionally substituted C1-C12 alkynylene. In some embodiments, L1comprises optionally substituted C1-C6 alkynylene. In some embodiments, L1comprises optionally substituted C1-C3 alkynylene. In some embodiments, L1comprises substituted alkynylene. In some embodiments, L1comprises substituted C1-C12 alkynylene. In some embodiments, L1comprises substituted C1-C6 alkynylene. In some embodiments, L1comprises substituted C1-C3 alkynylene. In some embodiments, L1comprises unsubstituted alkynylene. In some embodiments, L1comprises unsubstituted C1-C12 alkynylene. In some embodiments, L1comprises unsubstituted C1-C6 alkynylene. In some embodiments, L1comprises unsubstituted C1-C3 alkynylene.

[0384] In some embodiments, L1comprises optionally substituted heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C12 heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C6 heteroalkylene. In some embodiments, L1comprises optionally substituted C1-C3 heteroalkylene. In some embodiments, L1comprises optionally substituted linear heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C12 heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C6 heteroalkylene. In some embodiments, L1comprises optionally substituted linear C1-C3 heteroalkylene.

[0385] In some embodiments, L1comprises substituted heteroalkylene. In some embodiments, L1comprises substituted C1-C12 heteroalkylene. In some embodiments, L1comprises substituted C1-C6 heteroalkylene. In some embodiments, L1comprises substituted C1-C3 heteroalkylene. In some embodiments, L1comprises substituted linear heteroalkylene. In some embodiments, L1comprises substituted linear C1-C12 heteroalkylene. In some embodiments, L1comprises substituted linear C1-C6 heteroalkylene. In some embodiments, L1comprises substituted linear C1-C3 heteroalkylene.

[0386] In some embodiments, L1comprises unsubstituted heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C12 heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C6 heteroalkylene. In some embodiments, L1comprises unsubstituted C1-C3heteroalkylene. In some embodiments, L1comprises unsubstituted linear heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1-C12heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1- C6heteroalkylene. In some embodiments, L1comprises unsubstituted linear C1-C3heteroalkylene.

[0387] In some embodiments, L1comprises or , wherein x is an integer between 1 and 100, inclusive. In some embodiments, L1is or, wherein x is an integer between 1 and 100, inclusive.

[0388] In some embodiments, x is an integer between 1 and 90, inclusive; between 1 and 80, inclusive; between 1 and 70, inclusive; between 1 and 60, inclusive; between 1 and 50, inclusive; between 1 and 40, inclusive; between 1 and 30, inclusive; between 1 and 20, inclusive; between 1 and 10, inclusive; orR0708.70175WO00 104 / 180 #13640937v1between 1 and 5, inclusive. In some embodiments, x is an integer between 1 and 10, inclusive. In some embodiments, x is an integer between 1 and 5, inclusive. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, x is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, x is 1, 2, 3, 4, 5, or 6. In some embodiments, x is 1, 2, 3, 4, or 5. In some embodiments, x is 1, 2, 3, or 4. In some embodiments, x is 1, 2, or 3. In some embodiments, x is 1 or 2. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10., wherein x is an integer between 1 and 10, inclusive. In some embodiments, L1comprisesorembodiments,inclusive.

[0390] In some embodiments, L1comprises optionally substituted heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C12 heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C6 heteroalkenylene. In some embodiments, L1comprises optionally substituted C1-C3 heteroalkenylene. In some embodiments, L1comprises substituted heteroalkenylene. In some embodiments, L1comprises substituted C1-C12 heteroalkenylene. In some embodiments, L1comprises substituted C1-C6 heteroalkenylene. In some embodiments, L1comprises substituted C1-C3 heteroalkenylene. In some embodiments, L1comprises unsubstituted heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C12 heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C6 heteroalkenylene. In some embodiments, L1comprises unsubstituted C1-C3 heteroalkenylene.

[0391] In some embodiments, L1comprises optionally substituted heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C12 heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C6 heteroalkynylene. In some embodiments, L1comprises optionally substituted C1-C3heteroalkynylene. In some embodiments, L1comprises substituted heteroalkynylene. In some embodiments, L1comprises substituted C1-C12 heteroalkynylene. In some embodiments, L1comprises substituted C1-C6 heteroalkynylene. In some embodiments, L1comprises substituted C1-C3R0708.70175WO00 105 / 180 #13640937v1heteroalkynylene. In some embodiments, L1comprises unsubstituted heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C12 heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C6 heteroalkynylene. In some embodiments, L1comprises unsubstituted C1-C3 heteroalkynylene.

[0392] In some embodiments, L1comprises optionally substituted carbocyclylene. In some embodiments, L1comprises optionally substituted C3-C10 carbocyclylene. In some embodiments, L1comprises optionally substituted C3-C6 carbocyclylene. In some embodiments, L1comprises substituted carbocyclylene. In some embodiments, L1comprises substituted C3-C10 carbocyclylene. In some embodiments, L1comprises substituted C3-C6 carbocyclylene. In some embodiments, L1comprises unsubstituted carbocyclylene. In some embodiments, L1comprises unsubstituted C3-C10 carbocyclylene. In some embodiments, L1comprises unsubstituted C3-C6 carbocyclylene.

[0393] In some embodiments, L1comprises optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises optionally substituted 3-6 membered heterocyclylene. In some embodiments, L1comprises substituted heterocyclylene. In some embodiments, L1comprises substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises substituted 3-6 membered heterocyclylene. In some embodiments, L1comprises unsubstituted heterocyclylene. In some embodiments, L1comprises unsubstituted 3-10 membered heterocyclylene. In some embodiments, L1comprises unsubstituted 3-6 membered heterocyclylene.

[0394] In some embodiments, L1comprises optionally substituted arylene. In some embodiments, L1comprises optionally substituted phenylene. In some embodiments, L1comprises substituted arylene. In some embodiments, L1comprises substituted phenylene. In some embodiments, L1comprises unsubstituted arylene. In some embodiments, L1comprises unsubstituted phenylene.

[0395] In some embodiments, L1comprises optionally substituted heteroarylene. In some embodiments, L1comprises optionally substituted 5-10 membered heteroarylene. In some embodiments, L1comprises optionally substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L1comprises substituted heteroarylene. In some embodiments, L1comprises substituted 5-10 membered heteroarylene. In some embodiments, L1comprises substituted 5-6 membered monocyclic heteroarylene. In some embodiments, L1comprises unsubstituted heteroarylene. In some embodiments, L1comprises unsubstituted 5-10 membered heteroarylene. In some embodiments, L1comprises unsubstituted 5-6 membered monocyclic heteroarylene.

[0396] In some embodiments, at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –R0708.70175WO00 106 / 180 #13640937v1some embodiments, at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, –C(=O)RA, – C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA. In some embodiments, each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, –C(=O)RA, – C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA.

[0397] In some embodiments, at least one occurrence of RAis hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;

[0398] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.R0708.70175WO00 107 / 180 #13640937v1

[0400] In some embodiments, RCis -OH. In some embodiments, RCis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety. In some embodiments, RCis a peptide. In some embodiments, RNis hydrogen. In some embodiments, RNis a nitrogen protecting group. In some embodiments, RNis an amino acid moiety or a peptide. In some embodiments, RNis an amino acid moiety. In some embodiments, RNis a peptide. In some embodiments, RCis -OH, and RNis an amino acid moiety or a peptide. In some embodiments, RCis -OH, and RNis an amino acid moiety. In some embodiments, RCis -OH, and RNis a peptide. In some embodiments, RCis an amino acid moiety or a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety, and RNis hydrogen. In some embodiments, RCis a peptide, and RNis hydrogen. In some embodiments, RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide. In some embodiments, RCis an amino acid moiety; and RNis an amino acid moiety. In some embodiments, RCis an amino acid moiety; and RNis a peptide. In some embodiments, RCis a peptide; and RNis an amino acid moiety. In some embodiments, RCis a peptide; and RNis a peptide.

[0401] In some embodiments, the compound of Formula (II) is of Formula (II-A) or Formula (II-B):or a salt thereof, such that the sulfur atom of the cysteine residue in the functionalized peptide is bonded to a group of the formula:R0708.70175WO00 108 / 180 #13640937v1.

[0402] In some embodiments, the compound of Formula (II) is of formula:, or a salt thereof, such that a sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:.

[0403] In some embodiments, the method further comprises contacting the azide-functionalized peptide with a compound comprising a complementary moiety, such that the azide moiety of the azide- functionalized peptide reacts with the complementary moiety via click chemistry to provide a triazole- linked conjugated peptide.

[0404] In some embodiments, the method further comprises contacting the azide-functionalized peptide with a compound comprising a complementary moiety, wherein the compound comprising a complementary moiety is of Formula (X):or a salt thereof, to provide a triazole-linked conjugated peptide, such that a sulfur atom of a cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:, wherein: each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0405] In some embodiments, the sulfur atom of the cysteine residue in the triazole-linked conjugatedR0708.70175WO00 109 / 180 #13640937v1peptide is bonded to a group of the formula:

[0406] In some embodiments, the sulfur atom of the cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:.

[0407] In another aspect, provided herein is a method of sequencing a peptide having at least one free cysteine residue, comprising: reacting the peptide with a compound of Formula (VII):or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:performing a peptide sequencing protocol; wherein: L2is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof.

[0408] In some embodiments, L2comprises optionally substituted alkylene. In some embodiments, L2comprises optionally substituted C1-C12 alkylene. In some embodiments, L2comprises optionally substituted C1-C6 alkylene. In some embodiments, L2comprises optionally substituted C1-C3 alkylene. In some embodiments, L2comprises optionally substituted linear alkylene. In some embodiments, L2comprises optionally substituted linear C1-C12 alkylene. In some embodiments, L2comprises optionally substituted linear C1-C6 alkylene. In some embodiments, L2comprises optionally substituted linear C1-C3 alkylene.R0708.70175WO00 110 / 180 #13640937v1

[0409] In some embodiments, L2comprises substituted alkylene. In some embodiments, L2comprises substituted C1-C12 alkylene. In some embodiments, L2comprises substituted C1-C6 alkylene. In some embodiments, L2comprises substituted C1-C3 alkylene. In some embodiments, L2comprises substituted linear alkylene. In some embodiments,...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I′):or a salt thereof, wherein: is a single bond or a double bond; X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of RBis independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, – NO2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, or –S(=O)2N(RA)2; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3,R0708.70175WO00 146 / 180 #13640937v1Z is absent or is -SR2, wherein R2is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; provided that when is a double bond, Z is absent; and wherein the substituent moietylocated at a position ortho or para to N.

2. A compound of Formula (I):or a salt thereof, wherein: is a single bond or a double bond; X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together withR0708.70175WO00 147 / 180 #13640937v1their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3,Z is absent or is -SR2, wherein R2is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; provided that when is a double bond, Z is absent.

3. The compound of any one of claims 1 or 2, wherein the compound is of Formula (II):or a salt thereof.

4. The compound of any one of claims 1 or 2, wherein the compound is of Formula (III):or a salt thereof.R0708.70175WO00 148 / 180 #13640937v15. A compound of Formula (IV):or a salt thereof, wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, –C(=NRA)RA, – C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, – S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, – OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, – OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, – NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –Osi(RA)3, –Osi(RA)2ORA, – Osi(RA)(ORA)2, –Osi(ORA)3, or –B(ORA)2;R0708.70175WO00 149 / 180 #13640937v1R2is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

6. The compound of any one of claims 1, 2, 4, or 5, or a salt thereof, wherein R2is of the formula:or a salt thereof, wherein: RCis -OH, an amino acid moiety, or a peptide; and RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide.

7. The compound of claim 6, or a salt thereof, wherein R2is of the formula:or a salt thereof.

8. The compound of claim 6, wherein the compound is of Formula (III-i):or a salt thereof.R0708.70175WO00 150 / 180 #13640937v19. The compound of any one of claims 6-8, wherein the compound is of Formula (III-i-a):or a salt thereof.

10. The compound of claim 6, wherein the compound is of Formula (IV-i):or a salt thereof.

11. The compound of any one of claims 6, 7, or 10, wherein the compound is of Formula (IV-i-a):or a salt thereof.

12. The compound of any one of claims 6-11, wherein RCis -OH.

13. The compound of any one of claims 6-11, wherein: RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide.R0708.70175WO00 151 / 180 #13640937v114. The compound of any one of claims 1-13, wherein L1comprises optionally substituted alkylene.

15. The compound of any one of claims 1-14, wherein L1comprises optionally substituted C1-10 alkylene.

16. The compound of any one of claims 1-15, wherein L1comprises optionally substituted linear C1-6 alkylene.

17. The compound of any one of claims 1-16, wherein L1comprises unsubstituted linear C1-6 alkylene.

18. The compound of any one of claims 1-17, wherein L1is methylene, ethylene, n-propylene, n- butylene, n-pentylene, or n-hexylene.

19. The compound of any one of claims 1-18, wherein L1is ethylene.

20. The compound of any one of claims 1-19, wherein L1comprises optionally substituted heteroalkylene.

21. The compound of any one of claims 1-20, wherein L1comprises, and wherein x is an integer between 1 and 100, inclusive.

22. The compound of claim 21, wherein L1comprises.

23. The compound of any one of claims 21 or 22, wherein L1is.

24. The compound of any one of claims 1, 2, 3, or 14-23, wherein the compound is of Formula (II-A) or Formula (II-B):R0708.70175WO00 152 / 180 #13640937v1or a salt thereof, wherein x is an integer between 1 and 100, inclusive.

25. The compound of any one of claims 1, 2, 4, 6, 7, or 12-23, wherein the compound is of Formula (III-A) or Formula (III-B):or a salt thereof, wherein x is an integer between 1 and 100, inclusive.

26. The compound of any one of claims 8 or 12-23, wherein the compound is of Formula (III-A-i) oror a salt thereof, wherein x is an integer between 1 and 100, inclusive.

27. The compound of any one of claims 5 or 12-23, wherein the compound is of Formula (IV-A) or Formula (IV-B):R0708.70175WO00 153 / 180 #13640937v1or a salt thereof, wherein x is an integer between 1 and 100, inclusive.

28. The compound of any one of claims 6, 10, 12-23, or 27, wherein the compound is of Formula (IV-A-i) or Formula (IV-B-i):or a salt thereof, wherein x is an integer between 1 and 100, inclusive.

29. The compound of any one of claims 10-23 or 28, wherein the compound is of Formula (IV-A- i-a) or Formula (IV-B-i-a):R0708.70175WO00 154 / 180 #13640937v1or a salt thereof, wherein x is an integer between 1 and 100, inclusive.

30. The compound of any one of claims 21-29, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

31. The compound of any one of claims 1-30, wherein at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, – S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA.

32. The compound of any one of claims 1-30, wherein n is 0.

33. The compound of any one of claims 1-32, wherein X−is triflate.

34. The compound of any one of claims 1, 2, 3, or 14-19, wherein the compound is of formula:, or a salt thereof.R0708.70175WO00 155 / 180 #13640937v135. A method of preparing a compound of Formula (III-i):or a salt thereof, comprising contacting a compound of Formula (V):or a salt thereof, with a compound of Formula (II):or a salt thereof, to obtain the compound of Formula (III-i), or a salt thereof, wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3,R0708.70175WO00 156 / 180 #13640937v1–NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, –C(=NRA)RA, – C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, – S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, – OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, – OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, – NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, –OSi(RA)2ORA, – OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; RCis -OH, an amino acid moiety, or a peptide; and RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide.

36. The method of claim 35, wherein a molar ratio of the compound of Formula (II), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 1:1 and about 50:

1.

37. The method of any one of claims 35 or 36, wherein the compound of Formula (III-i) is of Formula (III-i-a):or a salt thereof. The method of any one of claims 35-37, wherein RCis -OH. The method of any one of claims 35-37, wherein: RCis an amino acid moiety or a peptide; and RNis an amino acid moiety or a peptide.R0708.70175WO00 157 / 180 #13640937v140. The method of any one of claims 35-39, wherein L1comprises optionally substituted alkylene.

41. The method of any one of claims 35-40, wherein L1comprises optionally substituted C1-10alkylene.

42. The method of any one of claims 35-41, wherein L1comprises optionally substituted linear C1-6 alkylene.

43. The method of any one of claims 35-42, wherein L1comprises unsubstituted linear C1-6 alkylene.

44. The method of any one of claims 35-43, wherein L1is methylene, ethylene, n-propylene, n- butylene, n-pentylene, or n-hexylene.

45. The method of any one of claims 35-44, wherein L1is ethylene.

46. The method of any one of claims 35-45, wherein L1comprises optionally substituted heteroalkylene.

47. The method of any one of claims 35-46, wherein L1comprises, and wherein x is an integer between 1 and 100, inclusive.

48. The method of any one of claims 35-47, wherein L1comprises. The method of any one of claims 35-48, wherein L1is.

50. The method of any one of claims 35-49, wherein the compound of Formula (II) is of Formula (II-A) or Formula (II-B):R0708.70175WO00 158 / 180 #13640937v1or a salt thereof, wherein x is an integer between 1 and 100, inclusive.

51. The method of any one of claims 47-50, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

52. The method of any one of claims 35-51, wherein at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, – S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA.

53. The method of any one of claims 35-51, wherein n is 0.

54. The method of any one of claims 35-53, wherein X−is triflate.

55. The method of any one of claims 35-45 or 52-54, wherein the compound of Formula (II) is of formula:, or a salt thereof.

56. A method of preparing a compound of Formula (VI):or a salt thereof, comprising contacting a compound of Formula (V):or a salt thereof, with a compound of Formula (VII):R0708.70175WO00 159 / 180 #13640937v1or a salt thereof, to obtain the compound of Formula (VI), or a salt thereof, wherein: L2is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; RCis -OH, an amino acid moiety, or a peptide; and RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide.

57. The method of claim 56, wherein a molar ratio of the compound of Formula (VII), or salt thereof, to the compound of Formula (V), or salt thereof, is between about 1:1 and about 10:

1.

58. The method of any one of claims 56 or 57, wherein L2comprises optionally substituted alkylene.

59. The method of any one of claims 56-58, wherein L2comprises optionally substituted heteroalkylene.

60. The method of any one of claims 56-59, wherein L2comprises, and wherein y is an integer between 1 and 100, inclusive.

61. The method of any one of claims 56-60, wherein the compound of Formula (VII) is of Formula (VII-A):or a salt thereof, wherein y is an integer between 1 and 100, inclusive.

62. The method of any one of claims 60 or 61, wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.R0708.70175WO00 160 / 180 #13640937v163. The method of any one of claims 56-62, wherein the compound of Formula (VII) is of formula: ,64. A method of preparing a compound of Formula (VIII):or a salt thereof, comprising contacting a compound of Formula (V):or a salt thereof, with a compound of Formula (IX):or a salt thereof, to obtain the compound of Formula (VIII), or a salt thereof, wherein: Y is a leaving group; L3is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; and R4is hydrogen, optionally substituted aliphatic, or a nitrogen protecting group; RCis -OH, an amino acid moiety, or a peptide; and RNis hydrogen, a nitrogen protecting group, an amino acid moiety, or a peptide.

65. The method of claim 64, wherein Y is halogen.R0708.70175WO00 161 / 180 #13640937v166. The method of any one of claims 64 or 65, wherein the compound of Formula (IX) is of Formula (IX-A):or a salt thereof.

67. The method of any one of claims 64-66, wherein L3comprises optionally substituted heteroalkylene.

68. The method of any one of claims 64-67, wherein L3comprises, and wherein z is an integer between 1 and 100, inclusive.

69. The method of any one of claims 64-68, wherein the compound of Formula (IX) is of Formula (IX-B):or a salt thereof, wherein z is an integer between 1 and 100, inclusive.

70. The method of any one of claims 64-69, wherein the compound of Formula (IX) is of Formula (IX-C):or a salt thereof, wherein z is an integer between 1 and 100, inclusive.

71. The method of any one of claims 68-70, wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

72. The method of any one of claims 64-71, wherein R4is hydrogen.

73. The method of any one of claims 64-72, wherein the compound of Formula (IX) is of formula:R0708.70175WO00 162 / 180 #13640937v1, or a salt thereof.

74. The method of any one of claims 35-73, wherein the compound of Formula (V), or salt thereof, is a peptide comprising a cysteine residue.

75. The method of claim 74, wherein the peptide comprises a C-terminal cysteine residue.

76. The method of claim 74, wherein the peptide comprises an internal cysteine residue.

77. The method of any one of claims 74-76, wherein the peptide is somatostatin 14 (SST-14), somatostatin 28 (SST-28), hepatitis B virus core antigen protein (HBcAg), vimentin, glial fibrillary acidic protein (GFAP), desmin, human serum albumin (HSA), interleukin-1 receptor antagonist protein (IL1RA), rabies virus glycoprotein (RVG), or Tau peptide (306-336).

78. The method of any one of claims 74-76, wherein the peptide is QP1094, Tet-20, QP300, QP1112, or QP1149.

79. The method of any one of claims 35-78, wherein the method is performed at a pH of between about 7.0 and about 9.0, preferably wherein the method is performed at a pH of about 7.4 or about 8.

0.

80. The method of any one of claims 35-79, wherein the method is performed at a temperature of between about 20 ℃ and about 50 ℃, preferably wherein the method is performed at a temperature of about 37 ℃.

81. The method of any one of claims 35-80, further comprising one or more steps selected from: contacting a reaction mixture comprising the product with a polymer particle comprising a thiol group or a dibenzocyclooctynyl group; subjecting the reaction mixture to dialysis; and subjecting the reaction mixture to a desalting column.

82. The method of any one of claims 74-81, further comprising enzymatic digestion of the peptide or the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof.R0708.70175WO00 163 / 180 #13640937v183. The method of claim 82, wherein enzymatic digestion of the peptide or the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, comprises exposing the peptide or the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, to a polypeptide-cleaving agent.

84. The method of claim 83, wherein the polypeptide-cleaving agent comprises a protease.

85. The method of claim 84, wherein the protease comprises Arg-C, Lys-C, Glu-C, trypsin, chymotrypsin, and / or Asp-N.

86. The method of any one of claims 84 or 85, wherein the protease comprises Lys-C, Glu-C, and / or Asp-N.

87. The method of any one of claims 82-86, wherein the peptide is a product of Lys-C digest of HSA, a product of Glu-C digest of HSA, a product of Glu-C digest of GFAP, a product of Asp-N digest of GFAP, or a product of Glu-C digest of vimentin.

88. The method of any one of claims 35-87, further comprising contacting the peptide or the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, with tris(2- carboxyethyl)phosphine (TCEP).

89. The method of any one of claims 35-88, further comprising contacting the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, with a compound comprising a complementary moiety, such that the azide moiety of the compound of any one of Formula (III-i), Formula (VI), or Formula (VIII), or salt thereof, reacts with the complementary moiety via click chemistry to form a triazole-linked conjugated peptide.

90. The method of claim 89, wherein the compound comprising a complementary moiety is of Formula (X):or a salt thereof, wherein: each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.R0708.70175WO00 164 / 180 #13640937v191. A method of functionalizing a peptide having at least one free cysteine residue, comprising reacting the peptide with a compound of Formula (II):or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:, wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3,R0708.70175WO00 165 / 180 #13640937v192. A method of sequencing a peptide having at least one free cysteine residue, comprising: reacting the peptide with a compound of Formula (II):or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:performing a peptide sequencing protocol; wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; andR0708.70175WO00 166 / 180 #13640937v1each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3,93. The method of any one of claims 91 or 92, further comprising contacting the azide- functionalized peptide with a compound comprising a complementary moiety, such that the azide moiety of the azide-functionalized peptide reacts with the complementary moiety via click chemistry to provide a triazole-linked conjugated peptide.

94. The method of any one of claims 91 or 92, further comprising contacting the azide- functionalized peptide with a compound comprising a complementary moiety, wherein the compound comprising a complementary moiety is of Formula (X):or a salt thereof, to provide a triazole-linked conjugated peptide, such that a sulfur atom of a cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:, wherein: each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together withR0708.70175WO00 167 / 180 #13640937v1their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

95. The method of any one of claims 91-94, wherein L1comprises optionally substituted alkylene.

96. The method of any one of claims 91-95, wherein L1comprises optionally substituted C1-10alkylene.

97. The method of any one of claims 91-96, wherein L1comprises optionally substituted linear C1-6 alkylene.

98. The method of any one of claims 91-97, wherein L1comprises unsubstituted linear C1-6 alkylene.

99. The method of any one of claims 91-98, wherein L1is methylene, ethylene, n-propylene, n- butylene, n-pentylene, or n-hexylene.

100. The method of any one of claims 91-99, wherein L1is ethylene.

101. The method of any one of claims 91-100, wherein L1comprises optionally substituted heteroalkylene.

102. The method of any one of claims 91-101, wherein L1comprises, and wherein x is an integer between 1 and 100, inclusive.

103. The method of any one of claims 91-102, wherein L1comprises.

104. The method of any one of claims 91-103, wherein L1is.

105. The method of any one of claims 91-104, wherein the compound of Formula (II) is of Formula (II-A) or Formula (II-B):R0708.70175WO00 168 / 180 #13640937v1or a salt thereof, such that a sulfur atom of a cysteine residue in the functionalized peptide is bonded to a group of the formula:

106. The method of any one of claims 94-105, wherein the sulfur atom of the cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:

107. The method of any one of claims 102-106, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

108. The method of any one of claims 91-107, wherein at least one occurrence of R1is halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(=O)2RA, – S(=O)2ORA, –S(=O)2N(RA)2, or –OC(=O)RA.

109. The method of any one of claims 91-107, wherein n is 0.

110. The method of any one of claims 91-109, wherein X−is triflate.

111. The method of any one of claims 91-100 or 105-110, wherein the compound of Formula (II) is of formula:R0708.70175WO00 169 / 180 #13640937v1, or a salt thereof, such that a sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:.

112. The method of any one of claims 94-111, wherein the sulfur atom of the cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:.

113. A method of sequencing a peptide having at least one free cysteine residue, comprising: reacting the peptide with a compound of Formula (VII):or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:performing a peptide sequencing protocol; wherein: L2is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substitutedR0708.70175WO00 170 / 180 #13640937v1heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof.

114. The method of claim 113, further comprising contacting the azide-functionalized peptide with a compound comprising a complementary moiety, wherein the compound comprising a complementary moiety is of Formula (X):or a salt thereof, to provide a triazole-linked conjugated peptide, such that a sulfur atom of a cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:, wherein: each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

115. The method of any one of claims 113 or 114, wherein L2comprises optionally substituted alkylene.

116. The method of any one of claims 113-115, wherein L2comprises optionally substituted heteroalkylene.

117. The method of any one of claims 113-116, wherein L2comprises, and wherein y is an integer between 1 and 100, inclusive.

118. The method of any one of claims 113-117, wherein the compound of Formula (VII) is of Formula (VII-A):R0708.70175WO00 171 / 180 #13640937v1or a salt thereof, wherein y is an integer between 1 and 100, inclusive, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:.

119. The method of any one of claims 117 or 118, wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

120. The method of any one of claims 113-119, wherein the compound of Formula (VII) is of formula:, or a salt thereof, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:.

121. The method of any one of claims 113-120, wherein the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:.R0708.70175WO00 172 / 180 #13640937v1122. The method of any one of claims 113-120, wherein the sulfur atom of the cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:.

123. A method of sequencing a peptide having at least one free cysteine residue, comprising: reacting the peptide with a compound of Formula (IX):or a salt thereof, to provide an azide-functionalized peptide, such that the sulfur atom of the cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:performing a peptide sequencing protocol; wherein: Y is a leaving group; L3is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; and R4is hydrogen, optionally substituted aliphatic, or a nitrogen protecting group.

124. The method of claim 123, further comprising contacting the azide-functionalized peptide with a compound comprising a complementary moiety, wherein the compound comprising a complementary moiety is of Formula (X): (X) or a salt thereof, to provide a triazole-linked conjugated peptide, such that a sulfur atom of a cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:R0708.70175WO00 173 / 180 #13640937v1, wherein: each of R3aand R3bis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R3aand R3bare joined together with their intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

125. The method of any one of claims 123 or 124, wherein Y is halogen.

126. The method of any one of claims 123-125, wherein the compound of Formula (IX) is of Formula (IX-A):or a salt thereof.

127. The method of any one of claims 123-126, wherein L3comprises optionally substituted heteroalkylene.

128. The method of any one of claims 123-127, wherein L3comprises, and wherein z is an integer between 1 and 100, inclusive.

129. The method of any one of claims 123, 124, 127, or 128, wherein the compound of Formula (IX) is of Formula (IX-B):or a salt thereof, such that a sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:R0708.70175WO00 174 / 180 #13640937v1.

130. The method of any one of claims 123-129, wherein the compound of Formula (IX) is of Formula (IX-C):or a salt thereof.

131. The method of any one of claims 123-130, wherein the sulfur atom of the cysteine residue in the triazole-linked conjugated peptide is bonded to a group of the formula:.

132. The method of any one of claims 123-131, wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

133. The method of any one of claims 123-132, wherein R4is hydrogen.

134. The method of any one of claims 123-133, wherein the compound of Formula (IX) is of formula:, or a salt thereof, such that a sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:.

135. A method of sequencing a peptide, comprising: reacting the peptide with a vinylpyridinium compound, or a salt thereof, wherein the vinylpyridinium compound comprises an azide moiety, to provide an azide-functionalized peptide,R0708.70175WO00 175 / 180 #13640937v1wherein a sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to an ethylenepyridinium moiety; and performing a peptide sequencing protocol.

136. A method of enriching a sample comprising one or more peptides, comprising: reacting a target peptide having at least one free cysteine residue with a compound of Formulaor a salt thereof, to provide an azide-functionalized peptide, such that a sulfur atom of a cysteine residue in the azide-functionalized peptide is bonded to a group of the formula:contacting the azide-functionalized peptide with a compound comprising a complementary moiety, such that the azide moiety of the azide-functionalized peptide reacts with the complementary moiety via click chemistry to provide a triazole-linked conjugated peptide; immobilizing the triazole-linked conjugated peptide to a surface; and removing any non-immobilized peptides or portions of peptides; wherein: X−is a counterion; n is 0, 1, 2, 3, or 4; L1is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substitutedR0708.70175WO00 176 / 180 #13640937v1heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each occurrence of RAis independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; each occurrence of R1is independently halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3,L2is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; L3is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; and R4is hydrogen, optionally substituted aliphatic, or a nitrogen protecting group.R0708.70175WO00 177 / 180 #13640937v1137. The method of any one of claims 89, 90, 93-112, 114-122, 125-134, or 136, wherein the compound comprising a complementary moiety comprises a strained alkyne.

138. The method of any one of claims 89, 90, 93-112, 114-122, 125-134, 136, or 137, wherein the compound comprising a complementary moiety comprises a cyclooctyne.

139. The method of any one of claims 89, 90, 93-112, 114-122, 125-134, or 136-138, wherein the compound comprising a complementary moiety comprises dibenzoazacyclooctyne (DIBAC or DBCO), biarylazacyclooctynone (BARAC), dibenzocyclooctyne (DIBO), difluorinated cyclooctyne (DIFO), bicyclononyne (BCN), dimethoxyazacyclooctyne (DIMAC), monofluorinated cyclooctyne (MOFO), cyclooctyne (OCT), and / or aryl-less cyclooctyne (ALO).

140. The method of any one of claims 89, 90, 93-112, 114-122, 125-134, or 136-139, wherein the compound comprising a complementary moiety comprises a linking group.

141. The method of claim 140, wherein the linking group comprises a polypeptidyl group.

142. The method of claim 141, wherein the polypeptidyl group comprises between 5 and 15 amino acid residues.

143. The method of any one of claims 141 or 142, wherein the polypeptidyl group comprises between 1 and 10 negatively charged moieties at physiological pH.

144. The method of any one of claims 141-143, wherein the polypeptidyl group comprises between 1 and 10 aspartate residues.

145. The method of any one of claims 141-144, wherein the polypeptidyl group comprises DDGGGDDDFF (SEQ ID NO: 13).

146. The method of any one of claims 140-145, wherein the linking group comprises an oligonucleotide.

147. The method of claim 146, wherein the oligonucleotide has a length of at least 25 nucleotides.

148. The method of any one of claims 146 or 147, wherein at least one strand of the oligonucleotide has a sequence that is at least 80% identical to 5'- CCACGCGTGGAACCCTTGGGATCCA-3' (SEQ ID NO: 19).R0708.70175WO00 178 / 180 #13640937v1149. The method of any one of claims 140-148, wherein the linking group further comprises at least one of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted heterocyclylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof.

150. The method of any one of claims 89, 90, 93-112, 114-122, 125-134, or 136-149, wherein the compound comprising a complementary moiety comprises a binding group.

151. The method of claim 150, wherein the binding group comprises a biotin moiety.

152. The method of claim 151, wherein the biotin moiety is a bis-biotin moiety.

153. The method of any one of claims 150 or 151, wherein the biotin moiety is conjugated to an avidin protein.

154. The method of claim 153, wherein the avidin protein is streptavidin.

155. The method of any one of claims 89, 90, 93-112, 114-122, 125-134, or 136-154, wherein the compound comprising a complementary moiety is immobilized to a surface of a sample well.R0708.70175WO00 179 / 180 #13640937v1

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